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

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ClinicalTrials.gov Identifier: NCT04550494
Recruitment Status : Recruiting
First Posted : September 16, 2020
Last Update Posted : April 12, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE September 15, 2020
First Posted Date  ICMJE September 16, 2020
Last Update Posted Date April 12, 2021
Actual Study Start Date  ICMJE December 29, 2020
Estimated Primary Completion Date December 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 17, 2020)
Percent of patients who demonstrate simultaneous Rad51 activation [ Time Frame: At cycle 2 day 1 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 15, 2020)
Percent of patients who demonstrate simultaneous Rad51 activation [ Time Frame: At cycle 2 day 1 ]
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, at the cycle 2 day 1 biopsy.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 15, 2020)
Overall response rate [ Time Frame: Up to 30 days after last dose ]
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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: September 15, 2020)
Tumor genomic alterations potentially associated with sensitivity or acquired resistance to talazoparib [ Time Frame: Up to 30 days after last dose ]
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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Measuring the Effects of Talazoparib in Patients With Advanced Cancer and DNA Repair Variations
Official Title  ICMJE 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
Brief Summary 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.
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 at baseline and 4 hours after talazoparib dose on day 1 of cycle 2, and an optional biopsy either at the restaging follow up or at the time of disease progression.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Breast Carcinoma
  • Advanced Gastric Carcinoma
  • Advanced Malignant Solid Neoplasm
  • Advanced Ovarian Carcinoma
  • Advanced Pancreatic Carcinoma
  • Advanced Prostate Carcinoma
  • Anatomic Stage III Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • Anatomic Stage IIIB Breast Cancer AJCC v8
  • Anatomic Stage IIIC Breast Cancer AJCC v8
  • Anatomic Stage IV Breast Cancer AJCC v8
  • Castration-Resistant Prostate Carcinoma
  • Clinical Stage III Gastric Cancer AJCC v8
  • Clinical Stage IV Gastric Cancer AJCC v8
  • Clinical Stage IVA Gastric Cancer AJCC v8
  • Clinical Stage IVB Gastric Cancer AJCC v8
  • HER2 Positive Breast Carcinoma
  • Metastatic Breast Carcinoma
  • Metastatic Gastric Carcinoma
  • Metastatic Malignant Solid Neoplasm
  • Metastatic Ovarian Carcinoma
  • Metastatic Pancreatic Carcinoma
  • Metastatic Prostate Carcinoma
  • Pathologic Stage III Gastric Cancer AJCC v8
  • Pathologic Stage IIIA Gastric Cancer AJCC v8
  • Pathologic Stage IIIB Gastric Cancer AJCC v8
  • Pathologic Stage IIIC Gastric Cancer AJCC v8
  • Pathologic Stage IV Gastric Cancer AJCC v8
  • Platinum-Sensitive Ovarian Carcinoma
  • Postneoadjuvant Therapy Stage III Gastric Cancer AJCC v8
  • Postneoadjuvant Therapy Stage IV Gastric Cancer AJCC v8
  • Prognostic Stage III Breast Cancer AJCC v8
  • Prognostic Stage IIIA Breast Cancer AJCC v8
  • Prognostic Stage IIIB Breast Cancer AJCC v8
  • Prognostic Stage IIIC Breast Cancer AJCC v8
  • Prognostic Stage IV Breast Cancer AJCC v8
  • Stage II Pancreatic Cancer AJCC v8
  • Stage IIA Pancreatic Cancer AJCC v8
  • Stage IIB Pancreatic Cancer AJCC v8
  • Stage III Pancreatic Cancer AJCC v8
  • Stage III Prostate Cancer AJCC v8
  • Stage IIIA Ovarian Cancer AJCC v8
  • Stage IIIA Prostate Cancer AJCC v8
  • Stage IIIA1 Ovarian Cancer AJCC v8
  • Stage IIIA2 Ovarian Cancer AJCC v8
  • Stage IIIB Ovarian Cancer AJCC v8
  • Stage IIIB Prostate Cancer AJCC v8
  • Stage IIIC Ovarian Cancer AJCC v8
  • Stage IIIC Prostate Cancer AJCC v8
  • Stage IV Ovarian Cancer AJCC v8
  • Stage IV Pancreatic Cancer AJCC v8
  • Stage IV Prostate Cancer AJCC v8
  • Stage IVA Ovarian Cancer AJCC v8
  • Stage IVA Prostate Cancer AJCC v8
  • Stage IVB Ovarian Cancer AJCC v8
  • Stage IVB Prostate Cancer AJCC v8
Intervention  ICMJE
  • Procedure: Biopsy
    Undergo biopsy
    Other Names:
    • BIOPSY_TYPE
    • Bx
  • Drug: Talazoparib
    Given PO
    Other Names:
    • BMN 673
    • BMN-673
Study Arms  ICMJE 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 at baseline and 4 hours after talazoparib dose on day 1 of cycle 2, and an optional biopsy either at the restaging follow up or at the time of disease progression.
Interventions:
  • Procedure: Biopsy
  • Drug: Talazoparib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 15, 2020)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2023
Estimated Primary Completion Date December 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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; this list is restricted to genes from the NCI-Molecular Profiling-Based Assignment of Cancer Therapy (MPACT) protocol aMOIs panel for temozolomide plus veliparib (NCT01827384), the ongoing trial of Rucaparib in Patients with Metastatic Hormone-Sensitive Prostate Cancer Harboring Germline DNA Repair Gene Mutations (TRIUMPH) (NCT03413995), and published results from TRITON2: A Phase 2 Study of Rucaparib in Patients with Metastatic Castration-Resistant Prostate Cancer Associated with Homologous Recombination Repair Gene Alterations:

    • 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: ATM, BACH1 (BRIP1), BARD1, CDK12, CHK1, CHK2, IDH1, IDH2, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD54L
  • 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
  • Total bilirubin =< 1.5 x institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional upper limit of normal
  • 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 biopsiable disease in addition to a Response Evaluation Criteria in Solid Tumors (RECIST) measurable lesion
  • 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 capacity and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 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
  • Patients with breast cancer who are eligible for a PARP inhibitor by Food and Drug Association (FDA) approvals must have had prior PARP inhibitor. 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
  • 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 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04550494
Other Study ID Numbers  ICMJE NCI-2020-06906
NCI-2020-06906 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10371 ( Other Identifier: National Cancer Institute LAO )
10371 ( Other Identifier: CTEP )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.
URL: https://grants.nih.gov/policy/sharing.htm
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: A P Chen National Cancer Institute LAO
PRS Account National Cancer Institute (NCI)
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP