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Veliparib and Dinaciclib With or Without Carboplatin in Treating Patients With Advanced Solid Tumors

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Advanced Malignant Neoplasm; BRCA1 Mutation Carrier; BRCA2 Mutation Carrier

Intervention: Carboplatin (Drug); Dinaciclib (Drug); Laboratory Biomarker Analysis (Other); Pharmacological Study (Other); Veliparib (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Geoffrey Shapiro, Principal Investigator, Affiliation: Dana-Farber Cancer Institute

Summary

This phase I trial studies the side effects and the best dose of veliparib and dinaciclib when given together with or without carboplatin 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. Drugs used in chemotherapy, such as carboplatin, 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. Giving veliparib and dinaciclib with or without carboplatin may kill more tumor cells.

Clinical Details

Official title: Phase 1 Trial of ABT-888 and SCH727965 Without or With Carboplatin in Patients With Advanced Solid Tumors

Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Recommended phase 2 dose of veliparib/dinaciclib with or without carboplatin determined by dose-limiting toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0)

Secondary outcome:

Anti-tumor activity of veliparib/dinaciclib with or without carboplatin as assessed by Response Evaluation Criteria in Solid Tumors 1.1

Changes in immunohistochemical or biochemical measurements of cyclin-dependent kinase (cdk), poly (ADP-ribose) polymerase 1 activity

Expression of homologous recombination repair proteins

Level of deoxyribonucleic acid damage in tissue samples

Pharmacokinetic parameters (Cmax, AUC, t1/2) of dinaciclib in the presence of veliparib

Pharmacokinetic parameters (maximum concentration [Cmax], area under the curve [AUC], and half-life [t1/2]) of veliparib in the absence or presence of dinaciclib

Detailed description: PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of ABT-888 (veliparib) and SCH727965 (dinaciclib) without or with carboplatin in patients with advanced solid tumors. II. To determine the recommended phase 2 dose (RP2D) for ABT-888 in combination with SCH727965 without or with carboplatin, 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 without or with carboplatin 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 without or with carboplatin. III. To assess the pharmacodynamic effects of ABT-888 in combination with SCH727965 without or with carboplatin, both in surrogate tissues and in tumor. IV. To assess preliminary antitumor activity of the ABT-888/SCH727965 and ABT-888/SCH727965/carboplatin combinations in subjects with solid tumors. OUTLINE: This is a dose-escalation study of veliparib and dinaciclib followed by an expanded BRCA-proficient and BRCA-deficient cohort study. PART 1: 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. Once the maximum-tolerated dose (MTD) is determined, part 2 of study is initiated. PART 2: Patients receive veliparib and dinaciclib as patients in Part 1. Patients also receive carboplatin IV over 60 minutes on days 8 and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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; 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 cohort must have a documented BRCA1 or BRCA2

germline mutation

- 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 enrolling in Part 2 are excluded if they have a known allergy to platinum

drugs (cisplatin or carboplatin)

- 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

Locations and Contacts

Brigham and Women's Hospital, Boston, Massachusetts 02115, United States; Recruiting
Scott J. Rodig, Phone: 617-525-7825, Email: srodig@partners.org
Scott J. Rodig, Principal Investigator

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States; Recruiting
Geoffrey I. Shapiro, Phone: 617-632-4942, Email: geoffrey_shapiro@dfci.harvard.edu
Geoffrey I. Shapiro, Principal Investigator

Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, United States; Recruiting
Jeffrey Supko, Phone: 617-724-1970, Email: jsupko@partners.org
Jeffrey Supko, Principal Investigator

Additional Information

Starting date: November 2011
Last updated: June 26, 2015

Page last updated: August 23, 2015

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