Dose Escalation Study of a PD1-LAG3 Bispecific Antibody in Patients With Advanced and/or Metastatic Solid Tumors
Study Details
Study Description
Brief Summary
This is a first-in-human, open-label, multicenter, Phase I multiple-ascending dose (MAD) study of RO7247669, an anti PD-1 (programmed death-1) and LAG-3 (Lymphocyte-activation gene 3) bispecific antibody, for participants with advanced and/or metastatic solid tumors. This study aims to establish the maximum tolerated dose (MTD) and/or define the recommended phase 2 dose (RP2D) based on the safety, tolerability, pharmacokinetic (PK) and/or pharmacodynamic (PD) profile of RO7247669, and to evaluate preliminary anti-tumor activity in participants with solid tumors. An expansion part of the study is planned to enroll tumor-specific cohorts to evaluate anti-tumor activity of the MTD and/or RP2D of RO7247669 and to confirm safety and tolerability in participants with selected tumor types.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part A: Single-Agent Dose Escalation Participants will receive RO7247669 every 2 weeks (Q2W) or every 3 weeks (Q3W) up to the maximum tolerated dose (MTD) until disease progression, unacceptable drug toxicity, or withdrawal of consent, for up to 24 months. |
Drug: RO7247669
Participants will receive intravenous (IV) RO7247669 at different doses either every 2 weeks (Q2W) or every 3 weeks (Q3W)
|
| Experimental: Part B: Tumor Specific Expansion Cohorts Participants with selected solid tumor indications will receive RO7247669 at a dose derived from Part A until disease progression, unacceptable drug toxicity, or withdrawal of consent, for up to 24 months. |
Drug: RO7247669
Participants will receive intravenous (IV) RO7247669 at different doses either every 2 weeks (Q2W) or every 3 weeks (Q3W)
|
Outcome Measures
Primary Outcome Measures
- Part A: Percentage of Participants with Dose-Limiting Toxicities (DLTs) [Days 1-21 (Q2W dosing) or Days 1-28 (Q3W dosing) of Cycle 1]
- Part A: Percentage of Participants with Adverse Events [Baseline through the end of study (up to 24 months)]
- Part B: Objective Response Rate (ORR) [Up to 24 months]
- Part B: Disease Control Rate (DCR), Defined as ORR + Stable Disease Rate (SDR) [Up to 24 months]
- Part B: Duration of Response (DOR) [Up to 24 months]
- Part B: Progression-free Survival (PFS), Defined as the Time from the First Study Treatment to the First Occurrence of Progression per Investigator Assessment or Death from any Cause, Whichever Occurs First [Up to 24 months]
Secondary Outcome Measures
- Parts A and B: Maximum Concentration (Cmax) of RO7247669 [At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)]
- Parts A and B: Time of Maximum Concentration (Tmax) of RO7247669 [At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)]
- Parts A and B: Clearance (CL) of RO7247669 [At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)]
- Parts A and B: Volume of Distribution at Steady State (Vss) of RO7247669 [At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)]
- Parts A and B: Area Under the Curve (AUC) of RO7247669 [At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)]
- Parts A and B: Half-Life (T1/2) of RO7247669 [At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)]
- Parts A and B: Percentage of Participants with Anti-Drug Antibodies (ADA) to RO7247669 [Day 1 of each Cycle, starting with Cycle 1, through final study visit (up to 24 months)]
- Part B: Change from Baseline in T-Cell Activity [At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)]
- Part A: Percentage of Receptors Occupied by RO7247669 [At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)]
- Part A: ORR [At pre-defined intervals from initial dose up to 24 months]
- Part A: DCR [At pre-defined intervals from initial dose up to 24 months]
- Part A: PFS [At pre-defined intervals from initial dose up to 24 months]
- Part A: DOR [At pre-defined intervals from initial dose up to 24 months]
- Part B: Percentage of Participants with Adverse Events [Baseline through the end of study (up to 24 months)]
Eligibility Criteria
Criteria
Inclusion criteria
-
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
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Eastern Cooperative Oncology Group Performance Status 0-1
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Fresh biopsies may be required
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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
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Histologically confirmed, unresectable stage III or stage IV melanoma
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Not more than 2 prior lines of treatment for metastatic disease are allowed prior to enrolling in the study
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Prior treatment with an approved anti-PD-1 or anti-PD-L1 agent
Additional Specific Inclusion Criteria for Participants with Non-Small Cell Lung Cancer who Previously Received Treatment for Metastatic Disease
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Participants with histologically confirmed advanced non-small cell lung cancer
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Not more than 2 prior lines of treatment for metastatic disease are allowed prior to enrolling in the study
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Previously treated with approved PD-L1/PD-1 inhibitors
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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 Esophageal Squamous Cell Carcinoma
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Participants whose major lesion was histologically confirmed as squamous cell carcinoma or adenosquamous cell carcinoma of the esophagus
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Participants who have previously received not more than 1 prior line of treatment for metastatic disease prior to enrolling in the study
Additional Specific Inclusion Criteria for Participants with Non-Small Cell Lung Cancer who Previously did not Receive Treatment for Metastatic Disease
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Participants with histologically confirmed advanced non-small cell lung cancer
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Tumor PD-L1 expression as determined by immunohistochemistry assay of archival tumor tissue or tissue obtained at screening
Exclusion criteria
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Pregnancy, lactation, or breastfeeding
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Known hypersensitivity to any of the components of RO7247669
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Active or untreated central nervous system (CNS) metastases
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An active second malignancy
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Evidence of concomitant 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
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Positive HIV, hepatitis B, or hepatitis C test result
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Known active or uncontrolled bacterial, viral, fungal, mycobacterial, parasitic, or other infection
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Vaccination with live vaccines within 28 days prior to Cycle 1 Day 1
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Treatment with oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1
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Active or history of autoimmune disease or immune deficiency
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Prior treatment with adoptive cell therapies, such as CAR-T therapies
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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
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Regular immunosuppressive therapy
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Radiotherapy within the last 4 weeks before start of study drug treatment, with the exception of limited palliative radiotherapy
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Prior treatment with a lymphocyte activation gene-3 (LAG-3) inhibitor
Additional Specific Exclusion Criteria for Participants with Non-Small Cell Lung Cancer who Previously Received Treatment for Metastatic Disease
- Participants with the following muations, rearrangements, translocations are not eligible: EGFR, ALK, ROS1, BRAFV600E, and NTRK
Additional Specific Exclusion Criteria for Participants with Esophageal Squamous Cell Carcinoma
- Prior therapy with any immunomodulatory agents
Additional Specific Exclusion Criteria for Participants with Non-Small Cell Lung Cancer who Previously did not Receive Treatment for Metastatic Disease
-
Prior therapy for metastatic disease is not permitted
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Neo-adjuvant anti-PD-1 or anti-PD-L1 therapy is not allowed
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sharp Memorial Hospital | San Diego | California | United States | 92123 |
| 2 | Henry Ford Hospital; Hematology/Oncology Phase 1 | Detroit | Michigan | United States | 48202 |
| 3 | Rigshospitalet; Fase 1 Enhed - Onkologi | København Ø | Denmark | 2100 | |
| 4 | Hadassah University Hospital - Ein Kerem; Oncology | Jerusaelm | Israel | 9112001 | |
| 5 | Rabin MC; Davidof Center - Oncology Institute | Petach Tikva | Israel | 4941492 | |
| 6 | Chaim Sheba medical center, Oncology division | Ramat Gan | Israel | 5262000 | |
| 7 | Seoul National University Bundang Hospital | Seongnam-si | Korea, Republic of | 13605 | |
| 8 | Seoul National University Hospital | Seoul | Korea, Republic of | 03080 | |
| 9 | Severance Hospital, Yonsei University Health System | Seoul | Korea, Republic of | 03722 | |
| 10 | Asan Medical Center | Seoul | Korea, Republic of | 05505 | |
| 11 | IPO do Porto; Servico de Oncologia Medica | Porto | Portugal | 4200-072 | |
| 12 | National University Hospital; National University Cancer Institute, Singapore (NCIS) | Singapore | Singapore | 119228 | |
| 13 | National Cancer Centre; Medical Oncology | Singapore | Singapore | 169610 | |
| 14 | Clinica Universitaria de Navarra; Servicio de Oncologia | Pamplona | Navarra | Spain | 31008 |
| 15 | Hospital del Mar; Servicio de Oncologia | Barcelona | Spain | 08003 | |
| 16 | Vall d´Hebron Institute of Oncology (VHIO), Barcelona | Barcelona | Spain | 08035 | |
| 17 | Clinica Universidad de Navarra Madrid; Servicio de Oncología | Madrid | Spain | 28027 | |
| 18 | START Madrid-FJD, Hospital Fundacion Jimenez Diaz | Madrid | Spain | 28040 | |
| 19 | START Madrid. Centro Integral Oncologico Clara Campal; CIOCC | Madrid | Spain | 28050 | |
| 20 | Queen Elizabeth Hospital | Birmingham | United Kingdom | B15 2TH | |
| 21 | Christie Hospital NHS Trust; Experimental Cancer Medicine Team | Manchester | United Kingdom | M20 4BX |
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.- NP41300
- 2019-000779-18