AO-176 in Multiple Solid Tumor Malignancies

• ClinicalTrials.gov Identifier: NCT03834948
• Recruitment Status: Completed
• First Posted: February 8, 2019
• Last Update Posted: August 22, 2023
• Sponsor: Arch Oncology
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Arch Oncology

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Solid Tumor	Drug: AO-176; Drug: AO-176 + Paclitaxel; Drug: AO-176 + Pembrolizumab	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 57 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

Intervention 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)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: February 4, 2019
• Actual Primary Completion Date: November 17, 2022
• Actual Study Completion Date: February 15, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Safety of AO-176 assessed by adverse events and laboratory abnormalities [ Time Frame: Up to 12 months ]
   Evaluate the safety of AO-176 measured by the number adverse events, serious adverse events and lab abnormalities.
2. Safety of AO-176 and paclitaxel assessed by adverse events and laboratory abnormalities [ Time Frame: Up to 12 months ]
   Evaluate the safety of AO-176 in combination with paclitaxel measured by the number adverse events, serious adverse events and lab abnormalities.
3. Safety of AO-176 and pembrolizumab assessed by adverse events and laboratory abnormalities [ Time Frame: Up to 12 months ]
   Evaluate the safety of AO-176 in combination with pembrolizumab measured by the number adverse events, serious adverse events and lab abnormalities.

Secondary Outcome Measures :

1. AO-176 anti-tumor activity assessed by changes in response criteria [ Time Frame: Up to 12 months ]
   Evaluate objective response rate of AO-176 using RECIST v1.1 and iRECIST.
2. AO-176 + paclitaxel anti-tumor activity assessed by changes in response criteria [ Time Frame: Up to 12 months ]
   Evaluate objective response rate of AO-176 in combination with paclitaxel using RECIST v1.1 and iRECIST.
3. AO-176 + pembrolizumab anti-tumor activity assessed by changes in response criteria [ Time Frame: Up to 12 months ]
   Evaluate objective response rate of AO-176 in combination with pembrolizumab using RECIST v1.1 and iRECIST.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, California

University of Southern California

Los Angeles, California, United States, 90033

University of California San Francisco

San Francisco, California, United States, 94143

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215-5450

United States, Oklahoma

Oklahoma University, Stephenson Cancer Center

Oklahoma City, Oklahoma, United States, 73104

United States, Oregon

Oregon Health Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Sidney Kimmel Cancer Center, Thomas Jefferson University

Philadelphia, Pennsylvania, United States, 19107

United States, Tennessee

Tennessee Oncology

Nashville, Tennessee, United States, 37203

United States, Virginia

University of Virginia

Charlottesville, Virginia, United States, 22908

Virginia Cancer Specialists

Fairfax, Virginia, United States, 22031

United States, Washington

Northwest Medical Specialties

Tacoma, Washington, United States, 98405

Sponsors and Collaborators

Arch Oncology

Merck Sharp & Dohme LLC

Investigators

• Study Director: Benajmin Oshrine, MD; Arch Oncology

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Arch Oncology
• ClinicalTrials.gov Identifier: NCT03834948
• Other Study ID Numbers: AO-176-101; KEYNOTE-C49 ( Other Identifier: Merck Sharp & Dohme Corp. )
• First Posted: February 8, 2019
• Last Update Posted: August 22, 2023
• Last Verified: August 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Arch Oncology:

CD47; AO-176; Immunotherapy

Additional relevant MeSH terms:

Paclitaxel; Pembrolizumab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors