Olaparib in Combination With Carboplatin for Refractory or Recurrent Women s Cancers
| Status: | Completed |
|---|---|
| Conditions: | Breast Cancer, Ovarian Cancer, Cervical Cancer, Cancer, Cancer, Women's Studies, Endometrial Cancer |
| Therapuetic Areas: | Oncology, Reproductive |
| Healthy: | No |
| Age Range: | 18 - 99 |
| Updated: | 1/12/2019 |
| Start Date: | November 15, 2010 |
| End Date: | February 3, 2017 |
A Pharmacokinetic/Pharmacodynamic Study With a Phase I Run-In With a PARP Inhibitor (Olaparib) in Combination With Carboplatin for Refractory or Recurrent Women's Cancers
Background:
- Olaparib is an experimental anti-cancer drug that is part of a class of drugs called PARP
inhibitors. PARP is a protein that is involved in repairing DNA damage, but it may also
encourage precancerous cells to develop into cancer cells. Olaparib has been given safely in
combination with carboplatin, a drug used to treat breast, ovarian, uterine, and cervical
cancer, but more research is needed to determine whether the drugs are more effective when
given together or which drug should be given first.
Objectives:
- To determine the safety and effectiveness of combined carboplatin and olaparib as a
treatment for gynecologic (female organ) or breast cancer.
Eligibility:
- Women at least 18 years of age who have breast, ovarian, uterine, or cervical cancer
that has not responded to standard treatments.
- Men at least 18 years of age who have metastatic breast cancer and have a BRCA-1/2
mutation.
Design:
- Participants will be screened with a physical examination and medical history, as well
as blood and tumor samples and imaging studies as required by the researchers. Study
participants will then be divided into two groups.
- Group 1: Participants will receive olaparib tablets twice a day for 7 days (14 doses)
and will receive carboplatin by vein on day 1 or 2, for a 21-day treatment cycle. Group
1 study is designed to determine the safety of new tablet formulation of olaparib.
- Group 2: Participants will be divided into two smaller groups, with reversed treatment
schedules. Group 2 study is designed to evaluate which drug should be given first
through endpoint studies in blood samples.
- Group 2A: Participants will receive olaparib tablets twice a day for 7 days (14 doses)
and then carboplatin on day 8 of the first cycle. Cycle 2 will start with carboplatin on
day 1 and olaparib starting on day 2 for 7 days (14 doses).
- Group 2B: Participants will receive carboplatin on the first day of the first cycle, and
then olaparib on day 2, twice a day for 7 days (14 doses) of the first cycle. Cycle 2
will start with 7 days of olaparib (14 doses) and carboplatin will be given on day 8.
- From cycle 3 until completion of therapy, all Group 2 participants will follow the
schedule used for Group 1 (carboplatin on day 1 or 2 of the week of olaparib therapy,
also in 21-day cycles).
- Additional blood and tissue samples and imaging studies will be conducted throughout the
treatment period.
- All participants may receive no more than 8 cycles of olaparib and carboplatin therapy,
but may continue to take olaparib if their cancer responds to the treatment.
- Olaparib is an experimental anti-cancer drug that is part of a class of drugs called PARP
inhibitors. PARP is a protein that is involved in repairing DNA damage, but it may also
encourage precancerous cells to develop into cancer cells. Olaparib has been given safely in
combination with carboplatin, a drug used to treat breast, ovarian, uterine, and cervical
cancer, but more research is needed to determine whether the drugs are more effective when
given together or which drug should be given first.
Objectives:
- To determine the safety and effectiveness of combined carboplatin and olaparib as a
treatment for gynecologic (female organ) or breast cancer.
Eligibility:
- Women at least 18 years of age who have breast, ovarian, uterine, or cervical cancer
that has not responded to standard treatments.
- Men at least 18 years of age who have metastatic breast cancer and have a BRCA-1/2
mutation.
Design:
- Participants will be screened with a physical examination and medical history, as well
as blood and tumor samples and imaging studies as required by the researchers. Study
participants will then be divided into two groups.
- Group 1: Participants will receive olaparib tablets twice a day for 7 days (14 doses)
and will receive carboplatin by vein on day 1 or 2, for a 21-day treatment cycle. Group
1 study is designed to determine the safety of new tablet formulation of olaparib.
- Group 2: Participants will be divided into two smaller groups, with reversed treatment
schedules. Group 2 study is designed to evaluate which drug should be given first
through endpoint studies in blood samples.
- Group 2A: Participants will receive olaparib tablets twice a day for 7 days (14 doses)
and then carboplatin on day 8 of the first cycle. Cycle 2 will start with carboplatin on
day 1 and olaparib starting on day 2 for 7 days (14 doses).
- Group 2B: Participants will receive carboplatin on the first day of the first cycle, and
then olaparib on day 2, twice a day for 7 days (14 doses) of the first cycle. Cycle 2
will start with 7 days of olaparib (14 doses) and carboplatin will be given on day 8.
- From cycle 3 until completion of therapy, all Group 2 participants will follow the
schedule used for Group 1 (carboplatin on day 1 or 2 of the week of olaparib therapy,
also in 21-day cycles).
- Additional blood and tissue samples and imaging studies will be conducted throughout the
treatment period.
- All participants may receive no more than 8 cycles of olaparib and carboplatin therapy,
but may continue to take olaparib if their cancer responds to the treatment.
Background:
- Olaparib (AZD2281) is an oral PARP-1/2 inhibitor (PARPi) that affects tumors by
impairing repair of single stranded DNA and causing double strand breaks. Carboplatin
covalently crosslinks DNA causing stalled replication forks repaired through nucleotide
excision repair and homologous recombination (HR).
- There is no published data on sequence-specificity of PARPi with platinums. Our
preclinical data indicate sequence may be important in growth inhibition and DNA damage
and repair.
- We have demonstrated activity and safety with concomitant administration of olaparib and
carboplatin.
- We hypothesize that elucidation of sequence specificity may improve upon that clinical
benefit by optimizing drug administration and potentially safety.
Objectives:
- To determine safe dose of olaparib tablet with carboplatin.
- To estimate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of two schedules
of olaparib and carboplatin using peripheral blood mononuclear cells (PBMCs).
- To determine the schedule-associated safety of olaparib and carboplatin in women s
cancers.
Eligibility:
- Adult women with recurrent/refractory epithelial ovarian cancer, fallopian, primary
peritoneal, uterine papillary serous cancer, or malignant mixed mullerian tumors, or
recurrent/refractory breast cancer that is metastatic or unresectable and for which
standard therapies do not exist or are no longer effective. BRCA1/2 mutation carriers
will be eligible with any metastatic disease.
- Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or
biological therapy for at least 4 weeks.
- ECOG performance status 0-2 and adequate organ and marrow function.
Design:
- A phase I 3 plus 3 safety run-in will optimize tablet olaparib dose (d1-7) in
combination with carboplatin on day 1. The carboplatin dose through the trial will be
AUC4.
- Subsequent accrual will randomize patients to one of 2 schedules on cycle 1 with the
other schedule on cycle 2. A: olaparib d1-7 > carbo d8; B: carbo d1 > olaparib d2-8.
- Cycle 3-8 will be schedule B. After 8 cycles of carboplatin, olaparib will be
administered alone on a daily basis.
- Research samples will be obtained for PD endpoints prior to and approximately 24 hours
after carboplatin infusion and prior to the 1st and 3rd of olaparib.
- Blood samples for olaparib PK will be obtained in all patients after the first dose of
olaparib in cycles 1 and 2.
- Patients will be evaluated for toxicity in clinic every 3 weeks and every two cycles for
response using RECIST criteria. Imaging studies will be obtained every 3 cycles for
patients who stay on the study longer than four years.
- Olaparib (AZD2281) is an oral PARP-1/2 inhibitor (PARPi) that affects tumors by
impairing repair of single stranded DNA and causing double strand breaks. Carboplatin
covalently crosslinks DNA causing stalled replication forks repaired through nucleotide
excision repair and homologous recombination (HR).
- There is no published data on sequence-specificity of PARPi with platinums. Our
preclinical data indicate sequence may be important in growth inhibition and DNA damage
and repair.
- We have demonstrated activity and safety with concomitant administration of olaparib and
carboplatin.
- We hypothesize that elucidation of sequence specificity may improve upon that clinical
benefit by optimizing drug administration and potentially safety.
Objectives:
- To determine safe dose of olaparib tablet with carboplatin.
- To estimate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of two schedules
of olaparib and carboplatin using peripheral blood mononuclear cells (PBMCs).
- To determine the schedule-associated safety of olaparib and carboplatin in women s
cancers.
Eligibility:
- Adult women with recurrent/refractory epithelial ovarian cancer, fallopian, primary
peritoneal, uterine papillary serous cancer, or malignant mixed mullerian tumors, or
recurrent/refractory breast cancer that is metastatic or unresectable and for which
standard therapies do not exist or are no longer effective. BRCA1/2 mutation carriers
will be eligible with any metastatic disease.
- Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or
biological therapy for at least 4 weeks.
- ECOG performance status 0-2 and adequate organ and marrow function.
Design:
- A phase I 3 plus 3 safety run-in will optimize tablet olaparib dose (d1-7) in
combination with carboplatin on day 1. The carboplatin dose through the trial will be
AUC4.
- Subsequent accrual will randomize patients to one of 2 schedules on cycle 1 with the
other schedule on cycle 2. A: olaparib d1-7 > carbo d8; B: carbo d1 > olaparib d2-8.
- Cycle 3-8 will be schedule B. After 8 cycles of carboplatin, olaparib will be
administered alone on a daily basis.
- Research samples will be obtained for PD endpoints prior to and approximately 24 hours
after carboplatin infusion and prior to the 1st and 3rd of olaparib.
- Blood samples for olaparib PK will be obtained in all patients after the first dose of
olaparib in cycles 1 and 2.
- Patients will be evaluated for toxicity in clinic every 3 weeks and every two cycles for
response using RECIST criteria. Imaging studies will be obtained every 3 cycles for
patients who stay on the study longer than four years.
- INCLUSION CRITERIA:
- Patients must have confirmed at the NCI, histologically or cytologically
recurrent/refractory gynecologic cancers such as but not restricted to epithelial
ovarian, fallopian, primary peritoneal, uterine papillary serous cancer, cervix
cancer, malignant mixed mullerian tumors, or any type of breast cancer that is
metastatic or unresectable and for whom curative therapies do not exist.
- All patients must have measurable and/or evaluable disease; biomarker-only disease is
not considered measurable or evaluable; eligibility of bone only disease is a PI
decision on an individual patient basis.
- Breast cancer patients with locally advanced, unresectable disease must have been
previously treated with standard therapy.
- Breast cancer patients with deleterious mutation in DNA repair enzymes with locally
advanced or metastatic disease do not have to have had prior therapy for their
progressive disease. Men with BRCA1/2 mutation and metastatic breast cancer will be
eligible for study. Ovarian or endometrial cancer patients with deleterious mutation
in DNA repair enzymes may be treated in first recurrence independent of
platinum-sensitivity history.
- There is no limit on number of prior therapies. Patients must be at least 6 months
from their last platinum exposure and platinum-resistant patients may participate.
- Age greater than or equal to 18 years
- ECOG performance status less than or equal to 2
- Patients must have normal organ and marrow function as defined below:
Absolute neutrophil count greater than or equal to 1,500/mm3
Platelets greater than or equal to 100,000/mm3
Serum Creatinine less or than or equal to 1.5 mg/dL or if low, Cr Cl greater than 60 mL/min
Total bilirubin less than or equal to 1.5 times the limit of normal (ULN) in the absence of
Gilbert s syndrome
AST(SGOT0/ALT(SGPT) less than or equal to 3 times the ULN (CTCAE4.0 grade 2)
- Women of child-bearing potential 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 at least three months following the last dose of
experimental therapy.
- Women of childbearing potential must have a negative urine or serum pregnancy test
within 7 days prior to the start of the study.
- Ability to understand and the willingness to sign a written informed consent document
- Inclusion of Women and Minorities: Women and members of all races and ethnic groups
are eligible for this trial.
EXCLUSION CRITERIA:
- Patients who have had treatment for their disease, such as chemotherapy, biological
therapy, radiotherapy, surgery, or complementary and alternative therapy within 4
weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
- Patients who were treated with other PARP inhibitors greater than 28 days prior to
study are eligible.
- Must be at least 2 weeks from the last phase 0 intervention (longer at the discretion
of the PI) and at least 1 day from non-cancer-related complementary and alternative
medicine prior to entering the study.
- Previous treatment with olaparib (AZD2281).
- Invasive cancer, other than co-existent breast/gynecologic cancers, within the past 2
years. Noninvasive nonmelanoma skin cancers are not exclusions.
- Patients with known brain metastases diagnosed within 1 year will be excluded from
this clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events.
- Patients with brain metastases diagnosed greater than 1 year prior to study entry may
be considered if they received sterilizing therapy to the CNS (resection or radiation)
and have been CNS recurrence-free for a full 1-year period
- History of grade 4 allergic reactions to platinums:
Patients with allergic reaction to platinums (up to and including grade 3 without a
reaction protocol, and up to and including grade 2 in the face of aggressive pre-treatment)
may be eligible pending review of experience, and PI approval.
Patients who have not been rechallenged after a severe reaction may be eligible on a
case-by-case basis.
- Clinically significant GI bleeding or hemoptysis within 28 days prior to the start of
the study
- Inability to swallow pills
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection (no antibiotics prior to entering the study within 7 days), symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.
- Pregnant and breast-feeding women: If a woman becomes pregnant or suspects she is
pregnant while participating in this study, she should inform her treating physician
immediately.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with AZD2281. In addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy such as carboplatin. HIV- positive patients who are not on
combination antiretroviral therapy but with CD4 counts >500, eligibility is a PI
decision on an individual patient basis.
- Major surgery within the past 28 days
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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