Niraparib and Carboplatin in Treating Patients with Homologous Recombination Deficient Advanced Solid Tumors

Inclusion Criteria

• 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 * 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 ** 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 * 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
• Advanced, solid tumor malignancy that is amenable to biopsy; patient must consent to 4 mandatory biopsies during study * Note: If there are any issues with obtaining the study required pre-treatment biopsy (ie. it is deemed unsafe to obtain the biopsy or it is determined that the initial biopsy sample obtained did not contain tumor tissue), the subject may only be allowed to enroll after receiving permission from the study chair(s); additionally, they will be exempt from being required to obtain additional on study biopsies
• Life expectancy of more than 3 months
• Measurable disease by RECIST v1.1 criteria (tumor >= 1 cm in longest diameter on axial image on computed tomography (CT) or magnetic resonance imaging (MRI) and/or lymph node(s) >= 1.5 cm in short axis on CT or magnetic resonance imaging [MRI]) on baseline imaging
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1
• Patients who have received and failed, or have been intolerant to, standard first line therapies known to confer clinical benefit; patients who refuse standard therapy would also be eligible, as long as their refusal is documented
• Absolute neutrophil count (ANC) >= 1,500/mm^3, at the time of enrollment
• Platelets >= 100,000/mm^3, at the time of enrollment
• Hemoglobin >= 9.0 g/dL, at the time of enrollment
• Patients must be able to meet the criteria without transfusion or receipt of colony stimulating factors within 4 weeks before obtaining sample
• Serum creatinine =< 2.0 mg/dL OR creatinine clearance >= 50 mL/min/1.73 m^2, at the time of enrollment
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x the upper normal limit of institution's normal range, at the time of enrollment; for subjects with liver metastases, AST and ALT =< 5 x the upper normal limit of institution's normal range are acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
• Total bilirubin =< 1.5 x the upper normal limit of institution's normal range, at the time of enrollment; for subjects with liver metastases, total bilirubin > 1.5 - 3.0 x the upper normal limit of institution's normal range are acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
• Prothrombin time (PT) and partial thromboplastin time (PTT) must be =< 2 x the upper limit of the institution's normal range, at the time of enrollment
• International normalized ratio (INR) < 2, at the time of enrollment; subjects on anticoagulation (such as coumadin) will be permitted to enroll as long as the INR is in the acceptable therapeutic range as determined by the investigator
• Patients may have received an unlimited number of prior therapies; prior anti-cancer therapies must be given >= 2 weeks prior to cycle 1, day 1 on trial (and the patient must have recovered from all side effects of prior therapies that are exclusionary)
• Patients must have fully recovered from all effects of surgery; patients must have had at least two weeks after minor surgery and four weeks after major surgery before starting therapy; minor procedures requiring conscious sedation such as endoscopies or mediport placement may only require a 24-hour waiting period, but this must be discussed with an investigator
• Female patient has a negative serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment, or is of non-childbearing potential; non-childbearing potential is defined as follows (by other than medical reasons): * >= 45 years of age and has not had menses for > 1 year * Patients who have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation; documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound; tubal ligation must be confirmed with medical records of the actual procedure; otherwise the patient must be willing to employ methods to avoid pregnancy; abstinence is an acceptable method to avoid pregnancy if this is the established and preferred method for the patient; alternatively, the patient and partner must use 2 adequate barrier methods throughout the study, starting with the screening visit through 180 days after the last dose of study treatment; information must be captured appropriately within the site’s source documents ** Male patients must also agree to use an adequate method to avoid pregnancy, which may include abstinence, if this is the established and preferred method for the patient starting with the first dose of study treatment through 180 days after the last dose of study treatment. ** Additionally, the participants must agree to not breastfeed during the study or for 180 days after the last dose of study treatment
• Patient is capable of swallowing pills whole
• Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures

Exclusion Criteria

• Prior disease progression while receiving platinum chemotherapy; or any platinum chemotherapy within the last 6 months * For all patients (except breast cancer patients) who received platinum-based adjuvant or neo-adjuvant chemotherapy, at least 6 months must have passed between the last dose of platinum-based therapy and the development of metastatic disease * For breast cancer patients, at least 12 months must have passed between the last dose of platinum-based adjuvant or neo-adjuvant therapy and the development of metastatic disease
• Patients must not require “support” to maintain adequate blood counts, as defined by: * Patients must not have received a transfusion (platelets or red blood cells) =< 4 weeks prior to initiating protocol therapy * Patient must not have received colony stimulating factors (eg, granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy * Participant has had any known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment
• Prior PARP inhibitor-based therapy
• Known or suspected central nervous system (CNS) metastases, unless at least one month has passed since last local CNS therapy and there is no evidence for recurrent or progressive CNS disease on follow up imaging; participants may remain on steroids for CNS disease if they are taking a stable dose
• Active severe infection, or known chronic infection with human immunodeficiency virus (HIV) or hepatitis B virus (testing not required prior to enrollment) * Patients with chronic hepatitis C virus may be enrolled if there is no clinical/laboratory evidence of cirrhosis AND the patient’s liver function tests fall within the parameters
• Cardiovascular disease problems including unstable angina, therapy for life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months
• Life-threatening visceral disease or other severe concurrent disease that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Presence of a psychiatric illness or social situation that would limit compliance with study requirements
• Women who are pregnant or breastfeeding
• The subject must not have had diagnosis, detection, or treatment of another type of cancer =< 2 years prior to randomization (except basal or squamous cell carcinoma of the skin that has been definitively treated); questions regarding the inclusion of individual subjects should be directed to the principal investigators, Dr. Isaacs
• Patients with a current diagnosis of prostate cancer will be excluded
• Clinically significant peripheral neuropathy at the time of enrollment (defined in the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v4.0) as grade 2 or greater neurosensory or neuromotor toxicity)
• Patients must not have had investigational therapy administered =< 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study
• Patients must not have had radiotherapy encompassing > 20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to day 1 of protocol therapy
• Patients must not have a known hypersensitivity to the components of niraparib or the excipients
• Patients must not have current evidence of any condition, therapy, or laboratory abnormality (including active or uncontrolled myelosuppression [ie, anemia, leukopenia, neutropenia, thrombocytopenia]) that might confound the results of the study or interfere with the patient's participation for the full duration of the study treatment or that makes it not in the best interest of the patient to participate
• Patients must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection; examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent
• Patient must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)