Nivolumab plus Talazoparib for the Treatment of Unresectable or Metastatic Melanoma in Patients with Mutations in BRCA or BRCA-ness
- Subjects must have a germline or somatic DNA damage repair mutation or deletion including any one of the following: ARID1A, ARID1B, ARID2, ATM, ATR, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK4, CDK12, CHEK1, CHEK2, DSS1, EMSY, ERCC3, FANCA, FANCD2, HDAC2, IDH1, LIG3, LIG4, MDC1, MLH1, MLH3, MRE11, NBN, PALB2, PRKDC, RAD50, RAD51, RAD54, XRCC6. The result may have been obtained from one of the following test providers: Myriad Genetics, Invitae, Ambry, Quest, Color Genomics, Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT), Foundation Medicine (tissue or circulating tumor-derived DNA [ctDNA] based), Guardant, or another Clinical Laboratory Improvement Act (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 including cutaneous, mucosal, or uveal 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
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Hemoglobin >= 9.0 g/dl
- Absolute neutrophil count >= 1,500/mcL
- Platelet count >= 90,000/mcL
- Bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert Syndrome, who can have a total bilirubin < 3.0mg/dL)
- Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) =< 3.0 X upper limit of normal
- Alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 3.0 X upper limit of normal
- Serum creatinine clearance >= 30mL/minute. Creatinine clearance (CrCl) < 30mL/minute has not been studied in talazoparib
- Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- 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
- Prior treatment with a PARP inhibitor
- Prior anti-cancer therapy 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 human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (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: * Intranasal, inhaled, topical steroids, eye drops or local steroid injection (e.g., intra-articular injection) * Systemic corticosteroids at physiologic doses =<10 mg/day of prednisone or equivalent * Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [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 ribonucleotide acid [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
I. To determine the clinical efficacy of nivolumab plus talazoparib in patients with unresectable or metastatic melanoma with BRCA1/2 or other deoxyribonucleic acid (DNA) damage repair mutations (defined as BRCA-ness), as measured by objective response rate (ORR) every 12 weeks for a period of approximately 12 months.
I. Determine progression free survival (PFS) in unresectable or metastatic melanoma patients treated with nivolumab plus talazoparib.
II. Determine overall survival (OS) in unresectable or metastatic melanoma patients treated with nivolumab plus talazoparib.
III. Evaluate treatment-related adverse events in patients treated with nivolumab plus talazoparib.
IV. To assess the anti-tumor activity of nivolumab in combination with talazoparib in unresectable or metastatic melanoma patients with BRCA1/2 or other DNA damage repair mutations (defined as BRCA-ness), as measured by immune-related objective response rate (irORR) every 12 weeks for a period of approximately 12 months.
V. Determine immune-related progression free survival (irPFS) in unresectable or metastatic melanoma patients treated with nivolumab plus talazoparib.
I. Measure adaptive and innate cellular immunofiltration into tumor (by tumor biopsies) and peripheral circulating T cells (by peripheral blood mononuclear cells [PBMCs]) at baseline (pretreatment), after treatment initiation (at about 12 weeks), and at time of progression, and to correlate activity with response to treatment.
II. Assess total somatic tumor mutation burden by sequencing at baseline (pretreatment), after therapy at 12 weeks, and at time of progression to evaluate DNA landscape and its effect on sensitivity of combination nivolumab and talazoparib therapy.
III. Assess patient reported outcomes for adverse events while on combination therapy at baseline and before each cycle (about every 4 weeks) of nivolumab.
Patients receive talazoparib orally (PO) once daily (QD) on day 1 through day 28 of each cycle, and nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
After the completion of study treatment, patients are followed up for 30 days and then every 90 days for up to 24 months.
Trial Phase Phase II
Trial Type Treatment
Case Comprehensive Cancer Center
- Primary ID CASE2619
- Secondary IDs NCI-2020-00416
- Clinicaltrials.gov ID NCT04187833