Metastatic Breast Cancer With BRCA 1 or BRCA 2 Genetic MutationNCT02985658
Expanded Access With ABT-888 (Veliparib) to Treat Metastatic Breast Cancer
A study testing Veliparib, Cisplatin and Vinorelbine in people with Metastatic Breast Cancer With BRCA 1 or BRCA 2 Genetic Mutation and Triple-Negative Breast Cancer, run by University of Washington at 1 site in United States.
Trial summary
This is an expanded access protocol to allow continued maintenance therapy with ABT-888 (veliparib) for three patients with metastatic triple negative breast cancer who are currently receiving the investigational product in association with clinical trial participation. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Metastatic Breast Cancer With BRCA 1 or BRCA 2 Genetic Mutation, Triple-Negative Breast Cancer
- What is being tested?
- Veliparib, Cisplatin and Vinorelbine
- Type of treatment
- Injection or infusion
- How many people
- Not given
- Where
- 1 siteUnited States
- Study dates
- Start not givento not given
- Phase
- Expanded access
- Are there results?
- None posted in the registry
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 years and older
- Women only
- Adult, Older adult
- Inclusion Criteria Roll-over patients: This protocol allows for the inclusion of 3 patients actively participating in protocol 7161 who are expected to continue to benefit from uninterrupted dosing of veliparib monotherapy. For newly enrolled patients the following criteria should be satisfied within 28 days of Day 1 of protocol treatment. Results from routine clinical evaluations within 28 days prior to enrollment may be used to determine eligibility:
- Locally recurrent and not amenable to surgical therapy, and/or metastatic breast cancer
- Confirmed HER2-, BRCA1 or BRCA2 mutation-associated breast cancer or sporadic triple negative breast cancer.
- No opportunity to receive veliparib under a current clinical trial.
- Patients may have had any number of prior lines of chemotherapy, endocrine therapy, immunologic, or biologic regimens for metastatic breast cancer.
- Patients receiving bisphosphonates, denosumab or LHRH-agonists are eligible.
- 18 years and older.
- Performance status > 60% on the Karnofsky scale (ECOG < 2).
- Adequate hematologic, renal and hepatic function as follows:
- Bone Marrow: Absolute neutrophil count (ANC) > 1,500/mm3 (1.5 × 109/L); Platelets > 100,000/mm3 (100 × 109/L); Hemoglobin > 9.0 g/dL
- Serum creatinine < 1.5 × upper normal limit of institution's normal range OR creatinine clearance > 50 mL/min/1.73m2 for patients with creatinine levels above institutional normal;
- Hepatic function: AST and/or ALT < 2.5 × the upper normal limit of institution's normal range.
- For patients with liver metastases, AST and/or ALT < 5 × the upper normal limit of institution's normal range;
- Bilirubin < 1.5 × the upper normal limit of institution's normal range;
- Patients with Gilbert's Syndrome may have a bilirubin > 1.5 × the upper normal limit of institution's normal range.
- Women of childbearing potential must agree to use adequate contraception (one of the following listed below) prior to protocol entry, for the duration of protocol participation and for 90 days following completion of therapy. Women of childbearing potential must have a negative serum pregnancy test within 21 days prior to initiation of treatment and/or be confirmed as having postmenopausal status. Criteria for determining menopause include any of the following: prior bilateral oopherectomy; age > 60 years; age < 60 years and amenorrheic for at least 12 months in the absence of chemotherapy, endocrine therapy, or ovarian suppression and FSH and estradiol in the postmenopausal range.
- Total abstinence from sexual intercourse (minimum one complete menstrual cycle);
- Vasectomized partner of female patients;
- Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug administration;
- Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream);
- IUD (Intra-Uterine Device).
- Additionally, male patients (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the treatment plan and for 90 days following completions of therapy.
- Radiation therapy must have been completed at least 2 weeks prior to the enrollment date.
- Patients with known brain metastases must have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 14 days of stable neurologic function prior to the first dose of study drug.
- Ability to understand and the willingness to sign a written informed consent document.
- Exclusion Criteria
- Prior treatment with PARP inhibitor (excluding iniparib). Patients participating in protocol 7161 (NCI-2010-00356) are eligible.
- Clinically significant and uncontrolled major medical condition(s) including but not limited to:
- Active uncontrolled infection;
- Symptomatic congestive heart failure;
- Unstable angina pectoris or cardiac arrhythmia;
- Psychiatric illness/social situation that would limit compliance with protocol requirements;
- Any medical condition, which in the opinion of the investigator, places the patient at an unacceptably high risk for toxicities;
- Myelodysplastic syndrome;
- History of seizures within last 12 months or known neurological disorder pre-disposing to seizures
- Patient is pregnant or lactating.
Trial locations and contacts
1 site in 1 country.
United States1 site
Seattle Cancer Care Allliance
Seattle, Washington, 98109
About this study
Official title: Expanded Access Protocol With ABT-888 (Veliparib) in Patients With Metastatic BRCA-Mutation Associated or Triple Negative Breast Cancer
This is an expanded access protocol to allow continued maintenance therapy with ABT-888 (veliparib) for three patients with metastatic triple negative breast cancer who are currently receiving the investigational product in association with clinical trial participation. Additionally, the protocol will enroll up to 7 new patients with metastatic BRCA associated or triple negative breast cancer to allow for additional access to veliparib monotherapy, or at the investigator's discretion, veliparib in combination with cisplatin and/or vinorelbine.
Read the detailed description
ABT-888 (Veliparib) or Poly(ADP-ribose)-polymerase (PARP) is a nuclear enzyme that recognizes deoxyribonucleic acid (DNA) damage and facilitates DNA repair. Inactive PARPs 1 and 2 bind to damaged DNA, which leads to their auto-activation. The resulting activated PARP then poly(ADP-ribosyl)ates many nuclear target proteins, including those that facilitate DNA repair of both single-stranded or double-stranded DNA breaks. Thus, PARP inhibition will result in less efficient DNA repair following a DNA damage insult.
Since cancer cells are genetically unstable, often exhibiting complex karyotypes that include large deletions, insertions, and unbalanced translocations of chromosomal fragment, these cells are more susceptible than normal tissues to cytotoxicity induced by DNA-damaging agents.Of these, deficiencies in mismatch repair and homologous recombination are associated with the largest number of malignancies, including many sporadic TNBCs. These deficiencies render cells more dependent on PARP for DNA repair and, hence, are more prone to cytotoxicity induced by PARP inhibition. In particular, tumor cells with BRCA1 or BRCA2 deficiencies are exquisitely sensitive to PARP inhibition, even in the absence of any other insults. Identification of sporadic TNBC with defects in homologous recombination and mismatch repair independent of germline mutation of BRCA 1 and 2 is an active area of research interest.
PARP-enabled DNA repair may also compensate for the loss of other repair pathways. Higher expression of PARP in cancer cells compared to normal cells has been linked to drug resistance and the overall ability of cancer cells to sustain genotoxic stress.
The combination of platinum based chemotherapy and PARP inhibition may be most effective in TNBC, and particularly in subsets of TNBC. This combination may also be active in tumors with a germline BRCA1-deficiency and/or basal phenotype, since a defect in the DNA double-strand break repair pathway should increase sensitivity to these agents. The addition of a PARP inhibitor to platinum based chemotherapy may induce a "double hit" to tumor cells lacking homologous recombination without causing excess toxicity to normal cells. ABT-888 may be used in combination with the DNA damaging agent, cisplatin, to potentiate its cytotoxic effect and with vinorelbine to enhance tumor response rate. Safety and preliminary efficacy of veliparib in combination with cisplatin and vinorelbine in patients with advanced triple negative and BRCA-associated breast cancer has been reported.
- Conditions
- Metastatic Breast Cancer With BRCA 1 or BRCA 2 Genetic Mutation, Triple-Negative Breast Cancer
- Being tested
- Veliparib, Cisplatin, Vinorelbine
- Medical subject headings
- Triple Negative Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VeliparibDrug
Also called ABT-888
Patients will start veliparib at 300 mg po BID days 1 through 21 of the first 21 day cycle, then increase to 400 mg po BID days 1 through 21 of each subsequent cycle, as tolerated by the patient.
At the treating investigator's discretion, and with principal investigator approval, veliparib may be used in combination with cisplatin and/or vinorelbine. Veliparib (300mg) will be dosed po BID on Days 1 through 14 of each 21-day cycle.
The patient will receive therapy as long as there is therapeutic benefit
CisplatinDrug
Also called Platinol-AQ, Platinol
Cisplatin will be administered intravenously (75 mg/m2) on Day 1 of each cycle
VinorelbineDrug
Also called Navelbine
Vinorelbine will be administered intravenously on Day 1 and Day 8 of each 21-day cycle
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Dec 2016 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Metastatic Breast Cancer With BRCA 1 or BRCA 2 Genetic MutationStudies of the same condition, open and under way.
- More trials run by University of WashingtonThe 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
- Expanded access
Sponsor and investigators
- Lead sponsor
- University of Washington
- Sponsor type
- University, hospital or other
- Collaborators
- AbbVie
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02985658
- Sponsor's protocol ID
- 9763
- Other IDs
- RG1716061, NCI-2020-11567
- Status last verified
- Jul 2021
- First submitted
- 5 Dec 2016
- Last updated
- 21 Jul 2021
- Results posted
- No
Publications
Chiarugi A. Poly(ADP-ribose) polymerase: killer or conspirator? The 'suicide hypothesis' revisited. Trends Pharmacol Sci. 2002 Mar;23(3):122-9. doi: 10.1016/S0165-6147(00)01902-7.
PubMed 11879679Virag L, Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev. 2002 Sep;54(3):375-429. doi: 10.1124/pr.54.3.375.
PubMed 12223530Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. J Clin Invest. 2004 Jan;113(2):160-8. doi: 10.1172/JCI20761.
PubMed 14722605Curtin NJ, Wang LZ, Yiakouvaki A, Kyle S, Arris CA, Canan-Koch S, Webber SE, Durkacz BW, Calvert HA, Hostomsky Z, Newell DR. Novel poly(ADP-ribose) polymerase-1 inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. Clin Cancer Res. 2004 Feb 1;10(3):881-9. doi: 10.1158/1078-0432.ccr-1144-3.
PubMed 14871963Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005 Apr 14;434(7035):917-21. doi: 10.1038/nature03445.
PubMed 15829967Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005 Apr 14;434(7035):913-7. doi: 10.1038/nature03443.
PubMed 15829966Wielckens K, Garbrecht M, Kittler M, Hilz H. ADP-ribosylation of nuclear proteins in normal lymphocytes and in low-grade malignant non-Hodgkin lymphoma cells. Eur J Biochem. 1980 Feb;104(1):279-87. doi: 10.1111/j.1432-1033.1980.tb04426.x.
PubMed 6245868Hirai K, Ueda K, Hayaishi O. Aberration of poly(adenosine diphosphate-ribose) metabolism in human colon adenomatous polyps and cancers. Cancer Res. 1983 Jul;43(7):3441-6.
PubMed 6406058
Study at a glance
From the registry record, last updated by the sponsor on 21 Jul 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Expanded Access Protocol With ABT-888 (Veliparib) in Patients With Metastatic BRCA-Mutation Associated or Triple Negative Breast Cancer
- ClinicalTrials.gov ID
- NCT02985658
- Acronym / sponsor ID
- 9763
- Conditions
- Metastatic Breast Cancer With BRCA 1 or BRCA 2 Genetic Mutation, Triple-Negative Breast Cancer
- Study type
- Expanded access
- Recruitment status
- No Longer Available
- Lead sponsor
- University of WashingtonUniversity, hospital or other
- Collaborators
- AbbVie
- First posted
- 7 Dec 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is an expanded access protocol to allow continued maintenance therapy with ABT-888 (veliparib) for three patients with metastatic triple negative breast cancer who are currently receiving the investigational product in association with clinical trial participation. Additionally, the protocol will enroll up to 7 new patients with metastatic BRCA associated or triple negative breast cancer to allow for additional access to veliparib monotherapy, or at the investigator's discretion, veliparib in combination with cisplatin and/or vinorelbine.
Detailed description
ABT-888 (Veliparib) or Poly(ADP-ribose)-polymerase (PARP) is a nuclear enzyme that recognizes deoxyribonucleic acid (DNA) damage and facilitates DNA repair. Inactive PARPs 1 and 2 bind to damaged DNA, which leads to their auto-activation. The resulting activated PARP then poly(ADP-ribosyl)ates many nuclear target proteins, including those that facilitate DNA repair of both single-stranded or double-stranded DNA breaks. Thus, PARP inhibition will result in less efficient DNA repair following a DNA damage insult.
Since cancer cells are genetically unstable, often exhibiting complex karyotypes that include large deletions, insertions, and unbalanced translocations of chromosomal fragment, these cells are more susceptible than normal tissues to cytotoxicity induced by DNA-damaging agents.Of these, deficiencies in mismatch repair and homologous recombination are associated with the largest number of malignancies, including many sporadic TNBCs. These deficiencies render cells more dependent on PARP for DNA repair and, hence, are more prone to cytotoxicity induced by PARP inhibition. In particular, tumor cells with BRCA1 or BRCA2 deficiencies are exquisitely sensitive to PARP inhibition, even in the absence of any other insults. Identification of sporadic TNBC with defects in homologous recombination and mismatch repair independent of germline mutation of BRCA 1 and 2 is an active area of research interest.
PARP-enabled DNA repair may also compensate for the loss of other repair pathways. Higher expression of PARP in cancer cells compared to normal cells has been linked to drug resistance and the overall ability of cancer cells to sustain genotoxic stress.
The combination of platinum based chemotherapy and PARP inhibition may be most effective in TNBC, and particularly in subsets of TNBC. This combination may also be active in tumors with a germline BRCA1-deficiency and/or basal phenotype, since a defect in the DNA double-strand break repair pathway should increase sensitivity to these agents. The addition of a PARP inhibitor to platinum based chemotherapy may induce a "double hit" to tumor cells lacking homologous recombination without causing excess toxicity to normal cells. ABT-888 may be used in combination with the DNA damaging agent, cisplatin, to potentiate its cytotoxic effect and with vinorelbine to enhance tumor response rate. Safety and preliminary efficacy of veliparib in combination with cisplatin and vinorelbine in patients with advanced triple negative and BRCA-associated breast cancer has been reported.
Study design
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Age groups
- Adult, Older adult
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 |
|---|---|---|
| VeliparibAlso: ABT-888Patients will start veliparib at 300 mg po BID days 1 through 21 of the first 21 day cycle, then increase to 400 mg po BID days 1 through 21 of each subsequent cycle, as tolerated by the patient. At the treating investigator's discretion, and with principal investigator approval, veliparib may be used in combination with cisplatin and/or vinorelbine. Veliparib (300mg) will be dosed po BID on Days 1 through 14 of each 21-day cycle. The patient will receive therapy as long as there is therapeutic benefit | Drug | – |
| CisplatinAlso: Platinol-AQ, PlatinolCisplatin will be administered intravenously (75 mg/m2) on Day 1 of each cycle | Drug | – |
| VinorelbineAlso: NavelbineVinorelbine will be administered intravenously on Day 1 and Day 8 of each 21-day cycle | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jul 2021.
- Background: PubMed 11879679Chiarugi A. Poly(ADP-ribose) polymerase: killer or conspirator? The 'suicide hypothesis' revisited. Trends Pharmacol Sci. 2002 Mar;23(3):122-9. doi: 10.1016/S0165-6147(00)01902-7.
- Background: PubMed 12223530Virag L, Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev. 2002 Sep;54(3):375-429. doi: 10.1124/pr.54.3.375.
- Background: PubMed 14722605Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. J Clin Invest. 2004 Jan;113(2):160-8. doi: 10.1172/JCI20761.
- Background: PubMed 14871963Curtin NJ, Wang LZ, Yiakouvaki A, Kyle S, Arris CA, Canan-Koch S, Webber SE, Durkacz BW, Calvert HA, Hostomsky Z, Newell DR. Novel poly(ADP-ribose) polymerase-1 inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. Clin Cancer Res. 2004 Feb 1;10(3):881-9. doi: 10.1158/1078-0432.ccr-1144-3.
- Background: PubMed 15829967Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005 Apr 14;434(7035):917-21. doi: 10.1038/nature03445.
- Background: PubMed 15829966Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005 Apr 14;434(7035):913-7. doi: 10.1038/nature03443.
- Background: PubMed 6245868Wielckens K, Garbrecht M, Kittler M, Hilz H. ADP-ribosylation of nuclear proteins in normal lymphocytes and in low-grade malignant non-Hodgkin lymphoma cells. Eur J Biochem. 1980 Feb;104(1):279-87. doi: 10.1111/j.1432-1033.1980.tb04426.x.
- Background: PubMed 6406058Hirai K, Ueda K, Hayaishi O. Aberration of poly(adenosine diphosphate-ribose) metabolism in human colon adenomatous polyps and cancers. Cancer Res. 1983 Jul;43(7):3441-6.
Related trials for Metastatic Breast Cancer With BRCA 1 or BRCA 2 Genetic Mutation
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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Veliparib, Cisplatin and Vinorelbine in people with Metastatic Breast Cancer With BRCA 1 or BRCA 2 Genetic Mutation and Triple-Negative Breast Cancer, run by University of Washington 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?
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: status not confirmed, as of the sponsor's last update on 21 Jul 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.
Are results available for this study?
Results are not available in the source record.
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.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02985658, which also lists 8 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 21 Jul 2021.