A Dose Escalation and Expansion Study of Lomvastomig, a PD-1/TIM-3 Bispecific Antibody, in Participants With Advanced and/or Metastatic Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This is a first-in-human, open-label, multicenter, Phase I multiple-ascending dose (MAD) study of single agent lomvastomig (RO7121661), an anti PD-1 (programmed death-1) and TIM-3 (T-cell immunoglobulin and mucin domain 3) bispecific antibody, for participants with advanced and/or metastatic solid tumors. The study consists of 2 parts: Dose Escalation (Part A) and Expansion (Parts B1, B2, B3, B4, and B5). The Dose Escalation part will be conducted first to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) based on safety, tolerability, pharmacokinetic, and/or the pharmacodynamic profile of escalating doses of lomvastomig. The Expansion part will enroll tumor-specific cohorts to evaluate anti-tumor activity of the MTD and/or RDE of lomvastomig from Part A (Q2W) and to confirm safety and tolerability in participants with selected tumor types.

Official Title
-----------------
An Open Label, Multicenter, Dose Escalation and Expansion, Phase 1 Study to Evaluate Safety, Pharmacokinetics, and Preliminary Anti-Tumor Activity of RO7121661, a PD-1/TIM-3 Bispecific Antibody, in Patients With Advanced and/or Metastatic Solid Tumors

Conditions
-----------------
Solid Tumors, Metastatic Melanoma, Non-small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), Esophageal Squamous Cell Carcinoma (ESCC)

Intervention / Treatment
-----------------
* Drug: Lomvastomig


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: General Inclusion Criteria: Part A: 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 Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Fresh biopsies may be required Negative HIV, hepatitis B, or hepatitis C test result 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 Previously treated with approved anti-programmed death-ligand 1 (PD-L1)/anti-programmed death-1 (PD-1) agents with or without approved anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy and up to one additional treatment regimen Additional Specific Inclusion Criteria for Participants with Non-small Cell Lung Cancer (NSCLC) who Previously Received Treatment for Metastatic Disease: Histologically confirmed advanced NSCLC Previously treated with approved PD-L1/PD-1 inhibitors and platinum-based chemotherapy Not more than 2 prior lines of treatment for metastatic disease are allowed prior to enrolling to the study Participants must have experienced initial clinical benefit (stable disease or better) from most recent checkpoint inhibitor (CPI) therapy 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 Non-small Cell Lung Cancer (NSCLC) who Previously Did Not Receive Treatment for Metastatic Disease: Histologically confirmed advanced NSCLC 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 Small Cell Lung Cancer (SCLC): Histologically confirmed SCLC Participants may have had prior chemotherapy, radiation therapy, or declined approved therapies for SCLC Additional Specific Inclusion Criteria for Participants with Esophageal Squamous Cell Carcinoma (ESCC): Participants whose major lesion was histologically confirmed as squamous cell carcinoma or adenosquamous cell carcinoma of the esophagus Patients who have previously received not more than 1 prior line of treatment for metastatic disease prior to enrolling to the study Exclusion Criteria: General Exclusion Criteria: Pregnancy, lactation, or breastfeeding Known hypersensitivity to any of the components of RO7121661 Active or untreated central nervous system (CNS) metastases An active second malignancy Evidence of concomitant diseases, metabolic dysfunction, physical examination findings, or clinical laboratory findings 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 Known active or uncontrolled bacterial, viral, fungal, mycobacterial, parasitic, or other infection 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 T-cell immunoglobulin and mucin domain-3 (TIM-3) inhibitor Additional Specific Exclusion Criteria for Participants with NSCLC who Previously Received Treatment for Metastatic Disease: - Patients with the following mutations, rearrangements, translocations are not eligible: epidermal growth factor receptor (EGFR); anaplastic lymphoma kinase (ALK); ROS proto-oncogene 1 (ROS1), BRAFV600E, and neurotrophic receptor tyrosine kinase (NTRK) Additional Specific Exclusion Criteria for Participants with NSCLC who Did Not Previously Receive Treatment for Metastatic Disease: Prior therapy for metastatic disease Adjuvant anti-PD-1 or anti-PD-L1 therapy Additional Specific Exclusion Criteria for Participants with Small-Cell Lung Cancer (SCLC): - Prior therapy with any immune CPIs (such as anti-PD-L1/PD-1, CTLA-4) Additional Specific Exclusion Criteria for Participants with Esophageal Squamous Cell Carcinoma (ESCC): - Prior therapy with any immunomodulatory agents

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Part A: Once Every 2 Weeks (Q2W)<br>Lomvastomig will be administered in treatment cycles once every 2 weeks (Q2W). Dose escalation will be carried out according to a modified continual reassessment method (mCRM) with escalation with overdose control (EWOC) design. | Drug: Lomvastomig<br>* Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.<br>* Other names: RG7769;|
| Experimental: Expansion Part B1: Metastatic Melanoma Cohort<br>This cohort will comprise participants with checkpoint inhibitor (CPI) experienced, second line and beyond metastatic melanoma. The starting dose of lomvastomig for Expansion will be derived from the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) and the best dosing schedule determined during Dose Escalation. | Drug: Lomvastomig<br>* Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.<br>* Other names: RG7769;|
| Experimental: Expansion Part B2: NSCLC Cohort 1<br>This cohort will comprise participants with CPI and platinum experienced, second or third line PD-L1 positive non-small cell lung cancer (NSCLC). The starting dose of lomvastomig for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation. | Drug: Lomvastomig<br>* Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.<br>* Other names: RG7769;|
| Experimental: Expansion Part B3: NSCLC Cohort 2<br>This cohort will comprise participants with PD-L1 high, cancer immunotherapy (CIT) naïve first line NSCLC. The starting dose of lomvastomig for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation. | Drug: Lomvastomig<br>* Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.<br>* Other names: RG7769;|
| Experimental: Expansion Part B4: SCLC Cohort<br>This cohort will comprise participants with CPI naïve small cell lung cancer (SCLC) with prior failure of, progression on, or intolerance to, standard therapy. The starting dose of lomvastomig for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation. | Drug: Lomvastomig<br>* Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.<br>* Other names: RG7769;|
| Experimental: Expansion Part B5: ESCC Cohort<br>This cohort will comprise participants with CPI-naïve esophageal squamous cell carcinoma (ESCC). The starting dose of lomvastomig for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation. | Drug: Lomvastomig<br>* Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.<br>* Other names: RG7769;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Number of Participants with a Dose-Limiting Toxicity (DLT) |  | For Part A (1 cycle is 14 days): From Cycle 1 Day 1 to Cycle 2 Day 7 (up to 35 days) | 
| Dose Escalation: Number of Participants with at Least One Adverse Event, Severity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) |  | Up to 27 months | 
| Expansion: Objective Response Rate, Assessed According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) |  | Up to 27 months | 
| Expansion: Disease Control Rate, Assessed According to RECIST v1.1 |  | Up to 27 months | 
| Expansion: Duration of Response, Assessed According to RECIST v1.1 |  | Up to 27 months | 
| Expansion: Progression Free Survival, Assessed According to RECIST v1.1 |  | Up to 27 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation and Expansion: Area Under the Concentration-Time Curve (AUC) of Lomvastomig |  | Days 1, 2, 3, 5, 8, and 12 of Cycle 1; Days 1, 2, and 5 of Cycle 2; Day 1 of Cycles 3-4, Days 1, 2, 5, and 8 of Cycle 5 and Day 1 of Cycle 6 onwards (1 cycle is 14 days) through study completion (up to 27 months) | 
| Dose Escalation and Expansion: Maximum Concentration (Cmax) of Lomvastomig |  | Days 1, 2, 3, 5, 8, and 12 of Cycle 1; Days 1, 2, and 5 of Cycle 2; Day 1 of Cycles 3-4, Days 1, 2, 5, and 8 of Cycle 5 and Day 1 of Cycle 6 onwards (1 cycle is 14 days) through study completion (up to 27 months) | 
| Dose Escalation and Expansion: Total Cnlearance (CL) of Lomvastomig |  | Days 1, 2, 3, 5, 8, and 12 of Cycle 1; Days 1, 2, and 5 of Cycle 2; Day 1 of Cycles 3-4, Days 1, 2, 5, and 8 of Cycle 5 and Day 1 of Cycle 6 onwards (1 cycle is 14 days) through study completion (up to 27 months) | 
| Dose Escalation and Expansion: Volume of Distribution at Steady State of Lomvastomig |  | Days 1, 2, 3, 5, 8, and 12 of Cycle 1; Days 1, 2, and 5 of Cycle 2; Day 1 of Cycles 3-4, Days 1, 2, 5, and 8 of Cycle 5 and Day 1 of Cycle 6 onwards (1 cycle is 14 days) through study completion (up to 27 months) | 
| Dose Escalation and Expansion: Terminal Half-Life (t1/2) of Lomvastomig |  | Days 1, 2, 3, 5, 8, and 12 of Cycle 1; Days 1, 2, and 5 of Cycle 2; Day 1 of Cycles 3-4, Days 1, 2, 5, and 8 of Cycle 5 and Day 1 of Cycle 6 onwards (1 cycle is 14 days) through study completion (up to 27 months) | 
| Dose Escalation and Expansion: Number of Participants with Anti-Drug Antibodies |  | Day 1 of Cycles 1 to 5; Day 1 of Cycle 7, and every 6 cycles (1 cycle is 14 days) afterwards through study completion (up to 27 months) | 
| Expansion: Number of Participants with at Least One Adverse Event, Severity Graded According to NCI CTCAE v5.0 |  | Up to 27 months | 
| Expansion: Examine Profile and Status of T-cell Proliferation/Activation in Tumor Biopsies and Peripheral Blood |  | Days 1, 2, and 8 of Cycles 1 and 5; Day 1 of Cycles 2 and 3; and Day 1 of Cycles 9, 22, 35, and 48 (1 cycle is 14 days) through study completion (up to 27 months) | 
| Dose Escalation: Receptor Occupancy of Lomvastomig, Assessed via an Ex-Vivo Assay |  | Days 1 and 8 of Cycles 1 and 5; Day 1 of Cycles 2 and 3; and Day 1 of Cycles 9, 22, 35, and 48 (1 cycle is 14 days), and at study completion (up to 27 months) | 
| Dose Escalation: Objective Response Rate, Assessed According to RECIST v1.1 |  | Up to 27 months | 
| Dose Escalation: Disease Control Rate, Assessed According to RECIST v1.1 |  | Up to 27 months | 
| Dose Escalation: Duration of Response, Assessed According to RECIST v1.1 |  | Up to 27 months | 
| Dose Escalation: Progression Free Survival, Assessed According to RECIST v1.1 |  | Up to 27 months |