A Phase I/II Pharmacokinetic and Pharmacodynamic Study of ABT-751 in Combination With Carboplatin in Patients With Advanced Lung Cancer
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.
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 and PD 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 During this portion of the study patients will be withdrawn from the study if any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
• 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
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.
Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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).
This will be determined during the phase 1 portion of the study
Konstantin H Dragnev, MD
Dartmouth-Hitchcock Medical Center
United States: Food and Drug Administration
|Dartmouth-Hitchcock Medical Center||Lebanon, New Hampshire 03756|