A Study to Evaluate the Safety and Tolerability of Immunotherapy Combinations in Participants With Advanced Malignancies

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1, open-label, dose-escalation and dose-expansion study to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and clinical activity of etrumadenant (AB928) in combination with zimberelimab (AB122) (an anti-PD-1 antibody) in participants with advanced malignancies.

Detailed Description
-----------------
In the dose-escalation phase, escalating doses of etrumadenant in combination with zimberelimab will be assessed in participants with advanced malignancies. Eligible participants will receive oral administration of etrumadenant as well as IV infusion of zimberelimab. The recommended Phase 2 dose (RP2D) of etrumadenant will be determined upon completion of the dose-escalation phase. In the dose-expansion phase, etrumadenant at RP2D in combination with zimberelimab may be assessed in participants with advanced clear-cell renal cell carcinoma (RCC) or metastatic castrate-resistant adenocarcinoma of the prostate (mCRPC). Overall duration of treatment will depend on how well the treatment is tolerated. Treatment may continue until unacceptable toxicity or progressive disease or other reasons specified in the protocol.

Official Title
-----------------
A Phase 1 Study to Evaluate the Safety and Tolerability of Immunotherapy Combinations in Participants With Advanced Malignancies

Conditions
-----------------
Non-small Cell Lung Cancer, Breast Cancer, Squamous Cell Carcinoma of the Head and Neck, Colorectal Cancer, Melanoma, Bladder Cancer, Ovarian Cancer, Endometrial Cancer, Merkel Cell Carcinoma, GastroEsophageal Cancer, Renal Cell Carcinoma, Castration-resistant Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Etrumadenant
* Drug: Zimberelimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female participants ≥ 18 years Must have at least 1 measurable lesion per RECIST v1.1. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Must have received standard of care, including potentially curative available therapies or interventions. Confirm that an archival tissue sample is available and ≤ 6 months old; if not, a new biopsy of a tumor lesion must be obtained. Biopsy must not put participant at undue risk and the procedure must not be more invasive than a core biopsy. Adequate organ and marrow function Dose escalation only: Pathologically confirmed non-small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, breast cancer, colorectal cancer, melanoma, bladder cancer, ovarian cancer, endometrial cancer, Merkel cell carcinoma, or gastroesophageal cancer that is metastatic, advanced or recurrent with progression for which no alternative or curative therapy exists or standard therapy is not considered appropriate by the participant and treating physician (reason must be documented in medical records). Dose expansion only: Participants with advanced clear-cell RCC or mCRPC.9. Clear-cell RCC participants may have received up to 2 prior lines of therapy, one of which must have included an anti-PD-(L)1 based therapy and must not have progressed within 16 weeks during an anti-PD-(L)1 therapy. mCRPC participants must have progressed during or following treatment with an androgen synthesis inhibitor, and have also had one prior line of a taxane-containing regimen or the physician and participant consider the taxane-containing regimen to be inappropriate. mCRPC participants must be naive to any immunotherapy (including but not limited to anti-PD-(L)1 or anti-CTLA-4 antagonists, sipuleucel-T, etc.). Exclusion Criteria: Use of any live vaccines against infectious diseases (eg, influenza, varicella) within 4 weeks (28 days) of initiation of investigational product. Underlying medical conditions that, in the Investigator's or Sponsor's opinion, will make the administration of investigational product hazardous (eg, interstitial lung disease, active infections requiring antibiotics, recent hospitalization with unresolved symptoms) or obscure the interpretation of toxicity determination or AEs, or concurrent medical condition requiring the use of immunosuppressive medications or immunosuppressive doses of systemic or absorbable topical corticosteroids. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the pre-screening or screening visit through 90 days after the last dose of etrumadenant in combination with zimberelimab. Any active or documented history of autoimmune disease, or history of a syndrome that required systemic steroids or immunosuppressive medications, except for vitiligo or resolved childhood asthma/atopy. Participants with asthma who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study. Prior malignancy active within the previous year except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix, breast, or prostate cancer. Dose escalation: Prior treatment with an anti-PD-L1, anti-PD-1, anti-CTLA-4, or other immune checkpoint inhibitor or agonist as a monotherapy or in combination; Use of other investigational drugs (drugs not marketed for any indication) within 28 days or at least 5 half-lives (whichever is longer) before investigational product administration.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 Dose escalation design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>3+3 design, including a DLT evaluation period. Etrumadenant RP2D will be determined in this part with escalating doses of oral etrumadenant in combination with a fixed dose of IV zimberelimab. | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist.<br>* Other names: AB928;Drug: Zimberelimab<br>* Zimberelimab is a fully human anti-PD-1 monoclonal antibody.<br>* Other names: AB122;|
| Experimental: Dose Expansion-advanced clear-cell RCC<br>Etrumadenant at RP2D + zimberelimab | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist.<br>* Other names: AB928;Drug: Zimberelimab<br>* Zimberelimab is a fully human anti-PD-1 monoclonal antibody.<br>* Other names: AB122;|
| Experimental: Dose Expansion-mCRPC<br>Etrumadenant at RP2D + zimberelimab | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist.<br>* Other names: AB928;Drug: Zimberelimab<br>* Zimberelimab is a fully human anti-PD-1 monoclonal antibody.<br>* Other names: AB122;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with Adverse Events | Safety will be assessed by monitoring adverse events and clinically relevant changes in Eastern Cooperative Oncology Group (ECOG) performance status, 12 lead Electrocardiogram (ECG), vital signs, physical examination and clinical laboratory results. | From first dose date to 90 days after the last dose (approximately 3 years) | 
| Percentage of participants who experience a Dose Limiting Toxicity |  | From first study treatment administration through Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Etrumadenant Peak Serum Concentration: Cmax |  | Recorded at baseline (screening), during the first 4 cycles of treatment (4 months) and 30 and 90 days post last dose (approximately 7 months) | 
| Zimberelimab Peak Serum Concentration: Cmax |  | Recorded at baseline (screening), during the first 4 cycles of treatment (4 months) and 30 and 90 days post last dose (approximately 7 months) | 
| Etrumadenant Time of Peak Concentration: Tmax |  | Recorded at baseline (screening), during the first 4 cycles of treatment (4 months) and 30 and 90 days post last dose (approximately 7 months) | 
| Zimberelimab Time of Peak Concentration: Tmax |  | Recorded at baseline (screening), during the first 4 cycles of treatment (4 months) and 30 and 90 days post last dose (approximately 7 months) | 
| Percentage of participants with anti-drug antibodies to zimberelimab |  | Recorded at baseline (screening), during the first 4 cycles of treatment (4 months), at end of treatment, and 30 and 90 days post last dose (approximately 7 months) | 
| Progression Free Survival (PFS) | PFS as determined by Investigator according to Prostate Cancer Working Group 3 (PCWG3) for prostate adenocarcinoma and per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for all other tumor types | From start of treatment up to the first occurrence of progressive disease or death from any cause (approximately 1-3 years) | 
| Overall Survival (OS) | OS as determined by the Investigator according to PCWG3 for prostate adenocarcinoma and per RECIST v1.1 for all other tumor types | From study start of treatment up to death from any cause (approximately 1-3 years) | 
| Duration of Response (DOR) | DOR as determined by the Investigator according to PCWG3 for prostate adenocarcinoma and per RECIST v1.1 for all other tumor types | From the date of first occurrence of a documented objective response to first documentation of disease progression or death from any cause, whichever occurs first (approximately 1-3 years) | 
| Percentage of Participants with Disease Control | Disease Control (complete response, partial response, or stable disease) for >6 months as determined by the Investigator per PCWG3 for prostate adenocarcinoma and per RECIST v1.1 for all other tumor types | From study enrolment until disease progression or loss of clinical benefit (approximately 1-3 years) | 
| Percentage of participants with Objective Response | Objective Response as determined by Investigator according to PCWG3 for prostate adenocarcinoma and per RECIST v1.1 for all other tumor types | From study enrolment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 1-3 years) |