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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Melanoma; Non-small Cell Lung Cancer (NSCLC); Solid Tumors; Esophageal Squamous Cell Carcinoma (ESCC); Small Cell Lung Cancer (SCLC)
• Intervention / Treatment: Drug: Lomvastomig

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Herlev Hospital; Afdeling for Kræftbehandling
  • København Ø, Denmark, 2100
    • Rigshospitalet; Onkologisk Klinik
• France
  • Bordeaux, France, 33076
    • Institut Bergonie; Oncologie
  • Lyon, France, 69008
    • Centre Leon Berard; Service Oncologie Medicale
  • Marseille, France, 13005
    • CHU Timone; Centre d'Essais Précoces en Cancérologie de Marseille (CEPCM)
  • St Herblain, France, 44805
    • ICO Rene Gauducheau; CEC
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
• New Zealand
  • Auckland, New Zealand, 1023
    • Auckland City Hospital; Clinical Oncology
• Spain
  • Barcelona, Spain, 08035
    • Vall d?Hebron Institute of Oncology (VHIO), Barcelona
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal; Servicio de Oncologia
  • Madrid, Spain, 28040
    • START Madrid-FJD, Hospital Fundacion Jimenez Diaz
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia; Servicio de Oncología
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universitaria de Navarra; Servicio de Oncologia
• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia Univ Med Ctr
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

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

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

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation Part A: Once Every 2 Weeks (Q2W); 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; Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.; Other Names: RG7769; RO7121661
Experimental: Expansion Part B1: Metastatic Melanoma Cohort; 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; Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.; Other Names: RG7769; RO7121661
Experimental: Expansion Part B2: NSCLC Cohort 1; 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; Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.; Other Names: RG7769; RO7121661
Experimental: Expansion Part B3: NSCLC Cohort 2; 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; Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.; Other Names: RG7769; RO7121661
Experimental: Expansion Part B4: SCLC Cohort; 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; Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.; Other Names: RG7769; RO7121661
Experimental: Expansion Part B5: ESCC Cohort; 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; Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.; Other Names: RG7769; RO7121661

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	Time Frame
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: 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
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: 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)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2018
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: October 9, 2018
• First Submitted That Met QC Criteria: October 12, 2018
• First Posted (Actual): October 17, 2018

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Esophageal Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Esophageal Squamous Cell Carcinoma
• Other Study ID Numbers: NP40435; 2018-000982-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Qualified researchers may request access to individual patient level data through the request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/).

For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

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