OLAParib COmbinations

Inclusion Criteria:

* Histologically documented metastatic cancer (solid tumors, not including hematologic malignancies)
* Patients who have received standard first-line therapy for metastatic cancer (except for the tumors for which no first-line therapy exists) and in whom a trial of targeted therapy is considered the best available treatment option. Eligible patients should not have available therapies that will convey clinical benefit.
* Progressive cancer at the time of study entry
* Measurable disease by RECIST v1.1
* Age ≥ 18 years
* Life expectancy ≥ 16 weeks
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 (APPENDIX A: Performance Status Criteria)
* Able to understand the nature of this trial and provide written informed consent
* Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
* Molecular testing or appropriate IHC results from CLIA-certified laboratories used for patient eligibility should be obtained from the most recent tumor biopsy (baseline tumor biopsies and on-progression tumor biopsies are optional)
* No previous treatment with olaparib or any other drug sharing the same target. Prior treatment with PARP inhibitor monotherapy is allowed in the combination arms.
* Prior radiation therapy is allowed. Patients must not have received radiation therapy within 21 days prior to the initiation of study treatment.
* Other therapies: Prior experimental (non-FDA approved) therapies and immunotherapies are allowed. Patients must not have received these therapies for 21 days or five half-lives of the drug (whichever is less) prior to the initiation of study treatment and must have full recovery from any acute clinically significant effects of these therapies.
* Adequate hematologic function defined as:

  * Absolute neutrophil count (ANC) ≥ 1500/μL
  * White blood cells (WBC) \> 3x109/L
  * Hemoglobin (Hgb) ≥ 10 g/dL (may be achieved with erythropoietin agents; no blood transfusions in the 28 days prior to entry)
  * Platelets ≥ 100,000/μL
  * No features suggestive of MDS/AML on peripheral blood smear
* Adequate renal and liver function defined as:

  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × the upper limit of normal (ULN) (≤ 5 × ULN if considered due to primary or metastatic liver involvement)
  * Total bilirubin ≤ 1.5 ×ULN
  * Alkaline phosphatase ≤ 2× ULN (≤ 5 × ULN if considered due to tumor)
  * Serum creatinine ≤ 1.5 ULN
* At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) or ≥ 10 mm with calipers by clinical exam OR At least one lesion (measurable and/or non-measurable) that can be accurately assessed by CT/MRI/plain x-ray/clinical exam at baseline and follow up visits.
* Women of child-bearing potential must have a negative pregnancy test (urine or serum) within 28 days prior to starting the study drug. Both males and females must agree to adequate birth control if conception is possible during the study and for 6 months after the last dose. Female patients are considered to not be of child-bearing potential if they have a history of tubal ligation or hysterectomy or are post-menopausal with a minimum of 1 year without menses.

Exclusion Criteria:

* Patients with known germline BRCA mutations in breast cancers will be excluded from the study, however testing is not required for inclusion in the study.
* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
* Prior standard of care cancer chemotherapy, immunotherapy, or radiotherapy \<21 days prior to first dose of study agent(s)
* Patients with hematologic malignancies (includes patients with myelodysplastic syndrome/acute myeloid leukemia).
* Patients with primary CNS malignancies
* Patients must not have received allogeneic stem cell transplant
* Concurrent administration of any other anti-cancer therapy

  * Bisphosphonates and Denosumab for bone metastases are allowed if started at least 4 weeks prior to treatment with study agent(s).
  * Octreotide is allowed if dose is stable for \>3 months with no worsening of carcinoid syndrome
  * Hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with castrate-resistant prostate cancer is permitted
* Patients who have not demonstrated stable recover (28 days or greater) from ≤ CTCAE grade 2 non-hematological toxicities related to prior therapy such as peripheral neuropathy or alopecia, or incomplete recovery from previous surgery, unless agreed by the Principal Investigator (PI) and documented are not eligible to participate in this study.
* Active or untreated brain metastases or spinal cord compression

  * A scan to confirm the absence of brain metastases is not required.
  * Patients with treated brain metastases or spinal cord compression are eligible if they have minimal neurologic symptoms and evidence of stable disease (for at least 1 month) or response on follow-up scan. The patient can receive a stable dose of corticosteroids before and during the study if started at least 28 days prior to initiating the study agent(s)..
* History of carcinomatous meningitis
* Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated stage I cancers (cervix, breast, colon, lung, or prostate as examples) or other advanced (\> Stage I)solid tumors curatively treated with no evidence of disease for ≥ 5 years.
* Patient must not have a co-morbid condition(s) that, in the opinion of the investigator, prevent safe treatment.
* Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy (testing is not part of the protocol).

  \- Patients with known (testing is not part of the protocol) active hepatic disease (i.e., Hepatitis B or C) due to risk of drug interactions with anti-viral therapy.
* Any of the following cardiovascular events within 6 months prior to study entry: myocardial infarction, malignant hypertension, severe/unstable angina, symptomatic congestive heart failure, cerebral vascular accident, or transient ischemic attack
* History or presence of clinically significant ventricular or atrial dysrhythmia \> Grade 2 (NCI CTCAE v4.0)

  \- Patients with chronic, rate-controlled atrial arrhythmias who do not have other cardiac abnormalities are eligible.
* Major surgery within 3 weeks prior to first dose of study treatment, and patients must have recovered from the effects of surgery
* Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
* Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) or significant bowel resection that would preclude adequate absorption
* Patients with uncontrolled seizures
* Inadequate bone marrow reserve within past 28 days prior to study treatment as demonstrated by:

  * Absolute neutrophil count (ANC) \< 1500/μl,
  * WBC ≤ 3x109/L
  * Platelet count (PLT) \< 100,000/μl, or
  * Hemoglobin (Hgb) \< 10 g/dL
* Blood (packed red blood cells, platelets) transfusions within 1 month prior to study start
* Whole blood transfusion in the last 120 days prior to entry to the study
* Patients with concomitant use of drugs, herbal supplements and/or ingestion of foods known to strongly modulate CYP3A4 enzyme activity as specified in the drug specific appendix.
* Women who are pregnant or lactating (breastfeeding)
* Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
* Patients with a known hypersensitivity to the combination/comparator agent
* Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results

  \- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, superior vena cava syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent
* Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol