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 hasprogressed after one or more prior lines of anticancer therapy and no other standardof 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 documenteddisease 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 listedbelow:

• Small Cell Lung Cancer (SCLC): Patients with locally recurrent or metastatic SCLCwhose disease has progressed after having received one or more prior lines ofchemotherapy.
• Gastric or gastroesophageal (GEJ) adenocarcinoma: Patients with locally recurrentor metastatic gastric or GEJ adenocarcinoma whose disease has progressed afterhaving 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 moreprior lines of chemotherapy, including those whose disease has progressed afterpostoperative adjuvant chemotherapy or neoadjuvant chemotherapy prior toradiation or surgery.
• Pancreatic adenocarcinoma (PDAC): Patients with locally recurrent or metastaticPDAC whose disease has progressed after having received one or more prior linesof chemotherapy, including those whose disease has progressed within 6 months ofpostoperative adjuvant chemotherapy.
• Endometrial adenocarcinoma (EC): Patients with locally recurrent or metastatic ECwhose disease has progressed after having received one or more prior lines ofchemotherapy, including those whose disease has progressed within 6 months ofpostoperative adjuvant chemotherapy.

10. For Phase 1b patients receiving PEN-866 in combination with fluorouracil and folinicacid only:

• Patients with metastatic PDAC who have progressed after having received one ormore prior lines of chemotherapy, including those whose disease has progressedwithin 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 afterone or more prior lines of anticancer therapy and no other standard of caretherapies 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 wkfor nitrosureas or mitomycin C) before C1D1, and any drug-related toxicities must haverecovered 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, myocardialinfarction within 6 months of screening, NY Heart Association Class III - IV heartfailure, QTc greater than 470 msec, congenital long Qt syndrome, symptomaticorthostatic hypotension within 6 months of screening, uncontrolled hypertension, orclinically important abnormalities in heart rhythm, conduction, morphology of restingECG. -For Phase 1b patients receiving the Niraparib combination only: hypertension asdefined 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 substratesof CYP1A2, P-gP, BCRP, OATP1B1, OATP1B3 or OCT1 transporters
8. Leptomeningeal disease or spinal cord compression unless controlled and asymptomaticwith surgery, radiation, and not requiring steroids within 4 weeks prior to C1D1.
9. Brain metastases unless previously treated and asymptomatic. Stable low dose ofsteroids 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 livertransplant, 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 thepatient'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 thepatient's participation in the study. For Phase 1b patients receiving niraparib combination only, the following additionalexclusion criteria apply:
17. Prior treatment with niraparib.
18. Current active liver or biliary disease (with the exception of Gilbert's syndrome orasymptomatic gallstones, liver metastatses or otherwise stable chronic liver diseaseper investigator assessment).
19. Severe hepatic impairment.
20. Treatment with transfusions and/or erythropoietin for the treatment of anemia within 4weeks prior to C1D1.
21. Any known or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloidleukemia (AML).
22. History of prostate cancer.