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

Hoffmann-La Roche134 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

134

Conditions

Solid Tumors Metastatic Melanoma Non-small Cell Lung Cancer (NSCLC)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (17)

Columbia Univ Med Ctr

New York, New York, United States

MD Anderson Cancer Center

Houston, Texas, United States

Herlev Hospital

Herlev, Denmark

Rigshospitalet

København Ø, Denmark

Institut Bergonie

Bordeaux, France

Centre Leon Berard

Lyon, France

CHU Timone

Marseille, France

ICO Rene Gauducheau

Saint-Herblain, France

Auckland City Hospital

Auckland, New Zealand

Seoul National University Hospital

Seoul, South Korea

...and 7 more locations

Outcomes

Primary Outcomes

Part A: Number of Participants With a Dose-Limiting Toxicity (DLT)

A DLT was defined as a clinically significant adverse event (AE) or significant laboratory abnormality: 1) occurring during DLT assessment period of 21 days; 2) considered to be related to study treatment RO7121661 by the Investigator; 3) is not attributed to disease progression or another clearly identifiable cause. Following AEs were considered DLTs: Hematological toxicities (Grade 4 neutropenia lasting \>5 days, Grade ≥3 febrile neutropenia, Grade 4 thrombocytopenia lasting \> 48 hours, Grade 3 thrombocytopenia associated with bleeding episodes, Grade 4 anemia, Grade ≥3 anemia with hemolysis); Non-hematological toxicity Grade ≥3 (Any Grade 3 immune-mediated AE, Grade 3 hyperbilirubinemia lasting for \>48 hours/Grade 4 hyperbilirubinemia; Grade ≥3 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations with hyperbilirubinemia of Grade ≥2, Grade 4 AST or ALT elevations, Grade ≥3 nausea, vomiting, or diarrhea, Grade ≥3 non-hematological laboratory abnormality.

Time frame: From Cycle 1 Day 1 to Cycle 2 Day 7 (Cycle length= 14 days)

Part A: Number of Participants With at Least One AE by Highest Severity, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

AE=any untoward medical occurrence in a participant administered a pharmaceutical product \& which does not necessarily have a causal relationship with treatment \& can therefore be any unfavorable \& unintended sign (including abnormal laboratory values/abnormal clinical test results), symptoms/disease temporally associated with the use of pharmaceutical product, whether or not considered related to pharmaceutical product. Severity of AEs was graded as: Grade 1=Mild, asymptomatic/mild symptoms, clinical/diagnostic observations only, or intervention not indicated; Grade 2=Moderate, minimal, local/non-invasive intervention indicated, or limiting age-appropriate instrumental activities of daily living; Grade 3=Severe/medically significant but not immediately life-threatening, hospitalization/prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living; Grade 4= Life-threatening consequences, urgent intervention indicated; Grade 5=Death related to AE.

Time frame: From signing of informed consent form up to 60 days after last treatment administration (up to 41.7 months)

Part B: Objective Response Rate (ORR) as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

ORR was defined as the percentage of participants with an objective tumor response of complete response (CR) or partial response (PR) as determined by the investigator using RECIST v.1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD.

Time frame: Cycle 1 Day 1 then every 8 weeks for the first year; every 12 weeks thereafter until disease progression or treatment discontinuation (whichever occurs last), initiation of a new line of therapy or death (Up to 43.3 months) (Cycle length= 14 days)

Part B: Disease Control Rate (DCR) as Determined by Investigator Using RECIST v1.1

DCR was defined as the percentage of participants with an objective tumor response of CR, PR or stable disease (SD) as determined by the investigator using RECIST v.1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression (PD). PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on the study including baseline (nadir). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Part B: Duration of Response (DOR) as Determined by Investigator Using RECIST v1.1

DOR was calculated for participants who had a best confirmed overall response (OR) of CR/PR. DOR was defined as time from first occurrence of a documented OR until the time of documented PD or death (within 30 days from last treatment) from any cause, whichever occurs first as determined by investigator assessment using RECIST v1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on the study including baseline (nadir). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Data for participants without PD or death as of the data cut-off date were censored at the time of the last tumor assessment.

Time frame: From first occurrence of documented OR up to disease progression or death (Up to 43.3 months) (Cycle length = 14 days)

Part B: Progression Free Survival (PFS) as Determined by Investigator Using RECIST v1.1

PFS was defined as the time from study treatment initiation (Cycle 1 Day 1) to the first occurrence of documented PD, as determined by the investigator according to RECIST v1.1 or death from any cause, whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Data for participants without PD or death as of the data cut-off date were censored at the time of the last tumor assessment.

Time frame: From treatment initiation (Cycle 1 Day 1) until disease progression or death (Up to 43.3 months) (Cycle length= 14 days)

Secondary Outcomes

Parts A and B: Number of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs)

Participants were considered to be ADA positive if they were ADA negative at baseline but developed an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 4-fold (treatment-enhanced ADA response).

Time frame: Baseline and Day 1 of Cycles 1 to 5; Day 1 of Cycle 7, and every 6 cycles thereafter (1 cycle is 14 days); study completion/discontinuation; safety follow-up visits (up to approximately 40.8 months - Part A and 45.4 months - Part B)

Part B: Biomarkers: T-cell Proliferation/Activation in Peripheral Blood

Biomarker analyses were performed using peripheral blood samples that were collected from participants in Part B of the study. The blood samples were assessed by flow cytometry for absolute counts of CD3⁺CD8⁺ T cells and proliferating CD3⁺CD8⁺Ki67⁺ T cells.

Time frame: Days 1, 2, and 8 of Cycles 1 and 5; Day 1 of Cycles 2, 3, and 9 (1 cycle is 14 days); study completion visit (28 days after last dose; up to 43.3 months); safety follow-up (SFU) (90 days after last dose; up to 45.4 months)

Part B: Biomarkers: CD8+ T-cell Densities in Tumor Biopsies

Fresh tumor biopsies were collected from participants in Part B of the study to assess changes in T-cell infiltration and activation within the tumor microenvironment. Tumor tissue was evaluated for CD8⁺ T-cell densities. The tumor tissue samples were collected at screening (archival metastasis and archival primary samples) and during the study (fresh samples).

Time frame: At screening and Cycle 3 Day 1

Parts A and B: Time to Maximum Observed Serum Concentration (Tmax) of Lomvastomig

Time frame: Predose, half infusion, end of infusion (EOI), 0.5, 2, 4, and 8 hours postdose on Cycle 1 Day 1 and Cycle 5 Day 1, and on Cycles 1 and 5 Days 2, 3, 4, 5, 8, and 12, and predose on Day 1 of Cycles 2 and 6 (1 cycle = 14 days)

Parts A and B: Maximum Observed Serum Concentration (Cmax) of Lomvastomig

Parts A and B: Time to Last Non-zero Concentration (Tlast) of Lomvastomig

For participants who experienced an adverse event (AE) following infusion with lomvastomig, a delay of the next administration for up to two cycles was acceptable to allow for resolution of toxicity to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 2 or lower for hematological toxicities or Grade 1 or lower for non-hematological toxicities (with the exception of a toxicity considered as not related to study drug). In the case of a delayed administration, the predose PK sample for Day 1 of Cycles 2 and/or 6 could have been collected up to 28 days after the end of the previous treatment cycle.

Parts A and B: Last Non-zero Concentration (Clast) of Lomvastomig

Parts A and B: Area Under the Curve From Dosing to Last Concentration (AUClast) of Lomvastomig

Part B: Number of Participants With at Least One AE by Highest Severity, Graded According to the NCI CTCAE v5.0

Time frame: From signing of informed consent form up to 90 days after last treatment administration (up to 46.2 months)

Part A: DCR as Determined by Investigator Using RECIST v1.1

DCR was defined as the percentage of participants with an objective tumor response of CR, PR or SD as determined by the investigator using RECIST v.1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on the study including baseline (nadir). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Part A: DOR as Determined by Investigator Using RECIST v1.1

DOR was calculated for participants who had a best confirmed OR of CR/PR. DOR was defined as time from first occurrence of a documented OR until the time of documented PD or death from any cause, whichever occurs first as determined by investigator assessment using RECIST v1.1. CR=the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR=at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. PD=at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on the study including baseline (nadir). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Data for participants without PD or death from any cause as of the data cut-off date were censored at the time of the last tumor assessment.

Time frame: From first occurrence of documented OR up to disease progression or death (Up to 39.7 months) (Cycle length= 14 days)