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Nivolumab in Combination With Talazoparib in Melanoma and Mutations in BRCA or BRCA-ness Genes

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ClinicalTrials.gov Identifier: NCT04187833
Recruitment Status : Recruiting
First Posted : December 5, 2019
Last Update Posted : March 23, 2022
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

Brief Summary:
The purpose of this study is to evaluate how effective the study drugs, nivolumab (also known as Opdivo®) and talazoparib (also known as Talzenna®) are when given as a combination treatment for unresectable or metastatic melanoma. The study team wants to know the effectiveness of these drugs together in treating cancer than if each study drug was given by itself.

Condition or disease Intervention/treatment Phase
Metastatic or Unresectable Melanoma Drug: Nivolumab Drug: Talazoparib Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 37 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Nivolumab in Combination With Talazoparib in Patients With Unresectable or Metastatic Melanoma and Mutations in BRCA or BRCA-ness Genes
Actual Study Start Date : June 5, 2020
Estimated Primary Completion Date : January 1, 2024
Estimated Study Completion Date : January 1, 2024


Arm Intervention/treatment
Experimental: Nivolumab + Talazoparib
Nivolumab 480mg intravenously every 4 weeks (28 days) + Talazoparib 1mg orally daily
Drug: Nivolumab
480mg intravenously every 4 weeks (28 days)
Other Name: Opdivo

Drug: Talazoparib
1mg orally daily
Other Name: Talzenna




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. Number of participants with treatment-related adverse events [ Time Frame: 30 days after start of treatment ]
    Number of participants with treatment-related adverse events, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0

  3. Immune-related overall response (irOR) defined by irRECIST [ Time Frame: up to 24 months after treatment ]
    Immune-related overall response (irOR), defined as immune-related complete response (irCR) and immune-related partial response (irPR) by irRECIST

  4. 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

  5. Overall survival (OS) [ Time Frame: up to 24 months after treatment ]
    Overall survival (OS)


Other Outcome Measures:
  1. Anti-tumor response as measured by immune-infiltration of tumor infiltrating lymphocytes [ Time Frame: At baseline, 12 weeks ]
    Anti-tumor response by measure of immune-infiltration of tumor infiltrating lymphocytes including flow cytometry on tumor biopsies and peripheral blood mononuclear cells (PBMCs)

  2. Patient reported outcomes for adverse events [ Time Frame: baseline and before each cycle (every 4 weeks) of nivolumab for a period of 12 months ]
    Patient reported outcomes for adverse events, as measured by PRO-CTCAE while on combination therapy

  3. 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

  4. Gene expression analysis [ Time Frame: At baseline, 12 weeks ]
    Gene expression by RNA sequencing



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04187833


Contacts
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Contact: Pauline Funchain, MD 1-866-223-8100 TaussigResearch@ccf.org

Locations
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United States, Ohio
Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44195
Contact: Pauline Funchain, MD    866-223-8100    TaussigResearch@ccf.org   
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
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Principal Investigator: Pauline Funchain, MD Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
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Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04187833    
Other Study ID Numbers: CASE2619
First Posted: December 5, 2019    Key Record Dates
Last Update Posted: March 23, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: IPD will not be shared to help protect the identity of our patients due to the small sample size and genetic information collected

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Nivolumab
Talazoparib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors