PEN-866 in Patients With Advanced Solid Malignancies

Inclusion Criteria: 1. M/F at least 18 years old 2. Performance status 0 or 1 3. Adequate bone marrow, liver, and kidney function within 28 days prior to first dose 4. Serum potassium, calcium, magnesium, phosphorus within normal limits 5. Adequate birth control 6. Central venous access line is required 7. Patients in Phase 1a must also have confirmed advanced solid malignancy that has progressed after one or more prior lines of anticancer therapy and no other standard of care therapies that are deemed appropriate for treatment of their malignancy 8. Patients in Phase 2a must have measurable disease per RECIST 1.1 and documented disease progression during or after their most recent line of anticancer therapy. 9. Patients in Phase 2a must have disease history specific to their disease as listed below: * Small Cell Lung Cancer (SCLC): Patients with locally recurrent or metastatic SCLC whose disease has progressed after having received one or more prior lines of chemotherapy. * Gastric or gastroesophageal (GEJ) adenocarcinoma: Patients with locally recurrent or metastatic gastric or GEJ adenocarcinoma whose disease has progressed after having received one or more prior lines of chemotherapy. * Squamous cell carcinoma (SCC) of the genitalia (anus, cervix, vulva, or penis): Patients with locally recurrent or metastatic SCC of the genitalia (anus, cervix, vulva, or penis) whose disease has progressed after having received one or more prior lines of chemotherapy, including those whose disease has progressed after postoperative adjuvant chemotherapy or neoadjuvant chemotherapy prior to radiation or surgery. * Pancreatic adenocarcinoma (PDAC): Patients with locally recurrent or metastatic PDAC whose disease has progressed after having received one or more prior lines of chemotherapy, including those whose disease has progressed within 6 months of postoperative adjuvant chemotherapy. * Endometrial adenocarcinoma (EC): Patients with locally recurrent or metastatic EC whose disease has progressed after having received one or more prior lines of chemotherapy, including those whose disease has progressed within 6 months of postoperative adjuvant chemotherapy. 10. For Phase 1b patients receiving PEN-866 in combination with fluorouracil and folinic acid only: * Patients with metastatic PDAC who have progressed after having received one or more prior lines of chemotherapy, including those whose disease has progressed within 6 months of postoperative adjuvant chemotherapy. 11. For Phase 1b patients receiving the Niraparib combination only: * Patients must have confirmed advanced solid malignancy that has progressed after one or more prior lines of anticancer therapy and no other standard of care therapies that are deemed appropriate for treatment of their malignancy Exclusion Criteria: 1. Treatment with anticancer therapy or investigational drug or device within 2 wk (6 wk for nitrosureas or mitomycin C) before C1D1, and any drug-related toxicities must have recovered to grade 1 or less with the exception of alopecia and peripheral neuropathy. 2. Phase 2a only: Prior treatment with topoisomerase I inhibitor(s). 3. Cardiac disease such as unstable angina within 6 months of screening, myocardial infarction within 6 months of screening, NY Heart Association Class III - IV heart failure, QTc greater than 470 msec, congenital long Qt syndrome, symptomatic orthostatic hypotension within 6 months of screening, uncontrolled hypertension, or clinically important abnormalities in heart rhythm, conduction, morphology of resting ECG. -For Phase 1b patients receiving the Niraparib combination only: hypertension as defined as diastolic \> 90 mmHg or systolic \> 140 mmHg 4. Stroke or transient ischemic attack within 6 months of screening 5. Prior history of posterior reversible excephalopathy scyndrome (PRES). 6. Peripheral neuropathy greater than grade 2 7. Patients requiring medications with drugs that are inhibitors of UGT1A1 or substrates of CYP1A2, P-gP, BCRP, OATP1B1, OATP1B3 or OCT1 transporters 8. Leptomeningeal disease or spinal cord compression unless controlled and asymptomatic with surgery, radiation, and not requiring steroids within 4 weeks prior to C1D1. 9. Brain metastases unless previously treated and asymptomatic. Stable low dose of steroids is permitted. 10. Major surgery within 28 days of first drug dose 11. If female, pregnant or breast feeding 12. Evidence of severe uncontrolled systemic disease, bleeding diatheses, renal or liver transplant, active infection with hep B or C or HIV 13. Hypersensitivity or anaphylactic reaction to ganetespib or other HSP90 inhibitors, irinotecan, SN-38 or its derivatives 14. Any medical, psychological, or social condition that would interfere with the patient's participation in the study. 15. Live virus and bacterial vaccines administered within 30 days prior to C1D1. 16. Any medical, psychological, or social condition that would interfere with the patient's participation in the study. For Phase 1b patients receiving niraparib combination only, the following additional exclusion criteria apply: 17. Prior treatment with niraparib. 18. Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastatses or otherwise stable chronic liver disease per investigator assessment). 19. Severe hepatic impairment. 20. Treatment with transfusions and/or erythropoietin for the treatment of anemia within 4 weeks prior to C1D1. 21. Any known or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). 22. History of prostate cancer.