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

Solid Tumors Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03708328
• Other study ID #: NP40435
• Secondary ID: 2018-000982-35
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: October 15, 2018
• Est. completion date: April 30, 2024

Study information

• Verified date: March 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 134
• Est. completion date: April 30, 2024
• Est. primary completion date: April 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Lomvastomig
Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Denmark,  France,  Korea, Republic of,  New Zealand,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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
Primary	Expansion: Objective Response Rate, Assessed According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)		Up to 27 months
Primary	Expansion: Disease Control Rate, Assessed According to RECIST v1.1		Up to 27 months
Primary	Expansion: Duration of Response, Assessed According to RECIST v1.1		Up to 27 months
Primary	Expansion: Progression Free Survival, Assessed According to RECIST v1.1		Up to 27 months
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Expansion: Number of Participants with at Least One Adverse Event, Severity Graded According to NCI CTCAE v5.0		Up to 27 months
Secondary	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)
Secondary	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)
Secondary	Dose Escalation: Objective Response Rate, Assessed According to RECIST v1.1		Up to 27 months
Secondary	Dose Escalation: Disease Control Rate, Assessed According to RECIST v1.1		Up to 27 months
Secondary	Dose Escalation: Duration of Response, Assessed According to RECIST v1.1		Up to 27 months
Secondary	Dose Escalation: Progression Free Survival, Assessed According to RECIST v1.1		Up to 27 months