- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04187833
Nivolumab in Combination With Talazoparib in Melanoma and Mutations in BRCA or BRCA-ness Genes
Phase II Trial of Nivolumab in Combination With Talazoparib in Patients With Unresectable or Metastatic Melanoma and Mutations in BRCA or BRCA-ness Genes
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This is a phase II, single arm, multi-institutional, open label trial in a sample size of 37 primary or recurrent, unresectable or metastatic melanoma patients progressed on prior checkpoint inhibitor therapy with germline or somatic mutations in BRCA1/2 or BRCA-ness.
The primary objective of this study is to estimate the clinical efficacy of nivolumab plus talazoparib in patients with unresectable or metastatic melanoma with BRCA1/2 or other DNA damage repair mutations (defined as BRCA-ness)
Secondary objectives and their endpoints include progression free survival (PFS) defined as time from first dose of treatment until disease progression, treatment related adverse events, anti-tumor activity , and immune-related progression free survival (irPFS).
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Ohio
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Cleveland, Ohio, United States, 44195
- Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Subjects must have a germline or somatic DNA damage repair mutation including any one of the following: BRCA1, BRCA2, ATM, CHEK1, CHEK2, PALB2, RAD50, RAD51, NBN, BLM, BRIP1, ATR, PARP1, MDC1, DSS1, ERCC3, MRE11, HDAC2, FANCA, MLH3, MLH1, EMSY, BAP1, LIG4, LIG3, PRKDC, XRCC6. The result may have been obtained from one of the following test providers: Myriad Genetics, Invitae, Ambry, Quest, Color Genomics, IMPACT, Foundation Medicine (tissue or ctDNA based), Guardant, or another CLIA approved tissue and/or serum based next generation sequencing-based assay.
- Subjects must have histologically or cytologically confirmed diagnosis of primary or recurrent metastatic melanoma.
- Subjects must have received prior checkpoint inhibitor therapy (defined as anti-CTLA4 or anti-PD-1 or combination anti-CTLA4/anti-PD-1), either for metastatic or unresectable disease or adjuvant therapy.
- ECOG Performance status ≤ 2.
Subjects must have normal organ and marrow function as defined below:
- Hemoglobin ≥ 9.0 g/dl
- Absolute neutrophil count ≥ 1,500/mcL
- Platelet count ≥ 90,000/mcL
- Bilirubin ≤ 1.5 x ULN (except in subjects with Gilbert Syndrome, who can have a total bilirubin < 3.0mg/dL)
- AST (SGOT) ≤ 3.0 X upper limit of normal
- ALT (SGPT) ≤ 3.0 X upper limit of normal
- Serum Creatinine Clearance ≥ 30mL/minute. See section 7.1 for talazoparib dose adjustment for renal impairment.
- CrCl< 30mL/minute has not been studied in talazoparib.
- Measurable disease as defined by RECIST 1.1 criteria
During screening, while taking study drug, and until 5 months after taking the final dose of study drug, women of childbearing potential (WOCBP) must practice one of the following methods of birth control:
- Use double-barrier contraception method defined as male use of a condom and female use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, diaphragm [always use with spermicidal jelly/cream]).
- Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 3 months before the first study drug administration.
- Use of an intrauterine device.
- Have a male partner who has had a vasectomy (at least 6 months prior to study enrollment).
- Or must abstain from sexual intercourse completely.
During screening, while taking study drug, and until 7 months after taking the final dose of study drug, men who are sexually active with WOCBP must practice one of the following methods of birth control:
- Have had a vasectomy (at least 6 months prior to study enrollment).
- Use double-barrier contraception method defined as male use of a condom and female use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, diaphragm [always use with spermicidal jelly/cream]).
- Partner use of an intrauterine device.
- Partner use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 3 months before the first study drug administration.
- Or must abstain from sexual intercourse completely
- Subjects must have the ability to understand and the willingness to sign a written informed consent document.
- Ability to swallow pills.
Exclusion Criteria:
- Prior treatment with a PARP inhibitor.
- Prior anti-cancer therapy for melanoma less than 14 days prior to first dose of study drug.
- Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.
- Subjects with 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.
- Known HIV or AIDS-related illness HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with talazoparib. In addition, these subjects are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in subjects receiving combination antiretroviral therapy when indicated.
- Prior organ transplantation including allogeneic stem-cell transplantation.
- Poorly controlled or uncontrolled autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition or prior therapy requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Patients with endocrinopathies controlled on replacement drugs are eligible.
- Major surgery within 4 weeks prior to study enrollment.
Current use of corticosteroids at the time of study enrollment, EXCEPT for the following:
- a. Intranasal, inhaled, topical steroids, eye drops or local steroid injection (eg, intra-articular injection)
- b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent
- c. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
- Diagnosis of Myelodysplastic Syndrome (MDS)
- Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or detectable HCV RNA if anti-HCV antibody screening test positive).
- Current or anticipated use of a P-glycoprotein (P-gp) inhibitor (amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, valspodar, and verapamil), P-gp inducer (avasimibe, carbamazepine, phenytoin, rifampin, and St. John's wort), or inhibitor of breast cancer resistance protein (BCRP) (curcumin, cyclosporine, elacridar [GF120918], and eltrombopag).
- Inability to swallow capsules or known intolerance to talazoparib or its excipients.
- Pregnant women are excluded from this study because animal studies have demonstrated that nivolumab and talazoparib may cause fetal harm when administered to pregnant women. Breastfeeding women are excluded from this study because nivolumab and talazoparib may be excreted in human breastmilk and the potential for serious adverse reactions in nursing infants.
- Persisting toxicity related to prior therapy > Grade 1.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Nivolumab + Talazoparib
Nivolumab 480mg intravenously every 4 weeks (28 days) + Talazoparib 1mg orally daily
|
480mg intravenously every 4 weeks (28 days)
Other Names:
1mg orally daily
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Best overall response as defined by by RECIST 1.1 criteria
Time Frame: up to 24 months after treatment
|
Best overall response, defined as complete response (CR) and partial response (PR) by RECIST 1.1 criteria
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up to 24 months after treatment
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Progression Free Survival (PFS)
Time Frame: up to 24 months after treatment
|
PFS, defined as the time from the first dose of study treatment to the date of disease progression by RECIST 1.1 or death due to any cause, whichever occurs first.
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up to 24 months after treatment
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Number of participants with treatment-related adverse events
Time Frame: 30 days after start of treatment
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Number of participants with treatment-related adverse events, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0
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30 days after start of treatment
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Immune-related overall response (irOR) defined by irRECIST
Time Frame: up to 24 months after treatment
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Immune-related overall response (irOR), defined as immune-related complete response (irCR) and immune-related partial response (irPR) by irRECIST
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up to 24 months after treatment
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Immune-related Progression Free Survival (irPFS)
Time Frame: up to 24 months after treatment
|
irPFS, defined as the time from the first dose of study treatment to the date of disease progression by irRECIST
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up to 24 months after treatment
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Overall survival (OS)
Time Frame: up to 24 months after treatment
|
Overall survival (OS)
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up to 24 months after treatment
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Anti-tumor response as measured by immune-infiltration of tumor infiltrating lymphocytes
Time Frame: At baseline, 12 weeks
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Anti-tumor response by measure of immune-infiltration of tumor infiltrating lymphocytes including flow cytometry on tumor biopsies and peripheral blood mononuclear cells (PBMCs)
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At baseline, 12 weeks
|
Patient reported outcomes for adverse events
Time Frame: baseline and before each cycle (every 4 weeks) of nivolumab for a period of 12 months
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Patient reported outcomes for adverse events, as measured by PRO-CTCAE while on combination therapy
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baseline and before each cycle (every 4 weeks) of nivolumab for a period of 12 months
|
Evaluation of DNA landscape as described by total somatic mutation burden
Time Frame: At baseline, 12 weeks
|
Evaluation of DNA landscape as described by total somatic mutation burden by DNA sequencing
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At baseline, 12 weeks
|
Gene expression analysis
Time Frame: At baseline, 12 weeks
|
Gene expression by RNA sequencing
|
At baseline, 12 weeks
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: James Isaacs, MD, Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neuroendocrine Tumors
- Nevi and Melanomas
- Melanoma
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Poly(ADP-ribose) Polymerase Inhibitors
- Immune Checkpoint Inhibitors
- Nivolumab
- Talazoparib
Other Study ID Numbers
- CASE2619
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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