Clinical trial NCT03281369: A Study of Multiple Immunotherapy-Based Treatment Combinations in Patients With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer (G/GEJ) or Esophageal Cancer (Morpheus-Gastric and Esophageal Cancer)
Official title: A Phase Ib/II, Open-Label, Multicenter, Randomized, Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer or Esophageal Cancer (Morpheus-Gastric and Esophageal Cancer)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma or Esophageal Carcinoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Halozyme Therapeutics
name: BioLineRx, Ltd.
First posted: 2017-09-13
Enrollment: 410
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A Phase Ib/II, open label, multi-center, randomized study designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations in patients with locally advanced unresectable or metastatic G/GEJ cancer (hereafter referred to as gastric cancer) and esophageal cancer. Two cohorts of patients with gastric cancer have been enrolled in parallel in this study: the second-line (2L) Gastric Cancer Cohort consists of patients with gastric cancer who have progressed after receiving a platinum-containing or fluoropyrimide-containing chemotherapy regimen in the first-line setting, and the first-line (1L) Gastric Cancer Cohort consists of patients with gastric cancer who have not received prior chemotherapy in this setting. In each cohort, eligible patients will be assigned to one of several treatment arms. Additionally, a cohort of patients with esophageal cancer who have not received prior systemic treatment for their disease will be enrolled in this study. Eligible patients will be randomized to chemotherapy or the combination of chemotherapy with checkpoint inhibitor immunotherapy.


Eligibility criteria: Inclusion Criteria:

Gastric Cancer Cohorts Inclusion Criteria:

* Age \>/= 18 years;
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;
* Life expectancy \>/= 3 months, as determined by the investigator;
* Histologically or cytologically confirmed locally advanced unresectable or metastatic adenocarcinoma of gastric or gastroesophageal junction; (for the 1L Gastric Cancer Cohort: no prior systemic therapy for the locally advanced or metastatic disease; for the 2L Gastric Cancer Cohort: disease progression during or following a first-line platinum-containing or fluoropyrimidine-containing chemotherapy regimen);
* Availability of a representative tumor specimen that is suitable for determination of PD-L1 and TIGIT levels by IHC and/or additional biomarker status by means of retrospective central testing;
* Only for the 1L Gastric Cancer Cohort: human epidermal growth factor receptor 2 (HER2)-negative tumors;
* Measurable disease (at least one target lesion) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1);
* Adequate hematologic and end organ function based on laboratory results obtained within 14 days prior to initiation of study treatment;
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures as outlined for each specific treatment arm;
* For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment arm.

Esophageal Cancer Cohort Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of squamous cell carcinoma or adenocarcinoma of the esophagus in locally advanced or metastatic disease;
* No prior systemic treatment for esophageal cancer, with the following exception:

For patients treated with chemotherapy in the locally advanced setting: occurrence of metastasis after 6 months from the last dose of chemotherapy;

* For patients with adenocarcinoma: absence of HER2 expression;
* Life expectancy \>/=3 months as determined by the investigator;
* Measurable disease per RECIST v1.1;
* Adequate hematologic and end-organ function;
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs;
* For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm;
* ECOG Performance Status of 0, 1, or 2.

Exclusion Criteria:

Exclusion criteria for the 2L Gastric Cancer Cohort:

* Urinary protein is \> 1 + on dipstick and the required following 24-hour urine collection shows urinary protein \> 2000 mg;
* Serious or non-healing wound, peptic ulcer, or bone fracture within 28 days prior to initiation of study treatment;
* History of gastrointestinal perforation and/or fistulae within 6 months prior to initiation of study treatment;
* Presence of a bowel obstruction, history or presence of inflammatory enteropathy, or extensive intestinal resection, Crohn disease, ulcerative colitis, or chronic diarrhea;
* Uncontrolled arterial hypertension \>/= 150/ \>/= 90 millimeter of mercury (mmHg) despite standard medical management;
* Chronic therapy with non-steroidal anti-inflammatory agents or other anti-platelet agents.

Gastric Cancer Exclusion Criteria:

* Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy;
* Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases;
* History of leptomeningeal disease;
* Active or history of autoimmune disease or immune deficiency;
* History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan;
* Positive test for human immunodeficiency virus (HIV) at screening;
* Active hepatitis B virus (HBV) or hepatitis C (HCV) infection;
* Severe infection within 4 weeks prior to initiation of study treatment;
* Significant cardiovascular disease;
* Significant bleeding disorder;
* Prior allogeneic stem cell or solid organ transplantation;
* Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study;
* Treatment with anticoagulation with warfarin, low-molecular-weight heparin, or similar agents for therapeutic purposes;
* History of malignancy other than gastric or gastroesophageal junction carcinoma within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death;
* Known allergy or hypersensitivity to any of the study drugs or their excipients.

Esophageal Cancer Cohort Exclusion Criteria:

* High risk for developing esophageal fistula by clinical assessment or imaging;
* Symptomatic, untreated, or actively progressing central nervous system (CNS) Metastases;
* Positive EBV viral capsid antigen IgM test at screening;
* History of leptomeningeal disease;
* Active or history of autoimmune disease or immune deficiency;
* History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan;
* Active tuberculosis;
* Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina;
* History of malignancy other than esophageal cancer within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death;
* Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab or within 90 days after the final dose of tiragolumab.

Primary outcomes:
measure: Percentage of Participants With Objective Response, as Determined by Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)
timeFrame: From Randomization until disease progression or loss of clinical benefit (up to approximately 3-6 years)
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: From first study treatment administration until 30 days after the last dose or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to approximately 3-6 years)
measure: For Arm 1L-A : Percentage of Participants with Serious and Non-serious Treatment-related AEs
timeFrame: During the safety run-in phase up to 28 days
Secondary outcomes:
measure: Progression-Free Survival (PFS), as Determined by Investigator According to RECIST v1.1
timeFrame: From randomization up to the first occurrence of disease (up to approximately 3-6 years)
measure: Overall Survival (OS)
timeFrame: From randomization up to death from any cause (up to approximately 3-6 years)
measure: Percentage of Participants Who Are Alive at Month 6 and at Month 12
timeFrame: Month 6, Month 12
measure: Duration of Response, as Determined by Investigator According to RECIST v1.1
timeFrame: From the date of first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 3-6 years)
measure: Percentage of Participants With Disease Control, as Determined by the Investigator per RECIST v1.1
timeFrame: From randomization until disease progression or loss of clinical benefit (up to approximately 3-6 years)
measure: Serum Concentration of Atezolizumab
timeFrame: Pre-infusion (0 hour [hr]), 30 minutes (min) post-infusion (infusion=60 min) on Day 1 of Cycle 1; pre-infusion (0 hr) on Day 1 of Cycles 2, 3, 4, 8, 12, 16 (each cycle=28 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
measure: Plasma Concentration of Cobimetinib
timeFrame: Prior to cobimetinib dose, 2-4 hr after cobimetinib dose on Day 15 of Cycle 1 (cycle length=28 days)
measure: Plasma Concentration of PEGPH20
timeFrame: Pre-infusion (0 hr) on Day 1 of Cycle 1 up to 30 days and 120 days after last dose (up to approximately 3-6 years) (Detailed timeframe is provided in outcome measure description)
measure: Plasma Concentration of BL-8040
timeFrame: Pre-dose (0 hr) on Day 1 of priming period (1 week prior to Day 1 of Cycle 1) up to 30 days after last dose (up to approximately 3-6 years) (Detailed timeframe is provided in outcome measure description)
measure: Plasma Concentration of Linagliptin
timeFrame: 2 hr postdose oral linagliptin on Day 1 of Cycle 1, prior to atezolizumab infusion and predose oral linagliptin on Day 15 of Cycle 1 as well as on Day 1 of Cycles 2, 3, and 4
measure: Percentage of Participants With Anti-Drug Antibody (ADA) to Atezolizumab
timeFrame: Pre-infusion (0 hr) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (each cycle=28 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
measure: Percentage of Participants With ADA to PEGPH20
timeFrame: Pre-infusion (0 hr) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 (each cycle=21 days); 30 days and 120 days after last dose (up to approximately 3-6 years)
measure: Percentage of Participants With ADA to BL-8040
timeFrame: Pre-dose (0 hr) on Day 1 of priming period (1 week prior to Day 1 of Cycle 1) up to 30 days after last dose (up to approximately 3-6 years) (Detailed timeframe is provided in outcome measure description)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: Uni of Southern California
state: California
city: Santa Monica
country: United States
facility: UCLA Jonsson Comprehensive Cancer Center
state: California
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Nashville
country: United States
facility: Tennessee Oncology - Nashville
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Blacktown
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Tel-Aviv
country: Israel
facility: Sourasky Medical Centre
city: Gyeonggi-do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital (SNUH) - Medical Oncology Center
city: Seoul
country: Korea, Republic of
facility: Yonsei University College of Medicine (YUCM)-Yonsei Cancer Center
city: Songpa-gu
country: Korea, Republic of
facility: University of Ulsan College of Medicine - Asan Medical Center (AMC) - Asan Cancer Center (ACC)
city: Suwon-si,
country: Korea, Republic of
facility: The Catholic University of Korea St. Vincent's Hospital
city: Pamplona
country: Spain
facility: Universidad de Navarra - Clinica Universitaria de Navarra (CUN)
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitari Vall dHebron
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Barts and The London School of Medicine and Dentistry - Barts Cancer Institute (BCI)-CECM
city: London
country: United Kingdom
facility: The Royal Marsden
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust - Royal Marsden Hospital (RMH) - Sutton
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: