Trial record 1 of 1 for:    NCT01434316
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Veliparib and Dinaciclib in Treating Patients With Advanced Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2016 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01434316
First received: September 13, 2011
Last updated: July 20, 2016
Last verified: July 2016

September 13, 2011
July 20, 2016
November 2011
June 2017   (final data collection date for primary outcome measure)
Recommended phase 2 dose of veliparib/dinaciclib determined by dose-limiting toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Frequency tables of worst grade of adverse event, drug-related adverse events, and worst grade of laboratory value will be presented by dose cohort.
  • Recommended phase 2 dose of ABT-888/SCH727965 and ABT888/SCH727965/carboplatin [ Designated as safety issue: No ]
  • Dose-limiting toxicities according to NCI CTCAE v. 4.0 [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01434316 on ClinicalTrials.gov Archive Site
  • Anti-tumor activity of veliparib/dinaciclib as assessed by Response Evaluation Criteria in Solid Tumors 1.1 [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
  • Change in homologous recombination deficiency (HRD) score [ Time Frame: Baseline to up to 56 days ] [ Designated as safety issue: No ]
    The relationship between change in HRD score and clinical response will be assessed with the Wilcoxon rank-sum test to compare percent change in marker levels in patients whose best response is PR or SD, compared to those whose best response is PD.
  • Changes in immunohistochemical or biochemical measurements of cyclin-dependent kinase (cdk), poly (ADP-ribose) polymerase 1 activity [ Time Frame: Baseline up to day 10 ] [ Designated as safety issue: No ]
    Levels of activity and percent changes post-treatment will be summarized using descriptive statistics.
  • Expression of homologous recombination repair proteins [ Time Frame: 56 days ] [ Designated as safety issue: No ]
  • Level of deoxyribonucleic acid damage in tissue samples [ Time Frame: Up to day 10 ] [ Designated as safety issue: No ]
  • Objective response rate [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
    Conducted using the Kaplan Meier method. Estimates will be provided with 95% confidence interval.
  • Pharmacokinetic parameters (Cmax, AUC, t1/2) of dinaciclib in the presence of veliparib [ Time Frame: At 0.25, 0.5, 1, 2, 2.25, 2.50, 3.0, 4.0, 6.0, 8.0, and 24.0 hours after dosing (days 1 and 8 of course 1) ] [ Designated as safety issue: No ]
  • Pharmacokinetic parameters (maximum concentration [Cmax], area under the curve [AUC], and half-life [t1/2]) of veliparib in the absence or presence of dinaciclib [ Time Frame: At 0.25, 0.5, 1, 2, 2.25, 2.50, 3.0, 4.0, 6.0, 8.0, and 24.0 hours after dosing (days 1 and 8 of course 1) ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
    Conducted using the Kaplan Meier method and overall survival estimates will be provided with 95% confidence interval.
  • Pharmacokinetics of ABT-888/SCH727965 and ABT888/SCH727965/carboplatin [ Designated as safety issue: No ]
  • Combined cdk2/cdk1/cdk9 inhibition and PARP inhibition in surrogate tissue and tumor [ Designated as safety issue: No ]
  • Level of DNA damage in surrogate tissue and tumor via assessment of γ-H2AX [ Designated as safety issue: No ]
  • Correlation between pharmacokinetic and pharmacodynamic findings [ Designated as safety issue: No ]
  • Association between pre-treatment expression of proteins involved in homologous recombination repair in archived tissue and tumor response [ Designated as safety issue: No ]
  • Anti-tumor activity of ABT-888/SCH727965 and ABT888/SCH727965/carboplatin [ Designated as safety issue: No ]
  • Change in BRCA1 and RAD51 expression [ Time Frame: Baseline to day 7 of course 1 ] [ Designated as safety issue: No ]
    A tumor biopsy pair will be classified as demonstrating proof-of-mechanism if there is at least a 50% decrease in the proportion of BRCA1 and/or RAD51 foci-positive cells between the biopsy obtained after veliparib alone and the biopsy obtained after veliparib and dinaciclib. A one-sided binomial test will be used.
  • Change in BRCA1 and RAD51 expression [ Time Frame: Baseline and within 48 hours of combination therapy in course 1 ] [ Designated as safety issue: No ]
    A tumor biopsy pair will be classified as demonstrating proof-of-mechanism if there is at least a 50% decrease in the proportion of BRCA1 and/or RAD51 foci-positive cells between the biopsy obtained after veliparib alone and the biopsy obtained after veliparib and dinaciclib. A one-sided binomial test will be used.
  • Change in parameters defining combined cdk and PARP inhibition [ Time Frame: Baseline to up to 56 days ] [ Designated as safety issue: No ]
    The relationship between change in parameters defining combined cdk and PARP inhibition and clinical response will be assessed with the Wilcoxon rank-sum test to compare percent change in marker levels in patients whose best response is PR or SD, compared to those whose best response is PD.
Not Provided
 
Veliparib and Dinaciclib in Treating Patients With Advanced Solid Tumors
Phase 1 Trial of ABT-888 and SCH727965 in Patients With Advanced Solid Tumors
This phase I trial studies the side effects and the best dose of veliparib and dinaciclib in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment. Veliparib and dinaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of ABT-888 (veliparib) and SCH727965 (dinaciclib) in patients with advanced solid tumors.

II. To determine the recommended phase 2 dose (RP2D) for ABT-888 in combination with SCH727965, determined by evaluating the feasibility, safety, dose-limiting toxicities, and the maximally tolerated dose(s).

SECONDARY OBJECTIVES:

I. To confirm the safety of the combination of ABT-888 and SCH727965 in patients with known breast cancer (BRCA)1 or BRCA2 germline mutation.

II. To characterize the pharmacokinetic parameters of ABT-888 both alone and in combination with SCH727965.

III. To assess the pharmacodynamic effects of ABT-888 in combination with SCH727965, both in surrogate tissues and in tumor.

IV. To assess preliminary antitumor activity of the ABT-888/SCH727965 combinations in subjects with solid tumors.

OUTLINE: This is a dose-escalation study of veliparib and dinaciclib followed by an expanded doublet cohort study of non-breast BRCA-proficient and BRCA-deficient patients.

PART 1A: Patients receive veliparib orally (PO) twice daily (BID) on days 1-28 and dinaciclib intravenously (IV) over 2 hours on days 8 and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PART 1B: Patients receive veliparib and dinaciclib as patients in Part 1A. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PART 1C: Patients receive veliparib PO BID on days 1-21 and dinaciclib IV over 2 hours on days 8 and 11 of course 0. Patients then receive veliparib PO BID on days 1-21 and dinaciclib IV on days 1, 4, 8, and 11 or days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Advanced Malignant Neoplasm
  • BRCA1 Mutation Carrier
  • BRCA2 Mutation Carrier
  • Solid Neoplasm
  • Drug: Dinaciclib
    Given IV
    Other Names:
    • CDK Inhibitor SCH 727965
    • MK-7965
    • SCH 727965
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
  • Drug: Veliparib
    Given PO
    Other Names:
    • ABT-888
    • PARP-1 inhibitor ABT-888
Experimental: Treatment (veliparib and dinaciclib)

PART 1A: Patients receive veliparib PO BID on days 1-28 and dinaciclib IV over 2 hours on days 8 and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PART 1B: Patients receive veliparib and dinaciclib as patients in Part 1A. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PART 1C: Patients receive veliparib PO BID on days 1-21 and dinaciclib IV over 2 hours on days 8 and 11 of course 0. Patients then receive veliparib PO BID on days 1-21 and dinaciclib IV on days 1, 4, 8, and 11 or days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions:
  • Drug: Dinaciclib
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Drug: Veliparib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
130
Not Provided
June 2017   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Participants must have histologically confirmed diagnosis of a solid tumor for which no curative therapy exists
  • Participants must have measurable or evaluable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Prior chemotherapy is allowed; patients must not have received chemotherapy for 3 weeks prior to the initiation of study treatment and must have full recovery from any acute effects of any prior chemotherapy; patients must not have had nitrosoureas or mitomycin C for 6 weeks prior to the initiation of study treatment
  • Prior exposure to approved receptor tyrosine kinase inhibitors is permitted; at least 5 half-lives must have elapsed since the completion of the kinase inhibitor and the initiation of study treatment
  • Prior radiation therapy is allowed; patients must not have received any radiation within 3 weeks prior to the initiation of study treatment; patients may not have areas of irradiated marrow exceeding 40% of bone marrow volume
  • Prior experimental (non-Food and Drug Administration [FDA] approved) therapies and immunotherapies are allowed; patients must not have received these therapies for 3 weeks prior to the initiation of study treatment and must have full recovery from any acute effects of these therapies
  • Prior exposure to ABT888 or other poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors is permitted in all cohorts except the cohort evaluating BRCA-mutated PARP inhibitor naïve patients, where prior PARP inhibitor treatment will not be permitted; prior exposure to cyclin-dependent kinase inhibitors other than SCH727965 is permitted
  • Absolute neutrophil count >= 1,500/mm^3
  • Hemoglobin (Hgb) > 9.0 g/dl
  • Platelets >= 100,000/mm^3
  • Total bilirubin < 1.5 mg/dl
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times the institutional upper limit of normal; for subjects with known liver metastases, AST and ALT =< 5 times institutional upper limit of normal
  • Creatinine =< 1.5 times institutional upper limit of normal or creatinine clearance >= 60 mL/min/1.73 m^2
  • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 times institutional upper limit of normal
  • Women of childbearing 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; additionally, if a man suspects that he has fathered a child while taking study agents, he should also inform his treating physician immediately
  • Eligible patients in the dose escalation phases of the trial must agree to biopsies of normal skin, unless they undergo optional tumor biopsies; the mandatory biopsy requirement can be waived at the discretion of Principal Investigator in the event of any medical contraindication (e.g. lidocaine allergy); patients enrolled to the expanded cohorts must agree to tumor sampling; patients on anticoagulation must be able to hold warfarin or low molecular weight heparin for a sufficient amount of time to make skin and tumor biopsies safe to perform; PT/INR and PTT should be =< 1.5 times the institutional upper limit of normal prior to performance of skin or tumor biopsies, with values re-checked after the eligibility screen as medically indicated
  • Patients must be able to swallow pills
  • Patients enrolling in the BRCA-deficient cohorts must have a documented BRCA1 or BRCA2 germline mutation; alternatively, patients with tumors harboring somatic BRCA mutations may also enroll after discussion with the principal investigator
  • All patients must agree to provide an archival tissue block or paraffin sample from archival tissue block (approximately 10 sections) for use in pharmacodynamic correlative studies; however, patients are not considered ineligible if archival tumor is not available
  • Ability to understand and the willingness to sign a written informed consent document; subjects must be willing to adhere to dose and visit schedules

Exclusion Criteria:

  • Patients must not receive any other anti-cancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) while on this study except for medications that are prescribed for supportive care but may potentially have an anti-cancer effect (i.e. megestrol acetate, bisphosphonates); in addition, men receiving treatment for prostate cancer will be maintained at castrate levels of testosterone by continuation of luteinizing-releasing hormone agonists
  • Patients with known active brain metastases are excluded; patients with a history of central nervous system (CNS) metastases that have been treated must be stable with no symptoms for > 3 months after completion of that treatment and off steroid treatment, with image documentation required prior to study enrollment
  • Patients with active seizure or a history of seizure
  • Any patient requiring chronic maintenance of white blood cell counts or granulocyte counts through the use of growth factor support (e.g. Neulasta, Neupogen)
  • Patients who have previously received SCH727965
  • Patients with other medical conditions judged by the investigator to be clinically relevant in the setting of this study, which may include active infectious processes, intractable emesis, or chronic diarrheal disease
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, 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 and SCH727965; these potential risks may also apply to other agents used in this study
  • Patients with prior seizure history who have experienced a seizure within the three months prior to enrollment are excluded
  • Subjects with a known allergy to lidocaine
  • Subjects on a potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitor or CPY3A4 inducer who cannot be changed to another medication are excluded
Both
18 Years and older   (Adult, Senior)
No
United States
 
NCT01434316
NCI-2011-03458, NCI-2011-03458, CDR0000710900, DFCI-11-144, 11-144, 8484, P30CA006516, R01CA090687, U01CA062490, UM1CA186709
Yes
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Geoffrey Shapiro Dana-Farber Cancer Institute
National Cancer Institute (NCI)
July 2016

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