Clinical trial NCT02289690: Dose Escalation and Double-blind Study of Veliparib in Combination With Carboplatin and Etoposide in Treatment-naive Extensive Stage Disease Small Cell Lung Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Small Cell Lung Cancer
Keywords: Extensive Stage Smal Cell Lung Cancer
ABT-888
Veliparib
PARP - Poly (ADP) ribose polymerase
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2014-11-13
Enrollment: 221
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1 Day -2 to pre-dose on Cycle 2 Day 1 (23 days)
measure: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib
timeFrame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
measure: Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib
timeFrame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
measure: Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib
timeFrame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
measure: Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib
timeFrame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
measure: Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib
timeFrame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
measure: Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib
timeFrame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
measure: Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib
timeFrame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
measure: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib
timeFrame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
measure: Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Etoposide With and Without Veliparib
timeFrame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
measure: Phase 1: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib
timeFrame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
measure: Phase 1: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib
timeFrame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
measure: Phase 1: Terminal Phase Elimination Half-life (t1/2) of Etoposide With and Without Veliparib
timeFrame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
measure: Phase 1: Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib
timeFrame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
measure: Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib
timeFrame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
measure: Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib
timeFrame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
measure: Phase 2: Progression-free Survival
timeFrame: From randomization up to the date the 126th PFS event was reached; Median time on follow-up was 7.3, 7.1, and 8.9 months in each treatment group respectively.
Secondary outcomes:
measure: Phase 2: Overall Survival
timeFrame: From randomization until the end of study; median time on follow-up was 10.0, 8.6, and 11.7 months in each treatment group respectively.
measure: Phase 2: Objective Response Rate
timeFrame: Tumor assessments were performed every 6 weeks for the first 30 weeks and every 9 weeks thereafter until disease progression; median time on follow-up was 7.3, 7.1, and 8.9 months in each group respectively.
measure: Phase 1: Number of Participants With Adverse Events
timeFrame: From first dose of any study drug to 30 days after the last dose; the median duration of treatment with veliparib across all groups in Phase 1 was 127.5 days.
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic - Scottsdale /ID# 129127
state: Arizona
city: Aurora
country: United States
facility: Univ of Colorado Cancer Center /ID# 129220
state: Colorado
city: Atlanta
country: United States
facility: Emory University Hospital /ID# 141682
state: Georgia
city: Augusta
country: United States
facility: Georgia Regents University /ID# 148567
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine /ID# 137088
state: Illinois
city: Lansing
country: United States
facility: Herbert Herman Cancer Center /ID# 167020
state: Michigan
city: Canton
country: United States
facility: Gabrail Cancer Center Research /ID# 129216
state: Ohio
city: Pittsburgh
country: United States
facility: Allegheny General Hospital /ID# 147328
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center /ID# 129213
state: Texas
city: Wollongong
country: Australia
facility: Southern Medical Day Care Ctr /ID# 155498
state: New South Wales
city: Douglas
country: Australia
facility: The Townsville Hospital /ID# 155499
state: Queensland
city: Frankston
country: Australia
facility: Peninsula & South Eastern Haem /ID# 155497
state: Victoria
city: Wodonga
country: Australia
facility: Border Medical /ID# 157894
state: Victoria
city: Woluwe-Saint-Lambert
country: Belgium
facility: Cliniques Universitaires Saint Luc /ID# 151024
state: Bruxelles-Capitale
city: Liège
country: Belgium
facility: CHU de Liege /ID# 151025
state: Liege
city: Edegem
country: Belgium
facility: UZ Antwerp /ID# 151026
city: Mons
country: Belgium
facility: C.H.U.de Mons Borinage /ID# 151023
city: Namur
country: Belgium
facility: CHU UCL Namur /ID# 151022
city: Calgary
country: Canada
facility: University of Calgary /ID# 152544
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute /ID# 132883
state: Alberta
city: Hamilton
country: Canada
facility: Juravinski Cancer Clinic /ID# 152543
state: Ontario
city: Montreal
country: Canada
facility: Hopital du Sacre Coeur Montreal /ID# 154436
state: Quebec
city: Nová Ves pod Pleší
country: Czechia
facility: Nemocnice Na Plesi s.r.o. /ID# 149825
state: Pribram
city: Nový Jičín 1
country: Czechia
facility: Nemocnice Novy Jicin /ID# 149838
city: Ostrava
country: Czechia
facility: Vitkovicka nemocnice a. s. /ID# 149839
city: Pardubice
country: Czechia
facility: Multiscan s.r.o. /ID# 150887
city: Limoges CEDEX 1
country: France
facility: CHU Dupuytren /ID# 153622
state: Franche-Comte
city: Le Mans CEDEX 9
country: France
facility: Centre Hospitalier Le Mans /ID# 158103
state: Sarthe
city: Creteil
country: France
facility: Centre Hosp Intercommunal de Creteil /ID# 157970
state: Val-de-Marne
city: Budapest XII
country: Hungary
facility: Orszagos Koranyi Pulmonologiai Intezet /ID# 151351
state: Budapest
city: Szombathely
country: Hungary
facility: Markusovszky Egyetemi Oktatókórház /ID# 158806
state: Vas
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Központ /ID# 151354
city: Farkasgyepu
country: Hungary
facility: Veszprem Megyei Tudogyogyintez /ID# 158807
city: Gyor
country: Hungary
facility: Petz Aladar Megyei Oktato Korh /ID# 155352
city: Kékesteto
country: Hungary
facility: Matrahaza Gyogyintezet /ID# 151355
city: Szekesfehervar
country: Hungary
facility: Fejer Megyei Szent Gyorgy Korh /ID# 151352
city: Szolnok
country: Hungary
facility: Jasz-Nagykun-Szolnok Megyei /ID# 155090
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital /ID# 153187
state: Busan Gwang Yeogsi
city: Cheongju
country: Korea, Republic of
facility: Chungbuk National Univ Hosp /ID# 153186
city: Jeonnam
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital /ID# 153188
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center /ID# 153185
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen /ID# 131252
city: Harderwijk
country: Netherlands
facility: Ziekenhuis St. Jansdal /ID# 151974
city: Heerlen
country: Netherlands
facility: Atrium-Orbis Zuyderland Medisch Centrum /ID# 149830
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum /ID# 131251
city: Zwolle
country: Netherlands
facility: Isala /ID# 151975
city: Craiova
country: Romania
facility: S.C. Centrul de Oncologie Sf. Nectarie S.R.L. /ID# 161137
state: Dolj
city: Timisoara
country: Romania
facility: Oncocenter Oncologie Clinica S /ID# 151694
state: Timis
city: Cluj
country: Romania
facility: S.C. Radiotherapy Center Cluj /ID# 165137
city: Moscow
country: Russian Federation
facility: NN Blokhin Russian Cancer /ID# 152329
state: Moskva
city: Ekaterinburg
country: Russian Federation
facility: Sverdlovsk Regional Oncology Center Dispensary /ID# 152328
state: Sverdlovskaya Oblast
city: Belgorod
country: Russian Federation
facility: Belgorod Oncology Dispensary /ID# 152330
city: Moscow
country: Russian Federation
facility: Univercity Headache Clynic,LTD /ID# 161708
city: Murmansk
country: Russian Federation
facility: Murmansk RCH P.A. Bayandina /ID# 152331
city: Saransk
country: Russian Federation
facility: Ogarev Mordovia State Univ /ID# 152327
city: St. Petersburg
country: Russian Federation
facility: Road Hospital Open Joint Stock Company Russian Railways /ID# 152731
city: Barcelona
country: Spain
facility: Hospital Stanta Creu i Sant Pau /ID# 151254
city: Barcelona
country: Spain
facility: Hosp Univ Quiron Dexues /ID# 130302
city: Madrid
country: Spain
facility: Hospital Universitario Gregori /ID# 164982
city: Madrid
country: Spain
facility: Hosp Univ 12 de Octubre /ID# 151252
city: Madrid
country: Spain
facility: Hosp Univ Madrid Sanchinarro /ID# 130301
city: Majadahonda
country: Spain
facility: Hosp Univ Puerta de Hierro Maj /ID# 151253
Study officials:
affiliation: AbbVie
name: AbbVie Inc.
role: STUDY_DIRECTOR
References:
citation: Atrafi F, Groen HJM, Byers LA, Garralda E, Lolkema MP, Sangha RS, Viteri S, Chae YK, Camidge DR, Gabrail NY, Hu B, Tian T, Nuthalapati S, Hoening E, He L, Komarnitsky P, Calles A. A Phase I Dose-Escalation Study of Veliparib Combined with Carboplatin and Etoposide in Patients with Extensive-Stage Small Cell Lung Cancer and Other Solid Tumors. Clin Cancer Res. 2019 Jan 15;25(2):496-505. doi: 10.1158/1078-0432.CCR-18-2014. Epub 2018 Oct 16.