Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01989546
Recruitment Status : Completed
First Posted : November 21, 2013
Last Update Posted : April 20, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE November 16, 2013
First Posted Date  ICMJE November 21, 2013
Last Update Posted Date April 20, 2020
Actual Study Start Date  ICMJE February 4, 2014
Actual Primary Completion Date March 26, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 20, 2018)
Percent of patients who achieve a sustained PD response, defined to be at least 10% nuclear area positive at the day 8 biopsy [ Time Frame: Cycle 1 day 8 ]
Evaluation of drug effect on DNA damage response will be performed using immunofluorescence assays to measure the DNA damagerepairmarker >=H2AX in the nucleus of tumor cells obtained via core biopsy.
Original Primary Outcome Measures  ICMJE
 (submitted: November 19, 2013)
Determine the pharmacodynamic effect of BMN 673 in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations. [ Time Frame: 2 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
The response rate (CR + PR) of treatment with talazoparib (BMN 673) in patients with deleterious BRCA mutations. [ Time Frame: CR or PR can be determined at any point while the patient is enrolled on study ]
Response and progression will be evaluated by the RECIST1. 1 guidelines; restaging scans will be carried out every 2 cycles.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 19, 2013)
Determine the response rate (CR + PR) of treatment with BMN 673 in patients with eligible cancers and deleterious BRCA mutations. [ Time Frame: 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations
Official Title  ICMJE Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations
Brief Summary

Background:

  • The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of DNA damage repair mechanisms.
  • BMN 673 is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development. BMN 673 has been shown to cause single-agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.
  • BMN 673 is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations.
  • This pilot study will evaluate the pharmacodynamic effects of BMN 673 on DNA damage and apoptosis markers in tumor biopsy tissue.

Primary Objective:

-Determine the pharmacodynamic effect of BMN 673 in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.

Secondary Objectives:

  • Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced ovarian or primary peritoneal carcinoma and deleterious BRCA mutations.
  • Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced breast carcinoma and deleterious BRCA mutations.
  • Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced solid tumor (other than breast or ovarian) and deleterious BRCA mutations.

Eligibility:

  • Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options.
  • No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.
  • Age greater than or equal to 18 years of age; ECOG performance status less than equal to 2
  • Adequate organ function.
  • Willingness to undergo tumor biopsies.

Study Design:

  • BMN 673 will be administered orally each day in 28-day cycles.
  • Dosing will be at the established recommended Phase II dose of 1000 mcg/day each day for

    28 days.

  • We plan to accrue a total of 12 evaluable patients per cohort for a total of 36 patients. To allow for some patients who will not be evaluable, the accrual ceiling is 42 patients.
  • Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6 hours post BMN 673 on day 8. An optional tumor biopsy may also be collected at time of disease progression.

SCHEMA

  • BMN 673 is administered orally each day in 28-day cycles
  • Tumor biopsies will be performed at baseline (pre-treatment) and 3-6 hrs post dose on cycle 1 day 8. An optional tumor biopsy may also be collected at time of disease progression. Tumor biopsies will be evaluated for PAR levels, DNA damage response markers such as >=H2AX, cleaved caspase 3, ERCC1, pNbs1, XPF, RAD51, and pT1989ATR, and, as indicators of ATR/ATM activation, chk1 and chk2
  • Blood samples for CTC analyses will be collected at baseline (pre-treatment), on cycle 1 day 1(3-6 hours post dose), on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 (3-6 hours post dose)
  • Blood samples for PK analysis will be collected on cycle 1 day 1 pre-dose and 0.5, 1, 2, 3, 4, 6,8, and 24 hours post-dose, on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 predose and 3-6 hours post dose.
Detailed Description

Background:

  • The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of DNA damage repair mechanisms.
  • Talazoparib (BMN 673) is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development. Talazoparib (BMN 673) has been shown to cause single-agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.
  • Talazoparib (BMN 673) is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations.
  • This pilot study will evaluate the pharmacodynamic effects of talazoparib (BMN 673) on DNA damage and apoptosis markers in tumor biopsy tissue.

Primary Objective:

-Determine the pharmacodynamic effect of talazoparib (BMN 673) in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.

Secondary Objectives:

-Determine the response rate (CR + PR) of treatment with talazoparib (BMN 673) in patients with deleterious BRCA mutations.

Eligibility:

  • Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options.
  • No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.
  • Age greater than or equal to 18 years of age; ECOG performance status less than equal to 2
  • Adequate organ function.
  • Willingness to undergo tumor biopsies.

Study Design:

  • Talazoparib (BMN 673) will be administered orally each day in 28-day cycles.
  • Dosing will be at the established recommended Phase II dose of 1000 microgram/day each day for 28 days.
  • To meet the primary, pharmacodynamic endpoint of the trial, we plan to accrue a total of 12 patients with matched, evaluable baseline and day 8 biopsies. To allow for some patients whose biopsies will not be evaluable (i.e., will contain <5% tumor content), the accrual ceiling is 24 patients. The number of patients evaluable for objective response, while relevant to the secondary objective of the trial, will not be considered in determining completion of accrual.
  • Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6 hours post talazoparib (BMN 673) on day 8. One optional tumor biopsy may also be collected either on day 1 (+/- 2 days) of the cycle following any restaging at which a 10-19% increase in tumor volume is observed (according to RECIST criteria) if the patient has been on study for at least 4 cycles, or at time of disease progression.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Ovarian Cancer
  • Primary Peritoneal Cancer
  • Advanced Breast Cancer
  • Advanced Solid Tumors
Intervention  ICMJE Drug: BMN 673
PARP inhibitor; has been shown to cause single-agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.
Study Arms  ICMJE Experimental: 1
Single agent
Intervention: Drug: BMN 673
Publications *

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: March 27, 2020)
9
Original Estimated Enrollment  ICMJE
 (submitted: November 19, 2013)
42
Actual Study Completion Date  ICMJE March 26, 2020
Actual Primary Completion Date March 26, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options.

Patients with ovarian cancer should have one prior platinum-based

chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound. This initial treatment may have included intraperitoneal therapy, consolidation, biologic/targeted (noncytotoxic) agents or extended therapy administered after surgical or non-surgical

assessment. Ovarian cancer patients with both platinum-sensitive and platinumresistant disease are eligible. Patients with platinum-refractory disease are NOT eligible.

Patients with metastatic disease must have received at least one line of standard of care (SOC) treatment for metastatic disease prior to enrollment

  • Age greater than or equal to 18 years of age.
  • ECOG performance status less than or equal to 2
  • Life expectancy of greater than 3 months.
  • Patients must have normal organ and marrow function as defined below:

    • leukocytes greater than or equal to 3,000/mcL
    • absolute neutrophil count greater than or equal to 1,500/mcL
    • platelets greater than or equal to 100,000/mcL
    • total bilirubin less than or equal to 1.5 times institutional upper limit of normal
    • AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of normal
    • creatinine less than or equal to 1.5 times institutional upper limit of normal

OR

--creatinine clearance greater than or equal to 60 mL/min for patients with creatinine levels above institutional normal.

The effects of BMN 673 on the developing human fetus are unknown. For this reason and because PARP inhibitors are known to be teratogenic, women of childbearing potential 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 3 months after completion of BMN 673 administration.

  • Patients must be able to swallow whole tablets or capsules. Nasogastric or 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 with HER2-positive advanced breast cancer or ovarian cancer should have received at least two lines of systemic therapy in the advanced setting.
  • 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 therapy.

EXCLUSION CRITERIA:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients who have had prior treatment with any PARP inhibitors are ineligible.
  • Patients who are receiving any other investigational agents.
  • Patients with known active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients whose brain metastatic disease status has remained stable for greater than or equal to 4 weeks following treatment of brain metastases are eligible to participate at the discretion of the principal investigator.
  • Eligibility of subjects receiving any medications or substances with the potential to affect the activity or pharmacokinetics of BMN 673 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.
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with BMN 673. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  • Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted for prophylactic or therapeutic use. Low-dose warfarin (less than or equal to 1 mg/day) is permitted.
  • Women who are currently lactating
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 120 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01989546
Other Study ID Numbers  ICMJE 140015
14-C-0015
Has Data Monitoring Committee Not Provided
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 Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Alice P Chen, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date March 31, 2020

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