AO-176 in Multiple Solid Tumor Malignancies

Arch Oncology

Status and phase: Completed; Phase 2; Phase 1

Conditions: Solid Tumor

Treatments: Drug: AO-176 + Paclitaxel; Drug: AO-176; Drug: AO-176 + Pembrolizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT03834948

KEYNOTE-C49 (Other Identifier)

AO-176-101

Details and patient eligibility

About

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.

Full 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.

Enrollment: 57 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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57 participants in 6 patient groups

AO-176 Dose Escalation

Experimental group

Description:

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.

Treatment:

Drug: AO-176

AO-176 Dose Expansion

Experimental group

Description:

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.

Treatment:

Drug: AO-176

AO-176 + Paclitaxel Dose Escalation

Experimental group

Description:

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.

Treatment:

Drug: AO-176 + Paclitaxel

AO-176 + Paclitaxel Dose Expansion

Experimental group

Description:

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.

Treatment:

Drug: AO-176 + Paclitaxel

AO-176 + Pembrolizumab Dose Escalation

Experimental group

Description:

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.

Treatment:

Drug: AO-176 + Pembrolizumab

AO-176 + Pembrolizumab Dose Expansion

Experimental group

Description:

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.

Treatment:

Drug: AO-176 + Pembrolizumab