AO-176 in Multiple Solid Tumor Malignancies

Sponsor

Arch Oncology (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03834948

Collaborator

Merck Sharp & Dohme LLC (Industry)

183

Enrollment

Locations

Arms

48.8

Anticipated Duration (Months)

18.3

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

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

Anticipated Enrollment :

183 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.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 :

Feb 4, 2019

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 1, 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

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 Outcome Measures

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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria

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

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

Key Exclusion Criteria:

Previous hypersensitivity reaction to treatment with another monoclonal antibody
Unresolved hypersensitivity to paclitaxel or any of its excipients (Part B only). Patients who have been desensitized may participate.
Part C Only
History of interstitial lung disease or a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
History of immune mediated colitis, hepatitis, endocrinopathies, nephritis or significant immune mediated skin reactions such as toxic epidermal necrolitis or Stevens -Johnson Syndrome
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)
Prior treatment with a checkpoint inhibitor (anti-PD-1, PD-L1, CTLA-4 etc.) within 4 weeks prior to the start of study drug
Prior treatment with a CD47-targeted therapy
Prior organ or stem cell transplant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Southern California	Los Angeles	California	United States	90033
2	University of California San Francisco	San Francisco	California	United States	94143
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215-5450
4	Oklahoma University, Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
5	Oregon Health Science University	Portland	Oregon	United States	97239
6	Sidney Kimmel Cancer Center, Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
7	Tennessee Oncology	Nashville	Tennessee	United States	37203
8	University of Virginia	Charlottesville	Virginia	United States	22908
9	Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
10	Northwest Medical Specialties	Tacoma	Washington	United States	98405