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

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03708328
Collaborator
(none)
134
17
6
51.9
7.9
0.2

Study Details

Study Description

Brief Summary

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
134 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Oct 15, 2018
Anticipated Primary Completion Date :
Feb 11, 2023
Anticipated Study Completion Date :
Feb 11, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dose Escalation Part A: Once Every 2 Weeks (Q2W)

RO7121661 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.

Drug: RO7121661
RO7121661 will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.
Other Names:
  • RG7769
  • Experimental: Expansion Part B1: Metastatic Melanoma Cohort

    This 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.

    Drug: RO7121661
    RO7121661 will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.
    Other Names:
  • RG7769
  • Experimental: Expansion Part B2: NSCLC Cohort 1

    This 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.

    Drug: RO7121661
    RO7121661 will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.
    Other Names:
  • RG7769
  • Experimental: Expansion Part B3: NSCLC Cohort 2

    This 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.

    Drug: RO7121661
    RO7121661 will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.
    Other Names:
  • RG7769
  • Experimental: Expansion Part B4: SCLC Cohort

    This 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.

    Drug: RO7121661
    RO7121661 will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.
    Other Names:
  • RG7769
  • Experimental: Expansion Part B5: ESCC Cohort

    This 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.

    Drug: RO7121661
    RO7121661 will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.
    Other Names:
  • RG7769
  • Outcome Measures

    Primary Outcome Measures

    1. 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)]

    2. 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]

    3. Expansion: Objective Response Rate, Assessed According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [Up to 27 months]

    4. Expansion: Disease Control Rate, Assessed According to RECIST v1.1 [Up to 27 months]

    5. Expansion: Duration of Response, Assessed According to RECIST v1.1 [Up to 27 months]

    6. Expansion: Progression Free Survival, Assessed According to RECIST v1.1 [Up to 27 months]

    Secondary Outcome Measures

    1. Dose Escalation and Expansion: Area Under the Concentration-Time Curve (AUC) of RO7121661 [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)]

    2. Dose Escalation and Expansion: Maximum Concentration (Cmax) of RO7121661 [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)]

    3. Dose Escalation and Expansion: Total Clearance (CL) of RO7121661 [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)]

    4. Dose Escalation and Expansion: Volume of Distribution at Steady State of RO7121661 [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)]

    5. Dose Escalation and Expansion: Terminal Half-Life (t1/2) of RO7121661 [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)]

    6. 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)]

    7. Expansion: Number of Participants with at Least One Adverse Event, Severity Graded According to NCI CTCAE v5.0 [Up to 27 months]

    8. 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)]

    9. Dose Escalation: Receptor Occupancy of RO7121661, 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)]

    10. Dose Escalation: Objective Response Rate, Assessed According to RECIST v1.1 [Up to 27 months]

    11. Dose Escalation: Disease Control Rate, Assessed According to RECIST v1.1 [Up to 27 months]

    12. Dose Escalation: Duration of Response, Assessed According to RECIST v1.1 [Up to 27 months]

    13. Dose Escalation: Progression Free Survival, Assessed According to RECIST v1.1 [Up to 27 months]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Columbia Univ Med Ctr New York New York United States 10032
    2 MD Anderson Cancer Center Houston Texas United States 77030
    3 Herlev Hospital; Afdeling for Kræftbehandling Herlev Denmark 2730
    4 Rigshospitalet; Onkologisk Klinik København Ø Denmark 2100
    5 Institut Bergonie; Oncologie Bordeaux France 33076
    6 Centre Leon Berard; Service Oncologie Medicale Lyon France 69008
    7 CHU Timone; Centre d'Essais Précoces en Cancérologie de Marseille (CEPCM) Marseille France 13005
    8 ICO Rene Gauducheau; CEC St Herblain France 44805
    9 Seoul National University Hospital Seoul Korea, Republic of 03080
    10 Severance Hospital, Yonsei University Health System Seoul Korea, Republic of 03722
    11 Asan Medical Center Seoul Korea, Republic of 05505
    12 Auckland City Hospital; Clinical Oncology Auckland New Zealand 1023
    13 Clinica Universitaria de Navarra; Servicio de oncología Pamplona Navarra Spain 31008
    14 Vall d´Hebron Institute of Oncology (VHIO), Barcelona Barcelona Spain 08035
    15 Hospital Ramon y Cajal; Servicio de Oncologia Madrid Spain 28034
    16 START Madrid-FJD, Hospital Fundacion Jimenez Diaz Madrid Spain 28040
    17 Hospital Clínico Universitario de Valencia; Servicio de Oncología Valencia Spain 46010

    Sponsors and Collaborators

    • Hoffmann-La Roche

    Investigators

    • Study Director: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT03708328
    Other Study ID Numbers:
    • NP40435
    • 2018-000982-35
    First Posted:
    Oct 17, 2018
    Last Update Posted:
    Aug 4, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 4, 2022