Dose Escalation and Double-blind Study of Veliparib in Combination With Carboplatin and Etoposide in Treatment-naive Extensive Stage Disease Small Cell Lung Cancer

A Phase 1 Dose Escalation and Phase 2 Randomized Double-Blind Study of Veliparib in Combination With Carboplatin and Etoposide as a Therapy of Treatment-Naïve Extensive Stage Disease Small Cell Lung Cancer

The study seeks to assess the efficacy of veliparib (ABT-888) in combination with carboplatin and etoposide in participants with extensive disease small cell lung cancer (ED SCLC).

This is a Phase 1, open-label, dose-escalation/Phase 2 randomized double-blind study of veliparib in combination with carboplatin and etoposide and maintenance veliparib monotherapy.

Participants in Phase 1 will be sequentially assigned to ascending dose levels of veliparib in combination with standard carboplatin/etoposide regimen for up to four 21-day cycles based on the observed toxicities. The study design for Phase 1 will follow a traditional "3 + 3" dose-escalation protocol.

Once the veliparib recommended Phase 2 dose (RPTD) and schedule is determined, enrollment into Phase 2 will begin. Participants from the Phase 1 dose-escalation portion of the study are not eligible for enrollment into the Phase 2 portion. Participants in Phase 2 will be randomized in a 1:1:1 ratio to carboplatin, etoposide, placebo followed by placebo maintenance (Arm C), or carboplatin, etoposide, veliparib followed by either veliparib (Arm A) or placebo (Arm B) maintenance. Randomization for Phase 2 will be stratified by baseline lactate dehydrogenase (LDH) level (> upper limit of normal [ULN] vs. ≤ ULN), and gender.

Inclusion Criteria:

1. Subject with histologically or cytologically confirmed extensive-stage disease SCLC which is newly diagnosed and chemotherapy naive
2. Phase 1 ONLY: histologically or cytologically confirmed advanced/metastatic solid tumors for which carboplatin/etoposide treatment is considered appropriate.
3. Subject in Phase 2 only: must have measurable disease per RECIST 1.1.
4. Subjects with ED SCLC must consent to provide available archived formalin fixed paraffin embedded (FFPE) tissue sample of SCLC lesion (primary or metastatic) for central review and biomarker analysis.
5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
6. Subject must have adequate hematologic, renal and hepatic function.

Exclusion Criteria:

1. Phase 1 ONLY: Subject has had any prior anti-cancer therapy other than:

   Hormonal, non-myelosuppressive, biologic, targeted, or immune therapy (must be completed ≥ 4 weeks prior to Cycle 1 Day -2).

   One line of cytotoxic chemotherapy (must be completed ≥ 4 weeks prior to Cycle 1 Day -2).

   Adjuvant/neoadjuvant radiotherapy (must be completed ≥ 12 months prior to Cycle 1 Day -2, with field not involving > 10% of bone marrow reserve).

2. Phase 2 ONLY: Subject has had any prior chemotherapy, radiotherapy, investigational anti-cancer agents or biologic therapy for the disease under study. Single non-target lesion irradiation with intent of symptom palliation is allowed if ≥ 4 weeks prior Cycle 1 Day -2.

3. Subject has current central nervous system (CNS) or leptomeningeal metastases or history of CNS or leptomeningeal metastases.

4. Subject has a history of seizures within 12 months of Cycle 1 Day-2 or diagnosed neurological condition placing subject at the increased risk of seizures.

5. Subject has received anti-cancer Chinese medicine or anti-cancer herbal remedies within 14 days prior to Cycle 1 Day-2.

6. Subject has had major surgery within 6 weeks prior to Cycle 1 Day-2 (subjects must have completely recovered from any previous surgery prior Cycle 1 Day-2).

7. Subject has clinically significant and uncontrolled major medical condition(s) including but not limited to:

   • Uncontrolled nausea/vomiting/diarrhea;
   • Active uncontrolled infection;
   • History of hepatitis B (HBV) with surface antigen (HBsAg) positivity within 3 months prior to the date of informed consent for this study (if no test has been performed within 3 months, it must be done at screening);
   • History of hepatitis C (HCV) with HCV ribonucleic acid (RNA) positivity within 3 months prior to the date of informed consent for this study (if no test has been performed within 3 months it must be done at screening);
   • Symptomatic congestive heart failure (Yew York Heart Association [NYHA] class ≥ II);
   • Unstable angina pectoris or cardiac arrhythmia (except atrial fibrillation);
   • Psychiatric illness/social situation that would limit compliance with study requirements;
   • Any other medical condition, which in the opinion of the Investigator, places the subject at an unacceptably high risk for toxicities.

8. The subject has a history of another active cancer within the past 3 years except cervical cancer in situ, in situ carcinoma of the bladder, squamous or basal cell carcinoma of the skin or another in situ cancer that is considered cured by the investigator (e.g., in situ prostate cancer, breast DCIS).