Hycamtin (topotecan) - 3 indications

Scroll down for information on each indication:

• the treatment of ovarian cancer; approved May 1996
• the treatment of Stage IV-B, recurrent, or persistent cervical cancer; approved July 2006
• the treatment of small cell lung cancer; approved October 2007

General Information

Hycamtin (topotecan) is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks.

Hycamtin is specifically indicated for the following indications:

• as a single agent, is indicated for the treatment of patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy
• for use in combination with cisplatin for the treatment of patients with Stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment
• as a single agent for the treatment of patients with small cell lung cancer (SCLC) with platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy

Hycamtin is supplied as an injection for intravenous administration. Scroll down to see the recommended dosing/administration for each indication.

Mechanism of Action

Hycamtin (topotecan) is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. The cytotoxicity of topotecan is thought to be due to double strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double strand breaks.

Side Effects

Adverse effects associated with the use of Hycamtin for ovarian cancer may include, but are not limited to, the following:

hematologic adverse reactions, including:

• neutropenia
• anemia
• thrombocytopenia
• febrile neutropenia

non-hematologic adverse reactions (all Grades), including:

• nausea
• vomiting
• fatigue
• diarrhea
• dyspnea

Adverse effects associated with the use of Hycamtin for cervical cancer may include, but are not limited to, the following:

hematologic adverse reactions, including:

• neutropenia
• anemia
• thrombocytopenia

non-hematologic adverse reactions, including:

• pain
• vomiting
• infection/febrile neutropenia

Adverse effects associated with the use of Hycamtin for SCLC may include, but are not limited to, the following:

hematologic adverse reactions, including: 

• neutropenia
• anemia
• thrombocytopenia
• febrile neutropenia

non-hematologic adverse reactions, including:

• asthenia
• dyspnea
• nausea
• pneumonia
• abdominal pain
• fatigue

The Hycamtin drug label comes with the following Black Box Warning: Hycamtin can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm3 and platelet counts greater than or equal to 100,000/mm3 . Monitor blood cell counts.

Indication 1 - the treatment of ovarian cancer

approved May 1996

Dosing/Administration

The recommended dosage of Hycamtin for injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity.

Clinical Trial Results

In an open, randomized comparison study, 20% of subjects receiving Hycamtin responded to treatment compared to 12% of subjects receiving paclitaxel. Response was defined as 50% or greater shrinkage in tumor size. Median progression-free survival or time to progression for all treated subjects, defined as the time when the tumor progresses, was both statistically and clinically significant, indicating that subjects receiving Hycamtin experienced progressive disease less rapidly--23 weeks compared to 14 weeks for paclitaxel.

The efficacy of Hycamtin was confirmed in an additional open, noncomparative study. In each study, the dosage of Hycamtin was 1.5 mg/m2 administered intravenously over 30 minutes daily for five days and repeated every 21 days.

Indication 2 - the treatment of Stage IV-B, recurrent, or persistent cervical cancer

approved July 2006

Dosing/Administration

The recommended dosage of Hycamtin for injection is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on Days 1, 2, and 3, in combination with cisplatin 50 mg/m2 on Day 1, of a 21-day cycle.

Clinical Trial Results

FDA approval was based on the phase-3 Gynecologic Oncology Group trial which enrolled women with measurable, histologically proven stage-IVB, recurrent or persistent carcinoma of the cervix who had recovered from the effects of prior surgery, radiation or chemoradiation. Patients were randomized into three arms: single-agent cisplatin (n=146, 50 mg/m2, every 21 days); topotecan hydrochloride plus cisplatin (n=147, Hycamtin 0.75 mg/m2, days one to three plus cisplatin 50 mg/m2 day one, every 21 days); or MVAC (methotrexate, vinblastine, doxorubicin and cisplatin every 28 days). The MVAC arm was closed after 64 patients experienced excessive toxicity. 

The study showed a statistically significant improvement in overall survival for the topotecan hydrochloride plus cisplatin arm. Median survival for topotecan hydrochloride plus cisplatin was 9.4 months compared with 6.5 months for cisplatin alone.

Indication 3 - the treatment of small cell lung cancer

approved October 2007

Dosing/Administration

The recommended dosage of Hycamtin for injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle.

Clinical Trial Results

Hycamtin was evaluated in 426 patients with recurrent or progressive small cell lung cancer (SCLC) in a randomized, comparative trial and in 3 single-arm trials.

Randomized Comparative Trial

In a randomized, comparative trial, 211 patients were randomized 1:1 to receive Hycamtin for injection (1.5 mg/m2 once daily intravenously for 5 days starting on Day 1 of a 21-day cycle) or CAV (cyclophosphamide 1,000 mg/m2 , doxorubicin 45 mg/m2 , vincristine 2 mg administered sequentially on Day 1 of a 21-day cycle). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed greater than or equal to 60 days after completion of first-line therapy). A total of 77% of patients treated with Hycamtin for injection and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy. The efficacy outcome measures were overall response rate, response duration, time to progression or OS. The results of the trial did not show statistically significant improvements in response rate, response duration, time to progression, or OS. The median time to response was similar in both arms: Hycamtin, 6 weeks (2.4 weeks to 3.6 months) versus CAV, 6 weeks (5.1 weeks to 4.2 months).

Single-Arm Trials

Hycamtin for injection was also studied in three open-label, non-comparative trials (Studies 014, 092 and 053) in a total of 319 patients with recurrent or progressive SCLC after treatment with first-line chemotherapy. In all three trials, patients were stratified as either sensitive (responders who then subsequently progressed greater than or equal to 90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy). Response rates ranged from 11% to 31% for sensitive patients and 2% to 7% for refractory patients. Median time to progression and median survival were similar in all three trials and the comparative trial.