A Dose Escalation and Confirmation Study of PT-112 in Advanced Solid Tumors in Combination With Avelumab

• Non Small Cell Lung Cancer (NSCLC)
• Urothelial Carcinoma (UC)
• Squamous Cell Carcinoma of the Head and Neck (SCCHN)
• Metastatic Breast Cancer (mBC)
• Castration-resistant Prostate Cancer (CRPC)

• Drug: PT-112
  The MTD and RP2D of PT-112 when used in combination with avelumab will be determined during dose escalation.
• Biological: avelumab
  Avelumab will be administered at a fixed dose of 800 mg.

Key Inclusion Criteria:

1. Histologically or cytologically proven metastatic or locally advanced disease. Specifically:

   • patients with NSCLC, UC, mBC, or SCCHN must have measurable disease by RECIST v1.1 criteria with at least one uni-dimensional measurable lesion;
   • patients with CRPC must meet PCWG3 criteria for disease progression at trial entry
2. Availability of tumor specimens is mandatory for patients in the confirmation phase;

2 ECOG Performance Status (PS) 0-1; 4 Estimated Life Expectancy > 3 months; 5 Adequate bone marrow (BM), renal, hepatic and metabolic function;

Key Exclusion Criteria:

1. Concurrent cancer treatment with cytoreductive therapy, radiotherapy, cytokine therapy, cytotoxic agents, targeted small molecule therapy or any investigational anticancer small molecule drugs within 2 weeks prior to the start of study treatment (except 5 weeks from last dose of nitrosourea compound) OR treatment with monoclonal antibodies within 4 weeks prior to the start of study treatment, with the following exceptions:

   • PD-1 / PD-L1 checkpoint inhibitor therapy is permitted;
   • Palliative bone-directed radiotherapy is permitted unless involving an area of ? 25% of bone marrow reserves and occurring within 5 weeks prior to the start of study treatment;
   • Erythropoietin and darbopoietin-? are permitted;
   • Hormonal therapies acting on the hypothalamic-pituitary-gonadal axis (i.e., LHRH agonist/antagonist) are permitted. No other hormonal therapy is permitted;
2. Known symptomatic central nervous system (CNS) metastases requiring steroids. Patients with previously diagnosed CNS metastases are eligible if they (1) have completed their treatment and have recovered from the acute effects of radiation therapy and/or surgery prior to enrollment, (2) have discontinued corticosteroid treatment for these metastases for at least 14 days, and (3) are neurologically stable;
3. Diagnosis of any other malignancy within 2 years prior to enrollment. However, adequately treated basal cell or squamous cell skin cancer or non-invasive superficial bladder cancer or carcinoma in situ of the bladder, breast or cervix; or prostate cancer of low grade (Gleason ?6) or surveillance without any plans for treatment intervention (e.g., surgery, radiation, or castration) are allowed;
4. Vaccination within 4 weeks of the first dose of study treatment is prohibited except for administration of inactivated vaccines;

5. Current use of immunosuppressive medication at study entry, with the following exceptions:

   • Intranasal, inhaled, or topical steroids or local steroid injections (eg, intra-articular injection) are permitted;
   • Systemic corticosteroids at physiologic doses ?10 mg/day of prednisone or equivalent are permitted;
   • Steroids as premedication for hypersensitivity reactions are permitted;
6. Active or prior autoimmune disease that might deteriorate with receiving an immunostimulatory agent. However, patients with diabetes type 1, vitiligo, psoriasis, or hypo- or hyper-thyroid disease not requiring immunosuppressive treatment are eligible;

7. Acute or chronic infections requiring systemic therapy, including, among others:

   • Active infection requiring systemic therapy;
   • History of testing positive to human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome;
   • Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test is positive);
   • Active tuberculosis (history of exposure or history of positive TB test with presence of clinical symptoms, physical or radiographic finding);
8. Known history of autoimmune colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis;
9. Known intolerance to checkpoint inhibitor therapy, defined by the occurrence of an AE leading to drug discontinuation;
10. Participation in other studies involving investigational drug(s) within 28 days prior to study entry and/or during study participation;

• Pfizer
• EMD Serono