• Assess initial safety and determination of recommended Phase 2 dose: Dose limiting toxicity [ Time Frame: Up to study day 21 ]
  Dose limiting toxicity measured by adverse events and serious adverse events will be reviewed by dose level by the Safety Oversight Committee and will result in a recommended Phase 2 dose.
• Efficacy of HPN536 at the recommended Phase 2 dose: overall response rate (ORR) [ Time Frame: 1 year ]
  Evaluate overall response rate (ORR) as assessed by RECIST

• Assess initial safety and determination of recommended Phase 2 dose: Dose limiting toxicity [ Time Frame: 1 year ]
  Dose limiting toxicity measured by adverse events and serious adverse events will be reviewed by dose level by the Safety Oversight Committee and will result in a recommended Phase 2 dose.
• Efficacy of HPN536 at the recommended Phase 2 dose: overall response rate (ORR) [ Time Frame: 2 years ]
  Evaluate overall response rate (ORR) as assessed by Prostate Cancer Working Group 3 (PCWG3) criteria

• Experimental: HPN536-2001 - Part 1 (Dose Escalation)
  Part 1 (Dose Escalation): will include eligible patients with epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, pancreatic adenocarcinoma, or malignant mesothelioma. HPN536 will be administered once weekly via IV infusion with a fix dose. Dose escalation per cohort until an estimated therapeutic dose level has been reached.
  Intervention: Biological: HPN536
• Experimental: HPN536-2001 - Part 2 (Dose Expansion)

  Part 2 (Dose Expansion): will include eligible patients with epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, malignant mesothelioma, pancreatic adenocarcinoma or malignant mesothelioma. HPN536 will be administered once weekly via IV infusion.

  Group 1: Eligible patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

  Group 2: Eligible patients with pancreatic adenocarcinoma.

  Group 3: Eligible patients with mesothelioma.

  Intervention: Biological: HPN536

1. Patients ≥18 years of age

2. One of the following progressive advanced or metastatic cancers:

   1. Epithelial ovarian, fallopian tube, or primary peritoneal cancer (Part 1 and Part 2, Group 1 only) that is platinum refractory or platinum resistant
   2. Pancreatic adenocarcinoma (Part 1 and Part 2, Group 2 only) that is locally advanced, and now with progressive disease on or after front-line treatment
   3. Malignant mesothelioma with epithelioid histology, pleural (Part 1 and Part 2, Group 3 only) or primary peritoneal (Part 1 and Part 2, Group 3 only)
3. For Part 2 only - Measurable disease according to RECIST v1.1 for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, pancreatic adenocarcinoma, and peritoneal mesothelioma, and mRECIST v1.1 for patients with pleural mesothelioma
4. Available archival tissue sample or fresh biopsy tissue sample must be obtained prior to enrollment
5. For patients previously treated with systemic chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent, discontinuation must have occurred ≥2 weeks, or at least 5 half-lives, whichever is longer, prior to start of study drug. The maximum washout period will not exceed 4 weeks
6. ECOG performance status of 0 or 1

7. Adequate bone marrow function, including:

   1. Absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5 x 109/L
   2. Platelets ≥100,000/mm3 or ≥100 x 109/L
   3. Hemoglobin (Hgb) ≥10 g/dL
8. Adequate renal function, including estimated creatinine clearance ≥30 mL/min

9. Adequate liver function, including:

   1. Total serum bilirubin ≤1.5 x upper limit of normal (ULN) unless the patient has documented Gilbert syndrome in which case the maximum total serum bilirubin should be <5 mg/dL
   2. Aspartate and alanine transaminase (AST and ALT) ≤2.5 x ULN or AST/ALT ≤5 x ULN for patients with liver metastases

10. Serum albumin as follows:

    1. ≥30 mg/mL for patients with epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, or mesothelioma
    2. Within normal limits for patients with pancreatic adenocarcinoma
11. Patients with pancreatic adenocarcinoma: C-reactive protein (CRP) within normal limits

Key Exclusion Criteria:

1. Previously treated or current brain metastases. Note: Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry and have no evidence of new or enlarging brain metastases
2. Concurrent treatment with anti- TNFα therapies, systemic corticosteroids, or other immune suppressive drugs within the 2 weeks prior to Screening
3. Patients with pancreatic adenocarcinoma: Any ascites within 1 month prior to screening
4. History of or known or suspected autoimmune disease
5. History of clinically significant cardiovascular disease
6. Pulmonary, hematologic, renal, hepatic, gastrointestinal, neurological or psychiatric disease that would limit compliance with study requirements