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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

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ClinicalTrials.gov Identifier: NCT03708328
Recruitment Status : Recruiting
First Posted : October 17, 2018
Last Update Posted : October 22, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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 (Parts A1 and A2) and Dose Expansion (Parts B1, B2, and B3). 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 Dose 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.

Condition or disease Intervention/treatment Phase
Solid Tumors Metastatic Melanoma Non-small Cell Lung Cancer Drug: RO7121661 Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 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 : October 15, 2018
Estimated Primary Completion Date : July 30, 2022
Estimated Study Completion Date : July 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose Escalation Part A1: 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. Dosing on the Q2W schedule will inform whether a once every 3 weeks (Q3W) schedule will be assessed.
Drug: RO7121661
RO7121661 will be administered intravenously (IV) with a flat dose, on the schedule described for each study arm, until disease progression, unacceptable toxicity, or withdrawal of consent (up to 24 months).

Experimental: Dose Escalation Part A2: Once Every 3 Weeks (Q3W)
RO7121661 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.
Drug: RO7121661
RO7121661 will be administered intravenously (IV) with a flat dose, on the schedule described for each study arm, until disease progression, unacceptable toxicity, or withdrawal of consent (up to 24 months).

Experimental: Dose 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 Dose 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, until disease progression, unacceptable toxicity, or withdrawal of consent (up to 24 months).

Experimental: Dose Expansion Part B2: NSCLC Cohort 1
This cohort will comprise participants with CPI and platinum experienced, second line and beyond non-small cell lung cancer (NSCLC). The starting dose of RO7121661 for Dose 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, until disease progression, unacceptable toxicity, or withdrawal of consent (up to 24 months).

Experimental: Dose 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 Dose 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, until disease progression, unacceptable toxicity, or withdrawal of consent (up to 24 months).




Primary Outcome Measures :
  1. 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) ]
  2. Dose Escalation: Maximum Tolerated Dose (MTD) of RO7121661 [ Time Frame: Approximately 12 months ]
  3. Percentage of Participants with at Least One Adverse Event [ Time Frame: Up to 27 months ]
  4. Percentage of Participants with at Least One Grade ≥3 Adverse Event, Severity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 [ Time Frame: Up to 27 months ]
  5. Objective Response Rate, As Assessed According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [ Time Frame: Up to 24 months ]
  6. Disease Control Rate, As Assessed According to RECIST v1.1 [ Time Frame: Up to 24 months ]
  7. Duration of Response, As Assessed According to RECIST v1.1 [ Time Frame: Up to 24 months ]
  8. Progression Free Survival, As Assessed According to RECIST v1.1 [ Time Frame: Up to 24 months ]

Secondary Outcome Measures :
  1. Area Under the Concentration-Time Curve (AUC) for 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 (24 months) ]
  2. Maximum Concentration for 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 (24 months) ]
  3. Total Clearance for 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 (24 months) ]
  4. Volume of Distribution at Steady State for 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 (24 months) ]
  5. Terminal Half-Life for 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 (24 months) ]
  6. 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 (24 months) ]
  7. Receptor Occupancy for RO7121661, Assessed via an Ex-Vivo Assay [ Time Frame: For Q2W (1 cycle is 14 days) and Q3W (1 cycle is 21 days), 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 (24 months) ]
  8. 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 (24 months) ]
    For Q2W: 1 cycle is 14 days; for Q3W: 1 cycle is 21 days



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

General Inclusion Criteria:

  • Life expectancy of ≥12 weeks
  • Eastern Cooperative Oncology Group Performance Status 0-1
  • Adequate cardiovascular function
  • All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade ≤1, except alopecia (any grade) and Grade 2 peripheral neuropathy
  • Adequate hematological, liver, renal function
  • 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 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: Woman of childbearing potential: Agree 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. Have 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 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 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 tumor lesion accessible to biopsy per clinical judgment of the treating physician and consent to undergo mandatory fresh baseline and on-treatment biopsy. Bone lesion biopsies, bronchoscopy/trans-bronchial biopsies, and cytology fine needle aspirates are not acceptable

Specific Inclusion Criteria for Part B Expansion in Checkpoint Inhibitor (CPI) Experienced Patients:

  • CPI experienced patients are defined as those who have had prior treatment with an anti-PD-1 or anti-PD-L1 (programmed death-ligand 1) agent. Participants must meet the following additional criteria to be eligible for inclusion in Part B of the study if they are CPI experienced
  • Participants with advanced and/or metastatic malignancies treated with anti-PD-L1/ anti-PD-1 with or without anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) checkpoint inhibitor therapy
  • The non-small cell lung cancer (NSCLC) and melanoma patients 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/PD-1 with or without anti-CTLA-4 as monotherapy and/or as combination therapy may have been administered at any time during a participant's treatment course, with the exception of adjuvant therapy
  • Participants must have at least one tumor lesion accessible and adequate for biopsy per clinical judgment of the treating physician and consent to undergo mandatory fresh baseline and an additional on−treatment biopsy. Bone lesion biopsies, bronchoscopy/trans-bronchial biopsies, and cytology fine needle aspirates are not

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

  • Participants must have at least one tumor lesion accessible to biopsy per clinical judgment of the treating physician and consent to undergo mandatory fresh baseline and on-treatment biopsy. Bone lesion biopsies, bronchoscopy/trans-bronchial biopsies, and cytology fine needle aspirates are not acceptable
  • Participants with histologically confirmed advanced NSCLC with PD-L1 high TPS ≥50%, used interchangeably with tumor cell staining, assessed locally, using 22C3 clone
  • Not previously treated with cancer immunotherapeutic agents, including anti-PD-L1/PD-1 and/or anti-CTLA-4

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 and history of thromboembolic events within 6 months of enrollment
  • 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
  • Adverse events from any prior anti-cancer therapy that have not resolved to Grade ≤1 except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy
  • Active or history of autoimmune disease or immune deficiency
  • For Part A and Part B1 (CPI experienced melanoma patients): prior treatment with CPIs, immunomodulatory monoclonal antibodies (mAbs), and/or mAb-derived therapies is allowed provided that at least 6 weeks have elapsed between the last dose and the proposed C1D1
  • 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 and TIM-3 inhibitor or lymphocyte-activation gene 3 (LAG-3) inhibitor 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
  • 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
  • Chronic use of steroids (excluding topical and inhaled) and concurrent high doses of systemic corticosteroids will not be allowed. High dose is considered as >20 mg of dexamethasone a day for >7 consecutive days.
  • Radiotherapy within the last 4 weeks before start of study drug treatment, 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-mediated adverse event (including Grade 4) 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-mediated adverse events related to prior immunomodulatory therapy must have resolved completely to baseline. Participants treated with corticosteroids for immune-mediated adverse events must demonstrate absence of related symptoms or signs for ≥4 weeks following discontinuation of corticosteroids

Specific Exclusion Criteria for Part B3 Expansion 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03708328


Contacts
Contact: Reference Study ID Number: NP40435 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. Only) global-roche-genentech-trials@gene.com

Locations
Denmark
Rigshospitalet; Onkologisk Klinik Recruiting
København Ø, Denmark, 2100
Spain
Clinica Universitaria de Navarra; Servicio de oncología Not yet recruiting
Pamplona, Navarra, Spain, 31008
Hospital Ramon y Cajal; Servicio de Oncologia Not yet recruiting
Madrid, Spain, 28034
START Madrid-FJD, Hospital Fundacion Jimenez Diaz Not yet recruiting
Madrid, Spain, 28040
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03708328     History of Changes
Other Study ID Numbers: NP40435
2018-000982-35 ( EudraCT Number )
First Posted: October 17, 2018    Key Record Dates
Last Update Posted: October 22, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Antibodies
Antibodies, Bispecific
Immunologic Factors
Physiological Effects of Drugs