Clinical trial NCT00735878
Conditions: Non Small Cell Lung Cancer Lung Cancer
Keywords: Lung Cancer Advanced Lung Cancer NSCLC
Sponsor: Konstantin Dragnev
Start date: 2004-09-01; Completion date: 2009-01-01
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objectives:

The primary objectives of this study are as follows:

• To determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of escalating ABT-751 in combination with fixed dose carboplatin in patients with advanced non small cell lung cancer (NSCLC).

• To evaluate the efficacy of the combination with ABT-751 and carboplatin in patients with advanced NSCLC

• To determine the median survival in the study population

Secondary Objectives

The secondary objectives are:

• To characterize the pharmacokinetic profile of ABT-751 given in combination with carboplatin in a subset of patients, treated at the MTD or recommended doses for Phase 2.

• To determine the pharmacodynamics of ABT-751 as a single agent and the combination of ABT-751 and carboplatin as evaluated by cell cycle analysis of buccal mucosa cells.

Detailed description:
This primary objective of this Phase 1/2 study is to evaluate the DLT and MTD of escalating oral doses of ABT-751 given BID (twice daily) on Day 1 of each cycle for 7 days in combination with carboplatin given on a 21-day schedule. The carboplatin dose is fixed at AUC 6 and will be administered on Day 4 during the first cycle to facilitate the pharmacokinetic analysis. During the subsequent cycles both agents will be administered on Day 1. ABT-751 is administered at the following dose levels using the Simon rapid dose escalation model: 100, mg, 125 mg, 150 mg, 175 mg and 200 mg BID.

Initially, 1 patient will be enrolled in dose level 1. If the patient experiences a Grade 2 toxicity, an additional 2 patients will be enrolled at the same dose level. If 1 of the 3 patients experiences a Grade 3 (or higher toxicity), the cohort will be expanded to 6 patients. However, if 1 patient completes one cycle at the assigned dose regimen without experiencing a Grade 2 toxicity, enrollment in the next cohort (dose level 2) can begin. This rapid dose escalation scheme will apply to cohorts 1 through 3.

Initially, in the 4th cohort (dose level 4), a minimum of three patients will be enrolled. If 1 of the 3 patients experiences a Grade 3 (or higher toxicity), the cohort will be expanded to 6 patients. However, if 3 patients complete one cycle at the assigned dose regimen without experiencing a Grade 3 (or higher toxicity), enrollment in the next cohort (dose level 5) can begin. This scheme will apply to cohorts 4, 5, and 6 MTD is defined as the highest dose of ABT-751 given in combination with carboplatin at which fewer than 33% of patients experience DLT. MTD will be evaluated at the end of the first cycle (21 days). Toxicities will be determined also at the end of cycle 2 to evaluate the safety of combining both agents on day 1. If the MTD has not been determined after completion of the 6th cohort (dose level 6), based on an overall review of toxicity at each cohort, the Investigator may select a dose thought to be the recommended dose for Phase 2 studies. Six patients treated at MTD will undergo PK (pharmacokinetic) and PD (pharmacodynamic) evaluation. An additional cohort of 14-20 patients will be enrolled at either the MTD or at the recommended Phase 2 dose level administering both drugs on day 1. During this portion of the study patients will be withdrawn from the study if any of the following occur:

• Patient or patient's legally acceptable representative decides to withdraw consent.

• Patient's response to therapy is unsatisfactory, as evidenced by progression of disease as defined by RECIST Criteria for Tumor Response (within 2 cycles)

• The patient experiences toxicities deemed possibly or probably related to drug that have not resolved to at least Grade 2 or lower within three weeks.

• The patient requires more than one dose reduction because of toxicities attributable to ABT-751.

• The patient requires during the study period alternate antineoplastin agent, concurrent radiotherapy or surgery of the only measurable site(s) of disease.

• The patient becomes pregnant or begins to breast-feed.

• The investigator believes it is in the best interest of the patient to discontinue study drug administration.

If grade 3 or higher toxicities develop in 2 or more out of the first 6 patients who receive both drugs on day 1 on a dose level at which no such toxicities were noted on the ABT-751 day 1/carboplatin day 4 schedule, the additional patients for the second portion of the study will receive the latter schedule.

If toxicities characteristic of carboplatin (myelosuppression and others) are observed at the AUC 6 dose, carboplatin dose will be lowered to AUC 4.5 and the following dose escalation schema will be employed, beginning at the same ABT-751 dose as the one at which the toxicity developed:

All patients should receive antiemetics prior to carboplatin. A regimen of dexamethasone 10 mg and dolasetron 100 mg IV prior to carboplatin infusion may be used.

The study enrollment will be limited to patients with advanced NSCLC. Treatment will continue until progression of disease, unacceptable toxicities or withdrawal of informed consent. Male and female cancer patients will be selected to participate in the study according to the selection criteria.

Arms: arm 1: 100 mg BID ABT-751 orally for 7 days. Carboplatin AUC 4.5 once every 21 days. arm 2: 125 mg BID ABT-751orally for 7 days. Carboplatin AUC 4.5 or 6 once every 21 days. arm 3: 150 mg BID ABT-751orally for 7 days. Carboplatin AUC 6 once every 21 days.
Interventions: intervention 1: ABT-751 and Carboplatin
Intervention descriptions: intervention 1: This primary objective of this Phase 1/2 study is to evaluate the DLT and MTD of escalating oral doses of ABT-751 given BID on Day 1 of each cycle for 7 days in combination with carboplatin given on a 21-day schedule. The carboplatin dose is fixed at AUC 6 and will be administered on Day 4 during the first cycle to facilitate the pharmacokinetic analysis. During the subsequent cycles both agents will be administered on Day 1. ABT-751 is administered at the following dose levels using the Simon rapid dose escalation model: 100, mg, 125 mg, 150 mg, 175 mg and 200 mg BID.

Protocol documents: