AO-176 in Multiple Solid Tumor Malignancies

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

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.

Study Overview

• Status: Completed
• Conditions: Solid Tumor
• Intervention / Treatment: Drug: AO-176; Drug: AO-176 + Paclitaxel; Drug: AO-176 + Pembrolizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Massachusetts
    • Boston, Massachusetts, United States, 02215-5450
      • Dana-Farber Cancer Institute
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University, Stephenson Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Sidney Kimmel Cancer Center, Thomas Jefferson University
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria

1. 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
2. Measurable disease
3. ECOG status 0-1
4. Resolution of prior-therapy-related adverse effects
5. Minimum of 4 weeks or 5 half-lives since last dose of cancer therapy

Key Exclusion Criteria:

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

3. Part C Only

   1. History of interstitial lung disease or a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
   2. History of immune mediated colitis, hepatitis, endocrinopathies, nephritis or significant immune mediated skin reactions such as toxic epidermal necrolitis or Stevens -Johnson Syndrome
   3. 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)
4. Prior treatment with a checkpoint inhibitor (anti-PD-1, PD-L1, CTLA-4 etc.) within 4 weeks prior to the start of study drug
5. Prior treatment with a CD47-targeted therapy
6. Prior organ or stem cell transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AO-176 Dose Escalation; 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; Humanized monoclonal antibody (mAb) targeting CD47
Experimental: AO-176 Dose Expansion; 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; Humanized monoclonal antibody (mAb) targeting CD47
Experimental: AO-176 + Paclitaxel Dose Escalation; 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; Humanized monoclonal antibody (mAb) targeting CD47 and paclitaxel
Experimental: AO-176 + Paclitaxel Dose Expansion; 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; Humanized monoclonal antibody (mAb) targeting CD47 and paclitaxel
Experimental: AO-176 + Pembrolizumab Dose Escalation; 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; Humanized monoclonal antibody (mAb) targeting CD47 and pembrolizumab
Experimental: AO-176 + Pembrolizumab Dose Expansion; 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; Humanized monoclonal antibody (mAb) targeting CD47 and pembrolizumab

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Arch Oncology
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Benajmin Oshrine, MD, Arch Oncology

Publications and helpful links

General Publications

• Andrejeva G, Capoccia BJ, Hiebsch RR, Donio MJ, Darwech IM, Puro RJ, Pereira DS. Novel SIRPalpha Antibodies That Induce Single-Agent Phagocytosis of Tumor Cells while Preserving T Cells. J Immunol. 2021 Feb 15;206(4):712-721. doi: 10.4049/jimmunol.2001019. Epub 2021 Jan 11.

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2019
• Primary Completion (Actual): November 17, 2022
• Study Completion (Actual): February 15, 2023

Study Registration Dates

• First Submitted: February 4, 2019
• First Submitted That Met QC Criteria: February 6, 2019
• First Posted (Actual): February 8, 2019

Study Record Updates

• Last Update Posted (Actual): August 22, 2023
• Last Update Submitted That Met QC Criteria: August 21, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Immunotherapy; CD47; AO-176
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Paclitaxel; Pembrolizumab
• Other Study ID Numbers: AO-176-101; KEYNOTE-C49 (Other Identifier: Merck Sharp & Dohme Corp.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No