AO-176 in Multiple Solid Tumor Malignancies

This is a first-in-human, Phase 1/2 multicenter, open-label, dose escalation and expansion study of AO-176 in patients with solid tumors. Part A of this study will examine escalating repeat doses of AO-176 monotherapy in patients with select advanced solid tumors, including epithelial ovarian carcinoma (EOC), which will include primary peritoneal and fallopian tube carcinoma; squamous cell carcinoma of the head and neck; endometrial carcinoma; castration resistant prostate cancer; non-small cell lung adenocarcinoma; papillary thyroid carcinoma; pleural or peritoneal malignant mesothelioma; and gastroesophageal adenocarcinoma, for which standard therapy proven to provide clinical benefit does not exist or is no longer effective.

Part B and Part C of this study will examine escalating repeat doses of AO-176 in combination with paclitaxel (Part B) or pembrolizumab (Part C) in platinum-resistant EOC, including primary peritoneal and fallopian tube carcinoma; endometrial carcinoma; and gastric adenocarcinoma/gastroesophageal adenocarcinoma.

The monotherapy and combination dose escalation portions of the study utilize a classic 3+3 design, with enrollment of 3 patients per cohort and expansion of the cohort in the event of a dose-limiting toxicity (DLT).

Once the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) has been established in dose escalation, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy of AO-176 as monotherapy, in combination with paclitaxel, and in combination with pembrolizumab.

Key Inclusion Criteria

• Select advanced solid tumor for which standard therapy proven to provide clinical benefit does not exist, or is no longer effective

Part A:

• Epithelial ovarian carcinoma (EOC)
• Endometrial carcinoma
• Castration resistant prostate cancer
• Non-small cell lung adenocarcinoma
• Papillary thyroid carcinoma
• Malignant mesothelioma (pleural or peritoneal)
• Gastroesophageal adenocarcinoma
• Squamous cell carcinoma of the head and neck

Part B and Part C:

• Platinum-resistant EOC (including fallopian tube or primary peritoneal cancer)
• Endometrial carcinoma
• Gastric adenocarcinoma/gastroesophageal adenocarcinoma
• Measurable disease
• ECOG status 0-1
• Resolution of prior-therapy-related adverse effects
• Minimum of 4 weeks or 5 half-lives since last dose of cancer therapy

Key Exclusion Criteria:

• Previous hypersensitivity reaction to treatment with another monoclonal antibody
• Unresolved hypersensitivity to paclitaxel or any of its excipients (Part B only). Patients who have been desensitized may participate.
• Part C Only

• History of interstitial lung disease or a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• History of immune mediated colitis, hepatitis, endocrinopathies, nephritis or significant immune mediated skin reactions such as toxic epidermal necrolitis or Stevens -Johnson Syndrome
• History of any autoimmune disease which required systemic therapy* in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs) including but not limited to: i. Inflammatory bowel disease (including ulcerative colitis and Crohn's Disease) ii. Rheumatoid arthritis iii. Systemic progressive sclerosis (scleroderma) iv. Systemic lupus erythematosus v. Autoimmune vasculitis (e.g. Wegener's granulomatosis) *Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed)
• Prior treatment with a checkpoint inhibitor (anti-PD-1, PD-L1, CTLA-4 etc.) within 4 weeks prior to the start of study drug
• Prior treatment with a CD47-targeted therapy
• Prior organ or stem cell transplant