The objectives of the Phase 1 dose escalation are:Primary Objectives:* To establish the Maximum Tolerated Dose (MTD) and to establish the Recommended Phase 2 Dose (RPTD) for veliparib in combination withcarboplatin and etoposide.* To evaluate the…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Objective Response Rate
The proportion of subjects with objective response (CR or PR) as assessed by
the investigator
Progression-Free Survival
Progression-Free Survival will be defined as the number of days from the date
of randomization to the date of earliest disease progression or death.
Overall Survival
Overall survival will be defined as the number of days from the date of
randomization to the date of death.
Duration of Overall Response
Duration of overall response will be defined as the number of days from the
date of first response (CR or PR) to the earliest documentation of progressive
disease.
Secondary outcome
Not applicable.
Background summary
Small cell lung cancer (SCLC) is a neuroendocrine carcinoma that exhibits
aggressive behavior, rapid growth, and early spread to distant sites. It
constitutes approximately 15% of lung carcinomas. SCLC is staged as limited or
extensive stage disease (LD and ED SCLC, respectively). At presentation, 60% to
70% of SCLC cases in the United States are diagnosed as extensive-stage
disease, for which at present there is no curative treatment. There has been no
significant improvement in the clinical outcome for subjects with ED SCLC in
the last 2 decades, and
it remains one of the most fatal cancers.
Veliparib is a PARP inhibitor. PARP is a nuclear enzyme that recognizes DNA
damage and facilitates DNA repair. Inhibition of PARP results in less efficient
DNA repair following a DNA damaging insult. As cancer cells are genetically
unstable, these cells are more susceptible than normal tissues to cytotoxicity
induced by DNA-damaging agents and PARP-inhibitors. The combination of DNA
damaging cytotoxic chemotherapy (cisplatin and etoposide) and a pharmacologic
inhibitor of DNA damage repair enzyme, poly (ADP) Ribose polymerase (PARP), may
result in greater cytotoxicity and antitumor efficacy of the cytotoxic agents.
It is postulated that that enhanced efficacy may translate into improved
disease progression without concomitant increased toxicity in subjects with
extensive stage SCLC.
Study objective
The objectives of the Phase 1 dose escalation are:
Primary Objectives:
* To establish the Maximum Tolerated Dose (MTD) and to establish the
Recommended Phase 2 Dose (RPTD) for veliparib in combination with
carboplatin and etoposide.
* To evaluate the pharmacokinetic interaction between veliparib and etoposide.
Secondary Objective:
* To evaluate the safety of maintenance veliparib monotherapy at 400 mg BID in
subjects completing 4 cycles of carboplatin, etoposide and veliparib without
evidence of disease progression.
The objectives of Phase 2 are:
Primary Objective:
* To evaluate if veliparib in combination with carboplatin and etoposide
followed by veliparib maintenance monotherapy results in improved
progression free survival (PFS) versus placebo in combination with carboplatin
and etoposide followed by placebo monotherapy in subjects with treatment-naïve
ED SCLC.
Secondary Objectives:
* To evaluate if veliparib in combination with carboplatin and etoposide
followed by placebo monotherapy results in improved progression free
survival (PFS) versus placebo in combination with carboplatin and etoposide
followed by placebo monotherapy in subjects with treatment-naïve ED SCLC.
* To evaluate if veliparib in combination with carboplatin and etoposide
results in improved objective response rate (ORR) versus placebo in combination
with carboplatin and etoposide, at the time of completion of combination
therapy.
* To evaluate if veliparib in combination with carboplatin and etoposide
followed by veliparib maintenance monotherapy results in improved overall
survival (OS) versus placebo in combination with carboplatin and etoposide
followed by placebo monotherapy.
* To evaluate if veliparib in combination with carboplatin and etoposide
followed by placebo monotherapy results in improved overall survival (OS)
versus placebo in combination with carboplatin and etoposide followed by
placebo monotherapy.
* To further evaluate the safety of veliparib in combination with carboplatin
and etoposide followed by veliparib maintenance monotherapy.
Tertiary Objectives are:
* To evaluate if veliparib in combination with carboplatin and etoposide
followed by veliparib maintenance monotherapy results in improved duration of
overall response (DOR) versus placebo in combination with carboplatin and
etoposide followed by placebo monotherapy.
* To evaluate if veliparib in combination with carboplatin and etoposide
followed by placebo monotherapy results in improved duration of overall
response (DOR) versus placebo in combination with carboplatin and etoposide
followed by placebo monotherapy.
* To compare PFS and OS of subjects treated with veliparib in combination with
carboplatin and etoposide followed by veliparib maintenance to PFS and OS of
subjects treated with veliparib in combination with carboplatin and etoposide
followed by placebo maintenance.
* To evaluate performance status.
Study design
This Phase 1, open-label, dose escalation/Phase 2 randomized double-blind study
of veliparib in combination with carboplatin and etoposide and maintenance
veliparib monotherapy. Subjects in Phase 1 will be group sequentially assigned
to the ascending dose levels of veliparib in combination of standard
carboplatin/etoposide regimen based on the observed toxicities. Subjects in
Phase 2 will be randomized in a 1:1:1 ratio to one of the following treatment
arms: carboplatin, etoposide, placebo followed by placebo maintenance, or
carboplatin, etoposide, veliparib followed by veliparib maintenance, or
carboplatin, etoposide, veliparib followed by placebo maintenance.
Approximately 215 adult male or female subjects diagnosed with extensive stage
disease SCLC or other advanced/metastatic solid tumors will be selected to
participate in the study according to the inclusion/exclusion criteria. The
study was designed to enroll approximately 35 subjects in Phase 1 and
approximately 180 subjects in Phase 2 to meet scientific and regulatory
objectives without enrolling an undue number of subjects in alignment with
ethical considerations.
Intervention
Screening procedures should be performed within 28 days prior to Cycle 1 Day -
2. If the screening visit is performed greater than 7 days prior to Cycle 1 Day
-2, the physical exam, laboratory tests, and pregnancy test (for female
subjects of childbearing potential) must be repeated on Cycle Day 2. Vital
signs and performance status assessments will be performed on Cycle 1 Day 2 for
all subjects. Baseline radiographic tumor assessments per computed tomography
(CT)/magnetic resonance imaging (MRI) of the chest, abdomen, and head will be
conducted within 14 days prior to Cycle 1 Day -2.
Dosing of oral veliparib/placebo (placebo only in phase 2) will begin 2 days
prior to the start of the carboplatin/etoposide infusion on C1D1 and will
continue twice a day (BID) through C1D5 (7 consecutive days). Carboplatin (AUC
5 mg/ml/min) will be administered intravenously on Day 1 of every 21-day cycle
(except for Cycle 2 which is administered on Day 2 in Phase 1). Etoposide (100
mg/m2) will be administered
intravenously on Days 1, 2 and 3 of every 21-day cycle. Etoposide will be
administered prior to carboplatin. On the days of chemotherapy veliparib will
be administered after the premedications are given for etoposide, prior to the
infusion of etoposide.
Phase 1 subjects with SD, PR, or CR at the completion of all scheduled
combination therapy cycles (4 cycles) will receive veliparib (400 mg)
monotherapy, BID continuously in 21-day cycles starting on Day 1 of each cycle.
Phase 2 subjects with SD, PR or CR at the completion of combination therapy
cycles (up to 6 cycles) will receive veliparib (400 mg) or placebo monotherapy,
BID continuously in 21-day cycles starting on Day 1 of each cycle.
Tumor assessments will be performed until disease progression for up to 24
months from the first dose of study drugs. Tumor assessment and assessment of
response will occur every 6 weeks (± 1 week) for the first 24 weeks after the
first dose of study drugs, then every 9 weeks (± 1 week) thereafter.
Post treatment tumor assessments will be collected via EDC at monthly intervals
(or as requested by the sponsor to support data analysis) beginning on the date
the subject is registered off study and continuing for up to two (2) years on
all subjects until the endpoint of death, the subject has become lost-to
follow-up, or if AbbVie terminates the study.
All subjects will be followed for survival information (i.e., the date and
cause of death or last known alive date if not deceased) unless the subject
requests to be withdrawn specifically from study survival follow-up.
Study burden and risks
The burden for the subject consist of extra visits to the site, ECGs,
additional blood draws besides the standard safety labs. Tumor assessment and
assessment of response will occur every 6 weeks (± 1 week) for the first 24
weeks after the first dose of study drugs, then every 9 weeks (± 1 week)
thereafter.
Subjects will receive veliparib/placebo (placebo only in phase 2) in
combination with carboplatin/etoposide for up to 4 cycles of
treatment (additional 2 cycles of combination therapy may be administered only
in phase 2) , followed by veliparib/placebo (placebo only in phase 2)
monotherapy.
Risks in this study include toxicity from the addition of veliparib to standard
therapy. Preliminary safety data from several Phase 1 and Phase 2 studies
indicate that veliparib is tolerated in combination with carboplatin and
paclitaxel at doses of up to 120 - 200 mg BID, and with cisplatin and etoposide
at the maximum tested dose of 100 mg BID. Standard clinical practices to manage
the toxicity of carboplatin + etoposide are well
established. Toxicity will be closely monitored at all study visits. Toxicities
of veliparib expected to overlap with the toxicity of carboplatin + etoposide
regimen include nausea/vomiting and myelosuppression. Other potential risks of
veliparib administration, identified in preclinical studies or based on
pharmacological mechanism, but not confirmed in clinical studies must also be
considered. These risks include seizures,
changes in testes/ovaries, toxicity to the developing fetus and secondary
malignancies.
Wegalaan 9
Hoofddorp 2132JD
NL
Wegalaan 9
Hoofddorp 2132JD
NL
Listed location countries
Age
Inclusion criteria
1. Subject with histologically or cytologically confirmed extensive stage SCLC which is newly diagnosed and chemotherapy naïve.;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 measureable 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 be >= 18 years of age.;7. Subject must have adequate hematologic, renal and hepatic function as follows:
• Bone Marrow: Absolute neutrophil count ANC >= 1,500/mm3 (1.5 × 10e9/L); White blood cells >= 3,000/mm3 (3 × 10e9/L); Platelets >= 100,000/mm3 (100 × 10e9/L); Hemoglobin >= 9 g/dL (5.58 mmol/L)
• Renal function: creatinine <= ULN or if creatinine > ULN calculated creatinine clearance via the Cockroft Gault formula of >= 50 mL/min
• Hepatic function:
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 × upper limits of normal (ULN). For subjects with liver metastases, AST and ALT <= 5 × ULN;
- Bilirubin: <= 1.5 × ULN; for subjects with Gilbert's syndrome bilirubin > 1.5 × ULN is allowed if no symptoms of compromised liver function are present.;8. Subject must be able to swallow pills.;9. Female and male patients of fertile age, and/or their partners should use contraception. If male, subject and subject's female partner(s) of childbearing potential should practice at least one of the following methods of birth control. If female, subject must be either postmenopausal for at least 1 year, surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or the subject and the subject's male partner(s) practicing at least one of the following methods of birth control:
• total abstinence from sexual intercourse (if it is the subject's preferred and usual lifestyle; for minimum one complete menstrual cycle prior to study drug administration and to extend 6 months after treatment);
• vasectomized subject or partner(s);
• hormonal contraceptives (oral, parenteral or transdermal) for at least 90 days prior to study drug administration for the subject or subject's female partner(s);
• intrauterine device (IUD) for the subject or subject's female partner(s); or
• double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with (spermicidal jellies or creams) for the subject or subject's female partner(s). ;If hormonal contraceptives are used, the specific contraceptive must have been used for at least 90 days prior to study drug administration. If the subject or subject's female partner(s) is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 6 months (or per local label) after study completion. ;Female subjects must have negative results for pregnancy tests performed:
• at Screening on a serum specimen obtained within 7 days prior to initial study drug administration, and
• prior to dosing on a urine sample obtained C1D-2 unless the serum pregnancy test was collected within 7 days of C1D-2. ;10. Must voluntarily sign and date each informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
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/neoaduvant 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 >= 2 weeks prior Cycle 1 Day -2.;3. Subject has known hypersensitivity to etoposide, platinum compounds or veliparib.;4. Phase 1 ONLY: Subject has received prior myelopoietic growth factors.;5. Subject has current central nervous system (CNS) or leptomeningeal metastases or history of CNS or leptomeningeal metastases. If CNS progression is suspected, a head CT should be performed at screening.;6. 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.;7. Subject has received traditional herbal anti-cancer medicine (e.g. Chinese, Asian, etc) within 14 days prior to Cycle 1 Day -2.;8. Subject has had major surgery within 6 weeks prior to Cycle 1 Day -2 (subjects must have
completely recovered from any previous surgery prior to Cycle 1 Day -2).;9. 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 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 (New York Heart Association [NYHA] class >= II);
* Unstable angina pectoris or cardiac arrhythmia;
* 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.;10. Subject is pregnant or lactating.;11. 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 ductal carcinoma in situ [DCIS]).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-001764-35-NL |
| ClinicalTrials.gov | NCT02289690 |
| CCMO | NL50299.042.14 |