Clinical trial NCT03834948: AO-176 in Multiple Solid Tumor Malignancies
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Solid Tumor
Keywords: CD47
AO-176
Immunotherapy
Lead sponsor: Arch Oncology
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2019-02-08
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Safety of AO-176 assessed by adverse events and laboratory abnormalities
timeFrame: Up to 12 months
measure: Safety of AO-176 and paclitaxel assessed by adverse events and laboratory abnormalities
timeFrame: Up to 12 months
measure: Safety of AO-176 and pembrolizumab assessed by adverse events and laboratory abnormalities
timeFrame: Up to 12 months
Secondary outcomes:
measure: AO-176 anti-tumor activity assessed by changes in response criteria
timeFrame: Up to 12 months
measure: AO-176 + paclitaxel anti-tumor activity assessed by changes in response criteria
timeFrame: Up to 12 months
measure: AO-176 + pembrolizumab anti-tumor activity assessed by changes in response criteria
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Oklahoma City
country: United States
facility: Oklahoma University, Stephenson Cancer Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health Science University
state: Oregon
city: Philadelphia
country: United States
facility: Sidney Kimmel Cancer Center, Thomas Jefferson University
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
Study officials:
affiliation: Arch Oncology
name: Benajmin Oshrine, MD
role: STUDY_DIRECTOR
References:
citation: 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.