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

Small Cell Lung Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02289690
• Other study ID #: M14-361
• Secondary ID: 2014-001764-35
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: October 13, 2014
• Est. completion date: April 17, 2019

Study information

• Verified date: May 2020
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 221
• Est. completion date: April 17, 2019
• Est. primary completion date: April 17, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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).

Related Conditions & MeSH terms

• Lung Neoplasms
• Small Cell Lung Cancer
• Small Cell Lung Carcinoma

Intervention

Drug:
• Veliparib
Capsules administered orally twice a day according to the dosing schedule.
• Carboplatin
Administered by intravenous infusion on Day 1 of each 21-day cycle over approximately 30 minutes at a target area under the curve (AUC) 5 mg/mL*minute.
• Etoposide
Administered by intravenous infusion on Days 1 to 3 of every 21-day cycle over approximately 60 minutes at 100 mg/m².
• Placebo
Placebo to veliparib administered orally twice a day according to the dosing schedule.

Locations

Country	Name	City	State
Australia	The Townsville Hospital /ID# 155499	Douglas	Queensland
Australia	Peninsula & South Eastern Haem /ID# 155497	Frankston	Victoria
Australia	Border Medical /ID# 157894	Wodonga	Victoria
Australia	Southern Medical Day Care Ctr /ID# 155498	Wollongong	New South Wales
Belgium	UZ Antwerp /ID# 151026	Edegem
Belgium	CHU de Liege /ID# 151025	Liège	Liege
Belgium	C.H.U.de Mons Borinage /ID# 151023	Mons
Belgium	CHU UCL Namur /ID# 151022	Namur
Belgium	Cliniques Universitaires Saint Luc /ID# 151024	Woluwe-Saint-Lambert	Bruxelles-Capitale
Canada	University of Calgary /ID# 152544	Calgary	Alberta
Canada	Cross Cancer Institute /ID# 132883	Edmonton	Alberta
Canada	Juravinski Cancer Clinic /ID# 152543	Hamilton	Ontario
Canada	Hopital du Sacre Coeur Montreal /ID# 154436	Montreal	Quebec
Czechia	Nemocnice Na Plesi s.r.o. /ID# 149825	Nová Ves pod Pleší	Pribram
Czechia	Nemocnice Novy Jicin /ID# 149838	Nový Jicín 1
Czechia	Vitkovicka nemocnice a. s. /ID# 149839	Ostrava
Czechia	Multiscan s.r.o. /ID# 150887	Pardubice
France	Centre Hosp Intercommunal de Creteil /ID# 157970	Creteil	Val-de-Marne
France	Centre Hospitalier Le Mans /ID# 158103	Le Mans CEDEX 9	Sarthe
France	CHU Dupuytren /ID# 153622	Limoges CEDEX 1	Franche-Comte
Hungary	Orszagos Koranyi Pulmonologiai Intezet /ID# 151351	Budapest XII	Budapest
Hungary	Debreceni Egyetem Klinikai Központ /ID# 151354	Debrecen
Hungary	Veszprem Megyei Tudogyogyintez /ID# 158807	Farkasgyepu
Hungary	Petz Aladar Megyei Oktato Korh /ID# 155352	Gyor
Hungary	Matrahaza Gyogyintezet /ID# 151355	Kékesteto
Hungary	Fejer Megyei Szent Gyorgy Korh /ID# 151352	Szekesfehervar
Hungary	Jasz-Nagykun-Szolnok Megyei /ID# 155090	Szolnok
Hungary	Markusovszky Egyetemi Oktatókórház /ID# 158806	Szombathely	Vas
Korea, Republic of	Dong-A University Hospital /ID# 153187	Busan	Busan Gwang Yeogsi
Korea, Republic of	Chungbuk National Univ Hosp /ID# 153186	Cheongju
Korea, Republic of	Chonnam National University Hwasun Hospital /ID# 153188	Jeonnam
Korea, Republic of	Asan Medical Center /ID# 153185	Seoul
Netherlands	Universitair Medisch Centrum Groningen /ID# 131252	Groningen
Netherlands	Ziekenhuis St. Jansdal /ID# 151974	Harderwijk
Netherlands	Atrium-Orbis Zuyderland Medisch Centrum /ID# 149830	Heerlen
Netherlands	Erasmus Medisch Centrum /ID# 131251	Rotterdam
Netherlands	Isala /ID# 151975	Zwolle
Romania	S.C. Radiotherapy Center Cluj /ID# 165137	Cluj
Romania	S.C. Centrul de Oncologie Sf. Nectarie S.R.L. /ID# 161137	Craiova	Dolj
Romania	Oncocenter Oncologie Clinica S /ID# 151694	Timisoara	Timis
Russian Federation	Belgorod Oncology Dispensary /ID# 152330	Belgorod
Russian Federation	Sverdlovsk Regional Oncology Center Dispensary /ID# 152328	Ekaterinburg	Sverdlovskaya Oblast
Russian Federation	NN Blokhin Russian Cancer /ID# 152329	Moscow	Moskva
Russian Federation	Univercity Headache Clynic,LTD /ID# 161708	Moscow
Russian Federation	Murmansk RCH P.A. Bayandina /ID# 152331	Murmansk
Russian Federation	Ogarev Mordovia State Univ /ID# 152327	Saransk
Russian Federation	Road Hospital Open Joint Stock Company Russian Railways /ID# 152731	St. Petersburg
Spain	Hosp Univ Quiron Dexues /ID# 130302	Barcelona
Spain	Hospital Stanta Creu i Sant Pau /ID# 151254	Barcelona
Spain	Hosp Univ 12 de Octubre /ID# 151252	Madrid
Spain	Hosp Univ Madrid Sanchinarro /ID# 130301	Madrid
Spain	Hospital Universitario Gregori /ID# 164982	Madrid
Spain	Hosp Univ Puerta de Hierro Maj /ID# 151253	Majadahonda
United States	Emory University Hospital /ID# 141682	Atlanta	Georgia
United States	Georgia Regents University /ID# 148567	Augusta	Georgia
United States	Univ of Colorado Cancer Center /ID# 129220	Aurora	Colorado
United States	Gabrail Cancer Center Research /ID# 129216	Canton	Ohio
United States	Northwestern University Feinberg School of Medicine /ID# 137088	Chicago	Illinois
United States	University of Texas MD Anderson Cancer Center /ID# 129213	Houston	Texas
United States	Herbert Herman Cancer Center /ID# 167020	Lansing	Michigan
United States	Allegheny General Hospital /ID# 147328	Pittsburgh	Pennsylvania
United States	Mayo Clinic - Scottsdale /ID# 129127	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Czechia,  France,  Hungary,  Korea, Republic of,  Netherlands,  Romania,  Russian Federation,  Spain, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)	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: 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; 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, hypersensitivity reactions or alopecia; Grade 2 non-hematologic toxicity of = 2 grade increase from baseline, attributed to veliparib treatment requiring delay of >14 days in initiation of Cycle 2; Any toxicity of = 2-grade increase from baseline, attributed to veliparib and requiring a dose modification in Cycle 1 or omission of carboplatin, >1 daily etoposide dose, or >30% veliparib doses in Cycle 1	Cycle 1 Day -2 to pre-dose on Cycle 2 Day 1 (23 days)
Primary	Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib	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.	Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Primary	Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib	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.	Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Primary	Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib	The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods.	Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Primary	Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib	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.	Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Primary	Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib	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.	Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Primary	Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib	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.	Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Primary	Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib	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.	Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Primary	Phase 1: Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib	Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.	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.
Primary	Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Etoposide With and Without Veliparib	Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.	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.
Primary	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	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.	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.
Primary	Phase 1: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-8]) of Etoposide With and Without Veliparib	The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods.	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.
Primary	Phase 1: Terminal Phase Elimination Half-life (t1/2) of Etoposide With and Without Veliparib	The terminal half-life of etoposide was estimated using using non-compartmental methods. Values reported represent the harmonic mean ± pseudo-standard deviation.	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.
Primary	Phase 1: Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib	Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL. Dose normalized Cmax is calculated as Cmax / etoposide dose in mg/m².	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.
Primary	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	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. Dose normalized AUC(0-t) is calculated as AUC(0-t) / etoposide dose in mg/m².	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.
Primary	Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-8]) of Etoposide With and Without Veliparib	The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-8) is calculated as AUC(0-8) / etoposide dose in mg/m².	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.
Primary	Phase 2: Progression-free Survival	Progression-free survival (PFS) is defined as the time from the date of randomization to the date of earliest radiographic disease progression or death provided no radiographic disease progression occurred.; If a participant did not have an event of disease progression and had not died on or prior to the cutoff for PFS analysis, the participant's data was censored at the date of their last disease assessment or randomization date provided participant did not have any post-baseline disease assessment.; Disease assessments were performed using computed tomography according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.; Progressive Disease (PD) was defined as at least a 20% increase in the size of target lesions and an absolute increase of at least 5 mm taking as reference the smallest lesion size recorded since the treatment started (baseline or after), or the appearance of one or more new lesions.	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	Phase 2: Overall Survival	Overall survival (OS) is defined as the time from the date of randomization to the date of death. If a participant did not die on or prior to the cut-off for OS analysis, the participant's data were censored at the date of their last known alive date, which is defined as the last date of the last survival follow-up visit, the start date of the last AE, the start date or end date of the last dose of any study drugs, the last lab and vital sign collection date, or the last disease assessment date, whichever occurred last.	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.
Secondary	Phase 2: Objective Response Rate	Objective response rate (ORR) is defined as the percentage of participants with objective response (confirmed) as assessed by the investigator using RECIST version 1.1. Objective response includes both complete response (CR) and partial response (PR). Response must be confirmed at a subsequent tumor assessment at least 28 days apart. Participants with no post-baseline confirmed response were counted as non-responders.; CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. No new lesions.; PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and no new lesions.	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.
Secondary	Phase 1: Number of Participants With Adverse Events	The intensity of each adverse event (AE) was assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0, and according to the following: Grade 1 (Mild): AE is transient and easily tolerated by the participant; Grade 2 (Moderate): AE causes the participant discomfort and interrupts the participant's usual activities; Grade 3/4 (Severe): The adverse event causes considerable interference with the participant's usual activities and may be incapacitating or life-threatening; Grade 5: Death.; Serious adverse events were those that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in congenital anomaly, or persistent or significant disability/incapacity.	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.