Dose Escalation Study of a PD1-LAG3 Bispecific Antibody in Patients With Advanced and/or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is a first-in-human, open-label, multicenter, Phase I multiple-ascending dose (MAD) study of RO7247669, an anti PD-1 (programmed death-1) and LAG-3 (Lymphocyte-activation gene 3) bispecific antibody, for participants with advanced and/or metastatic solid tumors. This study aims to establish the maximum tolerated dose (MTD) and/or define the recommended phase 2 dose (RP2D) based on the safety, tolerability, pharmacokinetic (PK) and/or pharmacodynamic (PD) profile of RO7247669, and to evaluate preliminary anti-tumor activity in participants with solid tumors. An expansion part of the study is planned to enroll tumor-specific cohorts to evaluate anti-tumor activity of the MTD and/or RP2D of RO7247669 and to confirm safety and tolerability in participants with selected tumor types.

Official Title
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An Open Label, Multicenter, Dose Escalation, Phase 1 Study to Evaluate Safety/Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Anti Tumor Activity of RO7247669, a PD1-LAG3 Bispecific Antibody, in Patients With Advanced and/or Metastatic Solid Tumors

Conditions
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Solid Tumors, Metastatic Melanoma, Non-small Cell Lung Cancer, Esophageal Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: RO7247669


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Patient must have histologically or cytologically confirmed advanced and/or metastatic solid tumor malignancies for which standard curative or palliative measures do not exist, are no longer effective, or are not acceptable to the patient Eastern Cooperative Oncology Group Performance Status 0-1 Fresh biopsies may be required Women of childbearing potential and male participants must agree to remain abstinent or use contraceptive methods as defined by the protocol Additional Specific Inclusion Criteria for Participants with Melanoma Histologically confirmed, unresectable stage III or stage IV melanoma Not more than 2 prior lines of treatment for metastatic disease are allowed prior to enrolling in the study Prior treatment with an approved anti-PD-1 or anti-PD-L1 agent Additional Specific Inclusion Criteria for Participants with Non-Small Cell Lung Cancer who Previously Received Treatment for Metastatic Disease Participants with histologically confirmed advanced non-small cell lung cancer Not more than 2 prior lines of treatment for metastatic disease are allowed prior to enrolling in the study Previously treated with approved PD-L1/PD-1 inhibitors Tumor PD-L1 expression as determined by immunohistochemistry assay of archival tumor tissue or tissue obtained at screening Additional Specific Inclusion Criteria for Participants with Esophageal Squamous Cell Carcinoma Participants whose major lesion was histologically confirmed as squamous cell carcinoma or adenosquamous cell carcinoma of the esophagus Participants who have previously received not more than 1 prior line of treatment for metastatic disease prior to enrolling in the study Additional Specific Inclusion Criteria for Participants with Non-Small Cell Lung Cancer who Previously did not Receive Treatment for Metastatic Disease Participants with histologically confirmed advanced non-small cell lung cancer Tumor PD-L1 expression as determined by immunohistochemistry assay of archival tumor tissue or tissue obtained at screening Exclusion criteria Pregnancy, lactation, or breastfeeding Known hypersensitivity to any of the components of RO7247669 Active or untreated central nervous system (CNS) metastases An active second malignancy Evidence of concomitant diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk from treatment complications Positive HIV, hepatitis B, or hepatitis C test result Known active or uncontrolled bacterial, viral, fungal, mycobacterial, parasitic, or other infection Vaccination with live vaccines within 28 days prior to Cycle 1 Day 1 Treatment with oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1 Active or history of autoimmune disease or immune deficiency Prior treatment with adoptive cell therapies, such as CAR-T therapies Concurrent therapy with any other investigational drug < 28 days or 5 half-lives of the drug, whichever is shorter, prior to the first RO7247669 administration Regular immunosuppressive therapy Radiotherapy within the last 4 weeks before start of study drug treatment, with the exception of limited palliative radiotherapy Prior treatment with a lymphocyte activation gene-3 (LAG-3) inhibitor Additional Specific Exclusion Criteria for Participants with Non-Small Cell Lung Cancer who Previously Received Treatment for Metastatic Disease Participants with the following muations, rearrangements, translocations are not eligible: EGFR, ALK, ROS1, BRAFV600E, and NTRK Additional Specific Exclusion Criteria for Participants with Esophageal Squamous Cell Carcinoma Prior therapy with any immunomodulatory agents Additional Specific Exclusion Criteria for Participants with Non-Small Cell Lung Cancer who Previously did not Receive Treatment for Metastatic Disease Prior therapy for metastatic disease is not permitted Neo-adjuvant anti-PD-1 or anti-PD-L1 therapy is not allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Single-Agent Dose Escalation<br>Participants will receive RO7247669 every 2 weeks (Q2W) or every 3 weeks (Q3W) up to the maximum tolerated dose (MTD) until disease progression, unacceptable drug toxicity, or withdrawal of consent, for up to 24 months. | Drug: RO7247669<br>* Participants will receive intravenous (IV) RO7247669 at different doses either every 2 weeks (Q2W) or every 3 weeks (Q3W)<br>|
| Experimental: Part B: Tumor Specific Expansion Cohorts<br>Participants with selected solid tumor indications will receive RO7247669 at a dose derived from Part A until disease progression, unacceptable drug toxicity, or withdrawal of consent, for up to 24 months. | Drug: RO7247669<br>* Participants will receive intravenous (IV) RO7247669 at different doses either every 2 weeks (Q2W) or every 3 weeks (Q3W)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Percentage of Participants with Dose-Limiting Toxicities (DLTs) |  | Days 1-21 (Q2W dosing) or Days 1-28 (Q3W dosing) of Cycle 1 | 
| Part A: Percentage of Participants with Adverse Events |  | Baseline through the end of study (up to 24 months) | 
| Part B: Objective Response Rate (ORR) |  | Up to 24 months | 
| Part B: Disease Control Rate (DCR), Defined as ORR + Stable Disease Rate (SDR) |  | Up to 24 months | 
| Part B: Duration of Response (DOR) |  | Up to 24 months | 
| Part B: Progression-free Survival (PFS), Defined as the Time from the First Study Treatment to the First Occurrence of Progression per Investigator Assessment or Death from any Cause, Whichever Occurs First |  | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A and B: Maximum Concentration (Cmax) of RO7247669 |  | At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months) | 
| Parts A and B: Time of Maximum Concentration (Tmax) of RO7247669 |  | At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months) | 
| Parts A and B: Clearance (CL) of RO7247669 |  | At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months) | 
| Parts A and B: Volume of Distribution at Steady State (Vss) of RO7247669 |  | At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months) | 
| Parts A and B: Area Under the Curve (AUC) of RO7247669 |  | At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months) | 
| Parts A and B: Half-Life (T1/2) of RO7247669 |  | At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months) | 
| Parts A and B: Percentage of Participants with Anti-Drug Antibodies (ADA) to RO7247669 |  | Day 1 of each Cycle, starting with Cycle 1, through final study visit (up to 24 months) | 
| Part B: Change from Baseline in T-Cell Activity |  | At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months) | 
| Part A: Percentage of Receptors Occupied by RO7247669 |  | At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months) | 
| Part A: ORR |  | At pre-defined intervals from initial dose up to 24 months | 
| Part A: DCR |  | At pre-defined intervals from initial dose up to 24 months | 
| Part A: PFS |  | At pre-defined intervals from initial dose up to 24 months | 
| Part A: DOR |  | At pre-defined intervals from initial dose up to 24 months | 
| Part B: Percentage of Participants with Adverse Events |  | Baseline through the end of study (up to 24 months) |