再発または難治性の小細胞肺癌患者の治療におけるテモゾロミドとベリパリブの併用または非併用
再発した感受性または難治性の小細胞肺癌患者を対象に、PARP阻害剤であるABT-888とプラセボをテモゾロミドと比較した多施設無作為化二重盲検第II相試験
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. Temozolomide works by damaging molecules inside the cancer cells, such as deoxyribonucleic acid (DNA), that are needed for cancer survival and growth. Veliparib may stop the growth of tumor cells by blocking proteins that are needed for repairing the damaged DNA and it may also help temozolomide to kill more cancer cells. It is not yet know whether temozolomide is more effective with or without veliparib in treating patients with relapsed or refractory small cell lung cancer.
調査の概要
状態
条件
詳細な説明
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-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.
研究の種類
入学 (実際)
段階
- フェーズ2
連絡先と場所
研究場所
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Florida
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Tampa、Florida、アメリカ、33612
- Moffitt Cancer Center
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Georgia
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Atlanta、Georgia、アメリカ、30322
- Emory University Hospital/Winship Cancer Institute
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Maryland
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Baltimore、Maryland、アメリカ、21287
- Johns Hopkins University/Sidney Kimmel Cancer Center
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Baltimore、Maryland、アメリカ、21224
- Johns Hopkins Bayview Medical Center
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Missouri
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St Louis、Missouri、アメリカ、63110
- Washington University School of Medicine
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New Jersey
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Basking Ridge、New Jersey、アメリカ、07920
- Memorial Sloan Kettering Basking Ridge
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New York
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Commack、New York、アメリカ、11725
- Memorial Sloan Kettering Commack
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New York、New York、アメリカ、10065
- Memorial Sloan Kettering Cancer Center
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Sleepy Hollow、New York、アメリカ、10591
- Memorial Sloan Kettering Sleepy Hollow
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Uniondale、New York、アメリカ、11553
- Memorial Sloan Kettering Nassau
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North Carolina
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Chapel Hill、North Carolina、アメリカ、27599
- UNC Lineberger Comprehensive Cancer Center
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Ohio
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Cleveland、Ohio、アメリカ、44106
- Case Western Reserve University
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Texas
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Houston、Texas、アメリカ、77030
- UT MD Anderson Cancer Center
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Virginia
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Richmond、Virginia、アメリカ、23298
- VCU Massey Comprehensive Cancer Center
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
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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
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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)
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Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
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Patients with asymptomatic brain metastases that do not require immediate whole brain radiation therapy and are on stable doses of steroids are allowed
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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
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Absolute neutrophil count >= 1,500/mcL
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Platelets >= 100,000/mcL
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Hemoglobin >= 8.5 g/dL; the use of transfusion to achieve this criterion should be at the discretion of the investigators
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Total bilirubin =< 1.5 mg/dL x institutional upper limit of normal
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Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal
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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
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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
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For women of child-bearing potential, negative pregnancy test within 14 days prior to starting temozolomide and ABT-888
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Ability to understand and the willingness to sign a written informed consent document
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Able to swallow pills
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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
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：ダブル
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的：Arm I (veliparib and temozolomide)
Patients receive veliparib PO BID on days 1-7 and temozolomide PO on days 1-5. |
Correlative studies Given PO
他の名前：
Given PO
他の名前：
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|
アクティブコンパレータ：Arm II (placebo and temozolomide)
Patients receive placebo PO BID on days 1-7 and temozolomide as in Arm I. |
Correlative studies Given PO Given PO
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Progression-free Survival, Calculated as the Proportion of Patients Alive and Without Evidence of Disease
時間枠：From randomization to time of progression or death, whichever occurs first, assessed at 4 months
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Compared across the two arms using a Fisher exact test. |
From randomization to time of progression or death, whichever occurs first, assessed at 4 months
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Overall Response (ORR) by RECIST 1.1 Criteria
時間枠：From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 months
|
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. |
From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 months
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Overall Survival
時間枠：From randomization to time of death
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Estimated in each treatment group using Kaplan-Meier method. Group comparisons will be performed using log-rank test. |
From randomization to time of death
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Number of Participants With Adverse Events
時間枠：From the start of treatment until 30 days from coming off treatment
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Tabulated According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Summary level. |
From the start of treatment until 30 days from coming off treatment
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その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
BRCA1 Expression, Assessed by Immunohistochemistry
時間枠：Up to 5 years
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Fisher's exact test will be used to correlate response and log-rank test to correlate with progression free survival and overall survival. |
Up to 5 years
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Changes in Plasma Markers
時間枠：Baseline to up to 5 years
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Correlated with outcome in the two treatment arms. |
Baseline to up to 5 years
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GammaH2AX Levels
時間枠：Up to 5 years
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Wilcoxon test will be used to compare the percentage increase of gammaH2AX positive cells between the two treatment groups. |
Up to 5 years
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MGMT Expression, Assessed by Immunohistochemistry
時間枠：Up to 5 years
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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. |
Up to 5 years
|
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Number of Circulating Tumor Cells
時間枠：Up to 5 years
|
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. |
Up to 5 years
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PARP-1 Expression
時間枠：Up to 5 years
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Fisher's exact test will be used to correlate response and log-rank test to correlate with progression free survival and overall survival. |
Up to 5 years
|
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Presence of MGMT Promoter Methylation, Assessed by the EpiTyper Assay
時間枠：Up to 5 years
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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. |
Up to 5 years
|
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PTEN Expression, Assessed by Immunohistochemistry
時間枠：Up to 5 years
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Fisher's exact test will be used to correlate response and log-rank test to correlate with progression free survival and overall survival. |
Up to 5 years
|
|
RAD51 Expression, Assessed by Immunohistochemistry
時間枠：Up to 5 years
|
Fisher's exact test will be used to correlate response and log-rank test to correlate with progression free survival and overall survival. |
Up to 5 years
|
協力者と研究者
捜査官
- 主任研究者：Charles M Rudin、Memorial Sloan Kettering Cancer Center
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (実際)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (推定)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- NCI-2012-01130
- U01CA070095 (米国 NIH グラント/契約)
- UM1CA186691 (米国 NIH グラント/契約)
- P30CA008748 (米国 NIH グラント/契約)
- N01CM00039 (米国 NIH グラント/契約)
- 9026 (その他の識別子：CTEP)
- NCI-2012-01130 (レジストリ識別子：CTRP (Clinical Trial Reporting Program))
- IRB #12-021
- 12-021
- CDR0000737062
- 9026 (その他の識別子：Memorial Sloan Kettering Cancer Center)
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