Clinical trial NCT03708328: A Dose Escalation and Expansion Study of Lomvastomig, a PD-1/TIM-3 Bispecific Antibody, in Participants With Advanced and/or Metastatic Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Metastatic Melanoma
Non-small Cell Lung Cancer (NSCLC)
Small Cell Lung Cancer (SCLC)
Esophageal Squamous Cell Carcinoma (ESCC)
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-10-17
Enrollment: 134
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Dose Escalation: Number of Participants with a Dose-Limiting Toxicity (DLT)
timeFrame: For Part A (1 cycle is 14 days): From Cycle 1 Day 1 to Cycle 2 Day 7 (up to 35 days)
measure: 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)
timeFrame: Up to 27 months
measure: Expansion: Objective Response Rate, Assessed According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: Up to 27 months
measure: Expansion: Disease Control Rate, Assessed According to RECIST v1.1
timeFrame: Up to 27 months
measure: Expansion: Duration of Response, Assessed According to RECIST v1.1
timeFrame: Up to 27 months
measure: Expansion: Progression Free Survival, Assessed According to RECIST v1.1
timeFrame: Up to 27 months
Secondary outcomes:
measure: Dose Escalation and Expansion: Area Under the Concentration-Time Curve (AUC) of Lomvastomig
timeFrame: 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)
measure: Dose Escalation and Expansion: Maximum Concentration (Cmax) of Lomvastomig
timeFrame: 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)
measure: Dose Escalation and Expansion: Total Cnlearance (CL) of Lomvastomig
timeFrame: 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)
measure: Dose Escalation and Expansion: Volume of Distribution at Steady State of Lomvastomig
timeFrame: 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)
measure: Dose Escalation and Expansion: Terminal Half-Life (t1/2) of Lomvastomig
timeFrame: 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)
measure: Dose Escalation and Expansion: Number of Participants with Anti-Drug Antibodies
timeFrame: 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)
measure: Expansion: Number of Participants with at Least One Adverse Event, Severity Graded According to NCI CTCAE v5.0
timeFrame: Up to 27 months
measure: Expansion: Examine Profile and Status of T-cell Proliferation/Activation in Tumor Biopsies and Peripheral Blood
timeFrame: 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)
measure: Dose Escalation: Receptor Occupancy of Lomvastomig, Assessed via an Ex-Vivo Assay
timeFrame: 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)
measure: Dose Escalation: Objective Response Rate, Assessed According to RECIST v1.1
timeFrame: Up to 27 months
measure: Dose Escalation: Disease Control Rate, Assessed According to RECIST v1.1
timeFrame: Up to 27 months
measure: Dose Escalation: Duration of Response, Assessed According to RECIST v1.1
timeFrame: Up to 27 months
measure: Dose Escalation: Progression Free Survival, Assessed According to RECIST v1.1
timeFrame: Up to 27 months
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia Univ Med Ctr
state: New York
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Herlev
country: Denmark
facility: Herlev Hospital; Afdeling for Kræftbehandling
city: København Ø
country: Denmark
facility: Rigshospitalet; Onkologisk Klinik
city: Bordeaux
country: France
facility: Institut Bergonie; Oncologie
city: Lyon
country: France
facility: Centre Leon Berard; Service Oncologie Medicale
city: Marseille
country: France
facility: CHU Timone; Centre d'Essais Précoces en Cancérologie de Marseille (CEPCM)
city: St Herblain
country: France
facility: ICO Rene Gauducheau; CEC
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Auckland
country: New Zealand
facility: Auckland City Hospital; Clinical Oncology
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra; Servicio de oncología
state: Navarra
city: Barcelona
country: Spain
facility: Vall d?Hebron Institute of Oncology (VHIO), Barcelona
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal; Servicio de Oncologia
city: Madrid
country: Spain
facility: START Madrid-FJD, Hospital Fundacion Jimenez Diaz
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia; Servicio de Oncología
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: