Clinical trial NCT04140500: Dose Escalation Study of a PD1-LAG3 Bispecific Antibody in Patients With Advanced and/or Metastatic Solid Tumors
Official title: An Open Label, Multicenter, Dose Escalation, Phase 1 Study to Evaluate Safety/Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Anti Tumor Activity of RO7247669, a PD1-LAG3 Bispecific Antibody, in Patients With Advanced and/or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Solid Tumors
Metastatic Melanoma
Non-small Cell Lung Cancer
Esophageal Squamous Cell Carcinoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2019-10-28
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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
* Eastern Cooperative Oncology Group Performance Status 0-1
* Fresh biopsies may be required
* 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
* Not more than 2 prior lines of treatment for metastatic disease are allowed prior to enrolling in the study
* 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

* Participants with histologically confirmed advanced non-small cell lung cancer
* Not more than 2 prior lines of treatment for metastatic disease are allowed prior to enrolling in the study
* Previously treated with approved PD-L1/PD-1 inhibitors
* 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

* Participants whose major lesion was histologically confirmed as squamous cell carcinoma or adenosquamous cell carcinoma of the esophagus
* 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

* Participants with histologically confirmed advanced non-small cell lung cancer
* Tumor PD-L1 expression as determined by immunohistochemistry assay of archival tumor tissue or tissue obtained at screening

Exclusion criteria

* Pregnancy, lactation, or breastfeeding
* Known hypersensitivity to any of the components of RO7247669
* Active or untreated central nervous system (CNS) metastases
* An active second malignancy
* 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
* Positive HIV, hepatitis B, or hepatitis C test result
* Known active or uncontrolled bacterial, viral, fungal, mycobacterial, parasitic, or other infection
* Vaccination with live vaccines within 28 days prior to Cycle 1 Day 1
* 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 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
* Neo-adjuvant anti-PD-1 or anti-PD-L1 therapy is not allowed

Primary outcomes:
measure: Part A: Percentage of Participants with Dose-Limiting Toxicities (DLTs)
timeFrame: Days 1-21 (Q2W dosing) or Days 1-28 (Q3W dosing) of Cycle 1
measure: Part A: Percentage of Participants with Adverse Events
timeFrame: Baseline through the end of study (up to 24 months)
measure: Part B: Objective Response Rate (ORR)
timeFrame: Up to 24 months
measure: Part B: Disease Control Rate (DCR), Defined as ORR + Stable Disease Rate (SDR)
timeFrame: Up to 24 months
measure: Part B: Duration of Response (DOR)
timeFrame: Up to 24 months
measure: 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
timeFrame: Up to 24 months
Secondary outcomes:
measure: Parts A and B: Maximum Concentration (Cmax) of RO7247669
timeFrame: At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)
measure: Parts A and B: Time of Maximum Concentration (Tmax) of RO7247669
timeFrame: At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)
measure: Parts A and B: Clearance (CL) of RO7247669
timeFrame: At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)
measure: Parts A and B: Volume of Distribution at Steady State (Vss) of RO7247669
timeFrame: At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)
measure: Parts A and B: Area Under the Curve (AUC) of RO7247669
timeFrame: At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)
measure: Parts A and B: Half-Life (T1/2) of RO7247669
timeFrame: At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)
measure: Parts A and B: Percentage of Participants with Anti-Drug Antibodies (ADA) to RO7247669
timeFrame: Day 1 of each Cycle, starting with Cycle 1, through final study visit (up to 24 months)
measure: Part B: Change from Baseline in T-Cell Activity
timeFrame: At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)
measure: Part A: Percentage of Receptors Occupied by RO7247669
timeFrame: At pre-defined intervals from Day 1 of Cycle 1 through final study visit (up to 24 months)
measure: Part A: ORR
timeFrame: At pre-defined intervals from initial dose up to 24 months
measure: Part A: DCR
timeFrame: At pre-defined intervals from initial dose up to 24 months
measure: Part A: PFS
timeFrame: At pre-defined intervals from initial dose up to 24 months
measure: Part A: DOR
timeFrame: At pre-defined intervals from initial dose up to 24 months
measure: Part B: Percentage of Participants with Adverse Events
timeFrame: Baseline through the end of study (up to 24 months)
Other outcomes:
Locations:
city: København Ø
country: Denmark
facility: Rigshospitalet
city: Odense C
country: Denmark
facility: Odense Universitetshospital, Onkologisk Afdeling R
city: Tbilisi
country: Georgia
facility: LLC Arensia Explorer Medicine
city: Jerusaelm
country: Israel
facility: Hadassah University Hospital - Ein Kerem
city: Petach Tikva
country: Israel
facility: Rabin MC
city: Ramat Gan
country: Israel
facility: Chaim Sheba medical center, Oncology division
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara Fray Antonio Alcalde
state: Jalisco
city: Mexico City
country: Mexico
facility: Inst. Nacional de Cancerología
state: Mexico CITY (federal District)
city: Querétaro
country: Mexico
facility: Consultorio Médico Jordi Guzmán Casta
state: Queretaro
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: National Cancer Centre
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Vall d?Hebron Institute of Oncology (VHIO), Barcelona
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra Madrid
city: Madrid
country: Spain
facility: START Madrid. Centro Integral Oncologico Clara Campal
city: Adana
country: Turkey
facility: Adana City Hospital, Medical Oncology
city: Ankara
country: Turkey
facility: Ankara City Hospital
city: Sihhiye/Ankara
country: Turkey
facility: Hacettepe Uni Medical Faculty Hospital
city: Yen?mahalle
country: Turkey
facility: Ankara Abdurrahman Yurtaslan Oncology Training and Research Hospital Phase 1 Center
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Manchester
country: United Kingdom
facility: Christie Hospital NHS Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: