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Camptosar

A Complete Product Profile

Table of Contents

Introduction

Cancer of the colon or rectum is diagnosed in an estimated 138,000 people in the United States annually and is responsible for 55,300 deaths annually.[1] Colorectal cancer is the third most common cancer after prostate and lung cancers in men and after breast and lung cancers in women.

First-line therapy of early-stage, primary colorectal cancer is surgery with removal of the involved segment, abdominoperineal resection, or anterior resection (with or without radiotherapy in patients with cancer of the rectum). In 20% of cases, however, the disease has already metastasized at the time of diagnosis and another 30% of patients eventually develop metastasis. These patients usually receive adjuvant chemotherapy, primarily with fluorouracil-based (5-FU) regimens.

Recently, in an attempt to study modulation of 5-FU, the Southwest Oncology Group conducted a seven-arm, phase II study in patients with metastatic colorectal cancer that was either recurrent or disseminated. [2] In that study, all first-line regimens (5-FU bolus alone or plus high-dose or low-dose leucovorin, 5-FU 24-hour infusion plus or minus phosphonacetyl-L-aspartate [PALA], or continuous-infusion 5-FU plus or minus low-dose leucovorin) produced comparable, confirmed response rates of 13% to 24%; no regimen achieved a higher response rate than that of single-agent bolus 5-FU. [2] This study further documented the modest advances, or lack thereof, in the development of treatment for patients with metastatic colon cancer. The situation is even more discouraging for patients whose disease has progressed on a 5-FU-containing regimen.

To date, the only therapeutic alternative after failure of first-line therapy with 5-FU-based therapies has been a second administration of a similar regimen, which has shown lower response rates. A literature review of experimental single-agent therapies for patients who failed first-line 5-FU-based therapy generally showed response rates from 0% to 5% (mean 2.8%). Only one study with streptozotocin reported a response rate of greater than 10%.

CAMPTOSAR® Injection (irinotecan hydrochloride injection), a semisynthetic derivative of the plant alkaloid camptothecin, is a promising agent for the second-line treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following 5-FU-based therapy. Irinotecan hydrochloride, clinically investigated with the name CPT-11, belongs to the camptothecin class of cytotoxic chemotherapeutic agents; CAMPTOSAR inhibits topoisomerase I function by binding to the topoisomerase I/DNA–cleavable complex.

The need for new, effective second-line oncolytic agents is critical for patients whose disease has progressed following 5-FU-based therapy. CAMPTOSAR is the first drug indicated for this disease since 5-FU was introduced more than 40 years ago. As single-agent therapy, CAMPTOSAR induces a tumor response in patients who have relapsed or failed to respond after receiving 5-FU-based treatment.

This monograph includes clinical data that demonstrate that CAMPTOSAR induces regression in patients with metastatic cancers of the colon or rectum whose disease has recurred or progressed following 5-FU-based therapy and represents a major advance in the treatment of these commonly occurring malignancies. These studies, designed to evaluate tumor response rate, do not provide information on actual clinical benefit, such as survival and disease-related symptoms.

Epidemiology

Men and women over age 40 have the greatest risk of colorectal cancer, and the incidence increases with age up to the eighth decade.[3] Colorectal cancer is the third most frequent cause of cancer death in both men and women.[4] It is estimated that there were 138,200 new cases in 1995, with 55,300 deaths. Disease mortality has fallen 29% in women and 7% in men over the past three decades.[4] Fig 1 shows US colorectal death rates over time.

Figure 1

Fig 1.—Colorectal cancer deaths in the United States, 1930-1991.
Adapted from Cancer Facts & Figures--1995. Atlanta, Ga: American Cancer Society Inc; 1995:[4].

Staging

The American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) each have developed a cancer staging system for colorectal cancer, based on the tumor-node-metastasis (TNM) classification, to eliminate discrepancies between numerous earlier coding systems that had made comparison of trial results difficult. Deficiencies were noted in both systems, including the fact that neither considered the number of positive nodes-an important prognostic indicator. The two organizations convened to improve and unify the two systems in 1987. The AJCC/UICC staging classification is shown in Table 1.[3]

The traditional Dukes' staging system is similar to TNM staging in that Dukes' A includes T1 and T2 and Dukes' B includes T3 and T4, all with no nodal involvement or metastases; Dukes' C is defined as any T rating of invasiveness with one or two involved nodes, and Dukes' C2 indicates three involved nodes; and Dukes' D refers to any case where metastases are present.


Table 1.—1987 AJCC/UICC Staging Classification for Colorectal Cancer
Primary Tumor (T)
TX Primary tumor cannot be assessed.
T0 No evidence of tumor in resected specimen (prior polypectomy or fulguration).
Tis Carcinoma in situ.
T1 Invades submucosa.
T2 Invades muscularis propria.
(T3-T4) (Depends on whether serosa is present).
Serosa present
T3 Invades through muscularis propria into subserosa.
Serosa (but not through).
Pericolic fat within the leaves of the mesentery.
T4 Invades through serosa into free peritoneal cavity or through serosa into a contiguous organ.
No serosa (distal two thirds rectum, posterior left or right colon)
T3 Invades through muscularis propria.
T4 Invades other organs (vagina, prostate, ureter, kidney).

Regional Lymph Nodes (N)
NX Nodes cannot be assessed (eg, local excision only).
N0 No regional node metastasis.
N1 1-3 positive nodes.
N2 4 or more positive nodes.
N3 Central nodes positive.

Distant Metastasis (M)
MX Presence of distant metastasis cannot be assessed.
M0 No distant metastasis.
M1 Distant metastasis present.

Prognosis

As with most cancers, 5-year survival rates for patients with colorectal cancer are highest when the cancer has been detected in an early, localized stage and are poor for patients with advanced disease. Table 2 shows survival rates for these cancers.

Table 2.—Survival Statistics for Cancers of the Colon and Rectum, by Disease Stage
5-Year Survival Rates
 LocalizedAdjacent organs or
lymph-node involvement
Distant metastases
Colon93%63%<7%
Rectum 87% 53%

Additional factors affecting prognosis include age, with a very poor prognosis for those under age 40. Gender also affects prognosis, with women having improved survival rates compared with men. Patients with symptoms at the time of diagnosis have a 5-year survival rate of 49% vs 71% for those who are asymptomatic. In addition, the presence of rectal bleeding has a positive impact on prognosis, possibly because early surface erosion leads to prompt treatment.[3]

Current therapeutic options

Surgery, sometimes with adjuvant radiotherapy, is the preferred treatment for colorectal cancer.[4] Postoperative chemotherapy is administered to patients who have a poor prognosis.[3] While early trials elicited poor results, studies conducted by the third and fourth Veterans Administration Surgical Oncological Group (VASOG) and the Central Oncology Group yielded a 5% to 10% survival benefit.[3] Patients with lymph-node involvement demonstrated a significant disease-free survival benefit from systemic chemotherapy.[3] The 1990 National Cancer Institute Consensus Development Conference recommended combination therapy with 5-FU and levamisole for patients with lymph-node involvement; however, questions regarding the benefit of levamisole remain unanswered.[3]

Researchers tried to maximize the benefit of 5-FU-based regimens--in response, if not in survival--using chronomodulated dose administration[5] or with hepatic infusions[6]. In a phase III study,[5] a chronomodulated schedule of 5-FU, oxaliplatin, and folic acid produced a significantly improved overall response rate compared with the constant infusion (51% v 28%). Survival time was not significantly different, which the study sponsor attributed to the crossover design. Side effects were more pronounced among patients receiving the constant infusion.

The technique of hepatic arterial infusion (HAI) for delivery of 5-FU has demonstrated superior tumor response rates compared with systemic infusion (51% vs 16%).[6] However, survival advantages have not been consistently demonstrated, and method difficulties, together with a high rate of morbid toxicities, continue to restrict the use of this technique to investigational trials.

Administration of leucovorin and interferon as part of combination regimens is currently being evaluated.[3] Combination treatments that include 5-FU have been administered using nitrosoureas, mitomycin C, methotrexate, or cisplatin; all have had disappointing results, and the nitrosoureas and mitomycin C have proved highly toxic without contributing to survival.[6]

Patients with advanced disease who receive 5-FU-based chemotherapy inevitably experience progressive disease, usually within 6 to 8 months of beginning treatment.[7] To date, the only therapeutic alternative after failure of first-line therapy including 5-FU has been a second administration of a similar regimen, which has shown very low response rates. Literature reviews of studies with experimental single-agent therapy for these patients generally report a response rate from 0% to 5% (mean 2.8%). Only one study with streptozotocin reported a response rate of greater than 10%.

The therapeutic goal for second-line therapy in patients with advanced metastatic colon or rectal cancer is palliative, aiming for a reduction in tumor burden, through radiation or chemotherapy, or both, that alleviates pain and other symptoms. In many cases, a reduction in tumor volume that does not qualify as an objective response (ie, tumor shrinkage of <50%) can achieve this goal for the patient.[6]

CAMPTOSAR® Injection (irinotecan hydrochloride injection)

Chemistry

Irinotecan hydrochloride is (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperi- dinopiperidino)carbonyloxy]-1H-pyrano [3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H) dione hydrochloride, a water-soluble analog of camptothecin with high antitumor activity.[8] It is a pale yellow to yellow crystalline powder, with the empirical formula C33H38N4O6·HCl·3H 2O and a molecular weight of 677.19. The chemical structure is shown in Fig 2.

Formula

Fig 2.-Chemical structure of CAMPTOSAR.

Conversion of irinotecan

Fig 3.—Conversion of irinotecan to SN-38 by deesterification.
From Slichenmyer WJ, Rowinsky EK, Donehower RC, et al. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst. 1993;85:271-290.

Irinotecan is a relatively inactive prodrug, which is converted by carboxylesterases to SN-38, a metabolite that is a twofold to 2,000-fold more potent inhibitor of the nuclear enzyme topoisomerase I than is the parent compound. However, the precise contribution of SN-38 to the activity of CAMPTOSAR is unknown.[9] The conversion of irinotecan to the active metabolite is depicted in Fig 3.

Clinical Pharmacology

Physiology of topoisomerases

CAMPTOSAR Injection (irinotecan hydrochloride injection) is one of a promising new class of antineoplastic agents known as topoisomerase I inhibitors. The enzyme topoisomerase I plays a key role in maintaining the structure of DNA during translation, transcription, and replication. [10] By covalently binding to double-stranded DNA, topoisomerase I forms a cleavable complex, which relaxes the torsionally strained, supercoiled DNA helix by causing transient single-strand breaks. This permits uncoiling of the helix during mitosis and transcription (Fig 4).[8]

Fig 4.—DNA relaxation by topoisomerase I.

As shown in Fig 5, the presence of a topoisomerase I inhibitor allows uncoiling of the double-stranded DNA but prevents subsequent religation. [11]

Fig 5.—Inhibition of topoisomerase I–mediated DNA religation by CAMPTOSAR, leading to strand breaks.

Two types of topoisomerases have been identified. In the case of topoisomerase I, there is a linkage to the 3'-terminus of a DNA single-strand break. Topoisomerase II causes a similar reaction at the 5'-terminus of a DNA double-strand break. [12]

Mechanism of Cytotoxicity

Irinotecan and its active metabolite SN-38 bind to the topoisomerase/DNA complex. Since topoisomerase I complexes with DNA only during DNA synthesis, the cytotoxic action of the irinotecan metabolite likely takes place during S-phase. The formation of a topoisomerase I/camptothecin/DNA–cleavable complex results in cell injury or death. Cleavable complexes effect DNA damage through interference with DNA metabolism and damage to the DNA replication fork. After exposure to irinotecan hydrochloride and SN-38 during DNA replication, DNA contains double-strand breaks in the replication forks, unlike the typical single-strand breaks associated with topoisomerase I. It is postulated that topoisomerase I inhibitors kill cells by stabilizing topoisomerase I DNA breaks, causing irreversible double-strand breaks through interference with the process ofreplication. [8] Mammalian cells cannot efficiently repair these double-strand breaks.

Sensitivity

Factors that help determine antitumor cytotoxic effects are outlined in Fig 6. Cells with higher levels of topoisomerase are likely more sensitive to topoisomerase inhibition. Resistant cells generally have low levels of topoisomerase and fewer cleavable complexes. Genomic distribution of cleavable complexes also appears to influence drug effect. Differential effects on selective oncogenes may be vital to determining sensitivity of a cell line to a particular agent. [12]

DNA repair can reverse drug-induced DNA damage. Cell lines deficient in DNA repair mechanisms have been shown to be hypersensitive to the toxic effects of the topoisomerase I inhibitor camptothecin. DNA damage that goes unrepaired may result in significant genetic alterations or apoptosis. [12]

Because CAMPTOSAR Injection (irinotecan hydrochloride injection) has a unique mechanism of action, clinical response can be achieved with single-agent therapy in patients who have developed resistance to 5-FU-based regimens.

Fig 6.—Schematic representation of cellular sensitivity and resistance to topoisomerase inhibitors.

TOPO=topoisomerase

From Pommier Y, Leteurtre F, Fesen MR, et al. Cellular determinants of sensitivity and resistance to DNA topoisomerase inhibitors. Cancer Invest. 1994;12(5):530-542.

Matsuoka et al examined the sensitivity of irinotecan and SN-38 for primary and recurrent carcinoma cells cultured on contact-sensitive plates. Irinotecan and SN-38 were cytotoxic to primary gastrointestinal carcinoma cells when other anticancer drugs had no effect. Five of seven tumors tested proved sensitive (<=75% survival) after exposure to irinotecan or SN-38, with a 71% response rate for each agent. This response rate was equal to or higher than that for other cytotoxic agents tested. [13]

Irinotecan and SN-38 also had marked cytotoxic effects on recurrent carcinoma cells. Three of five cultured recurrent tumors showed <70% survival in the presence of either irinotecan or SN-38, with a response rate of 60% for each agent. Average survival of all five tumors in the presence of SN-38 was 76%, the lowest for all anticancer agents tested.[13]

Resistance

Resistance to therapy is the main reason for treatment failure in cancer patients. At least two mechanisms of resistance to topoisomerase I inhibitors have been observed: reduced accumulation of drug and a decrease in the formation of cleavable complexes. Resistance to irinotecan may result from reduced conversion of the inactive prodrug to SN-38. Cleavable complexes may be reduced as a result of decreased enzyme levels or, possibly, enzyme mutations.[12]

Low levels of topoisomerase I in normal vs malignant tissues provide a therapeutic advantage during therapy with topoisomerase I inhibitors.[9] Demonstration of campothecin resistance in recombinant proteins from two mutant enzymes suggests that low levels of effective topoisomerase I represent a mechanism of resistance.([12]

It has been reported that human colon tumors express high levels of the multiple-drug-resistance 1 (MDR1) gene product, which in cultured cells may limit access of certain drugs to cells. [14]. In vitro data have demonstrated that camptothecin and its noncharged derivatives such as irinotecan overcome MDR1-mediated resistance. (Topotecan, a charged camptothecin derivative, showed reduced cytotoxicity against MDR1-overexpressing cells.) MDR1-mediated resistance to irinotecan may result from its rapid passive diffusion, its absence of interaction with MDR1, or a combination of both characteristics.


Fig 7.—Mean plasma concentration curves of CAMPTOSAR and SN-38.

From deForni M, Bugat R, Chabot GG, et al. Phase I and pharmacokinetic study of irinotecan administered on a weekly schedule in cancer patients. Cancer Res. 1994;54:4347-4354.

Pharmacokinetics

CAMPTOSAR Injection (irinotecan hydrochloride injection) and its active metabolite SN-38 exist both as an active lactone form and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two forms. An acid pH promotes formation of the lactone, whereas a more basic pH yields the hydroxy acid anion form. Fig 7 shows mean plasma concentrations in 26 patients of both CAMPTOSAR and SN-38 assayed by high-performance liquid chromatography following a 30-minute infusion. The peak plasma concentration of CAMPTOSAR ranged from 664 ng/mL at a 50-mg/m² dose to 2,578 ng/mL at a 115-mg/m² dose.[15]

After intravenous (IV) infusion of CAMPTOSAR Injection (irinotecan hydrochloride injection) in humans, irinotecan plasma concentrations decline in a multiexponential manner with a mean terminal elimination half-life of approximately 6 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid anion forms are in equilibrium. Although the pharmacokinetics of irinotecan are highly variable over the dose range of 50 mg/m² to 350 mg/m², area under the curve (AUC) of irinotecan increases linearly with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of CAMPTOSAR. SN-38 AUC values are about 2% to 8% of those observed for irinotecan.

Pharmacokinetic parameters for irinotecan and SN-38 following 90-minute infusions of CAMPTOSAR at 125 mg/m² were determined in a phase II study in patients with metastatic carcinoma of the colon or rectum and are summarized in Table 3.

Table 3.-Summary of Mean Irinotecan and SN-38 Pharmacokinetic Parameters in Patients With Metastatic Carcimoma of the Colon and Rectum

 IrinotecanSN-38
Dose
(mg/m²)
Cmax
(ng/mL )
AUC0-24
(ng·h/mL)
t½ (h)Varea
(L/m²)
CL
(L/h/m²)
Cmax
(ng/mL)
AUC0-24
(ng·h/mL)
t½ (h)
125 (n=64)1,660± 79710,200 ± 3,2705.8 ± 0.7 110 ± 48.513.3 ± 6.0126.3 ± 11.9229 ± 10810.4 ± 3.1
Values are ± standard deviation, where indicated. Cmax = maximum plasma concentration. AUC0-24 = plasma concentration AUC from time 0 to 24 hours after the end of the 90-minute infusion. = terminal elimination half-life. Varea = volume of distribution. CL = total systemic clearance.

Fig 8 depicts plasma concentration AUC, which increased proportionately with dose; however, there was substantial variability among patients.[15]

Fig 8.—Relationship between dose of CAMPTOSAR and AUC. Data are based on a French study in which 59 patients received a total of 304 weekly irinotecan doses of 50 mg/m² to 145 mg/m². [15]

Distribution

Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound (approximately 95%) to human plasma proteins. The major plasma protein to which irinotecan and SN-38 bind primarily is albumin.

Metabolism

The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and occurs primarily in the liver. SN-38 subsequently undergoes conjugation to form a glucuronide metabolite (SN-38 glucuronide). SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity assays using two cell lines in vitro. The disposition of irinotecan has not been fully elucidated in humans.

Excretion

The urinary excretion of irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of CAMPTOSAR Injection (irinotecan hydrochloride injection) in two patients ranged from approximately 25% (100 mg/m²) to 50% (300 mg/m²).

Pharmacokinetics in Special Populations

Geriatric

The terminal half-life of irinotecan was 6.0 hours in patients who were 65 years or older and 5.5 hours in patients younger than 65 years. Dose-normalized AUC0-24 for SN-38 in patients who were at least 65 years of age was 11% higher in patients younger than 65 years. No change in dosage and administration is recommended for geriatric patients.

Pediatric

The pharmacokinetics of irinotecan have not been studied in the pediatric population.

Gender

The pharmacokinetics of irinotecan do not appear to be influenced by gender[16]. In clinical trials of CAMPTOSAR in patients with metastatic carcinoma of the colon or rectum who received a dose of 100 mg/m² or 125 mg/m², the dose-normalized AUC0-24 for SN-38 was 200 ± 95.9 ng·h/mL in males and 194 ± 99.4 ng·h/mL in females.

Race

The influence of race on the pharmacokinetics of irinotecan has not been evaluated.

Hepatic insufficiency

The influence of hepatic insufficiency on the pharmacokinetic characteristics of irinotecan and its metabolites has not been formally studied. Among patients with known hepatic tumor involvement (a majority of patients), irinotecan and SN-38 AUC values were somewhat higher than values for patients without liver metastases. For patients having liver metastases without decreased hepatic function, no change in dosage and administration is recommended.

Renal insufficiency

The influence of renal insufficiency on the pharmacokinetics of of irinotecan has not been evaluated.

v

Preclinical Findings

Enzyme concentrations in normal, cancerous, and metastatic colonic tissues

Giovanella et al demonstrated that topoisomerase I concentrations in cancerous colonic tissue were greater than concentrations in normal colonic tissue.[17] Tumors were evaluated in 38 untreated patients at various stages, including advanced metastatic disease. Average topoisomerase I levels were 14-fold to 16-fold higher in cancerous tissue than in normal colonic mucosa and tended to increase with disease progression.[17]

Indication

CAMPTOSAR Injection (irinotecan hydrochloride injection) is indicated for the second-line treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following 5-FU-based therapy.

Clinical Experience

Phase II study designs

Three multicentered, phase II, open-label clinical trials were conducted to evaluate the efficacy of single-agent therapy with CAMPTOSAR Injection. They involved a total of 304 patients with metastatic colorectal cancer that recurred or progressed following prior 5-FU-based therapy. All three studies used the same dosage schedule. CAMPTOSAR was administered as a 90-minute intravenous infusion once weekly for 4 weeks, followed by a 2-week rest (one course). These studies were designed to evaluate tumor response rate and do not provide information on actual clinical benefits, such as effect on survival and disease-related symptoms.

The San Antonio Regional Study (San Antonio study) enrolled 48 patients with an initial starting dose of 150 mg/m²; after four of the first nine patients developed an unacceptably high rate of grade 4 diarrhea and febrile neutropenia, the starting dose was reduced to 125 mg/m2 for the subsequent 39 patients. Patients who achieved a complete response (CR) to therapy received an additional four courses of therapy. Patients who achieved a partial response (PR) or whose disease remained stable continued to receive therapy until their disease progressed or intolerable toxicity occurred. Tumor measurements were obtained at baseline, after the first and second courses of therapy, and after each additional course of therapy. If a 50% reduction in tumor size was noted, an additional tumor measurement was obtained after the next course of therapy to confirm response; thereafter, measurements were obtained after every other course of therapy. Tumors were reassessed in 43 patients who were evaluable for response following completion of one full course of therapy. [18]

The Mayo North Central Cancer Treatment Group (Mayo/NCCTG) enrolled 90 patients who received a starting dose of 125 mg/m2, with subsequent escalation of the dose to 150 mg/m² in patients who completed an entire course of therapy without experiencing any toxicities greater than grade 1. Dose was reduced based on toxicity. Patients who attained a CR received an additional four courses. Patients who attained a PR or whose disease remained stable continued to receive therapy until their disease progressed or intolerable toxicity occurred. Tumor measurements were obtained at baseline prior to the second and third courses of therapy and prior to every other subsequent course. If a patient responded to therapy, a tumor measurement was obtained 4 to 6 weeks later to confirm response.

The US Multicenter Study Group enrolled 166 patients. The first 64 patients received a starting dose of 125 mg/m2, which was reduced to 100 mg/m2 for the subsequent 102 patients because of greater toxicity observed than in other studies. Dose increases in increments of 25 mg/m2 up to a maximum dose of 150 mg/m2 were allowed at the start of a new course of therapy in patients who had completed a single-dose course without toxicity. Dose was reduced based on toxicity. Patients who attained a CR received an additional two courses of therapy; those who attained a PR or whose disease remained stable continued to receive treatment until their disease progressed or intolerable toxicity occurred. Tumor measurements were obtained at baseline and then after every two courses of therapy. If a patient responded to therapy, a tumor measurement was obtained 4 to 6 weeks later to confirm response.

Eligibility Criteria

Selected enrollment criteria for the three phase II studies are summarized in Table 4.

Table 4.--Selected Enrollment Criteria for Phase II Studies of CAMPTOSAR
San Antonio font= size="+1">Mayo/NCCTG US Multicenter Study Group
  • Histologic diagnosis of metastatic colorectal cancer

  • Measurable disease

  • Progression after one 5-FU regimen for metastatic disease or recurrent disease within 6 months of adjuvant 5-FU

  • No therapy within 28 days

  • ECOG*performance status 0 to 2
  • Histologic diagnosis of recurrent/metastatic colorectal cancer

  • Measurable disease

  • One prior 5-FU regimen

  • No therapy within 28 days

  • Off prior radiotherapy at least 4 weeks

  • ECOG performance status 0 to 2
  • Histologic diagnosis of colorectal cancer

  • Measurable disease

  • Evidence of progression within 6 months of one 5-FU-based or recurrent disease within 6 months of adjuvant 5-FU

  • No therapy within 28 days

  • No prior pelvic irradiation

  • SWOG** performance status 0 to 2
  • * Eastern Cooperative Oncology Group.
    ** Southwest Oncology Group.

    Efficacy Parameters

    The primary efficacy parameter was tumor response to treatment with CAMPTOSAR Injection (irinotecan hydrochloride injection), defined as the total percentage of patients who experienced either CR or PR. Patients also were evaluated for stable disease, which was defined as not meeting the criteria for response or progression. Secondary efficacy parameters included time to response, duration of response, time to disease progression, and survival time.

    Demographics

    Of the 304 patients in the three studies, 166 (54.6%) were males and 138 (45.4%) were females who ranged in age from 25 to 84 years (median 63 years); 133 (43.8%) of the patients were 65 or older, and 13 (4.3%) of the patients were younger than 35. Two hundred sixty-nine (88.5%) of the patients were white, 22 (7.2%) were black, 11 (3.6%) were Hispanic, and 2 (0.7%) were Asian. Two hundred eighty (92.1%) of the patients had a baseline performance status of 0 (48.0%) or 1 (44.1%), and 24 (7.9%) had a baseline performance status of 2. The demographic characteristics of patients given each starting dose were generally representative of the overall study population. Patient demographics are summarized in Table 5.

    Table 5.--Patient Characteristics (Intent-To-Treat)
    CharacteristicAll StudiesSan AntonioMayo/NCCTGUS Multicenter
    Study Group
    N3044890166
    Sex ratio (M:F)166:13826:2258:3282:84
    Median age
    (range)
    63 years
    (25-84)
    63 years
    (29-78)
    63 years
    (32-81)
    62 years
    (25-84)
    Metastases (n)
    1 site
    2 sites
    3 sites

    59 (19%)
    83 (27%)
    162 (53%)

    6 (12.5%)
    19 (39.6%)
    23 (47.9%)

    22 (24.2%)
    23 (25.6%)
    45 (50.0%)

    31 (18.7%)
    41 (24.7%)
    94 (56.6%)

    Race (n)
    White
    Black
    Hispanic
    Asian

    269 (88.5%)
    22 (7.2%)
    11 (3.6%)
    2 (0.7%)

    38 (79.2%)
    6 (12.5%)
    4 (8.3%)
    0

    86 (95.6%)
    4 (4.4%)
    0
    0

    145 (87.3%)
    12 (7.2%)
    7 (4.2%)
    2 (1.2%)

    Performance status (n)
    1
    2

    280 (92.1%)
    24 (7.9%)

    47 (97.9%)
    1 (2.1%)

    77 (85.6%)
    13 (14.4%)

    156 (94.0%)
    10 (6.0%)

    Dose Intensity

    Two hundred ten courses of CAMPTOSAR Injection (irinotecan hydrochloride injection) were given in the San Antonio study, with a median of 3.5 courses per patient. As of the data cutoff date, 290 courses were given in the Mayo/NCCTG study, with a median of 3.0 courses per patient, and 591 courses were given in the US Multicenter Study Group study, with a median of 3.0 courses per patient for both the 100-mg/m² and 125-mg/m² starting doses. Table 6 summarizes the number of courses given and dose intensity by study.

    Table 6.--Number of Courses of CAMPTOSAR Delivered and Dose Intensity by Study
    StudySan AntonioMayo/NCCTGUS Multicenter Study Group
    Starting dose (mg/m2)150/125*125125100
    N489064102
    Courses delivered
    Median
    Range

    3.5
    1-13

    3.0
    1 -14

    3.0
    1-12

    3.0
    1-13

    Dose intensity (mg/m²/wk)**
    Median
    Range

    62.0
    31.3-85.4

    56.1
    20.8-94.4

    61.0
    20.8-94.4

    53.9
    16.7-89.9

    *9/48 patients received the 150-mg/m² starting dose. **Total dose administered in a course divided by 6 (number of weeks in a course).

    Efficacy

    Based on the intent-to-treat population, the response to therapy was 20.8% (10/48) in the San Antonio study[18] and 13.3% (12/90) in the Mayo/NCCTG study. In the US Multicenter study, the response rate was 14.1% (9/64) for the patients who received the 125-mg/m2; starting dose and 7.8% (8/102) for the patients who received an initial dose of 100 mg/m2;.

    In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125-mg/m2;. Among these 193 patients, there were two CRs and 27 PRs for an overall response rate of 15% (29/304). In the intent-to-treat analysis of the pooled data across all three studies and all doses, there were two CRs and 37 PRs, for an overall response rate of 12.8% (39/304). The 39 responders included 8 (7.8%) of the 102 patients who received the 100-mg/m2 starting dose, 29 (15%) of the 193 patients who received the 125-mg/m2 starting dose, and 2 (22.2%) of the 9 patients who received the 150-mg/m2 starting dose. A considerably lower response was observed with a starting dose of 100 mg/m2 than with a starting dose of 125 mg/m2. Both of the patients who achieved a CR received the 125 mg/m2 starting dose. See Table 7 for a summary of the response to CAMPTOSAR in the three study groups.

    Table 7.--Response to CAMPTOSAR Injection (irinotecan hydrochloride injection)
    Study San Antonio Mayo/NCCTG US Multicenter Study Group
    Starting dose(mg/m²) 150*/125 125 125 100
    N 48 90 64 102
    CR (%) 1 (2.1) 0 (0.0) 1 (1.6) 0 (0.0)
    PR (%) 9 (18.8) 12 (13.3) 8 (12.5) 8 (7.8)
    Progressive disease (%) 4 (8.3) 24 (26.7) 18 (28.1) 45 (44.1)
    No follow-up scan (%) 4 (8.3) 4 (4.4) 9 (14.1) 9 (8.8)
    Overall response (%)
    [95% confidence interval]
    10 (20.8)
    [9.3-32.3]
    12 (13.3)
    [6.3-20.4]
    9 (14.1)
    [5.5-22.6]
    8 (7.8)
    [2.6-13.1]
    *9/48 patients received the 150-mg/m² starting dose.

    Response rates to CAMPTOSAR Injection were similar in males and females and among patients older and younger than 65 years.Rates were also similar in patients with cancer of the colon or cancer of the rectum and in patients with single and multiple metastatic sites. Response rate in performance status 0 patients was about twice that of performance status >=1 patients (18.5% versus 7.6%). Over half of the patients responding to CAMPTOSAR had not responded to prior 5-FU-based treatment given for metastatic disease. Patients who had received previous irradiation to the pelvis also responded to CAMPTOSAR at approximately the same rate as those who had not previously received irradiation.

    Based on Kaplan-Meier estimates, the median survival time was 10.4 months for those in the San Antonio study (range, 1.0 to 35.8 months) and 8.1 months (range, 0.4 to 30.7 months) for those in the Mayo/NCCTG study. In the US Multicenter study, median survival time was 10.7 months (range, 0.3 to 22.5 months) for the 64 patients who received the 125-mg/m² starting dose and 9.3 months (range, 0.6 to 20.0 months) for the 102 patients who received the 100-mg/m² starting dose.[18]

    For all 304 patients, median survival time was 9.0 months (range, 0.3 to 35.8 months). Survival time by study and response category is shown in Table 8.

    The overall effect of CAMPTOSAR on survival and disease-related symptoms has not been determined by randomized clinical trials.

    Table 8.--Kaplan-Meier Estimates of Survival Time by Study and Response Category
      San Antonio Mayo/NCCTG US Multicenter Study Group
    Starting dose 125/150 mg/m²* 125 mg/m² 125 mg/m² 100 mg/m²
    Response Category N Median
    Survival
    (months)
    N Median
    Survival
    (months)
    N Median
    Survival
    (months)
    N Median
    Survival
    (months)
    CR or PR 10 22.3 12 14.8 9 20.8 8 16.3
    Progressive disease 4 3.3 28 3.6 27 5.8 54 7.0
    All patients 48 10.4 90 8.1 64 10.7 102 9.3
    *9/48 patients received the 150-mg/m² dose.

    Duration of Response

    The median duration of response was 6.4 months (range, 2.7 to 13.7 months) in the San Antonio study; 5.9 months (range, 2.6 to 15.1 months) in the Mayo/NCCTG study; and 5.6 months (range, 2.8 to 12.8 months) for the 125-mg/m² starting dose and 6.2 months (range, 3.0 to 9.9 months) for the 100-mg/m² starting dose in the US Multicenter study.

    The median duration of response for the 39 responders in the three pivotal studies was 6.0 months (range, 2.6 to 15.1 months). Median duration of response was 6.2 months (range, 3.0 to 9.9 months) for the 8 responders who received the 100-mg/m² dose, 5.8 months (range, 2.6 to 15.1 months) for the 29 responders who received the 125-mg/m² starting dose, and 11.6 months (range, 9.5 to 13.7 months) for the 2 responders who received the 150-mg/m² starting dose.

    Time to disease progression

    Based on the Kaplan-Meier estimates, the median time to disease progression was 4.8 months (range, 0.5 to 16.6 months) for the 48 patients in the San Antonio study and 4.0 months (range, 0.3 to 19.9 months) for the 90 patients in the Mayo/NCCTG study. In the US Multicenter study, the median time to disease progression was 5.0 months (range, 0.4 to 16.6 months) for the 64 patients who received the 125-mg/m² starting dose and 3.3 months (range, 0.1 to 17.0 months) for the 102 patients who received the 100-mg/m² starting dose.

    For the 304 patients in the pivotal studies, the median time to disease progression was 4.0 months (range, 0.1 to 19.9 months).

    The effect of CAMPTOSAR Injection (irinotecan hydrochloride injection) on time to disease progression has not been evaluated in randomized clinical trials.

    Safety

    Contraindications

    CAMPTOSAR is contraindicated in patients with known hypersensitivity to the drug.

    Warnings

    CAMPTOSAR Injection (irinotecan hydrochloride injection) should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

    Diarrhea

    CAMPTOSAR Injection can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Early diarrhea (occurring during or within 24 hours of administration of CAMPTOSAR) is cholinergic in nature. It can be severe but is usually transient. It may be preceded by complaints of diaphoresis and abdominal cramping. Early diarrhea may be ameliorated by administration of atropine (see PRECAUTIONS, General, for dosing recommendations for atropine).

    Late diarrhea (occurring more than 24 hours after administration of CAMPTOSAR) can be prolonged, may lead to dehydration and electrolyte imbalance, and can be life threatening. Late diarrhea should be treated promptly with loperamide (see PRECAUTIONS, Information for Patients, for dosing recommendations for loperamide). Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. National Cancer Institute (NCI) grade 3 diarrhea is defined as an increase of seven to nine stools daily, or incontinence, or severe cramping; and NCI grade 4 diarrhea is defined as an increase of >= 10 stools daily, or grossly bloody stool, or need for parenteral support. If grade 3 or 4 late diarrhea occurs, administration of CAMPTOSAR should be delayed until the patient recovers and subsequent doses should be decreased (See DOSAGE AND ADMINISTRATION).

    Myelosupression

    Deaths due to sepsis following severe myelosuppression have been reported in patients treated with CAMPTOSAR Injection (irinotecan hydrochloride injection). Therapy with CAMPTOSAR should be temporarily discontinued if neutropenic fever occurs or if the absolute neutrophil count drops below 500/mm³. The dose of CAMPTOSAR should be reduced if there is a clinically significant decrease in the total white blood cell count (<2,000/mm³), neutrophil count (<1,000/mm³), hemoglobin level (<8 g/dL), or platelet count (<100,000/mm³) (see DOSAGE AND ADMINISTRATION). Routine administration of a colony-stimulating factor (CSF) is not necessary, but physicians may wish to consider CSF use in individual patients experiencing significant neutropenia.

    Pregnancy

    CAMPTOSAR Injection (irinotecan hydrochloride injection) may cause fetal harm when administered to a pregnant woman. Radioactivity related to 14C-irinotecan crosses the placenta of rats following intravenous administration of 10 mg/kg. CAMPTOSAR has been shown to be teratogenic in rats and rabbits at a dose of 6 mg/kg/day. Treatment-related changes in the fetuses included external and visceral abnormalities, skeletal variations, and skeletal abnormalities. There are no adequate and well-controlled studies in pregnant women. If the drug is used during pregnancy or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with CAMPTOSAR.

    PRECAUTIONS

    General

    Care of intravenous site

    CAMPTOSAR Injection (irinotecan hydrochloride injection) is administered by intravenous infusion. Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and application of ice are recommended.

    Premedication with antiemetics

    Irinotecan is emetigenic. It is recommended that patients receive premedication with antiemetic agents. In clinical studies, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT3 blocker (eg, ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of CAMPTOSAR. Physicians should also consider providing patients with an antiemetic regimen (eg, prochlorperazine) for subsequent use as needed.

    Treatment of Early diarrhea

    Administration of 0.25 to 1 mg of intravenous atropine should be considered (unless clinically contraindicated) in patients experiencing diaphoresis, abdominal cramping, or early diarrhea (diarrhea occurring during or within 24 hours following administration of CAMPTOSAR).

    Patients at Particular risk

    Physicians should exercise particular caution in monitoring the effects of CAMPTOSAR Injection (irinotecan hydrochloride injection) in the elderly (>=65 years) and in patients who had previously received pelvic/abdominal irradiation (see ADVERSE REACTIONS).

    The use of CAMPTOSAR in patients with significant hepatic dysfunction has not been established. In clinical trials, CAMPTOSAR was not administered to patients with serum bilirubin >2.0 mg/dL, transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >5 times the upper limit of normal with liver metastasis.

    Laboratory Tests

    Careful monitoring of the white blood cell count with differential, hemoglobin, and platelet count is recommended before each dose of CAMPTOSAR.

    Drug interactions

    The adverse effects of CAMPTOSAR Injection, such as myelosuppression and diarrhea, would be expected to be exacerbated by other antineoplastic agents having similar adverse effects.

    Patients who have previously received pelvic or abdominal irradiation, or both, are at increased risk of severe myelosuppression following the administration of CAMPTOSAR. The concurrent administration of CAMPTOSAR with irradiation has not been adequately studied and is not recommended.

    Lymphocytopenia has been reported in patients receiving CAMPTOSAR, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of this effect. However, serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia.

    Hyperglycemia has also been reported in patients receiving CAMPTOSAR. Usually, this has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of CAMPTOSAR. It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycemia in some patients.

    The incidence of akathisia in clinical trials was greater (8.5%, 4/47 patients) when prochlorperazine was administered on the same day as CAMPTOSAR than when these drugs were given on separate days (1.3%, 1/80 patients). The 8.5% incidence of akathisia, however, is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies.

    It would be expected that laxative use during therapy with CAMPTOSAR would worsen the incidence or severity of diarrhea, but this has not been studied.

    In view of the potential risk of dehydration secondary to vomiting or diarrhea, or both, induced by CAMPTOSAR, the physician may wish to withhold diuretics during dosing with CAMPTOSAR and, certainly, during periods of active vomiting or diarrhea.

    Drug-laboratory test interactions

    There are no known interactions between CAMPTOSAR Injection (irinotecan hydrochloride injection) and laboratory tests.

    Carcinogenesis, mutagenesis, and impairment of fertility

    Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25-mg/kg dose produced an irinotecan Cmax and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/m²) and were then allowed to recover for 91 weeks. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Neither irinotecan nor SN-38 was mutagenic in the in vitro Ames assay. Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to rats and rabbits. However, atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about 5 and 1 times, respectively, the corresponding values in patients administered 125 mg/m²) and dogs at 0.4 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about one half and 1/15th, respectively, the corresponding values in patients administered 125 mg/m²).

    Pregnancy

    Pregnancy Category D—see WARNINGS.

    Nursing mothers

    Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving therapy with CAMPTOSAR.

    Pediatric Use

    The safety and effectiveness of CAMPTOSAR Injection (irinotecan hydrochloride injection) in pediatric patients have not been established.

    Adverse Reactions

    US clinical trials

    In three clinical studies, 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5-FU-based therapy were treated with CAMPTOSAR Injection.

    Seventeen of the patients died within 30 days of the administration of CAMPTOSAR; in five cases (1.6%, 5/304), the deaths were potentially drug related. These five patients experienced a constellation of medical events that included known effects of CAMPTOSAR. Neutropenic fever, defined as NCI grade 4 neutropenia and grade 2 or greater fever, occurred in 9 (3.0%) other patients; these patients recovered with supportive care. One hundred and nineteen (39.1%) of the 304 patients were hospitalized a total of 156 times because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be related to administration of irinotecan. The primary reasons for drug-related hospitalization were diarrhea, with or without nausea or vomiting, or both (18.4%); neutropenia/leukopenia, with or without diarrhea or fever, or both (8.2%); and nausea or vomiting, or both (4.9%). Adjustments in the dose of CAMPTOSAR were made during the course of treatment and for subsequent courses based on individual patient tolerance. The first dose of at least one course of CAMPTOSAR was reduced for 67% of patients who began the studies at the 125-mg/m² starting dose. Within-course dose reductions were required for 32% of the courses initiated at the 125-mg/m² dose level. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with CAMPTOSAR because of adverse events. The adverse events in Table 9 are based on the experience of the 304 patients enrolled in the three studies described in the CLINICAL STUDIES section.

    Table 9.--Adverse Events Occurring in >10% of 304 Previously Treated Patients With Metastatic Carcinoma of the Colon or Rectum
    Body System & Event % of Patients Reporting
    NCI Grades 1-4NCI Grades 3 & 4
    GASTROINTESTINAL
    Diarrhea (late)*
    7-9 stools/day (grade 3)
    >=10 stools/day (grade 4)
    Nausea
    Vomiting
    Anorexia
    Diarrhea (early)**
    Constipation
    Flatulence
    Stomatitis
    Dyspepsia
    87.8


    86.2
    66.8
    54.9
    50.7
    29.9
    12.2< BR>11.8
    10.5
    30.6
    (16.4)
    (14.1)
    16.8
    12.5
    5.9
    7.9
    2.00.0
    0.7
    0.0
    HEMATOLOGIC
    Leukopenia
    Anemia
    Neutropenia
    500 to <1,000/mm³ (grade 3)
    <500/mm³ (grade 4)
    63.2
    60.5
    53.9

    28.0
    6.9
    26.3
    (14.8)
    (11.5)
    BODY AS A WHOLE
    Asthenia
    Abdominal cramping/pain
    Fever
    Pain
    Headache
    Back pain
    Chills
    Minor infection***
    Edema
    Abdominal enlargement
    75.7
    56.9
    45.4
    23.7
    16.8
    14.5
    13.8
    14.5
    10.2
    10.2
    12.2
    16.4
    0.7
    2.3
    0.7
    1.6
    0.3
    0.0
    1.30.3
    METABOLIC & NUTRITIONAL
    Decrease in body weight
    Dehydration
    Increase in alkaline phosphatase
    Increase in SGOT
    30.3
    14.8
    13.2
    10.5
    0.7
    4.3
    3.9
    1.3
    DERMATOLOGIC
    Alopecia
    Sweating
    Rash
    60.5
    16.4
    12.8
    NA****
    0.0
    0.7
    RESPIRATORY
    Dyspnea
    Increased coughing
    Rhinitis
    22.0
    17.4
    15.5
    3.6
    0.3
    0.0
    NEUROLOGIC
    Insomnia
    Dizziness
    19.4
    14.8
    0.0
    0.0
    CARDIOVASCULAR
    Vasodilation (flushing)
    11.20.0
    * Occurring >24 hours after administration of CAMPTOSAR.
    ** Occurring <=24 hours after administration of CAMPTOSAR.
    *** Primarily upper respiratory infections.
    **** Not applicable; complete hair loss = NCI grade 2.

    Gastrointestinal: Diarrhea, nausea, and vomiting were common adverse events following treatment with CAMPTOSAR and could be severe. These events occurred early (during or within 24 hours of administration of CAMPTOSAR) or late (more than 24 hours after administration of CAMPTOSAR). The median time to onset of late diarrhea was 11 days following administration of CAMPTOSAR. For patients starting treatment at the 125-mg/m² dose, the median duration of any grade of diarrhea was 3 days. Among those patients treated at the 125-mg/m² dose who experienced grade 3 or 4 diarrhea, the median duration of the entire episode of diarrhea was 7 days. The frequency of grade 3 or 4 late diarrhea was somewhat greater in patients starting treatment at 125-mg/m² than in patients given a 100-mg/m² starting dose (34% vs 24%). The frequency of grade 3 and 4 late diarrhea was significantly greater in patients >=65 years than in patients <65 years of age (39.8% vs 23.4%; P = .0025). In Study 2, the frequency of grade 3 and 4 late diarrhea was significantly greater in male than in female patients (43.1% vs 15.6%; P = .01). However, there were no gender differences in the frequency of grade 3 and 4 late diarrhea in the other two studies.

    Hematology: CAMPTOSAR commonly caused neutropenia, leukopenia (including lymphocytopenia), and anemia. Serious thrombocytopenia was uncommon. Neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3.0% of the patients; 5.6% of patients received granulocyte colony-stimulating factor (G-CSF) for the treatment of neutropenia. NCI grade 3 or 4 anemia was noted in 6.9% of the patients. Blood transfusions were given to 9.9% of the patients. The frequency of grade 3 and 4 neutropenia was significantly higher in patients who received previous pelvic/abdominal irradiation than in those who had not received irradiation (48.1% vs 24.1%; P = .0356). There were no significant differences in the frequency of grade 3 and 4 neutropenia by age or gender.

    Body as a whole: Asthenia, fever, and abdominal pain were the most common events of this type.

    Hepatic: NCI grade 3 or 4 liver enzyme abnormalities were observed in fewer than 10% of patients. These events typically occurred in patients with known hepatic metastases.

    Dermatologic: Alopecia was reported during treatment with CAMPTOSAR. Rashes have also been reported but did not result in discontinuation of treatment.

    Respiratory: Severe pulmonary events were infrequent; NCI grade 3 or 4 dyspnea was reported in 3.6% of patients. Over half the patients with dyspnea had lung metastases; the extent to which malignant pulmonary involvement or other preexisting lung disease may have contributed to dyspnea in these patients is unknown.

    Neurologic: Insomnia and dizziness were observed but were not usually considered to be directly related to the administration of CAMPTOSAR. Dizziness may sometimes have represented symptomatic evidence of orthostatic hypotension in patients with dehydration.

    Cardiovascular: Vasodilation (flushing) has been observed during administration of CAMPTOSAR but has not required intervention.

    Non-US Clinical Trials

    Irinotecan has been studied in more than 1,100 patients in Japan and in over 400 patients in France. Patients in these studies had a variety of tumor types, including cancer of the colon or rectum, and were treated with several different doses and schedules. In general, the types of toxicities observed were similar to those seen in US trials with CAMPTOSAR Injection (irinotecan hydrochloride injection). There is some information from Japanese trials that patients with considerable ascites or pleural effusions were at increased risk for neutropenia or diarrhea. A potentially life-threatening pulmonary syndrome, consisting of dyspnea, fever, and a reticulonodular pattern on chest X-ray, was observed in a small percentage of patients in early Japanese studies. The contribution of irinotecan to these pulmonary events was difficult to assess because these patients also had lung tumors and some had preexisting nonmalignant pulmonary disease. As a result of these observations, however, clinical studies in the United States have enrolled few patients with compromised pulmonary function, significant ascites, or pleural effusions.

    Overdosage

    In US phase I trials, single doses of up to 345 mg/m² of CAMPTOSAR Injection were administered to patients with various cancers. Single doses up to 750 mg/m² of irinotecan have been given in non-US trials. The adverse events in these patients were similar to those reported with the recommended dosage and regimen. There is no known antidote for overdosage of CAMPTOSAR. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.

    Lethality was observed after single IV irinotecan doses of approximately 111 mg/kg in mice and 73 mg/kg in rats (approximately 2.6 and 3.4 times the recommended human dose of 125 mg/m², respectively). Death was preceded by cyanosis, tremors, respiratory distress, and convulsions.

    Patient Management

    Information for Patients

    Patients and patients' caregivers should be informed of the expected toxic effects of CAMPTOSAR Injection (irinotecan hydrochloride injection), particularly of its gastrointestinal manifestations, such as nausea, vomiting, and diarrhea. Each patient should be instructed to have loperamide readily available and to begin treatment for late diarrhea (occurring more than 24 hours after administration of CAMPTOSAR) at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normally expected for the patient. One dosage regimen for loperamide used in clinical trials consisted of the following (Note: This dosage regimen exceeds the usual dosage recommendations for loperamide.): 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. During the night, the patient may take 4 mg of loperamide every 4 hours. The patient should also be instructed to notify the physician if diarrhea occurs. Premedication with loperamide is not recommended.

    The use of drugs with laxative properties should be avoided because of the potential for exacerbation of diarrhea. Patients should be advised to contact their physician to discuss any laxative use.

    Patients should consult their physician if vomiting occurs, if fever or evidence of infection develops, or if symptoms of dehydration, such as fainting, light-headedness, or dizziness, are noted following therapy with CAMPTOSAR.

    Patients should be alerted to the possibility of alopecia.

    Clinical Abstract

    Rothenberg ML, Eckardt JR, Kuhn JG, et al. A phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol. 1996;14:1128-1135.

    Study design: Forty-eight patients with metastatic cancer of the colon or rectum that had recurred or progressed following 5-FU-based therapy were treated with irinotecan 125 mg/m²/week to 150 mg/m²/week IV for 4 weeks with a 2-week rest. All patients were evaluable for toxicity, and 43 were assessable for response. Responses were determined by an independent review panel of two medical oncologists and one radiologist for patients who had an objective response to therapy.

    This study was designed to evaluate tumor response rates and does not provide information on actual clinical benefit, such as effect on survival and disease-related symptoms.

    Responses and survival: There was one complete response (CR) and nine partial responses (PR), for an overall response rate of 23% (10/43) (21% [10/48] response rate for the intent-to-treat population). The median duration of response was 6 months (range, 2 to 13 months); duration of the CR was 11 months; and median survival time for all 48 patients was 10.4 months.

    Diarrhea side effect: Among patients receiving the 150-mg/m² starting dose, 4/9 (44%) experienced grade 4 diarrhea and dehydration; subsequently enrolled patients received a 125-mg/m² starting dose. At the lower dose, 9/39 (23%) had grade 4 diarrhea; before an aggressive loperamide regimen was added as a protocol modification, the overall incidence of grade 4 diarrhea was 17% (11/65 courses). After adoption of the loperamide regimen, grade 4 diarrhea occurred in 7/145 courses (5%).

    Other side effects: Grade 4 neutropenia occurred in 13/210 courses (6%). In patients pretreated with the antiemetic prochlorperazine (n=2), episodes of akathisia were reported; investigators hypothesized a possible drug interaction with irinotecan.

    Dosage and Administration

    Starting dose and dose modifications

    The recommended starting dose of CAMPTOSAR Injection (irinotecan hydrochloride injection) is 125 mg/m². All doses should be administered as an intravenous infusion over 90 minutes (see Preparation of Infusion Solution). The recommended treatment regimen (one treatment course) is 125 mg/m² administered once weekly for 4 weeks, followed by a 2-week rest period. Thereafter, additional courses of treatment may be repeated every 6 weeks (4 weeks on therapy, followed by 2 weeks off therapy). Subsequent doses should be adjusted to as high as 150 mg/m² or to as low as 50 mg/m² in 25-mg/m² to 50-mg/m², increments depending upon individual patient tolerance of treatment (see Table 10). Provided intolerable toxicity does not develop, treatment with additional courses of CAMPTOSAR may be continued indefinitely in patients who attain a response or in patients whose disease remains stable. Patients should be carefully monitored for toxicity.

    Table 10 describes the recommended dose modifications during a course of therapy and at the start of each subsequent course of therapy. These recommendations are based on toxicities commonly observed with the administration of CAMPTOSAR Injection. Therapy with CAMPTOSAR should be interrupted when grade 3 or 4 late diarrhea occurs despite appropriate treatment with loperamide (see PRECAUTIONS, Information for Patients) or when other intolerable toxicity is observed. Dose modifications for hematologic toxicities other than neutropenia (eg, leukopenia, anemia or thrombocytopenia, and platelets) during a course of therapy and at the start of a subsequent course of therapy are the same as those recommended for neutropenia. Dose modifications for nonhematologic toxicities other than diarrhea (nausea, vomiting, etc) during a course of therapy are the same as those recommended for diarrhea. At the start of a subsequent course of therapy, the dose of CAMPTOSAR should be decreased by 25 mg/m², compared with the initial dose of the previous course, for other NCI grade 2 or by 50 mg/m² for other grade 3 or 4 nonhematologic toxicities. All dose modifications should be based on the worst preceding toxicity. A new course of therapy should not begin until the granulocyte count has recovered to >=1,500/mm³, the platelet count has recovered to >=100,000/mm³, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicity. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing CAMPTOSAR.

    It is recommended that patients receive premedication with antiemetic agents (see PRECAUTIONS, General).

    Table 10.-Dose Modifications for Therapy With CAMPTOSAR
    A new course of therapy should not begin until the granulocyte count has recovered to >= 1,500/mm³, the platelet count has recovered to >= 100,000/mm³, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing CAMPTOSAR.
    Toxicity
    NCI Grade** (Value)
    During a Course of Therapy* At the Start of the Next Course of Therapy* (After Adequate Recovery), Compared With the Starting Dose in the Previous Course.
    No toxicity Maintain dose levelIncrease by 25 mg/m² up to a maximum dose of 150 mg/m²
    Neutropenia
    1 (1,500 to 1,999/mm³)Maintain dose levelMaintain dose level
    2 (1,000 to 1,499/mm³)Decrease by 25 mg/m²Maintain dose level
    3 (500 to 999/mm³)Omit dose, then decrease by 25 mg/m² when resolved to <= grade 2Decrease by 25 mg/m²
    4 (< 500/mm³)Omit dose, then decrease by 50 mg/m² when resolved to <= grade 2Decrease by 50 mg/m²
    Neutropenic fever
    (grade 4 neutropenia & >= grade 2 fever)
    Omit dose, then decrease by 50 mg/m² when resolvedDecrease by 50 mg/m²
    Other hematologic toxicities Dose modifications for leukopenia, thrombocytopenia, and anemia during a course of therapy and at the start of subsequent courses of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.
    Diarrhea
    1 (2-3 stools/day > pretx)***Maintain dose levelMaintain dose level
    2 (4-6 stools/day > pretx)Decrease by 25 mg/m²Maintain, if the only grade 2 tox****
    3 (7-9 stools/day > pretx)Omit dose, then decrease by 25 mg/m² when resolved to <= grade 2Decrease by 25 mg/m², if the only grade 3 tox
    4 (>= 10 stools/day > pretx)Omit dose, then decrease by 50 mg/m² when resolved to <= grade 2Decrease by 50 mg/m²
    Other nonhematologic toxicities
    1Maintain dose levelMaintain dose level
    2Decrease by 25 mg/m²Decrease by 25 mg/m²
    3Omit dose, then decrease by 25 mg/m² when resolved to <= grade 2Decrease by 50 mg/m²
    4Omit dose, then decrease by 50 mg/m² when resolved to <= grade 2Decrease by 50 mg/m²
    *All dose modifications should be based on the worst preceding toxicity.
    **National Cancer Institute Common Toxicity Criteria.
    ***Pretreatment.
    ****Toxicity.

    Preparation and Administration Precautions

    As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions containing CAMPTOSAR. The use of gloves is recommended. If a solution of CAMPTOSAR Injection (irinotecan hydrochloride injection) contacts the skin, wash the skin immediately and thoroughly with soap and water. If CAMPTOSAR contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.

    Preparation of infusion solution

    Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe.

    CAMPTOSAR Injection must be diluted prior to infusion. CAMPTOSAR should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 to 1.1 mg/mL. In most clinical trials, CAMPTOSAR was administered in 500 mL of 5% Dextrose Injection, USP.

    Stability

    The solution is physically and chemically stable for up to 24 hours at room temperature (approximately 25ºC) and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2ºC to 8ºC) and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing CAMPTOSAR and admixtures of CAMPTOSAR may result in precipitation of the drug and should be avoided. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2ºC to 8ºC, 36ºF to 46ºF). In the case of admixture prepared with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, the solution should be used within 6 hours if kept at room temperature (15º to 30ºC, 59º to 86ºF).

    Other drugs should not be added to the infusion solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

    How supplied

    Each mL of CAMPTOSAR Injection (irinotecan hydrochloride injection) contains 20 mg irinotecan (on the basis of the trihydrate salt); 45 mg sorbitol; and 0.9 mg lactic acid. When necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid.

    CAMPTOSAR Injection is available as single-dose vials in the following package size:

    5-mL amber glass vial

    NDC 0009-7529-01

    Each 5-ml vial of CAMPTOSAR contains 100 mg irinotecan at a concentration of 20 mg/mL.

    This is packaged in a backing/plastic blister to protect against inadvertent breakage and leakage. The vial should be inspected for damage and visible signs of leaks before removing the backing/plastic blister. If damaged, incinerate the unopened package.

    Storage

    Store at controlled room temperature 15°C to 30°C (59°F to 86°F). Protect from light. It is recommended that the vial (and backing/plastic blister) should remain in the carton until the time of use.

    Caution: Federal law prohibits dispensing without prescription.

    Summary

    CAMPTOSAR Injection (irinotecan hydrochloride injection) is one of a new class of cytotoxic drugs known as topoisomerase I inhibitors that interact specifically with the enzyme topoisomerase I. The function of topoisomerase I is to maintain the proper three-dimensional conformation of DNA by removing supercoils (twists and kinks) generated during DNA replication and transcription. Irinotecan and its active metabolite bind to the topoisomerase I/DNA complex and prevent religation of these single-strand DNA breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis. Mammalian cells cannot efficiently repair these double-strand breaks.

    CAMPTOSAR is indicated for the second-line treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial 5-FU-based therapy. The recommended starting dose is 125 mg/m² once weekly for 4 consecutive weeks, followed by a 2-week rest (one course). Phase II trials in 304 patients demonstrated objective tumor response with therapy with CAMPTOSAR. These studies showed that CAMPTOSAR induced regression in tumors in 15.0% of patients treated with the recommended starting dose. The majority of responses were observed within the first two courses of therapy. A considerably lower response wasseen at a dose of 100mg/m².

    CAMPTOSAR is an effective second-line agent for the treatment of many patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following prior 5-FU-based therapy.

    References

    1. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin. 1995;45:8-30.
    2. Leichman CG, Fleming TR, Muggia FM, et al. Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol. 1995;13:1303-1311.
    3. Cohen AM, Minsky BD, Schilsky RL. Colon cancer. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer Principles & Practice of Oncology. 4th ed. Philadelphia, Pa: JB Lippincott Co; 1993: 929-977.
    4. American Cancer Society. Cancer Facts & Figures--1995. Atlanta, Ga: American Cancer Society, Inc; 1995.
    5. Lipner M. Increasing chemo's clout with chronomodulation in advanced colorectal cancer. Oncol Times. February 1995:20.
    6. Pelley RJ. Role of chemotherapy in the palliation of gastrointestinal malignancies. Semin Oncol. 1995;22:45-52.
    7. Forward WH. CPT-11: from DNA topology to clinical activity. Semin Oncol. 1996;23(suppl 3):1.

    8. Slichenmyer WJ, Rowinsky EK, Donehower RC, et al. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst. 1993;85:271-291.
    9. Potmesil M. Camptothecins: from bench research to hospital wards. Cancer Res. 1994;54:1431-1439.
    10. Burris H, Fields S. Clinical update on the topoisomerase I inhibitors. ASCO Educational Book. ASCO 31st Annual Meeting; May 20-23, 1995; Los Angeles, Calif: 109.

    11. Liu LF. Biochemistry of camptothecin. In: Potmesil M, Pinedo H, eds. Camptothecins: New Anticancer Agents. Ann Arbor, Mich: CRC Press; 1995:9-20.
    12. Pommier Y, Leteurtre F, Fesen MR, et al. Cellular determinants of sensitivity and resistance to DNA topoisomerase inhibitors. Cancer Invest. 1994;12:530-542.
    13. Matsuoka H, Furusawa M, Tomoda H, et al. Cytotoxicity of CPT-11 and SN-38 for gastrointestinal and recurrent carcinomas cultured on contact-sensitive plates. Anticancer Res. 1994;14:405-410.
    14. Chen AY, Yu C, Potmesil M, et al. Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells. Cancer Res. 1991;51:6039-6044.
    15. de Forni M, Bugat R, Chabot GG, et al. Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients. Cancer Res. 1994;54:4347-4354.
    16. Ratain MJ, Mick R, Gupta E, et al. Prospective evaluation of the effect of race and gender on irinotecan (CPT-11) pharmacokinetics (PK) and intestinal toxicity. Proc ASCO. 1996;15:472. Abstract 472.
    17. Giovanella BC, Stehlin JS, Wall ME, et al. DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science. 1989;246:1046-1048.
    18. Rothenberg ML, Eckardt JR, Kuhn JG, et al. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol. 1996;14:1128-1135.

    Information for Patients

    At the first sign of diarrhea, take 4 mg of loperamide, then 2 mg every 2 hours until free of diarrhea for at least 12 hours. A dose of 4 mg every 4 hours may be taken at night. Note that this dosage regimen exceeds the usual dosage recommendations for loperamide.

    While agents other than loperamide may have utility in the treatment of late diarrhea, the US clinical trial experience with such medications is limited.

    If you have signs of diarrhea following administration of CAMPTOSAR, do not consume dairy products, stimulant laxatives, or other foods or agents that are likely to trigger or worsen diarrhea.

    Notify a physician immediately if you experience any of the following: vomiting, fever over 101°F, diarrhea , or symptoms of dehydration.

    Information booklets are available from the manufacturer of CAMPTOSAR. If you would like one, please ask your doctor.

    Please see package insert for full prescribing information.


    Pharmacia & Upjohn
    Yakult

    © 1996 Pharmacia & Upjohn Company


    USX 5833.00 August 1996

    Manufactured by PHARMACIA & UPJOHN COMPANY, Kalamazoo, Michigan, USA
    Licensed from YAKULT HONSHA CO, LTD, Japan, and DAIICHI PHARMACEUTICAL CO, LTD, Japan

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