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Submitted by: Mrs. Nina Dalisay Bauzon 2021-02-19 08:08:07 Last Updated by: Principe, Jeverly Ann S 2021-02-22 14:19:12


A Phase 3 Study to Evaluate Zimberelimab (AB122) Monotherapy Compared to Standard Chemotherapy or Zimberelimab Combined with AB154 in Front-Line, PD-L1-Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer

PHRR210222-003371

ARC-10

2021-CT0589

A Phase 3 Study to Evaluate Zimberelimab (AB122) Monotherapy Compared to Standard Chemotherapy or Zimberelimab Combined with AB154 in Front-Line, PD-L1-Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer

This is a Phase 3, multicenter, 3-arm randomized, open-label study in male and female participants at least 18 years of age (or local legal age) with ≥ 1 measurable lesion(s) per RECIST v1.1, a diagnosis of locally advanced or metastatic (Stage IIIB - IV per AJCC version 8) squamous or non-squamous NSCLC, high PD-L1 expression (Tumor Proportion Score [TPS] ≥50%) as determined by 22C3 PharmDx assay, with no EGFR or ALK mutations or other genomic tumor aberrations (eg, ROS proto-oncogene [ROS], v-raf murine sarcoma viral oncogene homolog B [BRAF], neurotrophic tropomyosin-related kinase [NTRK]) for which there is an available and approved therapeutic, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. TPS will be assessed and confirmed by central laboratory at prescreening visit for study eligibility (see Section 8.6.1).

Randomization of a total of approximately 625 eligible participants will be stratified based on: ECOG PS (0 vs 1), sex (male vs female), and geographic region (Asia vs non-Asia). Participants will be prescreened to determine PD-L1 expression. Patients who meet the study eligibility for PD-L1 expression will then complete screening and, if eligible, be randomized in a ratio of 1:2:2 into one of treatment arms A, B or C, respectively:

   • Arm A (Platinum-doublet Chemotherapy): Participants receive carboplatin at a target area under the concentration−time curve of 6 mg.min/mL (AUC 6; maximum dose 900 mg) or 5 mg.min/mL (AUC 5; maximum dose 750 mg) on Day 1 of every 3 week cycle (Q3W) plus either paclitaxel 200 mg/m2 intravenously (IV) Q3W or pemetrexed 500 mg/m2 IV Q3W (non-squamous histology only) (for each 21-day cycle). The platinum-doublet regimen, selected based on Investigator’s choice, will be given for a maximum of 6 cycles. Thereafter participants with non-squamous histologies who previously received carboplatin and pemetrexed, may receive maintenance pemetrexed 500 mg/m2 IV Q3W until disease progression or intolerance. All other patients will be observed until disease progression, at which time they will have the opportunity to crossover to Arm B. Approximately 125 participants may be randomized.

   • Arm B (Zimberelimab Monotherapy): Participants will receive zimberelimab 360 mg by IV infusion Q3W (on Day 1 of each 21-day cycle) until disease progression or intolerance. Approximately 250 participants may be randomized.

   • Arm C (Zimberelimab + Domvanalimab Combination Therapy): Participants will receive zimberelimab 360 mg by IV infusion Q3W plus domvanalimab 15 mg/kg by IV infusion Q3W on Day 1 of each 21-day cycle until disease progression or intolerance. Approximately 250 participants may be randomized.

Except for the platinum chemotherapy agents which may be given for a maximum of 6 cycles, participants may continue to receive their assigned treatment in the absence of toxicity or disease progression.

Participants randomized to Arm A (platinum-doublet chemotherapy) will have the option to cross over to Arm B (zimberelimab monotherapy) at the time of documented PD as determined by the central imaging vendor using RECIST v1.1. Participants who crossover will remain in the study on Arm B regimen and receive zimberelimab monotherapy until further documented PD. No crossover is allowed for participants in Arm B to the Arm C regimen. Follow up for safety and survival will continue until death, withdrawal of consent, or the end of the study, whichever occurs first.

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2021-06-01 72 2027-06-01 0000-00-00

Ongoing

Institution Classification Region LTO #
Arcus Biosciences, Inc. Private Business United States of America NA
Institution Classification Region LTO #
Novotech (Australia) Pty. Ltd. - Philippine Branch Private Business NCR 3000006702080
Institution Region
Arcus Biosciences, Inc. United States of America
Name E-Mail Institution and Institution Address
Jennifer Olive B. Arellano jenny.arellano@novotech-cro.com Novotech (Australia) Pty Ltd. - Philippine Branch 5th Floor, Rockwell Business Tower 1, Rockwell Business Center, Ortigas Avenue, Baranggay Ugong, Pasig Metro Manila 1604 Philippines
Name E-Mail Institution and Institution Address
Dawn Colburn, PharmD, BCOP dcolburn@arcusbio.com Arcus Biosciences, Inc. 3928 Point Eden Way Hayward, CA 94545, USA
Name Expertise Affiliation
Jennifer Sandoval-Tan, MD Medical Oncology Philippine General Hospital
Karen C. Codnita-Tadeo, MD Medical Oncology Baguio General Hospital and Medical Center
Regina Edusma-Dy, MD Medical Oncology Makati Medical Center
Rubi K. Li, MD Medical Oncology St. Luke's Medcal Center Quezon City
Teresa T. Sy Ortin, MD Radiation Oncology University of Santo Tomas Hospital
Project Location Institutional Ethics Review Board
Philippine General Hospital Philippine General Hospital Ethics Review Board
Baguio General Hospital and Medical Center Baguio General Hospital and Medical Center Ethics Review Committee
Makati Medical Center Makati Medical Center Institutional Review Board
St. Luke's Medcal Center Quezon City N/A
University of Santo Tomas Hospital University of Santo Tomas Hospital Institutional Review Board

PD-L1-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Efficacy Objective(s)

• To evaluate the efficacy of zimberelimab monotherapy compared to platinum-doublet chemotherapy (Arm A vs. Arm B)

• To evaluate the efficacy of zimberelimab and domvanalimab combination therapy compared to zimberelimab monotherapy (Arm B vs. Arm C)

• To evaluate the clinical activity of zimberelimab monotherapy in participants who crossed over from platinum-doublet chemotherapy

Quality of Life Objective

• To evaluate the efficacy of zimberelimab monotherapy compared to platinum-doublet chemotherapy, or to zimberelimab and domvanalimab combination therapy on quality of life/health status

Safety Objective(s)

• To assess the safety of zimberelimab monotherapy compared to platinum-doublet chemotherapy, or to zimberelimab and domvanalimab combination therapy

Primary endpoint:

• Overall survival (OS)

Co-primary endpoints:

• PFS according to RECIST v1.1, as assessed by the investigator

• Presence of treatment-emergent adverse events

• Changes in vital signs and clinical laboratory parameters

Secondary endpoints:

• Progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by the investigator

• PFS as assessed by the investigator and OS at milestone timepoints

• Confirmed objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator

Exploratory endpoints:

• PFS and ORR according to RECIST v1.1 as assessed by IRC

• Duration of Response (DoR) for confirmed response per RECIST v1.1

• Time from randomization to the second documented disease progression (PFS2) according to RECIST v1.1 as assessed by investigator or death, whichever occurs first

• Time from crossover to the next documented disease progression according to RECIST v1.1 as assessed by investigator or death, whichever occurs first

• OS determined from the timepoint of crossover

• ORR determined from the timepoint of crossover

• TTD in patient-reported outcomes determined by European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) score

• Score and change in score(s) over time for EORTCQLQ-C30, Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ), and EuroQol standardized measure of health status (EQ5D-5L)

Pending

  • Argentina
  • Austria
  • Bangladesh
  • Belarus
  • Bosnia and Herzegovina
  • Brazil
  • Chile
  • Colombia
  • Cuba
  • Egypt
  • Finland
  • Hong Kong
  • India
  • Jordan
  • Malaysia
  • Mexico
  • Norway
  • Peru
  • Philippines
  • Puerto Rico
  • Russia
  • Serbia
  • Slovakia
  • South Africa
  • South Korea
  • Taiwan
  • Thailand
  • Turkey
  • Ukraine
  • Vietnam

Clinical Trial

ARC-10

20201203115320

2021-02-16

0000-00-00

28

Unspecified

Unspecified

01 Jun 2021

Inclusion Criteria

1. Male or female participants; age ≥ 18 years, or age ≥ regionally approved age of consent for participation in investigational clinical studies, at the time of prescreening.

2. Willing and able to comply with the requirements and restrictions in this protocol.

3. Histologically confirmed, treatment naïve, locally advanced or metastatic (stage IIIB - IV per AJCC version 8), squamous or non-squamous NSCLC with documented high PD-L1 expression (TPS ≥ 50% by PharmDx 22C3 IHC assay).

   a. Patients with locally advanced disease must not be eligible to receive other potentially curative therapies.

   b. Patients must be treatment naïve with respect to locally advanced or metastatic disease. Patients who received prior treatment with curative intent for early stage disease must have completed treatment at least 6 months prior to first dose of IP.

4. In regions where immune checkpoint inhibitors are approved as standard treatment, patients must not have access to and must decline treatment with locally approved immune checkpoint inhibitor.

5. ECOG PS of 0-1 (Appendix 3)

6. At least 1 measurable target lesion per RECIST v1.1 (Appendix 1)

7. Adequate organ and marrow function, as defined below:

   a. Neutrophils ≥ 1500/μL

   b. Platelets ≥ 100 x 103 /μL

   c. Hemoglobin ≥ 9.0 g/dL

   d. Aspartate aminotransferase ≤ 2.5 x upper limit of normal (ULN) without hepatic metastasis and ≤ 5 x ULN with hepatic metastasis

   e. Alanine aminotransferase ≤ 2.5 x ULN without hepatic metastasis and ≤ 5 x ULN with hepatic metastasis

   f. Bilirubin ≤ 2 x ULN (except participants with Gilbert’s syndrome who must have total bilirubin < 3.0 mg/dL)

   g. Creatinine ≤ 2 x ULN or calculated creatinine clearance (CrCl) > 45 mL/min. CrCl can be calculated using the Cockroft-Gault method

8. If a participant has brain or meningeal metastases, the participant must meet the following criteria:

   a. Have no evidence of progression by neurologic symptoms or sign for at least 4 weeks prior to the first dose.

   b. Metastatic brain lesions do not require immediate intervention.

   c. Carcinomatous meningitis is excluded regardless of clinical stability.

9. Women of childbearing potential (WOCBP), defined as not surgically sterilized and between menarche and 1-year post menopause, must have a negative serum pregnancy test.

10. WOCBP and male participants with WOCBP sexual partners must agree to use highly effective methods of contraception, according to Section 6.5.2, and to refrain from donating sperm from the time of consent through either 90 days after the last dose of zimberelimab or domvanalimab, and/or 6 months after the last dose of carboplatin, paclitaxel, or pemetrexed, whichever is later. Contraceptive requirements may be extended depending on local regulatory requirements.

11. Female participants must not be breast feeding.

Exclusion Criteria

1. Presence of ALK fusion oncogene or EGFR mutation. Patients with unknown ALK or EGFR status and non-squamous histology must be tested at prescreening. Note: EGFR and ALK mutational testing is not required for patients with squamous histology.

2. Presence of any other tumor genomic aberration or driver mutation (eg, ROS, BRAF, NTRK) for which a targeted therapy is approved by local health authority and available.

3. Use of any live vaccines against infectious diseases within 28 days of first dose of IP(s).

4. History of trauma or major surgery within 28 days prior to the first dose of IP. (Note that placement of central venous access catheter (eg, port or similar) is not considered a major surgical procedure).

5. Underlying medical conditions that, in the Investigator’s or Sponsor’s opinion, will make the administration of IP(s) hazardous, including but not limited to

   a. Interstitial lung disease, including history of interstitial lung disease or non-infectious pneumonitis (lymphangitic spread of NSCLC is not disqualifying),

   b. Active viral, bacterial, or fungal infections requiring parenteral treatment within 14 days of the initiation of the IP,

   c. Clinically significant cardiovascular disease,

   d. A condition that may obscure the interpretation of toxicity determination or AEs,

   e. History of prior solid-organ transplantation.

6. Concurrent medical condition requiring the use of supra-physiologic doses of corticosteroids (> 10 mg/day of oral prednisone or equivalent) or immunosuppressive medications (absorbable topical corticosteroids are not excluded).

7. Positive test results for hepatitis B surface antigen, hepatitis C virus antibody with presence of hepatitis C qualitative RNA or human immunodeficiency virus antibody (HIV-1 and/or HIV-2) at screening.

8. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

9. Has significant dementia or other mental condition that precludes the participant’s ability to consent to the study.

10. 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.

   a. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

   b. Participants with asthma who require intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections will not be excluded from this study. Participants on chronic systemic corticosteroids will be excluded from the study.

11. 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.

12. Prior treatment with any anti-PD-1, anti-PD-L1 or any other antibody targeting an immune checkpoint.

13. Use of other investigational drugs (drugs not marketed for any indication) within 28 days or 5 half-lives (whichever is longer) of first dose of IP.

14. Known hypersensitivity to recombinant proteins, or any excipient contained in the IP formulations.

Interventional

Carboplatin, Paclitaxel, Pemetrexed, Zimberelimab (AB122), Domvanalimab (AB154)

Carboplatin

Carboplatin is a derivative of cisplatin, in which chloride leaving groups have been replaced by a bidentate dicarboxylate (Dasari, 2014). This change alters the pharmacokinetics (PK), distribution and safety profile of carboplatin, relative to cisplatin, but does not change the anti-tumor mechanism of action: heavy metal intercalation into DNA, resulting in DNA damage and cell death (Dasari, 2014). The change in distribution results in the need for higher dosage of carboplatin, but reduced nephrotoxicity. Instead, carboplatin is associated with myelosuppression that is a minor component of the cisplatin toxicity profile (Dasari, 2014). Carboplatin has been used against NSCLC as monotherapy, with results reported in the 1980s (eg, Kreisman, 1987), and subsequently has been incorporated in to standard combination therapy (National Comprehensive Cancer Network, 2020).

Paclitaxel

Paclitaxel (Taxol) is an antimicrotubule agent with activity in a variety of tumors. Phase 1 studies of paclitaxel in solid tumors were first reported in the 1980s and showed some activity against NSCLC as a single agent (Donehower, 1987). Combination therapy with platinum agents followed, especially in ovarian cancer and NSCLC, where both classes of agents demonstrated some single agent activity (Langer, 1995). Paclitaxel in combination with carboplatin is a standard chemotherapy regimen (National Comprehensive Cancer Network, 2020), having demonstrated a response rate of >20% and median survival of approximately 10 months (Johnson, 1996).

Pemetrexed

Pemetrexed (Alimta™, Eli Lilly) is an antifolate antimetabolite small molecule and functions as an inhibitor of thymidylate synthesis (Shultz, 1999). Pemetrexed was initially approved as maintenance for the treatment of malignant pleural mesothelioma in 2004 (Vogelzang, 2003). Approval for the treatment of NSCLC was granted on the basis of a phase 3 study in combination with cisplatin. In this study, treatment with the combination of cisplatin and pemetrexed in chemotherapy-naïve patients with stage 3B or 4 NSCLC resulted in an OS of 10.3 months, progression free survival of 4.8 months and an objective response rate of 30.6% (Scagliotti, 2008). As an antifolate drug, patients treated with pemetrexed must also be co-administered vitamin B12 supplementation. A 1 mg dose of vitamin B12 is given intramuscularly 1 week prior to the first dose of pemetrexed and then every three cycles while on treatment (Alimta, USPI, 2019).

Zimberelimab (AB122)

Zimberelimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody targeting human PD-1. Zimberelimab was generated by WuXi Biologics using the genetically engineered OmniRat platform, which was developed by Open Monoclonal Technology Company. Zimberelimab comprises 2 heavy chains of the IgG4 subclass and 2 light chains of the lambda subclass. The 4 chains are stabilized by multiple disulfide bonds, with a single glycosylation site (Asn300) located on the heavy chain. The molecular weight of zimberelimab is 144 kDa (deglycosylated mass), and its isoelectric point is 7.0.

Domvanalimab (AB154)

Domvanalimab (AB154) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets TIGIT, which functions as an immune checkpoint. Domvanalimab comprises 2 heavy chains of the IgG1 isotype and 2 light chains of the kappa subclass. The 4 chains are stabilized by multiple disulfide bonds, with a single glycosylation site (Asn299) located on the heavy chain. The fragment crystallizable (Fc) domain sequence of the heavy chain contains 2 amino acid mutations to silence effector function. The molecular weight of domvanalimab is 144.7 kDa (deglycosylated mass), and its isoelectric point is 9.1.

 

None

Randomized

Double Blind

This is a Phase 3, multicenter, randomized, open-label study. Male and female participants at least 18 years of age or local legal age with ≥ 1 measurable lesion per RECIST v1.1, a diagnosis of locally advanced or metastatic (Stage IIIB ─ IV per American Joint Committee on Cancer [AJCC] version 8) squamous or non-squamous non-small cell lung cancer (NSCLC), high programmed death ligand 1 (PD-L1) expression (Tumor Proportion Score [TPS] ≥50%) as determined by 22C3 PharmDx assay, no genomic tumor aberrations (eg, epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], ROS proto-oncogene [ROS], v-raf murine sarcoma viral oncogene homolog B [BRAF], neurotrophic tropomyosin-related kinase [NTRK]) for which there is a locally available and approved therapeutic, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, will be randomized in a 1:2:2 ratio to one of the following Arms A, B or C, respectively:        • Arm A (Platinum-doublet Chemotherapy): Participants receive carboplatin at a target area under the concentration−time curve of 6 mg.min/mL (AUC 6; maximum dose 900 mg) or 5 mg.min/mL (AUC 5; maximum dose 750 mg) on Day 1 of every 3 week cycle (Q3W) plus either paclitaxel 200 mg/m2 intravenously (IV) Q3W or pemetrexed 500 mg/m2 IV Q3W (non-squamous histology only) (for each 21-day cycle). The platinum-doublet regimen, selected based on Investigator’s choice, will be given for a maximum of 6 cycles. Thereafter participants with non-squamous histologies who previously received carboplatin and pemetrexed, may receive maintenance pemetrexed 500 mg/m2 IV Q3W until disease progression or intolerance. All other patients will be observed until disease progression, at which time they will have the opportunity to crossover to Arm B. Approximately 125 participants may be randomized.        • Arm B (Zimberelimab Monotherapy): Participants will receive zimberelimab 360 mg by IV infusion Q3W (on Day 1 of each 21-day cycle) until disease progression or intolerance. Approximately 250 participants may be randomized.        • Arm C (Zimberelimab + Domvanalimab Combination Therapy): Participants will receive zimberelimab 360 mg by IV infusion Q3W plus domvanalimab 15 mg/kg by IV infusion Q3W on Day 1 of each 21-day cycle until disease progression or intolerance Approximately 250 participants may be randomized. A total of approximately 625 eligible participants will be stratified based on: Eastern Cooperative Oncology Group performance status (ECOG PS; 0 or 1), sex (male vs female), and geographic region (Asia vs non-Asia). TPS will be assessed and confirmed by a central laboratory, using the 22C3 PharmDx assay, for study eligibility. Participants randomized to Arm A (platinum-doublet chemotherapy) will have the option to cross over to Arm B (zimberelimab monotherapy) at the time of documented progressive disease (PD) upon confirmation by the central imaging vendor using RECIST v1.1. Participants who crossover may remain on study on the Arm B regimen until their next documented disease progression. No crossover is allowed for participants in Arm B to the Arm C regimen. Follow-up for safety and survival will continue until death, withdrawal of consent, or the end of the study, whichever occurs first.

Not Applicable

Immunotherapy based on the PD-1/PD-L1 axis has demonstrated activity against NSCLC. In many countries globally, platinum-doublet chemotherapy remains the standard treatment for patients with NSCLC. This study is designed to explore whether anti-PD-1 monotherapy (zimberelimab) is superior to standard platinum-doublet chemotherapy as front-line treatment in patients with NSCLC that is strongly positive for PD-L1. This study will further evaluate the efficacy of anti-PD-1 monotherapy compared to standard chemotherapy by allowing patients in the standard chemotherapy arm whose disease progresses to crossover to the zimberelimab arm.

As mentioned above, participants in the study will be required to have high tumor PD-L1 expression. Results of the KEYNOTE-001 study suggested a correlation between high tumor PD-L1 expression and antitumor activity of pembrolizumab in patients with metastatic NSCLC, and PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab (Garon, 2015). Indeed, the 61 patients in the efficacy population of KEYNOTE-001, which led to the first US FDA approval of pembrolizumab in NSCLC, had tumor samples that tested strongly positive for PD-L1 (Sul, 2016). In the KEYNOTE-024 study, which compared pembrolizumab and platinum-based chemotherapy in patients with advanced NSCLC and PD-L1 expression in at least 50% of tumor cells, the ORR for the pembrolizumab group was 44.8% versus 27.8% in the chemotherapy group, and PFS was 10.3 months versus 6.0 months, respectively (Reck, 2016).

Additionally, current data suggests that the TIGIT checkpoint pathway may be involved in immunosuppression and tumor evasion of immune response. Previously published data has shown limited monotherapy activity in advanced solid tumors with anti-TIGIT blockade alone (Golan, 2018; Bendell, 2020). However, emerging data with the combination of anti-PD-L1 and anti-TIGIT blockade in NSCLC has demonstrated improved ORR and progression-free survival compared to monotherapy anti-PD-L1, particularly in patients with high tumor PD-L1 expression (Rodriguez-Abreu, 2020). This study will also explore whether blockade of the TIGIT checkpoint pathway (with domvanalimab) combined with PD-1 inhibition (with zimberelimab) results in improved PFS and OS compared to PD-1 inhibitor monotherapy, as dual blockade of immunomodulatory checkpoints may show increased activity against NSCLC. Despite recent advances, lung cancer remains the primary cause of cancer related mortality worldwide, and an area of continued unmet need.

Phase III

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