Temozolomide med eller uten Veliparib ved behandling av pasienter med residiverende eller refraktær småcellet lungekreft
En multisenter, randomisert, dobbeltblind fase II-studie som sammenligner ABT-888, en PARP-hemmer, versus placebo med temozolomid hos pasienter med residiverende sensitiv eller refraktær småcellet lungekreft
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.
Studieoversikt
Status
Intervensjon / Behandling
Detaljert beskrivelse
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.
Studietype
Registrering (Faktiske)
Fase
- Fase 2
Kontakter og plasseringer
Studiesteder
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Florida
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Tampa, Florida, Forente stater, 33612
- Moffitt Cancer Center
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Georgia
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Atlanta, Georgia, Forente stater, 30322
- Emory University Hospital/Winship Cancer Institute
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Maryland
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Baltimore, Maryland, Forente stater, 21287
- Johns Hopkins University/Sidney Kimmel Cancer Center
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Baltimore, Maryland, Forente stater, 21224
- Johns Hopkins Bayview Medical Center
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Missouri
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St Louis, Missouri, Forente stater, 63110
- Washington University School of Medicine
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New Jersey
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Basking Ridge, New Jersey, Forente stater, 07920
- Memorial Sloan Kettering Basking Ridge
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New York
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Commack, New York, Forente stater, 11725
- Memorial Sloan Kettering Commack
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New York, New York, Forente stater, 10065
- Memorial Sloan Kettering Cancer Center
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Sleepy Hollow, New York, Forente stater, 10591
- Memorial Sloan Kettering Sleepy Hollow
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Uniondale, New York, Forente stater, 11553
- Memorial Sloan Kettering Nassau
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North Carolina
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Chapel Hill, North Carolina, Forente stater, 27599
- UNC Lineberger Comprehensive Cancer Center
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Ohio
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Cleveland, Ohio, Forente stater, 44106
- Case Western Reserve University
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Texas
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Houston, Texas, Forente stater, 77030
- UT MD Anderson Cancer Center
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Virginia
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Richmond, Virginia, Forente stater, 23298
- VCU Massey Comprehensive Cancer Center
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Deltakelseskriterier
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
Tar imot friske frivillige
Kjønn som er kvalifisert for studier
Beskrivelse
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
Studieplan
Hvordan er studiet utformet?
Designdetaljer
- Primært formål: Behandling
- Tildeling: Randomisert
- Intervensjonsmodell: Parallell tildeling
- Masking: Dobbelt
Våpen og intervensjoner
Deltakergruppe / Arm |
Intervensjon / Behandling |
|---|---|
|
Eksperimentell: 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
Andre navn:
Given PO
Andre navn:
|
|
Aktiv komparator: 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
Andre navn:
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Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
|
Progression-free Survival, Calculated as the Proportion of Patients Alive and Without Evidence of Disease
Tidsramme: From randomization to time of progression or death, whichever occurs first, assessed at 4 months
|
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
|
Sekundære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
|
Overall Response (ORR) by RECIST 1.1 Criteria
Tidsramme: 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
|
|
Overall Survival
Tidsramme: From randomization to time of death
|
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
Tidsramme: 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
|
Andre resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
|
BRCA1 Expression, Assessed by Immunohistochemistry
Tidsramme: 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
|
|
Changes in Plasma Markers
Tidsramme: Baseline to up to 5 years
|
Correlated with outcome in the two treatment arms. |
Baseline to up to 5 years
|
|
GammaH2AX Levels
Tidsramme: Up to 5 years
|
Wilcoxon test will be used to compare the percentage increase of gammaH2AX positive cells between the two treatment groups. |
Up to 5 years
|
|
MGMT Expression, Assessed by Immunohistochemistry
Tidsramme: Up to 5 years
|
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
|
|
Number of Circulating Tumor Cells
Tidsramme: 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
|
|
PARP-1 Expression
Tidsramme: 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
|
|
Presence of MGMT Promoter Methylation, Assessed by the EpiTyper Assay
Tidsramme: Up to 5 years
|
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
|
|
PTEN Expression, Assessed by Immunohistochemistry
Tidsramme: 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
|
|
RAD51 Expression, Assessed by Immunohistochemistry
Tidsramme: 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
|
Samarbeidspartnere og etterforskere
Sponsor
Etterforskere
- Hovedetterforsker: Charles M Rudin, Memorial Sloan Kettering Cancer Center
Publikasjoner og nyttige lenker
Studierekorddatoer
Studer hoveddatoer
Studiestart (Faktiske)
Primær fullføring (Faktiske)
Studiet fullført (Antatt)
Datoer for studieregistrering
Først innsendt
Først innsendt som oppfylte QC-kriteriene
Først lagt ut (Antatt)
Oppdateringer av studieposter
Sist oppdatering lagt ut (Faktiske)
Siste oppdatering sendt inn som oppfylte QC-kriteriene
Sist bekreftet
Mer informasjon
Begreper knyttet til denne studien
Ytterligere relevante MeSH-vilkår
- Neoplasmer etter nettsted
- Neoplasmer
- Sykdommer i luftveiene
- Lungesykdommer
- Neoplasmer i luftveiene
- Thoracale neoplasmer
- Lungeneoplasmer
- Karsinom, bronkogent
- Bronkiale neoplasmer
- Småcellet lungekarsinom
- Organiske kjemikalier
- Heterocykliske forbindelser, 1-ring
- Heterocykliske forbindelser
- Azoler
- Dacarbazine
- Triazener
- Imidazoles
- Temozolomid
- Veliparib
Andre studie-ID-numre
- NCI-2012-01130
- U01CA070095 (U.S. NIH-stipend/kontrakt)
- UM1CA186691 (U.S. NIH-stipend/kontrakt)
- P30CA008748 (U.S. NIH-stipend/kontrakt)
- N01CM00039 (U.S. NIH-stipend/kontrakt)
- 9026 (Annen identifikator: CTEP)
- NCI-2012-01130 (Registeridentifikator: CTRP (Clinical Trial Reporting Program))
- IRB #12-021
- 12-021
- CDR0000737062
- 9026 (Annen identifikator: Memorial Sloan Kettering Cancer Center)
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