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 July 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: July 18, 2014
Last verified: July 2014
  Purpose

This randomized phase II trial studies how well temozolomide with or without veliparib works in treating patients with relapsed or refractory small cell lung cancer. 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.


Condition Intervention Phase
Recurrent Small Cell Lung Cancer
Drug: veliparib
Drug: temozolomide
Other: placebo
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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.


Estimated Enrollment: 100
Study Start Date: June 2012
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (veliparib and temozolomide)
Patients receive veliparib PO BID on days 1-7 and temozolomide PO on days 1-5.
Drug: veliparib
Given PO
Other Name: ABT-888
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Other: laboratory biomarker analysis
Correlative studies
Active Comparator: Arm II (placebo and temozolomide)
Patients receive placebo PO BID on days 1-7 and temozolomide as in Arm I.
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Other: placebo
Given PO
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies

  Hide Detailed Description

Detailed Description:

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 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 M30, M65, pro-gastrin-releasing peptide (pro-GRP), soluble vascular endothelial growth factor (sVEGF), sVEGF receptor 2 (sVEGFR2), and 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01638546

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute Recruiting
Tampa, Florida, United States, 33612
Contact: Alberto A. Chiappori    813-745-3050    alberto.chiappori@moffitt.org   
Principal Investigator: Alberto A. Chiappori         
United States, Georgia
Emory University/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Taofeek K. Owonikoko    404-778-1900    towonik@emory.edu   
Principal Investigator: Taofeek K. Owonikoko         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Christine L. Hann    410-502-0678    chann1@jhmi.edu   
Principal Investigator: Christine L. Hann         
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21231
Contact: Christine L. Hann    410-502-0678    chann1@jhmi.edu   
Principal Investigator: Christine L. Hann         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Saiama N. Waqar    314-747-7409    swaqar@DOM.wustl.edu   
Principal Investigator: Saiama N. Waqar         
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Maria C. Pietanza    646-888-4203    pietanzm@mskcc.org   
Principal Investigator: Maria C. Pietanza         
United States, North Carolina
Lineberger Comprehensive Cancer Center Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Thomas E. Stinchcombe    919-996-9268    thomas_stinchcombe@med.unc.edu   
Principal Investigator: Thomas E. Stinchcombe         
United States, Ohio
Case Western Reserve University Recruiting
Cleveland, Ohio, United States, 44106
Contact: Afshin Dowlati    216-844-5181    afshin.dowlati@case.edu   
Principal Investigator: Afshin Dowlati         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Lauren A. Byers    713-792-6363    lbyers@mdanderson.org   
Principal Investigator: Lauren A. Byers         
United States, Virginia
Virginia Commonwealth University Recruiting
Richmond, Virginia, United States, 23298
Contact: Danielle A. Shafer    804-628-0279    dashafer@vcu.edu   
Principal Investigator: Danielle A. Shafer         
Sponsors and Collaborators
Investigators
Principal Investigator: Maria Pietanza Memorial Sloan-Kettering Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01638546     History of Changes
Other Study ID Numbers: NCI-2012-01130, NCI-2012-01130, CDR0000737062, 12-021, 9026, UM1CA186691, P30CA008748, U01CA070095, N01CM00039
Study First Received: July 9, 2012
Last Updated: July 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lung Neoplasms
Small Cell Lung Carcinoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 23, 2014