Advanced Ovarian CancerPhase 1/2NCT01989546
Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations
A Phase 1/2 study testing BMN 673 in people with Advanced Ovarian Cancer and Primary Peritoneal Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
Background: The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid (DNA) damage repair mechanisms. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Advanced Ovarian Cancer, Primary Peritoneal Cancer, Advanced Breast Cancer
- What is being tested?
- BMN 673
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- 4 Feb 2014to 26 Mar 2020
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult patients with documented deleterious breast cancer 1 and breast cancer 2 (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 platinum resistant 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.
Show all 22Show fewer
- Eastern Cooperative Oncology Group (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
- Aspartate aminotransferase (AST) Serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (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 human epidermal growth factor receptor 2 (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 Gonadotropin-releasing hormone (GnRH) agonists while on study, as long as there is evidence of disease progression on therapy.
Who cannot join
- 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.
Show all 9Show fewer
- human immunodeficiency virus (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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Background:
- The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid (DNA) damage repair mechanisms.
- Talazoparib (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 breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (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.
Read more
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 (Complete Response (CR) + Partial Response (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; Eastern Cooperative Oncology Group (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 protease activated receptor (PAR) levels, DNA damage response markers such as >=H2A.X Variant Histone (H2AX), cleaved caspase 3, excision repair cross-complementing group 1 (ERCC1), pNbs1, XPF, RAD51, and pT1989ATR, and, as indicators of ataxia telangiectasia and Rad3-related protein (ATR)/ataxia telangiectasia mutated (ATM) activation, Checkpoint kinase 1 (chk1) and Checkpoint kinase 2 (chk2)
- Blood samples for circulating tumor cells (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 pharmacokinetic (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 pre-dose and 3-6 hours post dose.
Read the detailed description
Background:
- The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid (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 breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (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 (Complete Response (CR) + Partial Response (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; Eastern Cooperative Oncology Group (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 Response Evaluation Criteria in Solid Tumors (RECIST) criteria) if the patient has been on study for at least 4 cycles, or at time of disease progression.
- Conditions
- Advanced Ovarian Cancer, Primary Peritoneal Cancer, Advanced Breast Cancer, Advanced Solid Tumors
- Being tested
- BMN 673
- Keywords
- DNA Damage, Advanced Solid Tumors, BRCA Mutations, PARP Inhibitor, Pharmacodynamics
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BMN 673Drug
Also called Talazoparib
Poly (ADP-ribose) polymerase (PARP) inhibitor; has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (PTEN)-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in deoxyribonucleic acid (DNA) repair pathways.
| Study group | Role | What they receive |
|---|---|---|
| 1/Talazoparib (BMN 673) | Experimental | Single agent Receives: Drug: BMN 673 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent of Participants Who Achieve a Sustained Progressive Disease (PD) Response, Defined to be at Least 4% Nuclear Area Positive (NAP) γH2AX at the Day 8 Biopsy
Evaluation of drug effect on deoxyribonuclecic acid (DNA) damage response will be performed using immunofluorescence assays to measure the DNA damage repair marker γH2A (the phosphorylated form of histone family member X, H2AX) in the nucleus of tumor cells obtained via core biopsy.
Measured: Cycle 1, day 8
Secondary outcomes (1)
Response Rate (Complete Response (CR) + Partial Response (PR) of Treatment With Talazoparib (BMN 673) in Participants With Deleterious Breast Cancer (BRCA) Mutations
Response will be evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST)1. 1 guidelines; restaging scans will be carried out every 2 cycles. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. And progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.
Measured: Restaging scans will be carried out every 2 cycles (8 weeks) until the end of treatment (average, 7 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Nov 2013 (estimated)
- Study start4 Feb 2014
- Primary completion26 Mar 2020
- Study completion26 Mar 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Advanced Ovarian CancerStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Alice Chen, M.D., National Cancer Institute (NCI)
- Investigators
- Alice P Chen, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01989546
- Sponsor's protocol ID
- 140015
- Other IDs
- 14-C-0015
- Status last verified
- Feb 2021
- First submitted
- 16 Nov 2013
- Last updated
- 23 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roche H, Im YH, Quek RGW, Markova D, Tudor IC, Hannah AL, Eiermann W, Blum JL. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018 Aug 23;379(8):753-763. doi: 10.1056/NEJMoa1802905. Epub 2018 Aug 15.
PubMed 30110579de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, Kaye S, Sachdev J, Heymach J, Smith DC, Henshaw JW, Herriott A, Patterson M, Curtin NJ, Byers LA, Wainberg ZA. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discov. 2017 Jun;7(6):620-629. doi: 10.1158/2159-8290.CD-16-1250. Epub 2017 Feb 27.
PubMed 28242752Wilsker DF, Barrett AM, Dull AB, Lawrence SM, Hollingshead MG, Chen A, Kummar S, Parchment RE, Doroshow JH, Kinders RJ. Evaluation of Pharmacodynamic Responses to Cancer Therapeutic Agents Using DNA Damage Markers. Clin Cancer Res. 2019 May 15;25(10):3084-3095. doi: 10.1158/1078-0432.CCR-18-2523. Epub 2019 Feb 21.
PubMed 30792217Mittra A, Coyne GHOS, Zlott J, Kummar S, Meehan R, Rubinstein L, Juwara L, Wilsker D, Ji J, Miller B, Navas T, Ferry-Galow KV, Voth AR, Chang TC, Jiwani S, Parchment RE, Doroshow JH, Chen AP. Pharmacodynamic effects of the PARP inhibitor talazoparib (MDV3800, BMN 673) in patients with BRCA-mutated advanced solid tumors. Cancer Chemother Pharmacol. 2024 Mar;93(3):177-189. doi: 10.1007/s00280-023-04600-0. Epub 2023 Nov 27.
PubMed 38010394
Study at a glance
From the registry record, last updated by the sponsor on 23 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Trial of BMN 673, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations
- ClinicalTrials.gov ID
- NCT01989546
- Acronym / sponsor ID
- 140015
- Conditions
- Advanced Ovarian Cancer, Primary Peritoneal Cancer, Advanced Breast Cancer, Advanced Solid Tumors
- Keywords
- DNA Damage, Advanced Solid Tumors, BRCA Mutations, PARP Inhibitor, Pharmacodynamics
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 4 Feb 2014 (actual)
- Primary completion
- 26 Mar 2020 (actual)
- Study completion
- 26 Mar 2020 (actual)
- First posted
- 21 Nov 2013 (estimated)
- Results
- Posted 27 Jan 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
- The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid (DNA) damage repair mechanisms.
- Talazoparib (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 breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (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 (Complete Response (CR) + Partial Response (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; Eastern Cooperative Oncology Group (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 protease activated receptor (PAR) levels, DNA damage response markers such as >=H2A.X Variant Histone (H2AX), cleaved caspase 3, excision repair cross-complementing group 1 (ERCC1), pNbs1, XPF, RAD51, and pT1989ATR, and, as indicators of ataxia telangiectasia and Rad3-related protein (ATR)/ataxia telangiectasia mutated (ATM) activation, Checkpoint kinase 1 (chk1) and Checkpoint kinase 2 (chk2)
- Blood samples for circulating tumor cells (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 pharmacokinetic (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 pre-dose 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 deoxyribonucleic acid (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 breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (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 (Complete Response (CR) + Partial Response (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; Eastern Cooperative Oncology Group (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 Response Evaluation Criteria in Solid Tumors (RECIST) criteria) if the patient has been on study for at least 4 cycles, or at time of disease progression.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1/Talazoparib (BMN 673) | Experimental | Drug: BMN 673Single agent |
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Adult patients with documented deleterious breast cancer 1 and breast cancer 2 (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 platinum resistant 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
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BMN 673Also: TalazoparibPoly (ADP-ribose) polymerase (PARP) inhibitor; has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (PTEN)-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in deoxyribonucleic acid (DNA) repair pathways. | Drug | 1/Talazoparib (BMN 673) |
Primary outcome
Percent of Participants Who Achieve a Sustained Progressive Disease (PD) Response, Defined to be at Least 4% Nuclear Area Positive (NAP) γH2AX at the Day 8 Biopsy
Time frame: Cycle 1, day 8
Evaluation of drug effect on deoxyribonuclecic acid (DNA) damage response will be performed using immunofluorescence assays to measure the DNA damage repair marker γH2A (the phosphorylated form of histone family member X, H2AX) in the nucleus of tumor cells obtained via core biopsy.
1 secondary outcome
Response Rate (Complete Response (CR) + Partial Response (PR) of Treatment With Talazoparib (BMN 673) in Participants With Deleterious Breast Cancer (BRCA) Mutations
Time frame: Restaging scans will be carried out every 2 cycles (8 weeks) until the end of treatment (average, 7 months)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Feb 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 30110579Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roche H, Im YH, Quek RGW, Markova D, Tudor IC, Hannah AL, Eiermann W, Blum JL. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018 Aug 23;379(8):753-763. doi: 10.1056/NEJMoa1802905. Epub 2018 Aug 15.
- Background: PubMed 28242752de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, Kaye S, Sachdev J, Heymach J, Smith DC, Henshaw JW, Herriott A, Patterson M, Curtin NJ, Byers LA, Wainberg ZA. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discov. 2017 Jun;7(6):620-629. doi: 10.1158/2159-8290.CD-16-1250. Epub 2017 Feb 27.
- Results publication: PubMed 30792217Wilsker DF, Barrett AM, Dull AB, Lawrence SM, Hollingshead MG, Chen A, Kummar S, Parchment RE, Doroshow JH, Kinders RJ. Evaluation of Pharmacodynamic Responses to Cancer Therapeutic Agents Using DNA Damage Markers. Clin Cancer Res. 2019 May 15;25(10):3084-3095. doi: 10.1158/1078-0432.CCR-18-2523. Epub 2019 Feb 21.
- Derived from this study: PubMed 38010394Mittra A, Coyne GHOS, Zlott J, Kummar S, Meehan R, Rubinstein L, Juwara L, Wilsker D, Ji J, Miller B, Navas T, Ferry-Galow KV, Voth AR, Chang TC, Jiwani S, Parchment RE, Doroshow JH, Chen AP. Pharmacodynamic effects of the PARP inhibitor talazoparib (MDV3800, BMN 673) in patients with BRCA-mutated advanced solid tumors. Cancer Chemother Pharmacol. 2024 Mar;93(3):177-189. doi: 10.1007/s00280-023-04600-0. Epub 2023 Nov 27.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alice P Chen, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing BMN 673 in people with Advanced Ovarian Cancer and Primary Peritoneal Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Jan 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent of Participants Who Achieve a Sustained Progressive Disease (PD) Response, Defined to be at Least 4% Nuclear Area Positive (NAP) γH2AX at the Day 8 Biopsy (time frame: Cycle 1, day 8). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01989546, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Feb 2021.