Participant must have a confirmed germline deleterious BRCA mutation; participants with a BRCA1 or BRCA2 classified as “variant, suspected deleterious” by Myriad Genetics are also eligible for the trial; participants with only a BRCA1 or BRCA2 VUS (variant of uncertain significance) are not eligible for this study; if a potential subject is considered high risk for carrying a BRCA1/BRCA2 mutation by National Comprehensive Cancer Network (NCCN) criteria but does not have insurance coverage for testing or if results from available testing options will not be ready in time for enrollment in the study Myriad Genetic Laboratories may cover the cost of the test; genetic testing does not have to be performed by Myriad Genetic Laboratories but a study-specific test request form is available for tests submitted to Myriad; this form may also be used for genetic testing which will be covered by the participant’s insurance and may lead to more expedited testing
Patients must also meet at least one of the following criteria:\r\n* Triple negative: histologically confirmed primary and/or metastatic site that is estrogen receptor (ER)-negative (=< 1%), progesterone receptor (PR)-negative (=< 1%), and HER2–negative\r\n* BRCA mutation: previously confirmed deleterious breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) germline mutation or suspected deleterious BRCA1 or BRCA2 germline mutation if the classification being used is the 5-tier classification; documentation of germline test results are required
Patients must have adequate tissue available and must agree to have specimens submitted for germline BRCA deoxyribonucleic acid (DNA) sequencing and other correlative studies\r\n* NOTE: Blood for BRCA mutation testing is to be collected and submitted after registration but before treatment
Documented germline mutation in BRCA1 or breast cancer 2, early onset (BRCA2) that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function); local germline (g)BRCA testing results, if available, will be used for establishing eligibility; if local gBRCA testing results are not available, central testing will be provided for those patients who otherwise appear to be eligible
Patients who do not have deleterious or suspected deleterious gBRCA1 and/or 2 mutations but only have BRCA1 and/or BRCA2 mutations that are considered to be non-detrimental (e.g., “variants of uncertain clinical significance” or “variant of unknown significance” or “variant, favor polymorphism” or “benign polymorphism” etc.)
BRCA 1/2- associated metastatic breast carcinoma
BRCA 1/2-associated metastatic breast carcinoma: at least one but no more than three prior chemotherapy-containing lines.
Documented germline mutation or somatic mutation (or homozygous deletion) in one of the DNA repair genes listed below that is deleterious or suspected to be deleterious; the mutation must be identified through a Clinical Laboratory Improvement Act (CLIA)-approved next generation sequencing (NGS) panel\r\n* Cohort 1: Germline mutation in one of the DNA repair genes listed below OR\r\n* Cohort 2: Somatic mutation or homozygous deletion in one of the DNA repair genes listed below or a somatic mutation of BRCA1 or BRCA2 (without germline BRCA 1 /2 mutation) \r\n* DNA Repair Gene List: ATM, ATR, BARD1, BRIP1 (FANCJ), CHEK2 , FANCA, FANCC, FANCD2, FANCE, FANCF, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, plus other hormone receptor (HR)-related genes at the discretion of Dr. Tung with the key study collaborators \r\n** All deep (homozygous) deletions, frameshift mutations and truncating mutations in the genes listed above are eligible as well as missense variants in these genes that have previously been reported as pathogenic or likely pathogenic
Germline BRCA1 or BRCA2 mutation
Have biopsiable and evaluable disease. Note: biopsy is optional for patients known to harbor a BRCA1/2 mutation
In Part B, the patients recruited to one of the eight expansion arms must have advanced solid tumors of the following types: Arm 1: Patients with relapsed, platinum-sensitive high grade epithelial, non-mucinous, ovarian cancer, fallopian tube, or primary peritoneal cancer must meet the following criteria: i. Patients must have at least 2 prior platinum-containing treatments in any treatment setting. • Note: patients could have received additional therapy after the last platinum-containing regimen if the other eligibility criteria are met. ii. Patients must have platinum-sensitive recurrent disease and must not have progressed (by RECIST v1.1 criteria) within 6 months of the completion of the last platinum containing regimen. • Note: patients can receive additional non-platinum based chemotherapy for recurrence after the last platinum containing regimen if the criteria for platinum sensitivity are met. iii. Arm 1a: Patients with relapsed, platinum-sensitive high grade epithelial, non-mucinous, ovarian cancer, fallopian tube, or primary peritoneal cancer (EOC) with either known deleterious or suspected deleterious germline or somatic BRCA1/2 mutations or with DNA HRD • If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated, then the patient must undergo tissue screening using the Myriad myChoice® diagnostic test to determine eligibility. iv. Arm 1b: Patients with relapsed, platinum-sensitive high grade epithelial, non-mucinous, ovarian cancer, fallopian tube, or primary peritoneal cancer (EOC) without either known deleterious or suspected deleterious germline or somatic BRCA1/2 mutations or without DNA HRD • If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated, then the patient must undergo tissue screening using the Myriad myChoice® diagnostic test to determine eligibility. Arm 2: Patients with triple negative breast cancer must meet the following criteria: i. Patients with either known deleterious or suspected deleterious germline or somatic BRCA1/2 mutations or with DNA HRD. • If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated, then the patient must undergo tissue screening using the Myriad myChoice® diagnostic test to determine eligibility. ii. Patients with 0-1 prior platinum-containing treatment in any treatment setting. • Note: patients could have received additional therapy after the last platinum-containing regimen if the other eligibility criteria are met. iii. Patients who have received ? 3 prior lines of therapy in the advanced or metastatic setting. Arm 3: Patients with metastatic castration-resistant prostate cancer, including but not limited to mutations in HR pathways and/or defined by HRD algorithms, and must meet the following criteria: i. Patients with either known deleterious or suspected deleterious germline or somatic BRCA1/2 mutations or with DNA HRD. • If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated, then the patient must undergo tissue screening using the Myriad myChoice® diagnostic test to determine eligibility. ii. The patient may be either chemotherapy-naïve, but must have received prior abiraterone acetate and/or enzalutamide treatment, or have previously had no more than two taxane-based chemotherapy regimens including docetaxel and carbazitaxel. If docetaxel is used more than once, this will be considered as one regimen. iii. At least 2 weeks since the completion of prior flutamide, bicalutamide, and nilutimide, or enzalutamide and abiraterone treatment. iv. At least 2 weeks from any radiotherapy, with the exception of a single fraction of radiotherapy for the purposes of palliation (confined to one field). v. Documented prostate cancer progression with one of the following:
Olaparib\r\n* Patients with solid tumors that harbor DNA damage repair gene mutations as exemplified below detected by next-generation sequencing (NGS) or real-time- polymerase chain reaction (RT-PCR) in assays performed at a CLIA-certified laboratory:\r\n** Examples of DNA damage repair deficiency “BRCA-ness” (somatic mutations in tumors), but not limited to, are: breast cancer 1, early onset (BRCA 1), breast cancer 2, early onset (BRCA2)/Fanconi anemia group D1 (FANCD1), partner and localizer of BRCA2 (PALB2 or FANCN), RAD51 recombinase (RAD51), RAD52 homolog, DNA repair protein (RAD52), BRCA1 interacting protein C-terminal helicase 1 gene (FANCJ), Fanconi anemia complementation group D2 (FANCD2), 26S proteasome complex subunit DSS1 (DSS1), MRE11 homolog A, double strand break repair nuclease (MRE11), RAD50 double strand break repair protein (RAD50), nibrin (NBS1), Bloom syndrome RecQ like helicase (BLM), ATM serine/threonine kinase (ATM), ATR serine/threonine kinase (ATR), checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2), Fanconi anemia complementation group (FANC) A,-B,-C, -E, -F, -G,-L, M, D2
Patients with known germline BRCA mutations will be excluded from the study, however testing is not required for inclusion in the study
Patients must have histologically confirmed solid malignancy (excluding lymphoma) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective, and for which: a) there is reasonable expectation of response to the combination of carboplatin/paclitaxel OR b) breast cancer (BRCA) 1/2 germline mutation is present; results from Myriad will be acceptable; if testing for BRCA 1 and 2 germline mutations is done through another organization, a report from a genetics consult with a qualified medical professional confirming that the laboratory results show a recognized germline deleterious BRCA 1 or 2 mutation or rearrangement is required; if the latter cannot be obtained, principal investigator (PI) or study chair review of the lab results and confirmation of BRCA mutation or rearrangement will be required OR c) BRCA 1/2 somatic mutation previously identified using a Clinical Laboratory Improvement Amendments (CLIA) certified assay
Cohorts 1 to 3: Have platinum-resistant disease and have documented test results assessing alterations in the BRCA1 and BRCA2 genes prior to receiving study treatment.
Cohort 3: Are BRCA positive and have previously received a PARP.
Patients with a deleterious or suspected deleterious BRCA1 or BRCA2 mutation (germline or somatic)
Have a deleterious mutation in BRCA1/2 or ATM, or molecular evidence of other homologous recombination deficiency
Patients known to have a BRCA gene mutation; genetic testing is not required
Patients with clear cell or low grade ovarian cancer unless the patient has a known germline or somatic breast cancer (BRCA) mutation or a mutation in another homologous recombination gene
Solid tumors with one or more of the following DNA repair defects:\r\n* BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L (validated from archival tumor tissue or germ line testing from any Clinical Laboratory Improvement Act [CLIA] approved lab); this testing should occur prior to study consent or enrollment
Eligible patients with germline or somatic BRCA mutations must have disease progression after treatment with a PARP inhibitor; patients with unknown BRCA status must undergo testing prior to enrollment; however, non-mutation patients will also be eligible for study
Patients PRE-identified as having either a germline deleterious mutation or tumor expression of a deleterious mutation) as determined by next-generation DNA sequencing only, in at least one gene involved in DNA damage repair through homologous recombination including but not limited to: ARID1A, ATM, ATRX, MRE11A, NBN, PTEN, RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, WRN, CHEK2, CHEK1, BAP1, FAM175A, SLX4, MLL2 or XRCC\r\n* Patients with somatic mutations will be PRE-identified as having a homologous recombination mutation based on next-generation sequencing (NGS) done in a Clinical Laboratory Improvement Act (CLIA) certified, College of American Pathologists (CAP) tested and bioinformatics-validated testing lab PRIOR to enrollment in this current protocol; the testing may have been done at any time prior to enrollment; HOWEVER, if any patient has had NGS testing more than 3 months prior to enrollment, or if there has been intervening therapy, then a repeat NGS test must be done and the deleterious somatic mutation must be re-identified for inclusion\r\n** The determination of a deleterious mutation must be supported in the documentation included in the testing, and should include clinical, or pre-clinical literature to support the finding that a specific mutation results in impaired function of the gene, and thus impaired DNA repair through homologous recombination; variants of unknown significance will not be eligible\r\n* Patients with germline deleterious mutations may have been identified at any time point prior to inclusion in the protocol and do NOT need to have this genetic testing repeated regardless of time frame and intervening therapy
Subjects must not be a known carrier of BRCA1 or BRCA2 gene mutation
For enrichment stage of trial only (if necessary): Confirmation of a suspected/known deleterious mutation in a gene of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or other DNA repair genes) via Clinical Laboratory Improvement Act (CLIA) certified testing
Patients must be germline BRCA 1 or 2 negative; (Note: if BRCA status was previously determined, that result is acceptable but documentation of status must be available; subjects with unknown status will be referred to genetic counselling for BRCA testing as per standard of care) and/or patients with previously identified genetic aberrations that are associated with HRD will be eligible even in the absence of family history [e.g. somatic BRCA mutation, Fanconi Anemia gene, ATM or RAD51 mutations]
Patients must have clear and documented evidence of biallelic inactivation BRCA1, BRCA2 or ATM by sequencing, for example University of Washington (UW)-Oncoplex, SU2C, or Foundation One testing and/or patients with clearly deleterious mutations of other genes involved in homologous DNA repair (e.g., partner and localizer of BRCA2 [PALB2], BRCA1-interacting protein 1 [BRIP1], etc.) by sequencing via UW-Oncoplex, SU2C, or Foundation One testing may be included at the investigator’s discretion
Patients with cytologically or histologically confirmed locally advanced or metastatic pancreas adenocarcinoma with a BRCA1 or 2 or PALB2 mutation confirmed by report from Myriad Genetics (United States of America [USA]); reports from other molecular diagnostic companies can be used to confirm mutations as well; BRCA 1 or 2 or PALB2 mutation can be confirmed locally for all international sites\r\n* For Part I, non-randomized, lead-in portion, patients with a known BRCA 1 or 2 or PALB2 mutation are eligible along with patients who potentially may have a likelihood of having a BRCA mutation (e.g., personal or family history of breast, pancreas, ovary, endometrial, prostate or other likely related malignancy); for Part I, randomized portion, a known BRCA 1 or 2 or PALB2 mutation is required
PHASE II STUDY COHORT 1 OVARIAN CANCER ELIGIBILITY CRITERIA (MEDI+O, MEDI+C AND MEDI+O+C): Documentation of germline breast cancer (BRCA)1 and BRCA2 mutation (gBRCAm) status will be requested; a documented deleterious germline BRCA1 and BRCA1 mutation (gBRCAm) obtained in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory will be requested, but it is not mandated for enrollment; Myriad testing will be accepted; if testing for BRCA is done by other organizations either by multi-gene panels or individual testing, genetic consultation report from a qualified medical professional listing the mutation and confirming that the laboratory results showed a recognized gBRCAm or germline deleterious BRCA rearrangement is required; if the patient refused genetic counseling, it should be documented in the medical records; variants of uncertain significance (VUS) of BRCA1 and BRCA2 are not considered deleterious; patients with VUS or deleterious mutation in other genes without gBRCAm or patients with negative BRCA testing are still eligible
PHASE II STUDY COHORT 5 TRIPLE NEGATIVE BREAST CANCER ELIGIBILITY CRITERIA (MEDI+O ONLY)\r\nDocumentation of germline BRCA1 and BRCA2 mutation (gBRCAm) status will be requested for eligibility; a documented deleterious gBRCAm obtained in a CLIA-certified laboratory, including but not limited to Myriad Genetics, either by multi-gene panels or individual testing, will be required prior to study enrollment; variants of uncertain significance (VUS) of BRCA1 and BRCA2 are not considered deleterious mutation; patients with VUS or deleterious mutation in other genes without gBRCAm or patients with negative BRCA testing are still eligible
Patients must have platinum-sensitive recurrent high-grade serous or high-grade endometrioid ovarian, primary peritoneal, or fallopian tube cancers; patients with other (clear cell, mixed epithelial, undifferentiated carcinoma, or transitional cell carcinoma) high-risk histologies are also eligible, provided that the patient has a known deleterious germline BRCA1 or BRCA2 mutation identified through testing at a clinical laboratory; Note: Due to the long acceptance of germline BRCA testing through Myriad, Myriad testing will be accepted; if testing for germline BRCA is done by other organizations, documentation from a qualified medical professional (e.g., ovarian cancer specialty physician involved in the field, high risk genetics physician, genetics counselor) listing the mutation and confirming that the laboratory results showed a recognized germline deleterious BRCA1 or BRCA2 mutation or BRCA rearrangement is required; please collect a copy of Myriad or other BRCA mutational analysis (positive or VUS or negative) reports\r\n* Platinum-sensitive disease defined as no clinical or radiographic evidence of disease recurrence for > 6 months (or 182 days) after last receipt of platinum-based therapy\r\n* Patients must have had a complete clinical response to their prior line of platinum therapy and cannot have had progression through prior platinum-based therapy
No deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation based on full sequencing and comprehensive rearrangement testing at an external reference laboratory; patients with variants of unknown significance will be eligible
Deleterious or suspected deleterious germline or somatic gene mutation implicated in the HR pathway, excluding BRCA1 or BRCA2, based on multiplex germline gene testing or direct tumor next generation deoxyribonucleic acid (DNA) sequencing; these genes include: PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51, RAD51D, MRE11, ATR, Fanconi anemia complementation group of genes (FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL), plus other HR-related genes at the discretion of the primary investigators
Any patient with a deleterious mutation in BRCA1 or BRCA2
Known BRCA 1 or BRCA 2 mutation.
BRCA1, BRCA2 and/or ATM gene defect.
The presence of homologous recombination deficiency defined by either; A) Inherited pathogenic variant of BRCA2, ATM, BRCA1, PALB2 by a Clinical Laboratory Improvement Act (CLIA) level germline assay or B) have evidence by somatic sequencing using a CLIA level assay of biallelic inactivation of BRCA1, BRCA2, PALB2, FANCA or biallelic inactivation or monoallelic inactivating mutation of ATM.  It is anticipated that the majority of patients will be germline carriers of a pathogenic variant of BRCA1, BRCA2 or ATM.
Germline BRCA 1/2 Mutation Positive
Documented evidence of at least ONE or MORE of the following:\r\n* Biallelic inactivation of genes involved in homologous recombination repair in the tumor\r\n* Biallelic inactivation of other genes involved in homologous DNA recombination repair in the tumor may be included at investigator’s discretion\r\n* Homologous recombination repair deficiency by genomic signature in the tumor\r\n* Clearly pathogenic or likely pathogenic germline mutation in BRCA2, BRCA1 and/or ATM\r\n* (Note: the following are not alone sufficient for eligibility and require additional criteria to be met: germline variant of uncertain significance in BRCA1, BRCA2 and/or ATM; germline mutations in other HR genes)
Patients with HRD identified by one of the following criteria: a) Tested positive for BRCA 1 or 2 germline deleterious mutation, b) Previously identified genetic aberrations that are associated with HRD (e.g., somatic BRCA mutation, PALB2, Fanconi anemia gene or RAD51 mutations), c) Patients with somatic ATM loss as identifiable with immunohistochemistry or with ATM mutation, d) Pancreatic ductal adenocarcinoma (PDAC) patients with family history of 2 or more first-degree relatives with BRCA-associated cancers (stomach, breast, ovary) or 1 or more first-degree relative with PDAC
Phase II only: Patients with metastatic adenocarcinoma of the pancreas with genomic markers (signature) of homologous recombination deficiency (HRD) or BRCA1 or BRCA2 or PALB2 mutation, or HRD (non-BRCA, non-PALB) who have not received any systemic therapy in the metastatic setting\r\n* NOTE: In pancreatic cancer: exposure to irinotecan is only allowed in the neoadjuvant setting and no progressive disease < 3 months from last dose of irinotecan
Breast cancer in BRCA1 or BRCA2 positive ovarian cancer patients.
Documented mutation of tumor protein 53 (TP53), breast cancer (BRCA)1, BRCA2, or other hereditary cancer syndromes
For expansion cohort patients, the profiling must reveal at least one mutation in the following selected DNA repair genes involved in cell cycle arrest signal transduction, BRCA1 pathway, Fanconi’s proteins pathway, and RAD51 pathway: (ATR, ATM, CHEK1, CHEK2, BRCA1, BAP1, BARD1, FANCD2, FANCE, FANCC, RAD50, FANCA, RAD51, BRCA2, PALB2, CDK12 [ENSG00000167258, also known as CRK7, CRKR, CRKRS], POLE, POLD1, BRAC2, PRKDC, ERCC2, POLQ, MRE11A, NBN [MBS1]), or at least one gene amplification in FANCD2, FANCE, FANCC, FANCA, C11orf30 (EMSY)\r\n*NOTE: Tissue or blood cell free DNA are allowed for genomic profiling of tumor; profiling should have been performed at a Clinical Laboratory Improvement Act (CLIA) certified lab =< 1 year prior to registration\r\n* NOTE: Patients in the dose escalation phase are not required to have such mutations; although genomic profiling is not required for dose escalation patients, it is encouraged in these patients prior to or after study registration if feasible
Patients with deleterious BRCA 1/2 mutated ovarian cancer are not eligible
TREATMENT: Patients with metastatic breast cancer and BRCA mutations must have received specific PARP inhibitor therapy; if these patients have other mutations of interest as defined in the protocol, they will be eligible to receive agents based on that mutation
Patients must have histologically or cytologically confirmed ovarian cancer, peritoneal cancer or fallopian tube cancer and must have a histological diagnosis of either serous or endometrioid cancer based on local histopathological findings; both endometrioid and serous histology should be high-grade for eligibility of non-mutation carriers; patients with clear cell, mixed epithelial, undifferentiated carcinoma, or transitional cell carcinoma histologies are also eligible, provided that the patient has a known deleterious germline BRCA1 or BRCA2 mutation identified through testing at a clinical laboratory\r\n* Note: Due to the long acceptance of BRCA testing through Myriad, Myriad testing will be accepted; if testing for BRCA is done by other organizations, documentation from a qualified medical professional (e.g., ovarian cancer specialty physician involved in the field, high risk genetics physician, genetics counselor) listing the mutation and confirming that the laboratory results showed a recognized germ line deleterious BRCA 1 or BRCA 2 mutation or BRCA rearrangement is required; a copy of Myriad or other BRCA mutational analysis (positive or variants of unknown significance [VUS] or negative) reports will be requested but not required for study enrollment
Known BRCA1/2 status is not required for study entry; however patients known to have a germline deleterious BRCA1/2 mutation should be encouraged to consider a preoperative trial specifically designed for BRCA1/2 carriers, if available
If an ovarian cancer patient has a different histology than HGSC, but has a known germline BRCA1 or BRCA2 mutation and meets all other criteria listed, that patient is eligible
TNBC participants with BRCA mutation, unless they've had prior PARP inhibitor
Phase I: Patients must have received at least one prior chemotherapy regimen for metastatic disease; patients with deleterious germ line mutations in breast cancer (BRCA)1 or BRCA2 are not required to have received prior chemotherapy for metastatic disease
Patients must be assigned to S1400G; S1400G biomarker eligibility defined as homologous recombination repair deficiency (HRRD) positive is as follows\r\n* Biomarker-positive group\r\n** HRRD by FMI\r\n*** Homologous recombination repair deficiency by Foundation Medicine Inc., criteria\r\n* Alteration type\r\n** Truncating mutation, frameshift deletions, indels missense and nonsense mutations predicted to have functional consequence in any of the specified genes\r\n* Eligible alteration\r\n** Mutation in any one of the following critical HRR pathway genes: ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCF, FANCM, NBN (NBS1), PALB2, RAD51, RAD51B (RAD51L1), RAD54L, RPA1
Suspected deleterious or deleterious BRCA1 and/or BRCA2 germline mutation.
Documentation of a deleterious, suspected deleterious, or pathogenic germline BRCA1 or BRCA2 mutation from Myriad Genetics or other laboratory approved by the Sponsor
Prior BRCA-associated cancer as long as there is no current evidence of the cancer
Have a known BRCA 1/2 mutation status (for participants who do not have a known BRCA 1/2 status at screening, a blood sample will be collected to determine the status with the results available prior to randomization
Known deleterious germline mutation of BRCA1/2 (Patients in Cohorts A and A1)
Documented germline mutation in Breast Cancer susceptibility genes: BRCA1 and/or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)
BRCA 1 and/or BRCA2 mutations that are considered to be non detrimental
Documented Breast Cancer Gene (BRCA) germline mutation testing.
Identified deleterious mutation in BRCA 1 or 2 genes (this does not include variants of uncertain significance)
Deleterious or pathogenic germline BRCA 1 or BRCA 2 mutation
Germline BRCA1 or BRCA2 mutation; patients with unknown BRCA status who meet NCCN BRCA screening criteria will be screened for BRCA mutation.
Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer, stage I-III at diagnosis (AJCC 6th edition) based on initial evaluation by clinical examination and/or breast imaging. NOTE: Patients with ER+ and/or PR+ may enroll ONLY if they are known carriers of a deleterious mutation in BRCA1 or BRCA2. Patients with HER2+ tumors may not enroll regardless of BRCA status.
Have a deleterious mutation in a BRCA1/2 or ATM gene
No evidence of deleterious or suspected deleterious germline mutation in BRCA1 or BRCA2 genes
BRCA 1/2 mutation; Note: Patients are not required to undergo BRCA1 and BRCA2 or other genetic mutation tests in order to enroll on the study. However, in the event a patient is tested and is found to be a mutation carrier, she would be excluded from the study
Dose expansion cohort only: Histological or cytological confirmation of advanced unresectable solid tumors for which no standard therapy is available in patients with a known BRCA germline mutation or those with metastatic triple negative breast cancer without known BRCA mutation; for the paclitaxel cohorts, any solid tumors with potential benefit from this combination and paclitaxel
Participants must have histologically or cytologically confirmed ovarian cancer, peritoneal cancer or fallopian tube cancer and must have a histological diagnosis of either high grade serous or high grade endometrioid cancer based on local histopathological findings; participants with a deleterious BRCA-mutation on a commercial Clinical Laboratory Improvement Amendments (CLIA) assay with other high-grade histologies are also eligible\r\n* Myriad testing will be accepted as documentation of a deleterious mutation; if testing for BRCA is done by other organizations, documentation from a qualified medical professional (e.g., ovarian cancer specialty physician involved in the field, high risk genetics physician, genetics counselor) listing the mutation and confirming that the laboratory results show a recognized germline deleterious BRCA1 or BRCA2 mutation or BRCA rearrangements is required to document the presence of a deleterious mutation
Patients must have one of the following: somatic mutations or deletions in BRCA1 or BRCA2; genomic alterations in other BRCA pathway genes (subcohorts: a. ATM, b. PALB2, c. other genes, e.g. Fanconi Anemia genes, ARID1A, MER11, RAD50, NBS1, ATR; amplification of EMSY); or germline mutation in BRCA1 or BRCA 2 (not breast or ovarian cancer)
Patients who have endometrial carcinosarcoma; patients with ovarian cancer who have histology other than high-grade serous in the absence of a deleterious BRCA mutation; if the patient has a deleterious BRCA mutation, any histology will be accepted
Subjects must agree to undergo genetic counseling and breast cancer (BRCA) testing; patients in the expansion cohort must have a germline BRCA 1 or 2 mutation
Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious.
Metastatic breast cancer and have formalin-fixed, paraffin–embedded primary tumor available for testing BRCA1 protein expression
Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).
BRCA 1 and/or BRCA2 mutations that are considered to be non detrimental (e.g., \Variants of uncertain clinical significance\ or \Variant of unknown significance\ or \Variant, favor polymorphism\ or \benign polymorphism\ etc.)
Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).
BRCA1 and/or BRCA2 mutations that are considered to be non detrimental (e.g. \Variants of uncertain clinical significance\ or \Variant of unknown significance\ or \Variant, favor polymorphism\ or \benign polymorphism\ etc).
Must have a documented deleterious Breast Cancer Gene BRCA1 or BRCA2 germline mutation.
Have a known deleterious BRCA mutation (gBRCA or sBRCA) (as determined by a local laboratory that has received an international or country-specific, quality standards certification)
Subjects who are BRCA positive.
Advanced breast cancer with positive BRCA1 or BRCA2 status
Recurrent, and/or metastatic germline BRCA 1/2 mutation-associated ovarian cancer, with progression on a PARP inhibitor monotherapy after attaining a response to that PARPi (CR, PR, or stable disease [SD] >= 4 months [mo])
Integral biomarkers: all patients who are eligible for the study due to a history of positive BRCA1/2 mutation must provide documented evidence of their deleterious germline mutation status, obtained in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory, including but not limited to Myriad Genetics prior to study enrollment; variants of uncertain significance (VUS) of BRCA1/2 and BRCA1/2 somatic mutations are not considered deleterious germline BRCA1/2 mutations; due to the long acceptance of BRCA 1 and BRCA 2 mutation testing through Myriad, Myriad results will be acceptable; if testing for BRCA 1 and BRCA 2 mutation is done by other organizations, a genetic consultation report from a qualified medical professional confirming that the laboratory results showed a recognized germ line deleterious BRCA 1 or BRCA 2 mutation or deleterious BRCA 1 rearrangement is required
Cancer in a patient with a known inherited susceptibility mutation in breast cancer (BRCA)1 or BRCA2
Part 1 and 2: Histologically or cytologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures or other therapy that may provide clinical benefit do not exist or are no longer effective. Subjects must also 1) have a documented BRCA1 or BRCA2 mutation that is considered to be deleterious by the investigator, OR 2) have high grade serous ovarian, fallopian tube, or peritoneal cancer. Subjects with molecular features indicative of DNA repair defects (such as mutation in the Fanconi anemia pathway genes or methylation of the BRCA1 promoter) may be considered eligible for following discussion with the medical monitor. Part 3: Histologically or cytologically confirmed breast, ovarian, fallopian tube or primary peritoneal cancer that is metastatic or unresectable and for which standard curative measures or other therapy that may provide clinical benefit do not exist or are no longer effective. Platinum-resistant ovarian cancer is not permitted. Subjects must also 1) have a documented BRCA1 or BRCA2 mutation that is considered to be deleterious by the investigator and 2) have received 3 or fewer regimens of cytotoxic chemotherapy in the metastatic setting and 3) have evaluable disease as defined by RECIST 1.1 or GCIC-CA-125 criteria.
A first-, second-, or third-degree relative (e.g., son, brother, nephew, or cousin) of an individual with a documented BRCA1 or BRCA2 pathogenic variant
Family history suggestive of a hereditary cancer syndrome not attributable to the BRCA1 or BRCA2 mutation in their family, based on pedigree review by the study team
An uncertain risk of carrying the familial BRCA1 or BRCA2 mutation (e.g., because it is not clear on what side of the family the mutation is segregating), based on pedigree review by the study team
Have one or more children who are BRCA1 or BRCA2 positive
Additionally, patients that have a high risk of breast cancer and are pursuing prophylactic mastectomies (for example BRCA mutation carriers) will also be considered
Women who are known to be positive for the breast cancer (BRCA) mutation
Have a known cancer gene mutation (such as breast cancer 1/2, early onset [BRCA 1/2])
Decided to have blood drawn for breast cancer, early onset gene (BRCA) 1/2 syndrome testing
Have one blood relative with a mutation in BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D, BARD1, MSH2, MSH6, MLH1, or PMS2
Have a personal or family history of any hereditary/genetic cancer syndrome such as BRCA1 and BRCA2 polymorphisms, hereditary nonpolyposis colon cancer, or familial adenomatous polyposis
Known to be at high risk for breast cancer due to known or suspected pathologic BRCA mutation (i.e. first-degree relative with known mutation) or prior chest radiation therapy before age 30
BRCA 1 or 2 mutation
Have a known high penetrance mutation associated with hereditary breast or ovarian cancer (including BRCA1, BRCA2, p53, PTRN, ATM, PALB2, mutations associated with the Lynch Syndrome, etc.)
PILOT II: BRCA positive OR Lynch syndrome positive individuals
A known deleterious mutation in BRCA1, BRCA2, PTEN, or TP53. (Note: The participant must be a documented carrier to meet this criterion. If there is a known mutation in a hereditary breast cancer susceptibility gene in a participant's family member, the participant herself must have undergone genetic testing as per National Comprehensive Cancer Network guidelines to be eligible per this criterion.)
Modified Gail/CARE model risk at 5 years ? 1.67%. (Note: Risk models are to be used only if there is no known previous diagnosis of resected ductal carcinoma in situ [DCIS] or LCIS and there is no known deleterious mutation in BRCA1, BRCA2, PTEN, or TP53)
10% or more probability of BRCA mutation by BRCAPRO or similar model
Documented germline pathogenic or likely pathogenic variant in the BRCA1 or BRCA2 genes
Known carrier of a BRCA1 or 2 mutation
Women seeking an RRSO or RRS at MSK, including breast cancer 1 (BRCA 1)/breast cancer 2 (BRCA2) mutation carriers and women with a strong family history of breast and or/ovarian cancer
Subject has BRCA 1 or 2 mutations. Note: Testing will only be required for Subjects presenting with bilateral breast cancer; testing is not required for unilateral cancers
Patients with known breast cancer (BRCA) mutations; patients who are not tested or whose testing result is not returned at the time of registration are not excluded from registering to this study
Patients enrolling in the BRCA-deficient cohorts must have a documented BRCA1 or BRCA2 germline mutation; alternatively, patients with tumors harboring somatic BRCA mutations may also enroll after discussion with the principal investigator
Premenopausal women with a documented BRCA1 or BRCA2 mutation; menopause is defined as >= 12 months of amenorrhea
Women without a documented BRCA mutation
No patients with known deleterious mutations in breast cancer (BRCA) genes
Participants with a known BRCA 1 or 2 mutation
Participants with a known breast cancer (BRCA) 1 or 2 mutation
Negative for BRCA1 and BRCA2 mutations
Patients must not have known deleterious mutations in breast cancer (BRCA) genes
INCLUSION:\n\n        All Patients\n\n          1. Male or female aged ?18 years.\n\n          2. ECOG PS score of 0-1.\n\n          3. Adequate organ function.\n\n          4. Ability to understand and willingness to sign informed consent form prior to\n             initiation of study procedures.\n\n          5. Measurable disease per RECIST, OR for patients with a primary diagnosis of castration\n             resistant prostate cancer, progressive disease (PD) by prostate surface antigen (PSA)\n             or imaging in the setting of medical or surgical castration.\n\n          6. Documented BRCA mutation, with the following exceptions: a) Patient is intended to be\n             enrolled in a Single-patient Cohort; b) Patient has an advanced DNA repair\n             mutation-positive solid tumor and is intended to be enrolled in Expansion Cohort 5.\n\n             Patients in the Dose-escalation Phase:\n\n          7. Locally advanced solid tumor other than a primary central nervous system (CNS) tumor\n             for which the patient has received ?3 prior lines\n\n          8. Confirmed solid tumor in one of the following categories:\n\n               -  BRCA mutation-positive pancreatic cancer for which the patient received up to 1\n                  prior line of cytotoxic chemotherapy in the advanced disease setting.\n\n               -  Advanced BRCA mutation-positive castration-resistant prostate cancer (CRPC) for\n                  which the patient received up to 2 prior lines of cytotoxic chemotherapy in the\n                  advanced disease setting.\n\n               -  Advanced BRCA mutation-positive ovarian cancer for which the patient received up\n                  to 3 prior lines of cytotoxic chemotherapy in the advanced disease setting.\n\n               -  Advanced BRCA mutation-positive triple-negative breast cancer (TNBC) for which\n                  the patient received up to 3 prior lines of cytotoxic chemotherapy in the\n                  advanced disease setting.\n\n               -  Advanced DNA repair mutation-positive solid tumors, including, but not limited to\n                  BRCA and non-BRCA DNA mutations, who have received up to 3 prior lines of\n                  cytotoxic chemotherapy in the advanced disease setting. DNA-repair mutations may\n                  include, but are not limited to ATM, CHEK2, PALB2, and RAD51D. Abnormal\n                  homologous repair deficiency (HRD) tests will also be allowed.\n\n        Note that in both dose escalation and dose expansion portions of the study, prior targeted\n        therapy including prior poly ADP ribose polymerase (PARP) inhibitor therapy, prior\n        immunotherapy, or prior hormonal therapy is permissible. Patients with castration resistant\n        prostate cancer may have received unlimited prior hormonal therapies.\n\n        EXCLUSION:\n\n          1. History of leptomeningeal disease or spinal cord compression.\n\n          2. Underwent major surgery within 4 weeks before first treatment.\n\n          3. Received cancer-directed therapy 14 days (6 weeks for mitomycin C and nitrosoureas)\n             before start of treatment.\n\n          4. Grade 2 or greater peripheral neuropathy at start of treatment.\n\n          5. If female, pregnant or breast-feeding.\n\n          6. Known human immunodeficiency virus (HIV) infection or hepatitis B or C infection\n\n          7. Any primary brain tumor (e.g., astrocytoma, glioblastoma).\n\n          8. Hypersensitivity or history of anaphylactic reaction to any platinum-containing\n             agents.