AO-176 in Multiple Solid Tumor Malignancies

Conditions

Solid Tumor

Keywords

CD47, AO-176, Immunotherapy

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.

William Casey Wilson, John O. Richards, Gabriela Andrejeva, Benjamin J. Capoccia, Robyn J. Puro et al. (9 authors)

Blood2021-11-052 citations

10.1182/blood-2021-152896

260 CD47 antibody, AO-176 demonstrates potent anti-tumor activity in pre-clinical solid tumor xenografts as a single agent and in combination with multiple classes of therapeutics

Gabriela Andrejeva, Benjamin J. Capoccia, Rachel B. Delston, Michael J. Donio, Ronald R. Hiebsch et al. (9 authors)

Regular and Young Investigator Award Abstracts2021-11-01

10.1136/jitc-2021-sitc2021.260

Abstract 954: AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma

Benjamin J. Capoccia, Michael J. Donio, John O. Richards, Ronald R. Hiebsch, Robyn J. Puro et al. (7 authors)

Cancer Research2021-07-01

10.1158/1538-7445.am2021-954

A first-in-human study of AO-176, a highly differentiated anti-CD47 antibody, in patients with advanced solid tumors.

Howard A. Burris, Alexander I. Spira, Matthew H. Taylor, Oladapo Yeku, Joyce F. Liu et al. (18 authors)

Journal of Clinical Oncology2021-05-2027 citations

10.1200/jco.2021.39.15_suppl.2516

Novel SIRPα Antibodies That Induce Single-Agent Phagocytosis of Tumor Cells while Preserving T Cells

Gabriela Andrejeva, Benjamin J. Capoccia, Ronald R. Hiebsch, Michael J. Donio, Isra Darwech et al. (7 authors)

The Journal of Immunology2021-01-1151 citations

10.4049/jimmunol.2001019

AO-176, a Highly Differentiated Clinical Stage Anti-CD47 Antibody, Exerts Potent Anti-Tumor Activity in Preclinical Models of Multiple Myeloma As a Single Agent and in Combination with Approved Therapeutics

William Casey Wilson, John O. Richards, Robyn J. Puro, Gabriela Andrejeva, Ben Capoccia et al. (10 authors)

Blood2020-11-0425 citations

10.1182/blood-2020-139655

Pre-Clinical Combination of AO-176, a Highly Differentiated Clinical Stage CD47 Antibody, with Either Azacitidine or Venetoclax Significantly Enhances DAMP Induction and Phagocytosis of Acute Myeloid Leukemia

Mike J Donio, Willie Wilson, Isra Darwech, Gabriela Andrejeva, Benjamin J. Capoccia et al. (8 authors)

Blood2020-11-043 citations

10.1182/blood-2020-140528

215 AO-176, a highly differentiated clinical stage anti-CD47 antibody, preferentially binds tumor versus normal cell CD47 when complexed to β1 integrin

Robyn J. Puro, Prabir Chakraborty, John O. Richards, Ronald R. Hiebsch, Michael J. Donio et al. (11 authors)

Regular and Young Investigator Award Abstracts2020-11-01

10.1136/jitc-2020-sitc2020.0215

Abstract B100: AO-176, a highly differentiated humanized anti-CD47 antibody, exhibits single-agent and combination antitumor efficacy with chemotherapy and targeted antibodies

Casey Wilson, Myriam N. Bouchlaka, Robyn J. Puro, Ben Capoccia, Ronald R. Hiebsch et al. (9 authors)

Molecular Cancer Therapeutics2019-12-012 citations

10.1158/1535-7163.targ-19-b100

Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

John O. Richards, Myriam N. Bouchlaka, Robyn J. Puro, Ben Capoccia, Ronald R. Hiebsch et al. (10 authors)

Blood2019-11-135 citations

10.1182/blood-2019-126298

Interventions

DRUGAO-176

Humanized monoclonal antibody (mAb) targeting CD47

DRUGAO-176 + Paclitaxel

Humanized monoclonal antibody (mAb) targeting CD47 and paclitaxel

DRUGAO-176 + Pembrolizumab

Humanized monoclonal antibody (mAb) targeting CD47 and pembrolizumab

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

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.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion 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

Design outcomes

Primary

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

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

Countries

United States

Outcome results

None listed