AO-176 in Multiple Solid Tumor Malignancies

Study Overview
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Brief Summary
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This is a first-in-human, Phase 1/2 multi-center, open-label, dose escalation and expansion study of AO-176 which will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and clinical effects of AO-176 in patients with advanced solid tumors.

Detailed Description
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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.

Official Title
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A Phase 1/2 Multicenter, Open-Label, Dose-Escalation and Dose-Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of AO-176

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: AO-176
* Drug: AO-176 + Paclitaxel
* Drug: AO-176 + Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Each dose escalation cohort will initially recruit 3 patients to receive AO-176 or AO-176 + paclitaxel or AO-176 + pembrolizumab in a standard 3+3 design; the cohort will be expanded in the event of a DLT. Once the MTD/RP2D has been established for monotherapy, AO-176 + paclitaxel or AO-176 + pembrolizumab, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AO-176 Dose Escalation<br>Each dose escalation cohort will initially recruit 3 patients to receive AO-176 in a standard 3+3 design; cohorts will be expanded in the event of a DLT. | Drug: AO-176<br>* Humanized monoclonal antibody (mAb) targeting CD47<br>|
| Experimental: AO-176 Dose Expansion<br>Once the MTD/RP2D has been established, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy of AO-176. | Drug: AO-176<br>* Humanized monoclonal antibody (mAb) targeting CD47<br>|
| Experimental: AO-176 + Paclitaxel Dose Escalation<br>Each dose escalation cohort will initially recruit 3 patients to receive AO-176 and paclitaxel in a standard 3+3 design; cohorts will be expanded in the event of a DLT. | Drug: AO-176 + Paclitaxel<br>* Humanized monoclonal antibody (mAb) targeting CD47 and paclitaxel<br>|
| Experimental: AO-176 + Paclitaxel Dose Expansion<br>Once the MTD/RP2D has been established, tumor-speciﬁc dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efﬁcacy of AO-176 + paclitaxel. | Drug: AO-176 + Paclitaxel<br>* Humanized monoclonal antibody (mAb) targeting CD47 and paclitaxel<br>|
| Experimental: AO-176 + Pembrolizumab Dose Escalation<br>Each dose escalation cohort will initially recruit 3 patients to receive AO-176 and pembrolizumab in a standard 3+3 design; cohorts will be expanded in the event of a DLT. | Drug: AO-176 + Pembrolizumab<br>* Humanized monoclonal antibody (mAb) targeting CD47 and pembrolizumab<br>|
| Experimental: AO-176 + Pembrolizumab Dose Expansion<br>Once the MTD/RP2D has been established, tumor-speciﬁc dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efﬁcacy of AO-176 + pembrolizumab. | Drug: AO-176 + Pembrolizumab<br>* Humanized monoclonal antibody (mAb) targeting CD47 and pembrolizumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of AO-176 assessed by adverse events and laboratory abnormalities | Evaluate the safety of AO-176 measured by the number adverse events, serious adverse events and lab abnormalities. | Up to 12 months | 
| Safety of AO-176 and paclitaxel assessed by adverse events and laboratory abnormalities | Evaluate the safety of AO-176 in combination with paclitaxel measured by the number adverse events, serious adverse events and lab abnormalities. | Up to 12 months | 
| Safety of AO-176 and pembrolizumab assessed by adverse events and laboratory abnormalities | Evaluate the safety of AO-176 in combination with pembrolizumab measured by the number adverse events, serious adverse events and lab abnormalities. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AO-176 anti-tumor activity assessed by changes in response criteria | Evaluate objective response rate of AO-176 using RECIST v1.1 and iRECIST. | Up to 12 months | 
| AO-176 + paclitaxel anti-tumor activity assessed by changes in response criteria | Evaluate objective response rate of AO-176 in combination with paclitaxel using RECIST v1.1 and iRECIST. | Up to 12 months | 
| AO-176 + pembrolizumab anti-tumor activity assessed by changes in response criteria | Evaluate objective response rate of AO-176 in combination with pembrolizumab using RECIST v1.1 and iRECIST. | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD47, AO-176, Immunotherapy