Temozolomide With or Without Veliparib in Treating Patients With Relapsed or Refractory Small Cell Lung Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01638546
First received: July 9, 2012
Last updated: October 2, 2014
Last verified: September 2014

July 9, 2012
October 2, 2014
June 2012
June 2017   (final data collection date for primary outcome measure)
Progression-free survival, calculated as the proportion of patients alive and without evidence of disease [ Time Frame: From randomization to time of progression or death, whichever occurs first, assessed at 4 months ] [ Designated as safety issue: No ]
Compared across the two arms using a Fisher exact test.
Same as current
Complete list of historical versions of study NCT01638546 on ClinicalTrials.gov Archive Site
  • ORR by RECIST 1.1 criteria [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
    Corresponding exact two-sided 95% confidence intervals will be calculated and reported in both arms of the study. Comparisons between treatment arms will be performed using Fisher-exact test.
  • Overall survival [ Time Frame: From randomization to time of death, assessed up to 5 years ] [ Designated as safety issue: No ]
    Estimated in each treatment group using Kaplan-Meier method. Group comparisons will be performed using log-rank test.
  • Incidence of adverse events, tabulated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Summarized using descriptive statistics.
  • ORR by RECIST 1.1 criteria [ Time Frame: Assessed up to 1 year ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: From randomization to time of death, assessed up to 3 years ] [ Designated as safety issue: No ]
  • Safety and tolerability of each treatment arm [ Time Frame: Assessed up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
  • Presence of MGMT promoter methylation, assessed by the EpiTyper assay [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Results will be expressed as binary variables. Associations with objective response, with progression free survival and with overall survival will be tested using Fisher's exact test and log-rank test, respectively.
  • MGMT expression, assessed by immunohistochemistry [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Results will be expressed as binary variables. Associations with objective response, with progression free survival and with overall survival will be tested using Fisher's exact test and log-rank test, respectively.
  • PARP-1 expression [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Fisher's exact test will be used to correlate response and log-rank test to correlate with progression free survival and overall survival.
  • RAD51 expression, assessed by immunohistochemistry [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Fisher's exact test will be used to correlate response and log-rank test to correlate with progression free survival and overall survival.
  • BRCA1 expression, assessed by immunohistochemistry [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Fisher's exact test will be used to correlate response and log-rank test to correlate with progression free survival and overall survival.
  • PTEN expression, assessed by immunohistochemistry [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Fisher's exact test will be used to correlate response and log-rank test to correlate with progression free survival and overall survival.
  • Number of circulating tumor cells [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    The number of CTCs will be correlated with PFS and OS using Cox proportional hazards model. The change in CTCs will be correlated with radiographic response. The number of CTCs at baseline will be correlated with patient characteristics (disease burden, location of metastases, and progression at existing sites or new sites of disease). The number of CTC will be explored as a continuous variable and the presence of a threshold predictive of the outcome will be investigated.
  • GammaH2AX levels [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Wilcoxon test will be used to compare the percentage increase of gammaH2AX positive cells between the two treatment groups.
  • Changes in plasma markers [ Time Frame: Baseline to up to 5 years ] [ Designated as safety issue: No ]
    Correlated with outcome in the two treatment arms.
Not Provided
 
Temozolomide With or Without Veliparib in Treating Patients With Relapsed or Refractory Small Cell Lung Cancer
A Multi-Center, Randomized, Double-Blind Phase II Study Comparing ABT-888, a PARP Inhibitor, Versus Placebo With Temozolomide in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer

This randomized phase II trial studies how well temozolomide with or without veliparib works in treating patients with small cell lung cancer that has returned or does not respond to treatment. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving temozolomide with veliparib may be an effective treatment for relapsed or refractory small cell lung cancer.

PRIMARY OBJECTIVES:

I. To demonstrate an improvement in progression free survival (PFS) at four months in patients with relapsed sensitive or refractory small cell lung cancer (SCLC) receiving ABT-888 (veliparib) and temozolomide compared to placebo and temozolomide.

SECONDARY OBJECTIVES:

I. Determine the objective response rate (ORR) (based on Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) in both arms of the study: ABT-888 and temozolomide and placebo and temozolomide.

II. Determine the overall survival (OS) of patients in both arms of the study. III. Determine the ORR, PFS and OS of ABT-888 and temozolomide and placebo and temozolomide, in the following patient groups: sensitive disease vs. refractory disease; second-line treatment vs. third-line treatment; brain metastases vs. no brain metastases.

IV. Determine the safety and tolerability of ABT-888 and temozolomide in patients with SCLC.

TERTIARY OBJECTIVES:

I. Evaluate available tumor samples for methylated O6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) promoter by the EpiTyper assay, as well as MGMT expression by immunohistochemistry and determine if these correlate with PFS, ORR, and OS.

II. Evaluate available tumor samples for poly (ADP ribose) polymerase (PARP)-1, breast cancer 1 (BRCA-1) and RAD51 recombinase (RAD51) expression by immunohistochemistry and determine if they correlate with PFS, ORR, and OS.

III. Evaluate available tumor samples for messenger ribonucleic acid (mRNA) BRCA-1 expression and determine if it correlates PFS, ORR, and OS.

IV. Evaluate available tumor samples for phosphatase and tensin homolog (PTEN) expression by immunohistochemistry and determine if it correlates PFS, ORR, and OS.

V. Identify and enumerate circulating tumor cells (CTCs) using the Cell Search System in these patients with SCLC at baseline and at the time of repeat imaging.

VI. Correlate the number of CTCs with PFS and OS at each time point. VII. Correlate the change in CTCs with radiographic response. VIII. Correlate the number of CTCs at baseline with patient characteristics (disease burden, location of metastases, progression at existing sites or new sites of disease).

IX. Evaluate gamma H2A histone family, member X (H2AX)-positive CTCs using the CellSearch.

X. Assess the percentage increase in DNA fragments during treatment and correlate with outcome in each of the treatment groups.

XI. Evaluate plasma markers for apoptosis and angiogenesis. XII. Assess changes in plasma markers for apoptosis and angiogenesis, including caspase-cleaved cytokeratin 18 fragment (M30), soluble cytokeratin 18 (M65), pro-gastrin-releasing peptide (pro-GRP), soluble vascular endothelial growth factor (sVEGF), sVEGF receptor 2 (sVEGFR2), and soluble v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (sKIT), and correlate these markers with outcome in the two treatment arms.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7 and temozolomide PO on days 1-5.

ARM II: Patients receive placebo PO BID on days 1-7 and temozolomide as in Arm I.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 8-12 weeks.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Recurrent Small Cell Lung Cancer
  • Drug: veliparib
    Given PO
    Other Name: ABT-888
  • Drug: temozolomide
    Given PO
    Other Names:
    • SCH 52365
    • Temodal
    • Temodar
    • TMZ
  • Other: placebo
    Given PO
    Other Name: PLCB
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Arm I (veliparib and temozolomide)
    Patients receive veliparib PO BID on days 1-7 and temozolomide PO on days 1-5.
    Interventions:
    • Drug: veliparib
    • Drug: temozolomide
    • Other: laboratory biomarker analysis
  • Active Comparator: Arm II (placebo and temozolomide)
    Patients receive placebo PO BID on days 1-7 and temozolomide as in Arm I.
    Interventions:
    • Drug: temozolomide
    • Other: placebo
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
100
Not Provided
June 2017   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed small cell lung cancer; confirmation will be done at Memorial Sloan-Kettering Cancer Center (MSKCC) or locally for participating sites
  • Patients' disease has relapsed or progressed after one or two prior chemotherapy regimens, one of which must have been an etoposide-platinum doublet; eligible patients will be defined as follows:

    • "Sensitive" disease: patients who had one previous line of chemotherapy and maintained an appropriate response for > 60 days
    • "Refractory" disease: those patients with either (a) no response to first-line chemotherapy or progression =< 60 days after completing treatment, or (b) "sensitive" or "refractory" disease in need of third-line therapy (i.e. completed or failed two previous lines of chemotherapy)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Patients with asymptomatic brain metastases that do not require immediate whole brain radiation therapy and are on stable doses of steroids are allowed
  • Patients must have measurable disease, which is defined as at least one lesion that can be accurately measured in at least one dimension on a computed tomography (CT) scan as per RECIST version 1.1; brain metastases can be considered measurable disease if they meet this criterion
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 8.5g/dL; the use of transfusion to achieve this criterion should be at the discretion of the investigators
  • Total bilirubin =< 1.5 mg/dL X institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 X institutional upper limit of normal
  • Creatinine =< 1.5 X institutional upper limit of normal OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels >= 1.5 X upper limit of institutional normal
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • For women of child-bearing potential, negative pregnancy test within 14 days prior to starting temozolomide and ABT-888
  • Ability to understand and the willingness to sign a written informed consent document
  • Able to swallow pills
  • Patients will not be excluded based on the diagnosis of acquired immune deficiency syndrome (AIDS); given the increased risk of infection, these patients should have cluster of differentiation (CD)4 counts above 200 cells/mm^3; patients with AIDS or human immunodeficiency virus (HIV) not receiving agents with the potential for pharmacokinetic interactions with ABT-888 may be eligible

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 3 weeks prior to entering the study
  • Patients who have not recovered from adverse events due to agents administered more than 3 weeks earlier; toxicities should have resolved to baseline or to within one grade level of their baseline (not to exceed grade 2)
  • Patients who have been administered ABT-888, any other PARP-inhibitor, or temozolomide
  • Patients may not be receiving any other investigational agents
  • Patients with leptomeningeal involvement
  • Patients with active seizures or a history of seizures
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 or temozolomide
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ABT-888; these potential risks also apply to temozolomide
  • Patients with either AIDS or HIV on combination antiretroviral therapy are ineligible
  • Patients with a synchronous active malignancy requiring treatment
Both
18 Years and older
No
United States
 
NCT01638546
NCI-2012-01130, NCI-2012-01130, 12-021, CDR0000737062, IRB # 12-021, 9026, N01CM00039, U01CA070095, P30CA008748, UM1CA186691
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Maria Pietanza Memorial Sloan-Kettering Cancer Center
National Cancer Institute (NCI)
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP