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Introducing

Camptosar

New Therapy for Metastatic Cancer of the Colon and Rectum Recurring or Progressing after 5-FU Based Therapy

Table of Contents

Scope of the Problem

In 1995 there were an estimated 138,200 new cases of cancers of the colon and rectum in the United States. In 20% of the cases, the disease has already metastasized at the time of diagnosis and another 30% of the patients eventually develop metastasis.[1] These common malignancies are the second leading cause of cancer death, killing 55,300 Americans annually.[2]

For more than 40 years, only one drug, fluorouracil (5-FU) injection, has been indicated for the treatment of colon and rectal cancers. Meta-analysis of nine clinical trials showed that approximately 23% of the patients respond to first-line 5-FU based regimens (eg, 5-FU+ leucovorin).[3] Studies of second-line, single-agent therapies in patients who have already received a first-line 5-FU containing treatment report response rates that are usually less than 5%. Until CAMPTOSAR® Injection (irinotecan hydrochloride injection), there has been no standard second-line therapy for patients whose disease has progressed following 5-FU based therapy.

New CAMPTOSAR Injection

For the first time, there is an innovative new drug indicated for metastatic cancer of the colon or rectum for patients who have failed prior 5-FU-based therapy. New CAMPTOSAR Injection (irinotecan HCL injection) provides objective tumor response in 15% of the patients when given at the recommended starting dose of 125 mg/m². A considerably lower response rate was seen with a starting dose of 100 mg/m².

font=>Mechanism of Action

Camptosar acts on topoisomerase I, a new target for DNA disruption.
Replicating DNA Model

CAMPTOSAR inhibits topoisomerase I, an enzyme that relaxes supercoiled DNA during replication and transcription. Binding of the drug to this enzyme stabilizes topoisomerase I and DNA. When advancing replication enzymes collide with the drug-topoisomerase-DNA complex, double-stranded DNA breaks occur that result in tumor cell death.

Pharmacokinetics

CAMPTOSAR is metabolized primarily in the liver into its lipophilic, active metabolite, SN-38

font=>CAMPTOSAR: Efficacy Demonstrated in Phase II, Open-Label Clinical Trials

Design of trials[6]

Three multicentered phase II, open-label clinical trials to evaluate the efficacy of single-agent therapy with CAMPTOSAR enrolled 304 patients with metastatic cancer of the colon or rectum. These studies were designed to evaluate tumor response rate and do not provide information on actual clinical benefit, i.e. survival and disease related symptoms. Of these patients, 81.9% had aggressive malignancies either experiencing disease progression </= 3 months after stopping 5-FU therapy for metastatic disease (62.8%) or disease recurrence </= 6 months after stopping adjuvant 5-FU therapy (19.1%).

USA

Trials were performed at 59 cancer centers and clinics throughout the United States

Baseline demographics

Of the 304 patients, 55% were men and 45% were women; 44% were 65 years of age or older; and 92.1% had a baseline performance status of 0 (48%) or 1 (44.1%). The demographic characteristics of the patients in each study and starting-dose group were generally representative of the overall study population.

Metastases

At baseline, 70.1% of the patients had liver metastases and 37.5% had lung metastases; 80.6% of the patients had two or more measured sites of metastases. All patients had adequate liver function as measured by serum levels of hepatic enzymes and bilirubin.

Dose-level studies

CAMPTOSAR, a new injectable antineoplastic agent, was administered weekly as a 90-minute intravenous (IV) infusion for 4 weeks, followed by a 2-week rest (one course). Starting doses of CAMPTOSAR in clinical trials were 100 mg/m², 125 mg/m², and 150 mg/m². The recommended starting dose of CAMPTOSAR is 125 mg/m².

A starting dose of 150 mg/m², initiated in a small number of patients (n=9), was associated with unacceptably high rates of grade 4 diarrhea and fibrile neutropenia.

Objective Tumor Measurements

MEASUREMENT

DEFINITION

Complete response (CR) (primary endpoint)

Disappearance of all measurable and evaluable disease (no new lesions) for at least 4 weeks

Partial response (PR) (primary endpoint)

>/=50% decrease in measurable lesions (no new lesions) for at least 4 weeks

Stable disease

Criteria for CR or PR or progressive disease not met

Progressive disease

Increase in tumor size or appearance of new lesions

Other Clinical Measurements

Duration of response

Time of onset of PR to time of objective evidence of disease progression

Time to progression

Time from first dose of CAMPTOSAR until date at which disease progression was documented

Survival time

Time from first dose of CAMPTOSAR to death (or last date patient was known to be alive)

CAMPTOSAR Produces Objective Tumor Response

Intent-to-Treat Population

Trial

San Antonio Regional[7]
(n=48)

Mayo/NCCTG*
(n=90)
US Multicenter Study
Group (n = 166)
Starting dose150 mg/m²**125 mg/m²125 mg/m²125 mg/m² 100 mg/m²
Objective response
CR & PR***
22.2%
(2/9)
20.5%
(8/39)
1 CR
13.3%
(12/90)
14.1%
(9/64)
1 CR
7.8%
(8/102)
Progressive disease11.1%
(1/9)
7.7%
(3/39)
26.7%
(24/90)
28.1%
(18/64)
44.1%
(45/102)
No Follow-up scan11.1%
(1/9)
7.7%
(3/39)
4.4%
(4/90)
14.1%
(9/64)
8.8%
(9/102)

* North Central Cancer Treatment Group.
** A dose of 150 mg/m² is not recommended because of unacceptable toxicity.
*** CR=Complete response, PR=Partial response.

The recommended starting dose of CAMPTOSAR is 125 mg/m²

Among patients with metastatic cancer of the colon or rectum that occurred or progressed after a 5-FU-based treatment regimen who received the 125 mg/m² starting dose of CAMPTOSAR, 13.3% to 20.5% responded to therapy. The response rate for the 125 mg/m² starting dose pooled across the three trials was 15.0% (29/193). A considerably lower response rate was seen with a starting dose of 100mg/m².

Response rates are based on independent review and intent-to-treat analysis. The intent-to-treat population includes all patients who received at least one dose of CAMPTOSAR.

Other Clinical Measurements

When to expect response

In patients whose disease had recurred or progressed following systemic chemotherapy with a fluorouracil-based regimen, most responses were observed within the first two courses of single-agent therapy with CAMPTOSAR. (One course of therapy consists of four weekly doses followed by a 2-week rest.) All but one response occurred by the fourth course of therapy.

font= SIZE=+2>Results From Three Phase II, Open-Label Clinical Studies
TrialSan Antonio
Regional
Mayo/NCCTGUS Multicenter Study Group
(n=48)(n=90)(n=64) (n=102)
Starting dose125 mg/m²* 125 mg/m² 125 mg/m² 100 mg/m²
No. courses (median) 3.53 33
Median dose intensity**
(mg/m²/wk)
62 5661 54
Objective response rate (%)***
(95% Confidence Interval)
20.8

[9.3, 32.3]

13.3

[6.3, 20.4]

14.1

[5.5, 22.6]

7.8

[2.6, 13.1]

Time to response
(median, months)
2.62.1 2.82.8
Response duration
(median, months)
6.4 5.9 5.6 6.2
Survival
(median, months)
10.4 8.1 10.7 9.3

* Nine patients received 150 mg/m² as a starting dose; 2 (22.2%) responded to CAMPTOSAR
** There were 2/304 complete responses; the remainder were partial responses.
*** Total dose administered in a course (weeks per course +6).

The effect of CAMPTOSAR on survival has not yet been determined in randomized trials.

Duration of response

The median duration of response for patients beginning therapy at 125 mg/m² was 5.8 months (range, 2.6 to 15.1 months).

Time to disease progression

The median time to disease progression for patients beginning therapy at 125 mg/m² was 4.2 months (range, 0.3 to 19.9 months).

Survival

The Kaplan-Meier estimate of survival time for patients beginning therapy at 125 mg/m² was 8.9 months (range, 0.3 to 33.4 months).

The effect of CAMPTOSAR on time to disease progression and survival has not yet been determined in randomized clinical trials.

Safety Profile of CAMPTOSAR

Gastrointestinal side effects[5]

Percent of Late Diarrhea by Grade and Day in Courses 1 and 2 to Therapy With CAMPTOSAR (N=304)
Percent Chart
Incidence of Diarrhea
Event % of Patients
(n=304)
All NCI* Grades
% NCI Grade 3
(7-9 Stools/Day > Pretreatment)
% NCI Grade 4
(>/= 10 Stools/Day > Pretreatment)
Late-onset diarrhea 87.8 16.4 14.1
Early-onset diarrhea 50.3 5.6 2.3

* National Cancer Institute common toxicity criteria.

  • Diarrhea was included as a reason for discontinuation of study medication for 1.6% of the patients (5/304) in the three pivotal trials.
  • Late Diarrhea: Frequency Before and After Intensive Loperamide Therapy in the San Antonio Study
    San Antonio Study

    Effect of loperamide treatment on the frequency of late diarrhea

  • In the San Antonio trial, for patients receiving the 125 mg/m² starting dose, 14% (6/42) of courses were associated with grade 4 diarrhea before systematic loperamide use (described above); only 4.4% (5/113) of courses were associated with grade 4 diarrhea after the loperamide use was instituted.[7]

Nausea and vomiting

NCI grade 3 or 4 nausea occurred in 16.8% of patients and grade 3 or 4 vomiting in 12.5%.

The suggested management of nausea and vomiting during infusion is 10 mg dexamethasone with another antiemetic agent such as a 5-HT3 blocker (starting at least 30 minutes before administration of CAMPTOSAR. Late-onset nausea and vomiting may be treated with of antiemetics; eg, prochloperazine.

Hematologic adverse events[6]

Incidence of Hematologic Adverse Events in Clinical Trials
Event % of Patients
(n=304)
All NCI Grades
NCI Grade 3 NCI Grade 4
Range % of Patients Range < 5 % of Patients
Neutropenia 53.9 0.5 - 0.9 x 10 x 109/L 14.8 <500 cells x 109/L 11.5
Leukopenia 63.2 1.0 to 1.9 cells x 109/L 21.1<1.0 cell x 109/L 6.9
Thrombocytopenia 2.8* 25.0 to 49.9 cells x 109/L 1 <25.0 cells x 109/L 0.3
Anemia 60.5 Hb 6.5 to 7.9 g/dL 6.3 Hb <6.5 g/dL 0.7
Febrile neutropenia** - - - - -
* n=302. ** Concurrent grade 4 neutropenia and body temperature > 101°F.

Neutropenia

Adverse events[5]

Only 4.3% of the patients discontinued CAMPTOSAR because of medical events.

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 1-4 NCI 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
11.8
10.5
30.6
(16.4)
(14.1)
16.8
12.5
5.9
7.9
2.0
0
0.7
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
1.3
0.3
METABOLIC & NUTRITIONAL
Decrease Body weight
Dehydration
IncreaseAlkaline phosphatase
Increase 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
0.7
RESPIRATORY
Dyspnea
Increased Coughing
Rhinitis
22.0
17.4
15.5
3.6
0.3
0
NEUROLOGIC
Insomnia
Dizziness
19.4
14.8
0
0
CARDIOVASCULAR
Vasodilation (flushing)
11.2 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.

Hospitalizations

Eighty-one (26.6%) patients were hospitalized for medical events judged by the investigators to be related to therapy with CAMPTOSAR. Most patients were hospitalized for a constellation of gastrointestinal symptoms and hematologic abnormalities; the primary causes of drug-related hospitalization were diarrhea, with or without nausea or vomiting, or both (18.4%; 56/304); neutropenia/leukopenia, with or without diarrhea or fever, or both (8.2%; 25/304); and nausea or vomiting, or both (4.9%; 15/304). Among patients receiving the 125-mg/m² starting dose of CAMPTOSAR, 30% (58/193) were hospitalized for drug-related medical events.

Seventeen of the 304 patients died within 30 days of the administration of CAMPTOSAR. Five deaths were potentially drug related; patients experienced a constellation of medical events that included known effects of CAMPTOSAR. No deaths were associated with diarrhea.

Dosing and Administration

Initiating therapy

The initial recommended dose of CAMPTOSAR is 125 mg/m² administered as a 90-minute IV infusion. The recommended treatment regimen (one treatment course) is 125 mg/m² administered once weekly for 4 weeks followed by a 2-week rest. Thereafter, additional treatment courses may be repeated every 6 weeks (4 weeks on therapy followed by 2 weeks off therapy). Additional courses of CAMPTOSAR may be continued indefinitely in patients who attain a response or whose disease remains stable, provided intolerable toxicity does not develop.

Dosing Schedule for CAMPTOSAR for a
Patient Experiencing No Toxicity
(First 6 Weeks of Therapy)

Week 1 2 3 4 5 6
Treatment 125-mg/m² as
one 90-min IV infusion
125-mg/m² as
one 90-min IV infusion
125-mg/m² as
one 90-min IV infusion
125-mg/m² as
one 90-min IV infusion
rest rest

Subsequent doses should be adjusted to as high as 150 mg/m² or as low as 50 mg/m² in 25-mg/m² to 50-mg/m² increments, depending on individual patient tolerance of treatment.

Next Courses of Therapy

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.

Recommended Dose Modifications*
A new course of therapy should not begin until the granulocyte count has recovered to >/= 1500/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 Courses of
Therapy - After Adequate Recovery
(See Above)
No toxicityMaintain dose levelIncrease 25 mg/m² up to a maximum dose of 150 mg/m²
Neutropenia
1 (1,500 to 1,999/mm³)
2 (1,000 to 1,499/mm³)
3 (500 to 900/mm³)
4 (< 500/mm³)
Maintain dose level
Decrease 25 mg/m²
Omit dose, then decrease 25 mg/m² when resolved to </= grade 2
Omit dose, then decrease 50 mg/m² when resolved to </= grade 2
Maintain dose level
Maintain dose level
decrease 25 mg/m²

decrease 50 mg/m²

Neutropenic fever
(grade 4 neutropenia & >/= grade 2 fever)
Omit dose, then decrease 50 mg/m² when resolveddecrease 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)***
2 (4-6 stools/day > pretx)
3 (7-9 stools/day > pretx)
4 (>/= 10 stools/day > pretx)
Maintain dose level
decrease 25 mg/m²
Omit dose, then decrease 25 mg/m² when resolved to </= grade 2
Omit dose, then decrease 50 mg/m² when resolved to </= grade 2
Maintain dose level
Maintain, if the only grade 2 tox****
decrease 25 mg/m², if the only grade 3 tox

decrease 50 mg/m²

Other nonhematologic toxicities
1
2
3
4

Maintain dose level
decrease 25 mg/m²
Omit dose, then decrease 25 mg/m² when resolved to </= grade 2
Omit dose, then decrease 50 mg/m² when resolved to </= grade 2

Maintain dose level
decrease 25 mg/m²
decrease 50 mg/m²

decrease 50 mg/m²

*All dose modifications should be based on the worst preceding toxicity.
**National Cancer Institute common toxicity criteria.
***Pretreatment.
****Toxicity.

Preparation of Infusion Solution

CAMPTOSAR must be diluted prior to infusion. Care should be exercised in handling and preparing the solution; use of gloves is recommended. Other drugs should not be added to the infusion solution.

CAMPTOSAR has not been shown to cause extravasational necroses in US studies.

Recommendations for Adverse-Reaction Management

Patient Information

Guidelines for Optimal Outcome

Parameter

Recommendations

Patient selection

The majority of patients studied in clinical trials had a baseline performance status of 0 or 1. Patients who recently have received myelosuppressive chemotherapy or radiotherapy, or both, should have adequate blood counts before therapy with CAMPTOSAR is initiated. Patients must be motivated to comply with toxicity management.

Patient information and education

Patient information booklets should be offered to all patients and care givers. Early patient reporting and response to adverse effects is essential to manage morbidity. Caution patients against prophylactic loperamide use.

Monitoring

Complete blood count is recommended before administering CAMPTOSAR. Periodic scans can be used to evaluate response to therapy. Patients and care givers should monitor temperature and must be reminded to report signs and symptoms of dehydration, fever, and other potentially serious adverse reactions. It is important to ask patients about any changes in usual bowel habits.

Management

Adverse reactions should be managed aggressively as soon as they are noted. Use 0.25 mg to 1 mg IV atropine for early-onset diarrhea and loperamide (see package insert for dosage regimen) for late-onset diarrhea. Suggested management of nausea and vomiting during infusion: 10 mg dexamethasone + another antiemetic agent (e.g. 5-HT3 blocker).

An important element of patient management is appropriate dose modification during therapy in response to toxicities. Patients should recover from dose-limiting toxicity prior to beginning a new course of therapy (see Recommended Dose Modifications table).

CAMPTOSAR: New Therapy for Metastatic Cancer of the Colon and Rectum

References

  1. Tierney LMJ, McPhee SJ, Papadakis MA. eds Current Medical Diagnosis and Treatment. 34th ed. Norwalk, CT: Appleton & Lange; 1995: 549-550.
  2. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. Cancer J Clin. 1995;45:8-30.
  3. Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol. 1992;10:896-903.
  4. Creemers GJ, Lund B, Verweij J. Topoisomerase I inhibitors: topotecan and irenotecan. Cancer Treat Rev. 1994;20:73-96.
  5. Rothenberg ML, Kuhn JG, Burris HA III, et al. Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol. 1993;11:2194-2004.
  6. Data on file, Pharmacia & Upjohn, Kalamazoo, Michigan.
  7. 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.


Manufactured by PHARMACIA & UPJOHN COMPANY, Kalamazoo, Michigan, USA
Licensed from YAKULT HONSHA CO, LTD, Japan, and DAIICHI PHARMACEUTICAL CO, LTD, Japan
©1996 Pharmacia & Upjohn Company      USX4767.00      August 1996

Pharmacia & Upjohn Yakult

©1996 Pharmacia & Upjohn Company

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