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

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

Study Description

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).

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

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

Locations

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

• Principal Investigator: Pauline Funchain, MD; Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

More Information

• Responsible Party: Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT04187833
• Other Study ID Numbers: CASE2619
• First Posted: December 5, 2019
• 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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