Clinical Trials

Designs and Patient Characteristics

GEMZAR for 1st-line Locally Advanced or Metastatic NSCLC
GEMZAR for 1st-line Locally Advanced or Metastatic Pancreatic Cancer
GEMZAR for 1st-line Metastatic Breast Cancer
GEMZAR for 2nd-line Advanced Ovarian Cancer

GEMZAR for 1st-line Locally Advanced or Metastatic NSCLC

Trial Designs
Data from 2 randomized clinical studies (657 patients) support the use of GEMZAR in combination with cisplatin for the first-line treatment of patients with locally advanced or metastatic NSCLC.

GEMZAR plus cisplatin versus cisplatin:
This study was conducted in Europe, the US, and Canada in 522 patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. GEMZAR 1000 mg/m² was administered on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m² administered on Day 1 of each cycle. Single-agent cisplatin
100 mg/m² was administered on Day 1 of each 28-day cycle. The primary endpoint was survival.

GEMZAR plus cisplatin versus etoposide plus cisplatin:
A second, multicenter, study in Stage IIIB or IV NSCLC randomized 135 patients to GEMZAR 1250 mg/m² on Days 1 and 8, and cisplatin 100 mg/m² on Day 1 of a 21-day cycle or to etoposide 100 mg/m² IV on Days 1, 2, and 3 and cisplatin 100 mg/m² on Day 1 of a 21-day cycle.

Patient Characteristics

^a 28-day schedule — GEMZAR plus cisplatin: GEMZAR 1000 mg/m² on Days 1, 8, and 15 and cisplatin 100 mg/m² on Day 1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m² on Day 1 every 28 days.
^b 21-day schedule — GEMZAR plus cisplatin: GEMZAR 1250 mg/m² on Days 1 and 8 and cisplatin 100 mg/m² on Day 1 every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m² on Day 1 and IV etoposide 100 mg/m² on Days 1, 2, and 3 every 21 days.
^c N/A Not applicable.
^d Karnofsky Performance Status.

View GEMZAR efficacy data for 1st-line locally advanced or metastatic NSCLC

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GEMZAR for 1st-line Locally Advanced or Metastatic Pancreatic Cancer

Trial Designs
Data from 2 clinical trials evaluated the use of GEMZAR in patients with locally advanced or metastatic pancreatic cancer.

The first trial compared GEMZAR to 5-Fluorouracil (5-FU) in patients who had received no prior chemotherapy. A second trial studied the use of GEMZAR in pancreatic cancer patients previously treated with 5-FU or a 5-FU-containing regimen.

In both studies, the first cycle of GEMZAR was administered intravenously at a dose of 1000 mg/m² over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitated holding a dose) followed by a week of rest from treatment with GEMZAR. Subsequent cycles consisted of injections once weekly for 3 consecutive weeks out of every 4 weeks.

The primary efficacy parameter in these studies was "clinical benefit response," which is a measure of clinical improvement based on analgesic consumption, pain intensity, performance status, and weight change. Definitions for improvement in these variables were formulated prospectively during the design of the 2 trials.

Patient Characteristics
The first study was a multicenter (17 sites in US and Canada), prospective, single-blinded, two-arm, randomized, comparison of GEMZAR and 5-FU in patients with locally advanced or metastatic pancreatic cancer who had received no prior treatment with chemotherapy. 5-FU was administered intravenously at a weekly dose of 600 mg/m² for 30 minutes.

The second trial was a multicenter (17 US and Canadian centers), open-label study of GEMZAR in 63 patients with advanced pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen.

* The study arm is not approved for pancreatic cancer; it is only an experimental arm.
† In these trials, the single-agent GEMZAR arm used 1000mg/m² weekly x 7 followed by 1 week of rest, then weekly x3 of every 4 weeks thereafter.
‡ The comparator arm is approved for pancreatic cancer.

View GEMZAR efficacy data for 1st-line locally advanced or metastatic pancreatic cancer

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GEMZAR for 1st-line Metastatic Breast Cancer

Eligibility criteria

• Unresectable, locally recurrent, or metastatic breast cancer
• All patients received one neoadjuvant/adjuvant anthracycline-containing chemotherapy regimen, unless clinically contraindicated
• No prior chemotherapy for metastatic disease
• Prior hormonal therapy permitted
• Karnofsky Performance Status (KPS) ≥70 (ECOG performance status ≤2)

Primary endpoint

• Overall survival
• Secondary endpoints
• Time to disease progression
• Response rate

View GEMZAR efficacy data for 1st-line metastatic breast cancer

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GEMZAR for 2nd-line Advanced Ovarian Cancer

Pivotal phase trial
GEMZAR was studied in a randomized phase III study of 356 patients with platinum-sensitive* advanced ovarian cancer. Patients were randomized to receive either GEMZAR plus carboplatin or single-agent carboplatin as the control arm.

Primary Endpoint

• Progression-free survival (PFS)

Secondary Endpoint

• Overall response rate
• Duration of response
• Overall survival
• Toxicity
• Quality of life

* Platinum-sensitive patients are defined as patients who develop disease progression ≥6 months after receiving first-line platinum-based chemotherapy.
† Patients were treated for 6 cycles in absence of progressive disease or unacceptable toxicity. At investigator discretion, benefiting patients could receive a maximum of 10 cycles.

* Nine patients (5 on the GEMZAR plus carboplatin arm and 4 on the carboplatin arm) did not have baseline Eastern Cooperative Oncology Group (ECOG) performance status recorded.
† Three patients (2 on the GEMZAR plus carboplatin arm and one on the carboplatin arm) had a platinum-free interval of less than 6 months.

View GEMZAR efficacy data for 2nd-line advanced ovarian cancer

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References:

1. Data on file, Eli Lilly and Company; ONC20061106B.
2. Br J Cancer. 2002;87(2):161-167.
3. Cancer. 2002;94:902-910.
4. J Chemotherapy. 2004;16(6):589-594.
5. Proc Am Soc Clin Oncol. 2004;23. Abstract 4006.
6. J Clin Oncol. 2004;22(18):3776-3783.
7. J Clin Oncol. 2004;22(8):1430-1438.
8. J Clin Oncol. 2007;25(16):2212-2217.
9. J Clin Oncol. 2005;23(15):3509-3516.
10. J Clin Oncol. 2007;25(15):1960-1966.
11. Lancet Oncol. 2005;6(6):369-376.
12. J Clin Oncol. 1997;15(6):2403-2413.
13. J Clin Oncol. 2001;19(15):3447-3455.
14. J Clin Oncol. 2003;21(17):3296-3302.
15. J Cancer. 2003;39:1377-1383.
16. Proc Am Soc Clin Oncol. 2004;23. Abstract 4005.
17. Proc Am Soc Clin Oncol. 2004;23. Abstract 4118.
18. Proc Am Soc Clin Oncol. 2005;24. Abstract 4009.
19. Br J Cancer. 2006;95:587-592.
20. J Clin Oncol. 2006;24:4441-4447.

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GEMZAR^® is a registered trademark of Eli Lilly and Company. GC 50579

About GEMZAR

GEMZAR is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (stage IIIA or IIIB), or metastatic (stage IV) non-small cell lung cancer.

GEMZAR in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

GEMZAR in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.

GEMZAR is indicated as first-line treatment for patients with locally advanced (nonresectable stage II or stage III) or metastatic (stage IV) adenocarcinoma of the pancreas. GEMZAR is indicated for patients previously treated with 5-FU.

Important Safety Information

Myelosuppression is usually the dose-limiting toxicity with GEMZAR therapy.

Contraindication
Known hypersensitivity to GEMZAR.

Warnings
Infusion times of GEMZAR longer than 60 minutes and more frequent than weekly dosing have been shown to increase toxicity.

Pulmonary toxicity has been reported. In cases of severe lung toxicity, GEMZAR therapy should be discontinued immediately and appropriate supportive care measures instituted.

Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of GEMZAR. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS.

Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving GEMZAR alone or in combination with other potentially hepatotoxic drugs.

GEMZAR is Pregnancy Category D. GEMZAR can cause fetal harm when administered to a pregnant woman.

Precautions
Use caution in patients with pre-existing renal impairment or hepatic insufficiency. Administration of GEMZAR may exacerbate underlying hepatic insufficiency.

The optimum regimen for safe administration of GEMZAR with therapeutic doses of radiation has not yet been determined in all tumor types. GEMZAR has radiosensitizing activity and radiation recall reactions have been reported.

It is not known whether GEMZAR or its metabolites are excreted in human milk.

The effectiveness of GEMZAR in pediatric patients has not been demonstrated.

The toxicities of GEMZAR observed in pediatric patients were similar to those reported in adults.

GEMZAR clearance is affected by age as well as gender.

Patients receiving therapy with GEMZAR should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.

Monitoring and Dosage Modifications
Dosage adjustments for hematologic toxicity may be required.

Serum creatinine, potassium, calcium, and magnesium should be monitored during combination therapy with cisplatin.

Patients should be assessed with a CBC, including differential and platelet count, prior to each dose of GEMZAR. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Hepatic and renal function (including transaminases and serum creatinine) should be evaluated prior to therapy with GEMZAR and periodically thereafter.

Abbreviated Adverse Events (% incidence)
The most severe adverse events (grades 3/4) with GEMZAR plus cisplatin for the first-line treatment of patients with NSCLC in comparative trials of a 28-day regimen (GEMZAR plus cisplatin versus cisplatin alone) and a 21-day regimen (GEMZAR plus cisplatin versus etoposide plus cisplatin), respectively, were neutropenia (57 vs 4, 64 vs 76); thrombocytopenia (50 vs 4, 55 vs 13); leukopenia (46 vs 3, 29 vs 43); anemia (25 vs 7, 22 vs 15); nausea 28d (27 vs 21); vomiting 28d (23 vs 19); nausea/vomiting 21d (39 vs 26); neuromotor 28d (12 vs 3); hypomagnesemia 28d (7 vs 2); neurohearing 28d (6 vs 6); creatinine elevation 28d (5 vs 3); and dyspnea (7 vs 5, 1 vs 0). The most common adverse events (all grades) of the 28-day regimen (GEMZAR plus cisplatin versus cisplatin alone) and the 21-day regimen (GEMZAR plus cisplatin versus etoposide plus cisplatin), respectively, were anemia (89 vs 67, 88 vs 77); leukopenia (82 vs 25, 86 vs 87); neutropenia (79 vs 20, 88 vs 87), thrombocytopenia (85 vs 13, 81 vs 45), lymphocytopenia 28d (75 vs 51); hematuria (15 vs 13, 22 vs 10); creatinine 28d (38 vs 31), hyperglycemia 28d (30 vs 23); hypomagnesemia 28d (30 vs 17); nausea 28d (93 vs 87); vomiting 28d (78 vs 71); nausea and vomiting 21d (96 vs 86); alopecia (53 vs 33, 77 vs 92); neuromotor 28d (35 vs 15); constipation (28 vs 21, 17 vs 15); neurohearing 28d (25 vs 21); paresthesias 21d (38 vs 16); and infection (18 vs 12, 28 vs 21).

The most severe adverse events (grades 3/4) with GEMZAR plus carboplatin versus carboplatin, respectively, for the treatment of patients with advanced ovarian cancer were neutropenia (71 vs 12), thrombocytopenia (35 vs 11), leukopenia (53 vs 7), anemia (28 vs 11), nausea (6 vs 3), vomiting (6 vs 3), and constipation (7 vs 3). The most common adverse events (all grades) were neutropenia (90 vs 58); leukopenia (86 vs 70); anemia (86 vs 75); and thrombocytopenia (78 vs 57); RBC transfusion (38 vs 15), alopecia (49 vs 17), neuropathy/sensory (29 vs 27), nausea (69 vs 61), fatigue (40 vs 32), vomiting (46 vs 36), diarrhea (25 vs 14), and constipation (42 vs 37).

The most severe adverse events (grades 3/4) with GEMZAR plus paclitaxel versus paclitaxel, respectively, for the treatment of patients with MBC were neutropenia (48 vs 11); alopecia (18 vs 22); leukopenia (11 vs 2); anemia (7 vs 4); fatigue (7 vs 2); thrombocytopenia (6 vs 2); ALT elevation (6 vs 1); and neuropathy-sensory (6 vs 3). The most common adverse events (all grades) were alopecia (90 vs 92); anemia (69 vs 51); neutropenia (69 vs 31); neuropathy-sensory (64 vs 58); nausea (50 vs 31); fatigue (40 vs 28); myalgia (33 vs 33); vomiting (29 vs 15); and thrombocytopenia (26 vs 7).

The most severe adverse events (grades 3/4) with GEMZAR versus 5-FU for the first-line treatment of patients with pancreatic cancer and data reported from a single agent safety database, respectively, were neutropenia (26 vs 5, 24); alkaline phosphatase elevation (16 vs 17, 20); AST elevation (12 vs 2, 17); nausea/vomiting (13 vs 5, 12); ALT elevation (10 vs 0, 11); anemia (10 vs 0, 10); leukopenia (10 vs 2, 9); thrombocytopenia (10 vs 2, 8); bilirubin elevation (4 vs 9, 8); and pain (2 vs 0, 7). The most common adverse events (all grades), defined as reported in > 25% of patients, were AST elevation (72 vs 52, 78); alkaline phosphatase elevation (71 vs 64, 77); anemia (65 vs 45, 73); ALT elevation (72 vs 38, 72); leukopenia (71 vs 15, 64); nausea and vomiting (64 vs 58, 71); neutropenia (62 vs 18, 61); thrombocytopenia (47 vs 15, 36); pain (10 vs 7, 42); fever (30 vs 16, 38); proteinuria (10 vs 2, 32); constipation (10 vs 11, 31); diarrhea (24 vs 31, 30); rash (24 vs 13, 28); and bilirubin elevation (16 vs 25, 26).

See complete Warnings, Precautions, Adverse Reactions, and Dosage and Administration sections in the full Prescribing Information for safety and dosing guidelines.

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