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
• To determine the median survival in the study population
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.
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.
1. At least 18 years of age.
2. Pathologically or cytologically confirmed diagnosis of NSCLC .
3. At least one measurable lesion (not amenable to resection) for Response Evaluation
Criteria in Solid Tumors (RECIST) tumor assessments. Target lesions must not have
been in the previous radiation port.
4. Advanced stage of disease (IIIB with malignant pleural effusion or Stage IV) with no
known curative treatment that has progressed despite therapy for recurrent/metastatic
disease or prior therapy was discontinued due to intolerable toxicities. During the
phase II portion of the study, previously untreated patients with IIIB with malignant
pleural effusion or Stage IV NSCLC may be enrolled.
5. For patients participating in the phase I part of the study, no alternative therapy
is available that is expected to prolong overall or progression-free survival.
Unacceptable toxicities during first- or second-line therapy or evidence for disease
6. Adequate hematologic, renal and hepatic function as follows:
- Hematologic: ANC ≥ 1200/mm3; Platelets; ≥ 100,000/mm3; hemoglobin: ≥ 8.5 g/dL;
- Renal function: serum creatinine ≤ 2.0 mg/dL; renal (CrCl > 50 ml/min by
Jelliffe or Cockcroft Gault Formula),
- Hepatic function: Bilirubin ≤ 2.0 mg/dL (≤ 3.0 mg/dL for patients with liver
metastases); AST and ALT ≤ 2.5 X the upper limits of normal (ULN) (≤ 5 X ULN for
patients with liver metastases).
7. Adequate performance status, Eastern Cooperative Oncology Group (ECOG) Performance
Score of 0-1.
8. Prior platinum (cisplatin, carboplatin or oxaliplatin) therapy is allowed.
9. Patient or patient's legally acceptable representative has voluntarily signed and
dated an informed consent form approved by an Institutional Review Board (IRB), prior
to any study-specific procedures.
1. Any other malignancy within 3 years except in situ carcinoma.
2. Untreated central nervous system (CNS) metastasis.
3. A greater than Grade 1 National Cancer Institute Common Toxicity Criteria (NCI CTC)
neurology category findings at baseline.
4. Concurrent anti-cancer therapy or radiotherapy.
5. Concurrent therapy with colchicines.
6. Prior therapy with ABT-751.
7. Cytotoxic chemotherapy within 3 weeks of initiating investigational treatment.
8. Any investigational therapy within 4 weeks.
9. Female patients that are pregnant or breastfeeding.
10. Patients of childbearing potential (male and female) that do not agree to use a
contraceptive method deemed acceptable by the investigator while in the study and for
up to three months following completion of therapy.
11. Documented allergy or hypersensitivity to carboplatin or sulfa.
12. Patient has received more than 2 prior chemotherapy regimens for advanced disease.
Adjuvant chemotherapy administered more than 6 months prior to enrollment does not
count towards this limit.
13. Patient is classified as 3 or 4 by New York Heart Association (NYHA) Functional
Classification, defined as:
- Class 3: Patients with marked limitation of physical activity, comfortable at rest,
but less than ordinary activity causes symptoms.
- Class 4: Patients are unable to carry on any physical activity without symptoms and
symptoms are present even at rest.
14. Evidence of clinically significant medical condition(s) that compromises safety,
compliance, or study conduct, and/or is considered by the investigator to be unable
to tolerate the proposed treatment or procedures.