Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations

A Pharmacodynamics-Driven Trial of Talazoparib, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Aberrations in Genes Involved in DNA Damage Response

This phase II trial studies if talazoparib works in patients with cancer that has spread to other places in the body (advanced) and has mutation(s) in deoxyribonucleic acid (DNA) damage response genes who have or have not already been treated with another PARP inhibitor. Talazoparib is an inhibitor of PARP, a protein that helps repair damaged DNA. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. All patients who take part on this study must have a gene aberration that changes how their tumors are able to repair DNA. This trial may help scientists learn whether some patients might benefit from taking different PARP inhibitors "one after the other" and learn how talazoparib works in treating patients with advanced cancer who have aberration in DNA repair genes.

Study Overview

• Status: Recruiting
• Conditions: Anatomic Stage III Breast Cancer AJCC v8; Anatomic Stage IV Breast Cancer AJCC v8; Advanced Pancreatic Carcinoma; Metastatic Pancreatic Carcinoma; Stage II Pancreatic Cancer AJCC v8; Stage III Pancreatic Cancer AJCC v8; Stage IV Pancreatic Cancer AJCC v8; Castration-Resistant Prostate Carcinoma; Metastatic Prostate Carcinoma; Stage IV Prostate Cancer AJCC v8; Locally Advanced Malignant Solid Neoplasm; Metastatic Malignant Solid Neoplasm; Stage III Prostate Cancer AJCC v8; Clinical Stage III Gastric Cancer AJCC v8; Clinical Stage IV Gastric Cancer AJCC v8; Metastatic Gastric Carcinoma; Platinum-Sensitive Ovarian Carcinoma; Locally Advanced Pancreatic Carcinoma; Metastatic Breast Carcinoma; Stage III Ovarian Cancer AJCC v8; Stage IV Ovarian Cancer AJCC v8; HER2-Positive Breast Carcinoma; Metastatic Ovarian Carcinoma; Locally Advanced Breast Carcinoma; Locally Advanced Ovarian Carcinoma; Locally Advanced Gastric Carcinoma; Locally Advanced Prostate Carcinoma
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Procedure: Biospecimen Collection; Procedure: Biopsy; Procedure: Computed Tomography; Drug: Talazoparib

Detailed Description

PRIMARY OBJECTIVE:

I. Determine the pharmacodynamic (PD) effect of talazoparib in tumor biopsies for patients with aberrations in deoxyribonucleic acid (DNA) damage response genes who have or have not received prior PARP inhibitor treatment (separately).

SECONDARY OBJECTIVE:

I. Determine the response rate (complete response [CR] + partial response [PR]) of treatment with talazoparib in patients with aberrations in DNA damage response genes.

EXPLORATORY OBJECTIVE:

I. Investigate tumor genomic alterations potentially associated with sensitivity or acquired resistance to talazoparib.

OUTLINE:

Patients receive talazoparib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo biopsy and blood sample collection throughout the study. Patients undergo computed tomography (CT) scan or magnetic resonance imaging (MRI) throughout the study.

After completion of study treatment, patients are followed up at 30 days.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • University of Florida Health Science Center - Gainesville
      • Contact: Site Public Contact; Phone Number: 352-273-8010; Email: cancer-center@ufl.edu
      • Principal Investigator: Thomas J. George
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: Site Public Contact; Phone Number: 800-411-1222
      • Principal Investigator: A P. Chen
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Cancer Institute Developmental Therapeutics Clinic
      • Contact: Site Public Contact; Phone Number: 800-411-1222
      • Principal Investigator: A P. Chen
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • University of Oklahoma Health Sciences Center
      • Contact: Site Public Contact; Phone Number: 405-271-8777; Email: ou-clinical-trials@ouhsc.edu
      • Principal Investigator: Abdul Rafeh Naqash

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients with solid tumors and documented germline or somatic aberrations in genes involved in DNA damage response (DDR) and whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options. Molecular testing performed at an National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) (NCT02465060) study-designated Clinical Laboratory Improvement Act (CLIA) laboratory or at Myriad Genetics, GeneDx, Invitae, or the Frederick National Laboratory for Cancer Research (FNLCR) Molecular Characterization Laboratory (MoCha) will be acceptable for determination of eligibility

• Patients with the following germline or somatic genetic aberrations will be eligible based on compelling preclinical and/or clinical data suggesting that these deleterious mutations confer sensitivity to PARP inhibitors; no more than 6 patients (across both cohorts) with an eligibility mutation in any one gene will be enrolled

  • Deleterious BRCA1 or BRCA2 mutations
  • Loss of function mutations (including novel loss of function frameshift or nonsense mutations) in the following Fanconi anemia genes: FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN
  • A known functional mutation (including novel loss of function frameshift or nonsense mutations) in any of the following DDR genes: ARID1A, ATM, ATR, BACH1 (BRIP1), BAP1, BARD1, CDK12, CHK1, CHK2, IDH1, IDH2, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD54L
• Age >= 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Life expectancy of greater than 3 months
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 10 g/dL
• Total bilirubin =< 1.5 x institutional upper limit of normal (=< 3 x upper limit of normal in the presence of documented Gilbert's syndrome or liver metastases at baseline)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional upper limit of normal
• Creatinine =< 1.5 x institutional upper limit of normal OR Creatinine clearance (CrCl) >= 60 mL/min/1.73m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73m^2
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Patients must have a tumor site amenable to biopsy. If avoidable, the lesion for biopsy should not be selected as a target lesion for RECIST measurements
• The effects of talazoparib on the developing human fetus are unknown. For this reason and because PARP inhibitors are known to be teratogenic, women of child-bearing potential must agree to use a highly effective method of contraception for the duration of study participation and for at least 7 months after completing study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Male patients with female partners of reproductive potential and pregnant partners who are treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation and for at least 4 months after completion of talazoparib administration
• Patients must be able to swallow whole tablets or capsules. Nasogastric or gastric-tube (G-tube) administration is not allowed. Any gastrointestinal disease which would impair ability to swallow, retain, or absorb drug is not allowed
• Ability to understand and the willingness to sign a written informed consent document
• Patients must have recurrent, locally advanced or metastatic disease
• Patients must have progressed on or after at least one line of standard-of-care (SOC) intervention, except for those patients without SOC or for whom talazoparib is SOC
• PATIENTS WITH OVARIAN CANCER:
• All patients with ovarian cancer should have one prior platinum-based therapy
• Patients with ovarian cancer with platinum-sensitive disease are eligible. Patients with platinum-refractory disease are not eligible
• Patients with gBRCAm ovarian cancer must also have progressed on a PARP inhibitor. The time and treatment between the prior PARP inhibitor and protocol initiation must be documented
• PATIENTS WITH PANCREATIC CANCER:
• All patients with pancreatic cancer should have received prior platinum-containing therapy
• PATIENTS WITH BREAST CANCER:
• Patients with HER2+ breast cancer should have had 2 prior systemic lines of therapy in the metastatic setting, including anti-HER2 therapy
• Patients with breast cancer who are eligible for a PARP inhibitor by Food and Drug Association (FDA) approvals must have had prior PARP inhibitor as per FDA indication. The time and treatment between the prior PARP inhibitor and protocol initiation must be documented
• PATIENTS WITH GASTRIC CANCER:
• Patients with HER2+ gastric cancer should have had received anti-HER2 therapy in the metastatic setting
• PATIENTS WITH PROSTATE CANCER:
• Patients with prostate cancer who are eligible for a PARP inhibitor by FDA approvals must have had prior PARP inhibitor for eligibility. The time and treatment between the prior PARP inhibitor and protocol initiation must be documented
• All patients with prostate cancer can continue to receive treatment with gonadotropin-releasing hormone (GnRH) agonists while on study, as long as there is evidence of disease progression on prior therapy
• Patients with castration resistant prostate cancer must have castrate levels of testosterone (< 50 ng/dL [1.74 nmol/L])
• Patients with metastatic hormone receptor (HR) prostate cancer and mutations in either BRCA1, BRCA2, or ATM should continue to receive anti-AR therapy

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks or 5 half-lives, whichever is shorter (6 weeks for nitrosoureas or mitomycin C). Patients must be >= 2 weeks since any prior administration of a study drug in a phase 0 or equivalent study and be >= 1 week from palliative radiation therapy. Patients must have recovered to eligibility levels from prior toxicity or adverse events
• Patients who have had prior treatment with talazoparib are ineligible
• Patients who have had prior monoclonal antibody therapy must have completed that therapy >= 6 weeks (or 3 half-lives of the antibody, whichever is shorter) prior to enrollment on protocol (minimum of 1 week between prior therapy and study enrollment) except for monoclonal antibody therapies that have been proven to be safe when combined with PARP inhibitor (PARPi) treatment (such as anti-PD-1/PD-L1 and anti-HER2), which must be completed >= 4 weeks prior to enrollment
• Patients who are receiving any other investigational agents
• Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients with treated brain metastases, whose brain metastatic disease has remained stable for >= 1 month without requiring steroid and anti-seizure medication are eligible to participate
• Eligibility of subjects receiving any medications or substances with the potential to affect the activity or pharmacokinetics of talazoparib will be determined following review by the principal investigator
• 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
• Pregnant women are excluded from this study because the effects of the study drugs on the developing fetus are unknown
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded. Low-dose warfarin (=< 1 mg/day) is permitted
• Women who are currently lactating
• History of prior malignancies within the past 3 years other than non-melanomatous skin cancers that have been controlled

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (talazoparib); Patients receive talazoparib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo biopsy and blood sample collection throughout the study. Patients undergo CT scan or MRI throughout the study.

Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Drug: Talazoparib; Given PO; Other Names: BMN 673; BMN-673

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of patients who demonstrate simultaneous Rad51 activation	Will be measured as the percent of patients who demonstrate simultaneous Rad51 activation, defined to be at least 5% cells with at least 5 Rad51 foci, and lack of gamma-H2AX activation, defined to be less than 4% nuclear area positive (NAP), at the cycle 2 day 1 biopsy.	At cycle 2 day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	Will estimate the overall response rate (complete response + partial response) among eligible patients who have received at least one dose of talazoparib. A 95% confidence interval for this response rate will also be computed. For this analysis, response classifications will follow Response Evaluation Criteria in Solid Tumors version 1.1 guidelines.	Up to 30 days after last dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor genomic alterations potentially associated with sensitivity or acquired resistance to talazoparib	Exploratory evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.	Up to 30 days after last dose

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: A P Chen, National Cancer Institute LAO

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: September 15, 2020
• First Submitted That Met QC Criteria: September 15, 2020
• First Posted (Actual): September 16, 2020

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Endocrine Gland Neoplasms; Genital Neoplasms, Male; Breast Diseases; Prostatic Diseases; Pancreatic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Genital Diseases, Female; Neoplasms; Stomach Neoplasms; Breast Neoplasms; Prostatic Neoplasms; Carcinoma; Ovarian Neoplasms; Pancreatic Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Talazoparib
• Other Study ID Numbers: NCI-2020-06906 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 000246; 10371 (Other Identifier: CTEP); 000264

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No