Ignite Creation Date:
2025-12-25 @ 4:58 AM
Ignite Modification Date:
2025-12-26 @ 3:58 AM
Study NCT ID:
NCT01445418
Status:
COMPLETED
Last Update Posted:
2019-10-22
First Post:
2011-09-30
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
AZD2281 Plus Carboplatin to Treat Breast and Ovarian Cancer
Sponsor:
National Cancer Institute (NCI)
Organization:
Study Overview
Official Title:
A Phase I Study With an Expansion Cohort of the PARP Inhibitor AZD2281 (KU-0059436) Combined With Carboplatin in Breast and Ovarian Cancer in BRCA1/2 Mutation Carriers (Familial Breast and Ovarian Cancer) and Sporadic Triple Negative Breast Cancer and Ovarian Cancer
Status:
COMPLETED
Status Verified Date:
2019-10-18
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background:
* Carboplatin is approved by the Food and Drug Administration to treat cancer.
* AZD2281 is an experimental drug in a class of agents called PARP inhibitors. PARP is a protein that is -involved in repairing DNA damage; PARP inhibitors interfere with that process.
Objectives:
* To determine the optimum doses of AZD2281 and carboplatin that can safely be used in patients with breast and ovarian cancer.
* To evaluate the response of the tumor to the drug combination and determine the side effects of the treatment.
Eligibility:
-Patients 18 years of age or older with breast or ovarian cancer who have a family history of cancer or who have a BRCA1 or BRCA2 mutation.
Design:
* In this dose escalation study, the first small group of patients receives the smallest study doses of AZD2281 and carboplatin. Subsequent groups receive incrementally higher doses of first AZD2281 and then carboplatin as long as the preceding group has not experienced unacceptable side effects. When the highest safe dose is determined, additional patients receive that dose.
* Patients receive treatment in 21-day cycles as follows: AZD2281 by mouth twice a day every day; carboplatin thorough a vein on day 8 of each cycle. Treatment may continue until it is no longer beneficial.
* Evaluations during treatment include the following:
* Physical examination 1 week after starting treatment and then every 3 weeks.
* Blood tests weekly for the first 4 weeks of treatment and then every 3 weeks.
* CT scans or other imaging tests such as ultrasound or MRI every 6 weeks to evaluate the tumor.
* Carboplatin is approved by the Food and Drug Administration to treat cancer.
* AZD2281 is an experimental drug in a class of agents called PARP inhibitors. PARP is a protein that is -involved in repairing DNA damage; PARP inhibitors interfere with that process.
Objectives:
* To determine the optimum doses of AZD2281 and carboplatin that can safely be used in patients with breast and ovarian cancer.
* To evaluate the response of the tumor to the drug combination and determine the side effects of the treatment.
Eligibility:
-Patients 18 years of age or older with breast or ovarian cancer who have a family history of cancer or who have a BRCA1 or BRCA2 mutation.
Design:
* In this dose escalation study, the first small group of patients receives the smallest study doses of AZD2281 and carboplatin. Subsequent groups receive incrementally higher doses of first AZD2281 and then carboplatin as long as the preceding group has not experienced unacceptable side effects. When the highest safe dose is determined, additional patients receive that dose.
* Patients receive treatment in 21-day cycles as follows: AZD2281 by mouth twice a day every day; carboplatin thorough a vein on day 8 of each cycle. Treatment may continue until it is no longer beneficial.
* Evaluations during treatment include the following:
* Physical examination 1 week after starting treatment and then every 3 weeks.
* Blood tests weekly for the first 4 weeks of treatment and then every 3 weeks.
* CT scans or other imaging tests such as ultrasound or MRI every 6 weeks to evaluate the tumor.
Detailed Description:
Background:
AZD2281 (KU-0059436) is an oral PARP-1 and PART-2 inhibitor that affects tumor growth by impairing the ability of the cell to repair damaged DNA. Carboplatin causes covalent cross-linking of DNA with stalled replication forks that would usually be repaired through nucleotide excision repair and homologous recombination (HR).
Sporadic breast (triple negative) and ovarian cancers have been shown to exhibit a BRCA1-like phenotype.
BRCA1/2 proteins have a critical function in the homologous DNA repair pathway. BRCA1/2 mutation carriers are at high risk for breast and ovarian cancer, and increased risk of pancreatic cancer and prostate cancer. Mutation carriers have been shown to have increased susceptibility to DNA damaging agents, such as the platinums.
BRCA1/2 deficient cells have been shown to be sensitive to PARP inhibition alone and in combination with DNA damaging agents.
Combining these two agents in a background of impaired HR in BRCA1/2 mutation potitive malignancies may result in synergistic anti-tumor effect.
Objectives:
Determine the safety and toxicity of the combination of AZD2281 and carboplatin in BRCA1/2-associated or familial recurrent breast and ovarian cancer patients (cohort 1, Group A), non-high risk serous ovarian cancer patients (Group B), and non-high risk triple negative breast cancer patients (Group C).
Determine pharmacodynamics, estimates of biochemical changes in the apoptosis and PARP signal transduction pathways in tumor and stromal cells in response to treatment of an expansion cohort (cohort 2) at the MTD in a pilot fashion.
Eligibility:
Adults with breast or ovarian CA that is metastatic or unresectable and for which standard curativetherapies do not exist or are no longer effective.
Documented deleterious BRCA1/2 mutation or a BRCAPRO score of greater than or equal to 30%.
Non-high risk serous ovarian cancer (negative family history, BRCAPRO score of less than or equal to 20% or negative BRCA1/2 mutation test).
Documented ER negative, PR negative, Her2neu negative breast cancer (negative family history and/or BRCAPRO score less than or equal to 10% (or negative BRCA1/2 mutation test).
Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks.
All patients enrolling in cohort 2 must have at least one lesion amenable to biopsy.
ECOG performance status 0-2 and adequate organ and marrow function.
Design:
Patients will receive AZD2281 for days 1-7 of each 21 day cycle to maximize PARP inhibition with carboplatin administration on day 2. Carboplatin will then be administered q3weeks and with continuation AZD2281 BID on days 1-7 of each 21 day cycle.
AZD2281 or carboplatin will be escalated sequentially in Cohort 1 (Groups A, B, and C), and after the maximum tolerated dose is determined, Cohort 2 will be enrolled for assessment of translational endpoints.
Patients will be evaluated for toxicity in clinic every 3 weeks and every other cycle for response using RECIST criteria. The clinic visit will be changed to every 4 weeks when patients continue to stay on the study longer than two years with no or minimal disease. Imaging studies will be obtained every 3 cycles for patients who stay on the study longer than four years. The clinic visit will be changed to every two months (+/- 7 days) and the imaging studies will be obtained every four months (+/- 7 days) for patients who stay on the study longer than five years.
Tumor biopsies and plasma and serum samples will be obtained from patients in Cohort 2 before treatment (biopsy mandatory), prior to treatment on cycle 2, day 1, and at time of disease progression (biopsies optional). Tumor biopsies (optional) will also be taken from "super responders" in Cohort 1 who have had a durable response longer than two years.
A minimum of 84 and a maximum of 101 patients will be needed to achieve the objectives of the trial.
AZD2281 (KU-0059436) is an oral PARP-1 and PART-2 inhibitor that affects tumor growth by impairing the ability of the cell to repair damaged DNA. Carboplatin causes covalent cross-linking of DNA with stalled replication forks that would usually be repaired through nucleotide excision repair and homologous recombination (HR).
Sporadic breast (triple negative) and ovarian cancers have been shown to exhibit a BRCA1-like phenotype.
BRCA1/2 proteins have a critical function in the homologous DNA repair pathway. BRCA1/2 mutation carriers are at high risk for breast and ovarian cancer, and increased risk of pancreatic cancer and prostate cancer. Mutation carriers have been shown to have increased susceptibility to DNA damaging agents, such as the platinums.
BRCA1/2 deficient cells have been shown to be sensitive to PARP inhibition alone and in combination with DNA damaging agents.
Combining these two agents in a background of impaired HR in BRCA1/2 mutation potitive malignancies may result in synergistic anti-tumor effect.
Objectives:
Determine the safety and toxicity of the combination of AZD2281 and carboplatin in BRCA1/2-associated or familial recurrent breast and ovarian cancer patients (cohort 1, Group A), non-high risk serous ovarian cancer patients (Group B), and non-high risk triple negative breast cancer patients (Group C).
Determine pharmacodynamics, estimates of biochemical changes in the apoptosis and PARP signal transduction pathways in tumor and stromal cells in response to treatment of an expansion cohort (cohort 2) at the MTD in a pilot fashion.
Eligibility:
Adults with breast or ovarian CA that is metastatic or unresectable and for which standard curativetherapies do not exist or are no longer effective.
Documented deleterious BRCA1/2 mutation or a BRCAPRO score of greater than or equal to 30%.
Non-high risk serous ovarian cancer (negative family history, BRCAPRO score of less than or equal to 20% or negative BRCA1/2 mutation test).
Documented ER negative, PR negative, Her2neu negative breast cancer (negative family history and/or BRCAPRO score less than or equal to 10% (or negative BRCA1/2 mutation test).
Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks.
All patients enrolling in cohort 2 must have at least one lesion amenable to biopsy.
ECOG performance status 0-2 and adequate organ and marrow function.
Design:
Patients will receive AZD2281 for days 1-7 of each 21 day cycle to maximize PARP inhibition with carboplatin administration on day 2. Carboplatin will then be administered q3weeks and with continuation AZD2281 BID on days 1-7 of each 21 day cycle.
AZD2281 or carboplatin will be escalated sequentially in Cohort 1 (Groups A, B, and C), and after the maximum tolerated dose is determined, Cohort 2 will be enrolled for assessment of translational endpoints.
Patients will be evaluated for toxicity in clinic every 3 weeks and every other cycle for response using RECIST criteria. The clinic visit will be changed to every 4 weeks when patients continue to stay on the study longer than two years with no or minimal disease. Imaging studies will be obtained every 3 cycles for patients who stay on the study longer than four years. The clinic visit will be changed to every two months (+/- 7 days) and the imaging studies will be obtained every four months (+/- 7 days) for patients who stay on the study longer than five years.
Tumor biopsies and plasma and serum samples will be obtained from patients in Cohort 2 before treatment (biopsy mandatory), prior to treatment on cycle 2, day 1, and at time of disease progression (biopsies optional). Tumor biopsies (optional) will also be taken from "super responders" in Cohort 1 who have had a durable response longer than two years.
A minimum of 84 and a maximum of 101 patients will be needed to achieve the objectives of the trial.
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| 08-C-0092 | None | None | View |