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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

Completed Phase 1, PHASE2 Results posted Last updated 14 May 2020
What this trial tests

Phase 1, PHASE2 trial testing Veliparib in Small Cell Lung Cancer in 221 participants. Completed in 17 April 2019.

Timeline
13 October 2014
Primary endpoint
17 April 2019
17 April 2019

Quick facts

Lead sponsorAbbVie
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designsequential
Maskingdouble
Primary purposetreatment
Enrollment221
Start date13 October 2014
Primary completion17 April 2019
Estimated completion17 April 2019
Sites62 locations across France, Netherlands, Russia, Belgium, Hungary, South Korea, Romania, Canada

Drugs / interventions tested

Conditions studied

Sponsor

AbbVie — full company profile →

Who can join

Adults 18 to 99, any sex, with Small Cell Lung Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) Primary · Cycle 1 Day -2 to pre-dose on Cycle 2 Day 1 (23 days)

A DLT was defined as any of the following drug-related toxicities, graded according to the Common Toxicity Criteria for Adverse Events (CTCAE), V.4.0: 1. Events associated with treatment delay \>14 days in initiating Cycle 2 therapy: Grade 4 thrombocytopenia, neutropenia, or febrile neutropenia, or Grade 3 febrile neutropenia with fever for \> 7 days 2. Grade ≥ 3 non-hematologic toxicity with ≥ 2 grade increase from baseline and attributed to veliparib treatment, excluding nausea or vomiting for ≤ 48 hours or inadequately treated, electrolyte abnormalities resolving in ≤ 24 hours, hyperse

GroupValue95% CI
Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide0
Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide0
Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide0
Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide0
Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide1
Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide0
Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide1
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib Primary · Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose

Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL.

GroupValue95% CI
Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide0.620± 17
Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide1.00± 31
Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide1.39± 29
Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide1.44± 10
Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide1.99± 25
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib Primary · Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose

Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL.

GroupValue95% CI
Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide2.01.0 – 2.0
Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide1.01.0 – 2.0
Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide1.51.0 – 2.0
Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide2.01.0 – 2.0
Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide1.01.0 – 3.0
Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib Primary · Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose

The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods.

GroupValue95% CI
Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide3.18± 14
Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide4.24± 25
Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide7.51± 28
Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide6.66± 4
Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide9.29± 37
Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib Primary · Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose

The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration.

GroupValue95% CI
Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide4.07± 15
Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide5.25± 27
Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide9.71± 31
Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide8.35± 6
Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide11.6± 40
Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib Primary · Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose

Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL. Dose normalized Cmax is calculated as Cmax / veliparib dose in mg.

GroupValue95% CI
Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide7.75± 16
Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide8.35± 31
Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide8.66± 29
Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide7.19± 10
Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide8.31± 25
Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib Primary · Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose

The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods. Dose normalized AUC(0-8) is calculated as AUC(0-8) / veliparib dose in mg.

GroupValue95% CI
Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide39.8± 14
Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide35.3± 25
Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide46.9± 28
Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide33.3± 4
Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide38.7± 37
Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib Primary · Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose

The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration. Dose normalized AUC(0-12) is calculated as AUC(0-12) / veliparib dose in mg.

GroupValue95% CI
Phase 1: Veliparib 80 mg BID + Carboplatin/Etoposide50.9± 15
Phase 1: Veliparib 120 mg BID + Carboplatin/Etoposide43.8± 27
Phase 1: Veliparib 160 mg BID + Carboplatin/Etoposide60.7± 31
Phase 1: Veliparib 200 mg BID + Carboplatin/Etoposide41.7± 6
Phase 1: Veliparib 240 mg BID + Carboplatin/Etoposide48.5± 40
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib Primary · 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.

Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.

GroupValue95% CI
Etoposide Cycle 1 Day 1 (With Veliparib)16.9± 18
Etoposide Cycle 2 Day 1 (No Veliparib)16.4± 21
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Etoposide With and Without Veliparib Primary · 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.

Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.

GroupValue95% CI
Etoposide Cycle 1 Day 1 (With Veliparib)0.90.8 – 3.0
Etoposide Cycle 2 Day 1 (No Veliparib)0.90.9 – 3.7
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 Primary · 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.

The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods.

GroupValue95% CI
Etoposide Cycle 1 Day 1 (With Veliparib)102± 23
Etoposide Cycle 2 Day 1 (No Veliparib)94.7± 18
Phase 1: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib Primary · 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.

The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods.

GroupValue95% CI
Etoposide Cycle 1 Day 1 (With Veliparib)112± 56
Etoposide Cycle 2 Day 1 (No Veliparib)99.5± 18

Adverse events — posted to ClinicalTrials.gov

Time frame: All-cause mortality is reported from enrollment to the end of study, maximum time on follow-up was 26 months. Treatment-emergent adverse events and serious adverse events were collected from first dose of study drug until 30 days after the last dose of study drug; Maximum duration of treatment in Phase 1 was 541 days and maximum duration of treatment in Phase 2 was 654 days.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide
Serious: 3/4 (75%)
Deaths: 0/4
Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide
Serious: 1/3 (33%)
Deaths: 0/3
Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide
Serious: 3/4 (75%)
Deaths: 1/4
Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide
Serious: 2/3 (67%)
Deaths: 1/3
Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide
Serious: 3/8 (38%)
Deaths: 0/8
Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide
Serious: 6/14 (43%)
Deaths: 0/14
Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide
Serious: 3/4 (75%)
Deaths: 0/4
Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib
Serious: 33/60 (55%)
Deaths: 50/61
Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo
Serious: 39/58 (67%)
Deaths: 45/59
Phase 2: Placebo + Carboplatin/Etoposide -> Placebo
Serious: 27/60 (45%)
Deaths: 41/61

Serious adverse events (107 terms)

ReactionSystemPhase 1: Veliparib 80 mg B…Phase 1: Veliparib 120 mg …Phase 1: Veliparib 160 mg …Phase 1: Veliparib 200 mg …Phase 1: Veliparib 240 mg …Phase 1: Veliparib 240 mg …Phase 1: Veliparib 240 mg …Phase 2: Veliparib + Carbo…Phase 2: Veliparib + Carbo…Phase 2: Placebo + Carbopl…
FEBRILE NEUTROPENIABlood and lymphatic system disorders
PNEUMONIAInfections and infestations
THROMBOCYTOPENIABlood and lymphatic system disorders
MALIGNANT NEOPLASM PROGRESSIONNeoplasms benign, malignant and unspecified (incl cysts and polyps)
NEUTROPENIABlood and lymphatic system disorders
METASTASES TO CENTRAL NERVOUS SYSTEMNeoplasms benign, malignant and unspecified (incl cysts and polyps)
ANAEMIABlood and lymphatic system disorders
DEHYDRATIONMetabolism and nutrition disorders
HYPONATRAEMIAMetabolism and nutrition disorders
PLEURAL EFFUSIONRespiratory, thoracic and mediastinal disorders
PANCYTOPENIABlood and lymphatic system disorders
ATRIAL FIBRILLATIONCardiac disorders
NAUSEAGastrointestinal disorders
CHEST PAINGeneral disorders
OEDEMA PERIPHERALGeneral disorders
PYREXIAGeneral disorders
INFECTIONInfections and infestations
URINARY TRACT INFECTIONInfections and infestations
DYSPNOEARespiratory, thoracic and mediastinal disorders
PULMONARY EMBOLISMRespiratory, thoracic and mediastinal disorders
LEUKOPENIABlood and lymphatic system disorders
ACUTE MYOCARDIAL INFARCTIONCardiac disorders
CARDIAC FAILURECardiac disorders
CARDIO-RESPIRATORY ARRESTCardiac disorders
MYOCARDIAL INFARCTIONCardiac disorders
Other adverse events (210 terms — click to expand)

ReactionSystemPhase 1: Veliparib 80 mg B…Phase 1: Veliparib 120 mg …Phase 1: Veliparib 160 mg …Phase 1: Veliparib 200 mg …Phase 1: Veliparib 240 mg …Phase 1: Veliparib 240 mg …Phase 1: Veliparib 240 mg …Phase 2: Veliparib + Carbo…Phase 2: Veliparib + Carbo…Phase 2: Placebo + Carbopl…
NEUTROPENIABlood and lymphatic system disorders
ANAEMIABlood and lymphatic system disorders
NAUSEAGastrointestinal disorders
THROMBOCYTOPENIABlood and lymphatic system disorders
ALOPECIASkin and subcutaneous tissue disorders
DECREASED APPETITEMetabolism and nutrition disorders
FATIGUEGeneral disorders
CONSTIPATIONGastrointestinal disorders
VOMITINGGastrointestinal disorders
LEUKOPENIABlood and lymphatic system disorders
DYSPNOEARespiratory, thoracic and mediastinal disorders
DIARRHOEAGastrointestinal disorders
ASTHENIAGeneral disorders
HYPOMAGNESAEMIAMetabolism and nutrition disorders
HEADACHENervous system disorders
HYPOKALAEMIAMetabolism and nutrition disorders
BACK PAINMusculoskeletal and connective tissue disorders
DIZZINESSNervous system disorders
PYREXIAGeneral disorders
DYSPEPSIAGastrointestinal disorders
WEIGHT DECREASEDInvestigations
HYPONATRAEMIAMetabolism and nutrition disorders
INSOMNIAPsychiatric disorders
COUGHRespiratory, thoracic and mediastinal disorders
OEDEMA PERIPHERALGeneral disorders
NEUTROPHIL COUNT DECREASEDInvestigations
HYPERGLYCAEMIAMetabolism and nutrition disorders
ARTHRALGIAMusculoskeletal and connective tissue disorders
ATRIAL FIBRILLATIONCardiac disorders
PNEUMONIAInfections and infestations
ALANINE AMINOTRANSFERASE INCREASEDInvestigations
ASPARTATE AMINOTRANSFERASE INCREASEDInvestigations
PLATELET COUNT DECREASEDInvestigations
HYPOPHOSPHATAEMIAMetabolism and nutrition disorders
MUSCULOSKELETAL CHEST PAINMusculoskeletal and connective tissue disorders
HYPOTENSIONVascular disorders
ABDOMINAL PAINGastrointestinal disorders
DRY MOUTHGastrointestinal disorders
NON-CARDIAC CHEST PAINGeneral disorders
PAINGeneral disorders

Most-reported serious reactions: FEBRILE NEUTROPENIA, PNEUMONIA, THROMBOCYTOPENIA, MALIGNANT NEOPLASM PROGRESSION, NEUTROPENIA, METASTASES TO CENTRAL NERVOUS SYSTEM, ANAEMIA, DEHYDRATION.

Data from ClinicalTrials.gov NCT02289690 adverse events section.

Sponsor's own description

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).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Unravelling the biology of SCLC: implications for therapy.
    Sabari JK, Lok BH, Laird JH, Poirier JT, et al · · 2017 · cited 375× · PMID 28534531 · DOI 10.1038/nrclinonc.2017.71
  2. Small cell lung cancer: will recent progress lead to improved outcomes?
    Pietanza MC, Byers LA, Minna JD, Rudin CM. · · 2015 · cited 176× · PMID 25979931 · DOI 10.1158/1078-0432.ccr-14-2958
  3. Randomized Phase II Trial of Cisplatin and Etoposide in Combination With Veliparib or Placebo for Extensive-Stage Small-Cell Lung Cancer: ECOG-ACRIN 2511 Study.
    Owonikoko TK, Dahlberg SE, Sica GL, Wagner LI, et al · · 2019 · cited 141× · PMID 30523756 · DOI 10.1200/jco.18.00264
  4. Molecular profiles of small cell lung cancer subtypes: therapeutic implications.
    Schwendenwein A, Megyesfalvi Z, Barany N, Valko Z, et al · · 2021 · cited 111× · PMID 33718595 · DOI 10.1016/j.omto.2021.02.004
  5. Small cell lung cancer (SCLC): no treatment advances in recent years.
    Koinis F, Kotsakis A, Georgoulias V. · · 2016 · cited 107× · PMID 26958492 · DOI 10.3978/j.issn.2218-6751.2016.01.03
  6. Targeting DNA damage repair in small cell lung cancer and the biomarker landscape.
    Sen T, Gay CM, Byers LA. · · 2018 · cited 95× · PMID 29535912 · DOI 10.21037/tlcr.2018.02.03
  7. Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions.
    Basourakos SP, Li L, Aparicio AM, Corn PG, et al · · 2017 · cited 91× · PMID 27978798 · DOI 10.2174/0929867323666161214114948
  8. Target engagement imaging of PARP inhibitors in small-cell lung cancer.
    Carney B, Kossatz S, Lok BH, Schneeberger V, et al · · 2018 · cited 77× · PMID 29330466 · DOI 10.1038/s41467-017-02096-w

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