A Study to Evaluate Immunotherapy Combinations in Participants With Lung Cancer (ARC-4)

A Phase 1/1b Study to Evaluate the Safety and Tolerability of Immunotherapy Combinations in Participants With Lung Cancer

This is a Phase 1/1b, multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and clinical activity of etrumadenant (AB928) in combination with carboplatin and pemetrexed, with or without an anti-PD-1 antibody (pembrolizumab or zimberelimab), in participants with non-squamous Non-Small Cell Lung Cancer (NSCLC).

Study Overview

• Status: Completed
• Conditions: Non Small Cell Lung Cancer; Nonsquamous Nonsmall Cell Neoplasm of Lung; Non Small Cell Lung Cancer Metastatic; Sensitizing EGFR Gene Mutation
• Intervention / Treatment: Drug: Etrumadenant; Drug: Carboplatin; Drug: Pemetrexed; Drug: Pembrolizumab; Drug: Zimberelimab

Detailed Description

In the dose-escalation phase, escalating doses of etrumadenant in combination with carboplatin and pemetrexed at standard doses (Arm A), and etrumadenant in combination with carboplatin, pemetrexed and pembrolizumab (Arm B), may be assessed in participants with advanced NSCLC. Eligible participants will receive oral administration of etrumadenant as well as IV infused carboplatin, pemetrexed, with or without pembrolizumab in this phase. The recommended dose for expansion (RDE) of etrumadenant will be determined upon completion of the dose-escalation phase.

In the dose-expansion phase, zimberelimab in combination with carboplatin and pemetrexed (Arm 1), and etrumadenant at RDE in combination with carboplatin, pemetrexed, and zimberelimab (Arm 2) may be assessed in eligible NSCLC participants who harbor an EGFR mutation and have progressed on EGFR Tyrosine Kinase Inhibitor (TKI) treatment(s).

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.

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Cheongju-si, Korea, Republic of, 28644
    • Chungbuk National University Hospital
  • Seongnam-si, Korea, Republic of, 13496
    • Bundang CHA Medical Center
  • Seoul, Korea, Republic of, 3722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 6591
    • Seoul St. Mary'S Hospital
  • Seoul, Korea, Republic of, 5505
    • Asan Medical Centre
  • Suwon, Korea, Republic of, 3080
    • Seoul National University Hospital
  • Gyeonggi
    • Suwon-si, Gyeonggi, Korea, Republic of, 16247
      • The Catholic University of Korea St. Vincent Hospital
• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Centre Singapore
  • Singapore, Singapore, 119228
    • National University Hospital
• Taiwan
  • Changhua, Taiwan, 500
    • Changhua Christian Hospital
  • New Taipei City, Taiwan, 23561
    • Taipei Medical University - Shuang Ho Hospital
  • Tainan City, Taiwan, 73657
    • Chi Mei Hospital, Liouying
  • Taipei City, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei City, Taiwan, 11490
    • Tri Service General Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85715
      • Arizona Cancer Research Center (ACRC)
  • Florida
    • Fort Myers, Florida, United States, 33901
      • SCRI Florida Cancer Specialists - South
    • Tavares, Florida, United States, 33705
      • SCRI Florida Cancer Specialists - North
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • SCRI Tennessee Oncology - Nashville
  • Texas
    • Dallas, Texas, United States, 75246
      • USO Texas Oncology - Dallas (Baylor Charles A. Sammons Cancer Center)
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • USO Virginia Cancer Specialist
    • Norfolk, Virginia, United States, 23502
      • USO Virginia Oncology Associates
  • Washington
    • Spokane, Washington, United States, 99208
      • Medical Oncology Associates/Summit Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female participants; age ≥ 18 years
• Pathologically confirmed nonsquamous NSCLC that is metastatic, locally advanced, or recurrent with progression

• Arm A participants must fulfill one of the following:

  • Participant has a genetic alteration (mutation or rearrangement) and has received all available targeted therapy. Previous treatment with chemotherapy or PD-1/-L1 therapy is not allowed.
  • Participant has not received any therapy for the disease under study and standard therapy is refused.
  • Participant has progressed on PD-1/-L1 therapy (monotherapy or combination regimen). Previous treatment with chemotherapy is not allowed.
  • Participant has progressed on PD-1/-L1 therapy (monotherapy or combination regimen) and has received less than 4 cycles of carboplatin/pemetrexed and further chemotherapy is appropriate.
  • Participant has received any number of prior treatments and is without alternative or curative therapy.

• Arm B participants must fulfill one of the following:

  • Participant has a genetic alteration (mutation or rearrangement) and has received all available targeted therapy. Previous treatment with chemotherapy or PD-1/-L1 therapy is not allowed.
  • Participant has not received any therapy for the disease under study and standard therapy is refused.
  • Participant has received any number of prior treatments and is without alternative or curative therapy.
• Arm 1 and Arm 2 participants must have a sensitizing epidermal growth factor receptor (EGFR) mutation with disease progression or treatment intolerance after one or more approved TKIs. Previous treatment with chemotherapy or PD-1/L-1 therapy is not allowed.
• No TKI therapy within 5 days of Cycle 1 Day 1
• The last dose of previous investigational therapy is at least 4 weeks or 5 half-lives prior to Cycle 1 Day 1.
• Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Confirm that an archival tissue sample is available and ≤ 24 months old; if not, a new biopsy of a tumor lesion should be obtained at screening
• Adequate organ and marrow function

Exclusion Criteria:

• Use of any live vaccines against infectious diseases within 4 weeks (28 days) of initiation of investigational product
• 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 30 days after the last dose of etrumadenant, 90 days after the last dose of zimberelimab or pembrolizumab, or 6 months after the last dose of pemetrexed, whichever is longer
• Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy
• Prior malignancy active within the previous 2 years 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
• Prior use of an adenosine pathway targeting agent

• Due to potential for drug-drug interactions with etrumadenant, participants must not have had:

  • Treatment with breast cancer resistance protein substrates or P-glycoprotein with a narrow therapeutic window, administered orally within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.
  • Treatment with known strong cytochrome P450 3A4 (CYP3A4) inducers and strong CYP3A4 inhibitors within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation Arm A; Dose escalation is a 3+3 design, including a Dose Limiting Toxicity (DLT) evaluation period. The RDE of etrumadenant will be determined in this part with escalating doses of etrumadenant in combination with standard doses of carboplatin/pemetrexed chemotherapy regimen in participants with Non-Small Cell Lung Cancer.	Drug: Etrumadenant; Etrumadenant is an A2aR and A2bR antagonist; Other Names: AB928; Drug: Carboplatin; Carboplatin administered as part of standard chemotherapy regimen; Drug: Pemetrexed; Pemetrexed administered as part of standard chemotherapy regimen
Experimental: Dose Escalation Arm B; Dose escalation is a 3+3 design, including a Dose Limiting Toxicity (DLT) evaluation period. The RDE of etrumadenant will be determined in this part with escalating doses of etrumadenant in combination with standard doses of carboplatin/pemetrexed chemotherapy regimen and pembrolizumab in participants with Non-Small Cell Lung Cancer.	Drug: Etrumadenant; Etrumadenant is an A2aR and A2bR antagonist; Other Names: AB928; Drug: Carboplatin; Carboplatin administered as part of standard chemotherapy regimen; Drug: Pemetrexed; Pemetrexed administered as part of standard chemotherapy regimen; Drug: Pembrolizumab; Pembrolizumab is a humanized anti-PD-1 monoclonal antibody
Experimental: Dose Expansion Arm 1; Zimberelimab will be administered in combination with standard carboplatin and pemetrexed chemotherapy regimen in participants with Non-Small Cell Lung Cancer harboring a sensitizing EGFR mutation.	Drug: Carboplatin; Carboplatin administered as part of standard chemotherapy regimen; Drug: Pemetrexed; Pemetrexed administered as part of standard chemotherapy regimen; Drug: Zimberelimab; Zimberelimab is a fully human anti-PD-1 monoclonal antibody; Other Names: AB122
Experimental: Dose Expansion Arm 2; The etrumadenant at RDE determined from the dose escalation phase will be administered in combination with standard carboplatin and pemetrexed chemotherapy regimen and zimberelimab in participants with Non-Small Cell Lung Cancer harboring a sensitizing EGFR mutation.	Drug: Etrumadenant; Etrumadenant is an A2aR and A2bR antagonist; Other Names: AB928; Drug: Carboplatin; Carboplatin administered as part of standard chemotherapy regimen; Drug: Pemetrexed; Pemetrexed administered as part of standard chemotherapy regimen; Drug: Zimberelimab; Zimberelimab is a fully human anti-PD-1 monoclonal antibody; Other Names: AB122

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of participants with Adverse Events	From first study treatment administration until up to 90 days after the last dose (Approximately 1 year)
Percentage of participants who experience a Dose Limiting Toxicity	From first study treatment administration through Day 21

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of participants with anti-drug antibodies to zimberelimab	Recorded at baseline (screening), during the first 4 cycles of treatment (4 months) and 30 days post last dose (i.e. in total approximately 5 months).
Plasma concentration of etrumadenant	Recorded at baseline (screening), during the first 4 cycles of treatment (4 months) and 30 days post last dose (i.e. in total approximately 5 months).
Serum concentration of zimberelimab	Recorded at baseline (screening), during the first 4 cycles of treatment (4 months) and 30 days post last dose (i.e. in total approximately 5 months).
Progression Free Survival (PFS)	From start of treatment up to the first occurrence of progressive disease or death from any cause, whichever occurs first (up to approximately 3-5 years)
Duration of Response	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 (up to approximately 3-5 years)
Percentage of Participants with Disease Control (complete response, partial response, or stable disease) for >6 months	From study enrollment until disease progression or loss of clinical benefit (up to approximately 3-5 years)
Percentage of participants with Objective Response	From study enrollment until participant discontinuation, first occurrence of progressive disease, or death from any cause, whichever occurs first (up to approximately 3-5 years)

Collaborators and Investigators

• Sponsor: Arcus Biosciences, Inc.
• Collaborators: Gilead Sciences
• Investigators: Study Director: Medical Director, Arcus Biosciences, Inc.

Publications and helpful links

Helpful Links

• ARC-4 - Public website

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Actual): November 18, 2024
• Study Completion (Actual): November 18, 2024

Study Registration Dates

• First Submitted: February 14, 2019
• First Submitted That Met QC Criteria: February 15, 2019
• First Posted (Actual): February 19, 2019

Study Record Updates

• Last Update Posted (Actual): December 9, 2024
• Last Update Submitted That Met QC Criteria: December 5, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Pemetrexed; Carboplatin; Pembrolizumab
• Other Study ID Numbers: ARC-4 (AB928CSP0004)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Arcus will provide access to individual de-identified participant data and related study documents (e.g., protocol, Statistical Analysis Plan [SAP], Clinical Study Report [CSR]) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions.

For more information, please visit our website.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No