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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 (Parts A1 and A2) and Expansion (Parts B1, B2, B3, and B4). 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 if available, Q3W) and to confirm safety and tolerability in participants with selected tumor types.

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)

Interventions

DrugSynonymsArms
RO7121661RG7769Dose Escalation Part A1: 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 (Parts A1 and A2) and Expansion (Parts B1, B2, B3, and B4). 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 if available, Q3W) and to confirm safety and tolerability in participants with selected tumor types.

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation Part A1: 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. Dosing on the Q2W schedule will inform whether a once every 3 weeks (Q3W) schedule will be assessed.
  • RO7121661
Dose Escalation Part A2: Once Every 3 Weeks (Q3W)ExperimentalRO7121661 will be administered in treatment cycles once every 3 weeks (Q3W). 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

Eligibility Criteria

        Inclusion Criteria:

        General Inclusion Criteria:

          -  Patients with advanced and/or metastatic solid tumors who have progressed on a cancer
             therapy, for whom no effective standard therapy exists, or who decline treatment with
             approved therapies, with a life expectancy of greater than or equal to (≥)12 weeks

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

          -  Adequate cardiovascular, hematological, liver, and renal function

          -  Adverse events from any prior radiotherapy, chemotherapy, or surgical procedure must
             have resolved to Grade ≤1, except alopecia (any grade), vitiligo, endocrinopathy
             managed with replacement therapy, and Grade 2 peripheral neuropathy

          -  Additional adequate laboratory parameters obtained within 14 days prior to the first
             study treatment (Cycle [C] 1, Day [D] 1)

          -  Participants on therapeutic anticoagulation should be on a stable anticoagulant
             regimen

          -  Negative HIV and hepatitis B surface antigen (HBsAg) test at screening

          -  Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total
             HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening

          -  Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody
             test followed by a negative HCV RNA test at screening

          -  Diagnosis of locally advanced and/or metastatic solid tumors with radiologically
             measurable disease according to RECIST v1.1

          -  Female participants who are not pregnant, not breastfeeding, and at least one of the
             following conditions applies: Not a woman of childbearing potential (WOCBP); or a
             WOCBP who: 1) Agrees to remain abstinent or use contraceptive methods that result in a
             failure rate of <1% per year during the treatment period and for at least 4 months
             after the last dose of RO7121661; and 2) Has a negative pregnancy test (blood) within
             the 7 days prior to the first study RO7121661 administration

          -  Male participants: During the treatment period and for at least 4 months after the
             last dose of RO7121661, agreement to: 1) Remain abstinent or use contraceptive
             measures such as a condom plus an additional contraceptive method that together result
             in a failure rate of <1% per year, with partners who are women of childbearing
             potential and/or with pregnant female partners; and 2) Refrain from donating sperm for
             4 months

        Specific Inclusion Criteria for Biopsies:

        - Participants who are enrolled on the parts of the study where fresh biopsies are
        requested must have at least one non-target tumor lesion accessible to biopsy per clinical
        judgment of the treating physician and consent to undergo mandatory fresh baseline and
        on-treatment biopsy. A lesion with evidence of progression by imaging (or measurement for
        cutaneous lesions) is preferred if it can be assessed accurately. Bone lesion biopsies,
        bronchoscopy/trans-bronchial biopsies, and cytology fine needle aspirates are not
        acceptable (applicable for Expansion in Parts B1 and B2 [CPI Experienced Patients], Part B3
        [Untreated CIT-Naïve NSCLC], and Part B4 [CPI-Naïve SCLC])

        Specific Inclusion Criteria for Part B1 and Part B2 Expansion Cohorts (Checkpoint Inhibitor
        [CPI] Experienced Patients):

          -  Participants with advanced and/or metastatic malignancies who have progressed on an
             anti-programmed death-ligand 1 (PD-L1)/anti-programmed death-1 (PD-1) agent

          -  The non-small cell lung cancer (NSCLC) participants must have experienced initial
             clinical benefit from CPI therapy for at least 4 months in which there was at least
             one interval scan prior to 4 months demonstrating no progression of disease

          -  Participants who are considered to be deriving benefit from treatment post
             progression, as per clinical judgment, are not considered eligible. Screening tumor
             assessment should confirm progression

          -  Prior anti-PD-L1/anti-PD-1 as monotherapy and/or as combination therapy may have been
             administered as indicated for the respective indications, with the exception of
             adjuvant therapy

          -  For Part B1 (CPI-Experienced Metastatic Melanoma): Participants with histologically
             confirmed advanced metastatic melanoma previously treated with approved
             anti-PD-L1/anti-PD-1 agents with or without approved anti-cytotoxic
             T-lymphocyte-associated protein 4 (CTLA-4) therapy and up to one additional treatment
             regimen

          -  For Part B2 (CPI-Experienced NSCLC): Participants with histologically confirmed
             advanced NSCLC previously treated with PD-L1/PD-1 inhibitors (investigational or
             approved) and platinum based chemotherapy, either sequentially or concurrently

        Specific Inclusion Criteria for Expansion Part B3 in Untreated Cancer Immunotherapy
        (CIT)-Naïve NSCLC Cohort:

        - Histologically confirmed advanced NSCLC with PD-L1 high. Can be based on historic results
        or analysis of archival or fresh biopsy.

        Specific Inclusion Criteria for Expansion Part B4 in CPI-Naïve Small Cell Lung Cancer
        (SCLC) Cohort:

          -  Histologically confirmed SCLC

          -  May have had prior chemotherapy, radiation therapy or declined approved therapies for
             SCLC

        Exclusion Criteria:

        General Exclusion Criteria:

          -  Known hypersensitivity to any of the components of RO7121661

          -  History or clinical evidence of central nervous system primary tumors or metastases
             including leptomeningeal metastases, unless they have been previously treated, are
             asymptomatic, and have had no requirement for steroids or enzyme-inducing
             anticonvulsants in the last 14 days prior to Screening

          -  Participants with an active second malignancy

          -  Evidence of significant, uncontrolled concomitant diseases that could affect
             compliance with the protocol or interpretation of results, including diabetes
             mellitus, history of relevant pulmonary disorders, and known autoimmune diseases or
             immune deficiency, or other disease with ongoing fibrosis

          -  Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed
             consent

          -  Severe dyspnea or requiring supplemental oxygen therapy at rest

          -  Significant cardiovascular/cerebrovascular vascular disease within 6 months prior to
             D1 of study drug administration

          -  Known active or uncontrolled bacterial, viral, fungal, mycobacterial, parasitic, or
             other infection or any major episode of infection requiring treatment with IV
             antibiotics or hospitalization within 4 weeks prior to the start of drug
             administration

          -  Vaccination with live vaccines within 28 days prior to the start of treatment

          -  Known clinically significant liver disease

          -  Major surgical procedure or significant traumatic injury within 28 days prior to C1D1,
             or anticipation of the need for major surgery during the course of the study

          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding 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

          -  Dementia or altered mental status that would prohibit informed consent

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures

          -  Active or history of autoimmune disease or immune deficiency

          -  For Part A, Part B1 (CPI experienced melanoma patients), and Part B2 (CPI and platinum
             experienced NSCLC patients): prior treatment with CPIs, immunomodulatory monoclonal
             antibodies (mAbs), and/or mAb-derived therapies is allowed (approved or
             investigational), with the following exceptions: <4 weeks have elapsed between the
             last dose of prior anti-PD-1 and the proposed C1D1; <5 half-lives or 28 days
             (whichever is shorter) have elapsed from prior treatment with specific
             immunomodulators, TLR agonists, inhibitors of IDO/TDO, or agonists; Prior treatment
             with adoptive cell therapies, such as CAR-T therapies is not permitted

          -  For Part B2 (PD-1/PD-L1 and chemotherapy experienced NSCLC patients): prior treatment
             with immunomodulatory agents for cancer therapy, other than anti-PD-1 or anti-PD-L1
             agents, is prohibited

          -  Prior treatment with a TIM-3 inhibitor or LAG-3 inhibitor is prohibited

          -  Concurrent therapy with any other investigational drug <28 days or 5 half-lives of the
             drug, whichever is shorter, prior to the first RO7121661 administration on C1D1, is
             prohibited

          -  Immuno-modulating agents: Last dose with any of the following agents, for example,
             etanercept, infliximab, tacrolimus, cyclosporine, mycophenolic acid, alefacept, or
             efalizumab <28 days prior to C1D1 and regular immunosuppressive therapy are prohibited

          -  Chronic use of steroids (excluding topical and inhaled) and concurrent high doses of
             systemic corticosteroids will not be allowed

          -  Radiotherapy within the last 4 weeks before start of study drug treatment is not
             allowed, with the exception of limited palliative radiotherapy

          -  Eligibility of participants who require blood transfusion before and after the start
             of the study treatment should be discussed by the Sponsor and Investigator

        Specific Exclusion Criteria for Part B1 and Part B2 Expansion Cohorts (CPI Experienced
        Patients):

          -  Any history of an immune-related Grade 4 adverse event attributed to prior CIT

          -  Any history of an immune-related adverse event attributed to prior CIT that resulted
             in permanent discontinuation of the prior immunotherapeutic agent and/or occurred ≤6
             months prior to planned C1D1

          -  All immune-related adverse events related to prior immunomodulatory therapy must have
             resolved completely to baseline. Participants treated with corticosteroids for
             immune-related adverse events must demonstrate absence of related symptoms or signs
             for ≥4 weeks following discontinuation of corticosteroids

        Specific Exclusion Criteria for Part B2 Expansion NSCLC Cohort:

        - NSCLC patients with the following mutations, rearrangements, translocations are not
        eligible for Part B2: epidermal growth factor receptor (EGFR); anaplastic lymphoma kinase
        (ALK); ROS proto-oncogene 1 (ROS1), BRAFV600E, neurotrophic receptor tyrosine kinase (NTRK)

        Specific Exclusion Criteria for Part B3 Expansion Untreated CIT-Naïve NSCLC Cohort:

          -  Prior therapy for metastatic disease is not permitted

          -  Adjuvant anti-PD-1 or anti-PD-L1 therapy is not allowed. Adjuvant chemotherapy is
             permitted as long as treatment was administered >6 months prior

        Specific Exclusion Criteria for Part B4 Expansion CPI-Naïve SCLC Cohort:

        - Prior therapy with any immune CPIs (such as anti-PD-L1/PD-1, CTLA-4), is not permitted
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Escalation: Percentage of Participants with a Dose-Limiting Toxicity (DLT)
Time Frame:For Part A1 (Q2W: 1 cycle is 14 days): From Cycle 1 Day 1 to Cycle 2 Day 7 (up to 35 days); For Part A2 (Q3W: 1 cycle is 21 days): From Cycle 1 Day 1 to Cycle 2 Day 7 (up to 42 days)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Area Under the Concentration-Time Curve (AUC) of RO7121661
Time Frame:For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), as indicated: Days 1-5, 8, 12 (plus Days 15 and 18 for Q3W) of Cycles 1 and 5; Days 1, 2, 5 of Cycle 2; Day 1 of Cycles 3-4 and Cycle 6 onwards through study completion (up to 27 months)
Safety Issue:
Description:
Measure:Maximum Concentration (Cmax) of RO7121661
Time Frame:For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), as indicated: Days 1-5, 8, 12 (plus Days 15 and 18 for Q3W) of Cycles 1 and 5; Days 1, 2, 5 of Cycle 2; Day 1 of Cycles 3-4 and Cycle 6 onwards through study completion (up to 27 months)
Safety Issue:
Description:
Measure:Total Clearance (CL) of RO7121661
Time Frame:For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), as indicated: Days 1-5, 8, 12 (plus Days 15 and 18 for Q3W) of Cycles 1 and 5; Days 1, 2, 5 of Cycle 2; Day 1 of Cycles 3-4 and Cycle 6 onwards through study completion (up to 27 months)
Safety Issue:
Description:
Measure:Volume of Distribution at Steady State of RO7121661
Time Frame:For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), as indicated: Days 1-5, 8, 12 (plus Days 15 and 18 for Q3W) of Cycles 1 and 5; Days 1, 2, 5 of Cycle 2; Day 1 of Cycles 3-4 and Cycle 6 onwards through study completion (up to 27 months)
Safety Issue:
Description:
Measure:Terminal Half-Life (t1/2) of RO7121661
Time Frame:For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), as indicated: Days 1-5, 8, 12 (plus Days 15 and 18 for Q3W) of Cycles 1 and 5; Days 1, 2, 5 of Cycle 2; Day 1 of Cycles 3-4 and Cycle 6 onwards through study completion (up to 27 months)
Safety Issue:
Description:
Measure:Percentage of Participants with Anti-Drug Antibodies
Time Frame:For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days): Day 1 of Cycles 1 to 5; Day 1 of Cycle 7, and every 3 (for Q3W) or every 6 (for Q2W) cycles afterwards through study completion (up to 27 months)
Safety Issue:
Description:
Measure:Receptor Occupancy of RO7121661, Assessed via an Ex-Vivo Assay
Time Frame:For Parts A1 (Q2W) and A2 (Q3W), as shown: Days 1, 8 (plus Day 15 for Q3W) of Cycles 1, 5; Day 1 of Cycles 2, 3; and Day 1 of Cycles 9, 22, 35, 48 (for Q2W) or Cycles 7, 15, 23, 31 (for Q3W) through study completion (up to 27 months)
Safety Issue:
Description:
Measure:Examine Profile and Status of T-cell Proliferation/Activation in Tumor Biopsies and Peripheral Blood
Time Frame:For Parts B1-3 (Q2W/Q3W): At screening; Days 1, 2, 8 (and Day 15 for Q3W) of Cycles 1, 5; Day 1 (and Day 5 for Q3W) of Cycle 2; Day 1 Cycle 3 and Cycles 9, 22, 35, 48 (for Q2W) or Cycles 7, 15, 23, 31 (for Q3W) through study completion (up to 27 months)
Safety Issue:
Description:For Q2W: 1 cycle is 14 days; for Q3W: 1 cycle is 21 days

Details

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

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