The primary objective of the study is to assess if treatment with veliparib plus carboplatin and paclitaxel results in improved survival compared to Investigator's choice of standard chemotherapy in Lung Subtype Panel (LSP) positive subjects…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is overall survival (OS) in LSP positive
subgroup.
Secondary outcome
The secondary efficacy endpoints are
- overall survival in all subjects and in the LSP positive subgroup
- progression-free survival (PFS) in the LSP positive subgroup
- objective response rate (ORR) in the LSP positive subgroup
Background summary
Lung cancer is the leading cause of cancer-related mortality in both men and
women throughout the world. The incidence of non-small cell lung cancer (NSCLC)
increases with age; 60% occur in subjects aged 60 years and older, and 30% to
40% occur in subjects aged 70 years and older. Non-small cell lung cancer is
divided further into adenocarcinoma (40%), squamous cell carcinoma (40%), and
large cell carcinoma histologies. Most NSCLC subjects are diagnosed at an
advanced stage, conferring a poor prognosis. Current standard therapy for NSCLC
provides time-to-progression of 4 to 6 months and overall survival of 10 to
1227 months.
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.
Data of a double-blind, randomized Phase 2 study of carboplatin and paclitaxel
with veliparib or placebo for subjects with advanced NSCLC showed an
improvement in median progression-free survival of 1.3 months and an
improvement in overall survival of 7.1 months in 95 current smokers with
non-squamous NSCLC. This suggests that the addition of veliparib to carboplatin
and paclitaxel may improve outcome of current-smokers with advanced or
metastatic squamous NSCLC.
Study objective
The primary objective of the study is to assess if treatment with veliparib
plus carboplatin and paclitaxel results in improved survival compared to
Investigator's choice of standard chemotherapy in Lung Subtype Panel (LSP)
positive subjects with metastatic or advanced NSCLC.
The secondary objectives of the study are to assess if treatment with veliparib
plus carboplatin and paclitaxel results in improved survival compared to
Investigator's choice of standard chemotherapy in the entire study population;
to compare progression-free survival (PFS) and to compare objective response
rate (ORR) between the two treatment arms in LSP positive subjects or in entire
study population.
The tertiary objectives are to compare duration of overall response (DOR), ECOG
performance status and Quality of Life (QoL) between the two treatment arms in
current smokers or in current plus former smokers.
Study design
This is a Phase 3, randomized, open-label, multi-center study evaluating the
efficacy, safety, and tolerability of veliparib plus carboplatin and paclitaxel
versus Investigator's choice of standard chemotherapy in subjects receiving
first cytotoxic chemotherapy for advanced or metastatic non-squamous NSCLC who
are current or former smokers. Subjects will be randomized in a 1:1 ratio to 6
cycles of carboplatin/paclitaxel plus 120 mg BID of veliparib or 6 cycles of
Investigator's choice of platinum doublet chemotherapy (carboplatin/paclitaxel,
cisplatin/pemetrexed, or carboplatin/pemetrexed). Investigators may elect to
administer maintenance pemetrexed regardless of which therapy their subjects
are randomized to receive. Following completion of platinum doublet therapy,
maintenance pemetrexed is strongly encouraged for all subjects who are suitable
candidates.
Subject randomization will be stratified by smoking status (current versus
former), by the Investigators' preferred platinum doublet therapy
(carboplatin/paclitaxel, carboplatin/pemetrexed or cisplatin/pemetrexed), by
gender (male versus female) and by ECOG performance status (0 versus 1).
Intervention
Screening procedures, and quality of life assessments within 28 days, and
baseline radiographic tumor assessments within 28 days will be performed prior
to randomization.
Subjects randomized to receive carboplatin/paclitaxel/veliparib will begin oral
veliparib dosing twice a day on Day -2, 2 days prior to the
carboplatin/paclitaxel infusion on Day 1. Veliparib dosing will continue
through C1D5 (7 consecutive days). Subjects will receive carboplatin (AUC 6
mg/mL/min) and paclitaxel (200 mg/m2) IV infusion on Day 1 of each cycle.
Subjects randomized to receive Investigator's choice of platinum doublet
therapy will receive therapy on Day 1 of each cycle.
For both arms, subjects will receive 6 cycles of treatment, unless toxicity
requires cessation of therapy, or radiographic progression occurs prior to
completing 6 cycles.
Subjects in either arm may receive pemetrexed maintenance therapy or
observation after completion of platinum doublet chemotherapy regimen.
Maintenance pemetrexed will be administered on Day 1 of each 21-day cycle.
Subjects will continue to receive maintenance therapy until toxicity requires
cessation of therapy, or radiographic progression occurs.
Subjects will have physician visits q3 weeks while receiving platinum doublet
and maintenance therapy. After cessation of therapy, physician visits and
quality of life measures will be performed every 9 weeks until one year after
randomization, then every 12 weeks until radiographic progression or death.
Tumor assessments will be performed at baseline, prior to Cycle 3 Day 1, and
prior to Cycle 5 Day 1, every 9 weeks until1 year after randomization, and then
every 12 weeks until radiographic progression or death.
All subjects who have a Final Visit <= 30 days after the last dose of study drug
will have a Follow-Up Visit approximately 30 days after the last dose of study
drug.
Subjects no longer undergoing clinical assessments will have survival
information reported via the eCRF at two month intervals (or as requested by
sponsor to support data analysis) beginning at the last clinical assessment and
continuing until the endpoint of death, the subject has become lost to
follow-up, or AbbVie terminates the study.
Study burden and risks
The burden for the subject consist of extra visits to the site, two times an
ECG, additional blood draws besides the standard safety labs. Next to this the
subject will complete 2 questionnaires on baseline, Cycle 3 Day 1, Cycle 5 Day
1, every 9 weeks until1 year after randomization, and then every 12 weeks.
Progression of disease will be measured every 9 weeks after treatment until1
year after randomization, and then every 12 weeks.
In one arm, subjects will receive veliparib in combination with
carboplatin/paclitaxel for up to a maximum 6 cycles of treatment, unless
toxicity requires cessation of therapy, or radiographic progression occurs
prior to completing 6 cycles. After that, subjects will go into the
post-treatment phase with assessments every 9 weeks until 1 year and then every
12 weeks.
Risks in this study include toxicity from the addition of veliparib to standard
therapy. Preliminary safety data from a blinded, randomized Phase 3 study of
the proposed combination therapy in subjects with advanced NSCLC suggest low
rates of additional toxicities and no compromise to the delivery of carboplatin
and paclitaxel.
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.
Standard clinical practices to manage the toxicity of carboplatin + paclitaxel
and the Investigator's choice of standard chemotherapy are well established.
Wegalaan 9
Hoofddorp 2132 JD
NL
Wegalaan 9
Hoofddorp 2132 JD
NL
Listed location countries
Age
Inclusion criteria
1. Subject must be >= 18 years of age.
2. Life expectancy > 12 weeks (as per Investigator's clinical assessment).
3. Subject must have cytologically or histologically confirmed advanced or metastatic non-squamous NSCLC. Subjects with mixed histology tumors will be eligible if the tumor is predominant non-squamous histology and does not include tumor with small cell histology. Subjects must have a pathologist's report confirming non-squamous NSCLC available for collection by the sponsor. Subjects with EGFR mutation (exon 19 deletion or L858R mutation in exon 21) and/or ALK gene rearrangement must have progressed after first line monotherapy treatment with targeted therapy.
4. Subject must have NSCLC that is not amenable to surgical resection or radiation with curative
intent at time of study Screening.
5. Subjects must be current smokers (defined as having > 100 smoking events lifetime and having
smoked within the past year) or former smokers (defined as having > 100 smoking events lifetime
and having not smoked within the past year).
6. Subject must have at least 1 unidimensional measurable NSCLC lesion on a CT scan as defined
by RECIST (version 1.1).
7. Subject must consent to provide archived tissue or cytology sample of NSCLC lesion (primary or
metastatic) for analysis if available.
8. Subject must have no history of brain metastases or evidence of CNS tumors at screening
assessment. Subjects with signs or symptoms of CNS involvement will undergo MRI (or CT scan
if MRI is contraindicated) to confirm absence of CNS metastases.
9. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 - 1.
10. Subjects with fluid retention, including ascites or pleural effusion, may be allowed at the
discretion of the Investigator.
11. Subject must have adequate bone marrow, renal and hepatic function as follows:
• Bone Marrow: Absolute neutrophil count (ANC) >= 1,500/mm3 (1.5 × 109/L);
• Platelets >= 100,000/mm3 (100 × 109/L); Hemoglobin >= 9.0 g/dL;
• Renal function: serum calculated creatinine clearance > 50 mL/min according to the
Cockroft-Gault formula; confirmation of creatinine clearance/GFR may be done by a local direct measurement method (e.g., 24 hour urine collection or radioisotope) at the investigator's discretion;
• Hepatic function: AST and ALT <= 2.5 × ULN unless liver metastases are present, then AST
and ALT < 5.0 × ULN; bilirubin <= 1.5 × ULN unless Gilbert's Syndrome is present, then
bilirubin >= 1.5 × ULN.
12. Female subjects of childbearing potential (i.e., those who are not postmenopausal for at least
1 year or surgically sterile by bilateral tubal ligation, bilateral oophorectomy or hysterectomy) and
their male partners should practice at least one of the methods of birth control listed below during
study and for at least 6 months after treatment with paclitaxel chemotherapy. Male subjects and
their female partners of childbearing potential should practice at least one of the methods of birth
control listed below during study and for at least 6 months after treatment with chemotherapy:
• • total abstinence from sexual intercourse (if it is the subject's preferred and usual lifestyle; for
• beginning a minimum one complete menstrual cycle prior to study drug administration and
• to extend 6 months after treatment):
• • vasectomized subject or partner(s); vasectomy (males);
• • intrauterine device (females);
• • double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with
• spermicidal jellies or creams; both males and females);
• • hormonal contraceptives (oral, parenteral or transdermal) for at least 90 days prior to study
• drug administration (females). If hormonal contraceptives are used, the subject and her
• partner should also use a single-barrier method.
13. Subject must be capable of understanding and complying with parameters as outlined in the
protocol and able to sign and date the 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. Subject has a known hypersensitivity to paclitaxel or to other drugs formulated with
polyethoxylated castor oil (Cremophor).
2. Subject has a known hypersensitivity to platinum compounds.
3. Subjects with peripheral neuropathy >= grade 2.
4. Subjects with squamous NSCLC, or those with an untreated EGFR mutation (exon 19 deletion or L858R mutation in exon 21) and/or ALK gene rearrangement. Subjects' EGFR mutation and ALK gene rearrangement status must be known prior to study entry.
5. A history of seizure within 12 months prior to study entry.
6. Subject has received prior cytotoxic chemotherapy or chemoradiotherapy for NSCLC, except adjuvant or neoadjuvant therapy > 12 months prior to C1D-2 or subject has received targeted small molecule monotherapy for EGFR and/or ALK-positive disease <= 14 days prior to C1D-2 or biologic therapy <= 21 days prior to C1D-2.
7. Subject has received anti-cancer Chinese medicine or anti-cancer herbal remedies within 14 days prior to C1D-2.
8. Subject has undergone focal External Beam Radiation Therapy (EBRT) to bone <= 2 weeks prior
to C1D-2; or subject has undergone EBRT to larger fields (i.e., 100 cm2 to thorax) <= 4 weeks
prior to C1D-2.
9. Any medical condition, which in the opinion of the Investigator, places the subject at an
unacceptably high risk for toxicities, or any subject circumstance which prohibits trial
participation according to local law.
10. Subject is pregnant or lactating.
11. Subject has previously been treated with a PARP inhibitor.
12. The subject has a history of another 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).
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 | EUCTR2014-002565-30-NL |
| CCMO | NL50469.060.14 |