Clinical Trials /

A Dose Escalation and Expansion Study of RO7121661, a PD-1/TIM-3 Bispecific Antibody, in Participants With Advanced and/or Metastatic Solid Tumors

NCT03708328

Description:

This is a first-in-human, open-label, multicenter, Phase I multiple-ascending dose (MAD) study of single agent 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 RO7121661. The Expansion part will enroll tumor-specific cohorts to evaluate anti-tumor activity of the MTD and/or RDE of RO7121661 from Part A (Q2W) and to confirm safety and tolerability in participants with selected tumor types. Recruitment into the Expansion Part B4: SCLC Cohort is now closed.

Related Conditions:
  • Malignant Solid Tumor
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Dose Escalation and Expansion Study of RO7121661, 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

Clinical Trial IDs

  • ORG STUDY ID: NP40435
  • SECONDARY ID: 2018-000982-35
  • NCT ID: NCT03708328

Conditions

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

Interventions

DrugSynonymsArms
RO7121661RG7769Dose Escalation Part A: Once Every 2 Weeks (Q2W)

Purpose

This is a first-in-human, open-label, multicenter, Phase I multiple-ascending dose (MAD) study of single agent 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 RO7121661. The Expansion part will enroll tumor-specific cohorts to evaluate anti-tumor activity of the MTD and/or RDE of RO7121661 from Part A (Q2W) and to confirm safety and tolerability in participants with selected tumor types. Recruitment into the Expansion Part B4: SCLC Cohort is now closed.

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation Part A: Once Every 2 Weeks (Q2W)ExperimentalRO7121661 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.
  • RO7121661
Expansion Part B1: Metastatic Melanoma CohortExperimentalThis cohort will comprise participants with checkpoint inhibitor (CPI) experienced, second line and beyond metastatic melanoma. The starting dose of RO7121661 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.
  • RO7121661
Expansion Part B2: NSCLC Cohort 1ExperimentalThis 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 RO7121661 for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation.
  • RO7121661
Expansion Part B3: NSCLC Cohort 2ExperimentalThis cohort will comprise participants with PD-L1 high, cancer immunotherapy (CIT) naïve first line NSCLC. The starting dose of RO7121661 for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation.
  • RO7121661
Expansion Part B4: SCLC CohortExperimentalThis 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 RO7121661 for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation.
  • RO7121661
Expansion Part B5: ESCC CohortExperimentalThis cohort will comprise participants with CPI-naïve esophageal squamous cell carcinoma (ESCC). The starting dose of RO7121661 for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation.
  • RO7121661

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Escalation: Number of Participants with a Dose-Limiting Toxicity (DLT)
Time Frame:For Part A (1 cycle is 14 days): From Cycle 1 Day 1 to Cycle 2 Day 7 (up to 35 days)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Dose Escalation and Expansion: Area Under the Concentration-Time Curve (AUC) of RO7121661
Time Frame: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)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion: Maximum Concentration (Cmax) of RO7121661
Time Frame: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)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion: Total Clearance (CL) of RO7121661
Time Frame: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)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion: Volume of Distribution at Steady State of RO7121661
Time Frame: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)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion: Terminal Half-Life (t1/2) of RO7121661
Time Frame: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)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion: Number of Participants with Anti-Drug Antibodies
Time Frame: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)
Safety Issue:
Description:
Measure:Expansion: Number of Participants with at Least One Adverse Event, Severity Graded According to NCI CTCAE v5.0
Time Frame:Up to 27 months
Safety Issue:
Description:
Measure:Expansion: Examine Profile and Status of T-cell Proliferation/Activation in Tumor Biopsies and Peripheral Blood
Time Frame: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)
Safety Issue:
Description:
Measure:Dose Escalation: Receptor Occupancy of RO7121661, Assessed via an Ex-Vivo Assay
Time Frame: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)
Safety Issue:
Description:
Measure:Dose Escalation: Objective Response Rate, Assessed According to RECIST v1.1
Time Frame:Up to 27 months
Safety Issue:
Description:
Measure:Dose Escalation: Disease Control Rate, Assessed According to RECIST v1.1
Time Frame:Up to 27 months
Safety Issue:
Description:
Measure:Dose Escalation: Duration of Response, Assessed According to RECIST v1.1
Time Frame:Up to 27 months
Safety Issue:
Description:
Measure:Dose Escalation: Progression Free Survival, Assessed According to RECIST v1.1
Time Frame:Up to 27 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

June 26, 2020