A Study of the Safety and Efficacy of Atezolizumab Administered in Combination With Bevacizumab and/or Other Treatments in Participants With Solid Tumors

Solid Tumor Clinical Trial

Official title:

An Open-Label, Multicenter Phase Ib Study of The Safety and Efficacy of Atezolizumab (Anti-PD-L1 Antibody) Administered in Combination With Bevacizumab and/or Other Treatments in Patients With Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02715531
• Other study ID #: GO30140
• Status: Completed
• Phase: Phase 1
• Start date: April 6, 2016
• Est. completion date: May 31, 2021

Study information

• Verified date: July 2021
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the safety, efficacy, and pharmacokinetics of atezolizumab in combination with bevacizumab, bevacizumab + oxaliplatin, leucovorin and 5-fluorouracil (5-FU) (FOLFOX), vanucizumab, nab-paclitaxel + gemcitabine, FOLFOX, or 5-FU + cisplatin, in participants with solid tumors.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 243
• Est. completion date: May 31, 2021
• Est. primary completion date: May 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

General Inclusion criteria

• Measurable disease per RECIST v1.1

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Adequate hematologic and end organ function

• Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade less than or equal to (</=) 1 prior to study entry, with the exception of alopecia

• Ready to use reliable contraceptive procedures

Inclusion Criteria Specific to HCC (Arm A and Arm F):

• Participants with advanced or metastatic and/or unresectable HCC

• The participant has disease that is not amenable to a curative approach

• No prior line of systemic therapy (includes participants who are sorafenib-naïve)

• Willing to undergo fresh liver biopsy if provided archival tissue was taken greater than (>) 6 months from Cycle 1 Day 1

• Child-Pugh Score of up to B7

• Serum bilirubin </= 3 times upper limit of normal (x ULN)

• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) </= 2 x ULN

• Albumin >2.8 grams per deciliter (g/dL)

• Documented virology status of hepatitis, as confirmed by screening hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and/or anti-hepatitis C virus (anti-HCV)

• Antiviral therapy per local standard-of-care if active hepatitis B virus (HBV)

Inclusion Criteria Specific to Arm A (Patients must also meet all of the following specific inclusion criteria to be eligible for enrollment in Arm A:)

• Child-Pugh score of up to B7

• Willing to undergo biopsy if archival tissue is not available or if archival tissue was taken >6 months from Cycle 1, Day 1

• Anti-viral therapy per local standard-of-care if active hepatitis B virus (HBV).

Inclusion Criteria Specific to Arm F (Patients must also meet all of the following specific inclusion criteria to be eligible for enrollment in Arm F:)

• LIfe expectancy >=3 months, as determined by the investigator

• Child-Pugh score A

• Platelet count = 75x109/L (75,000/uL) without transfusion

• Availability at the site of tumor specimens in paraffin blocks (preferred) or 16 unstained slides, with an associated pathology report, prior to study entry

• Anti-viral therapy per local standard-of-care if active hepatitis B virus (HBV).

Inclusion Criteria Specific to Gastric Cancer (Arm B) (Patients must also meet all of the following specific inclusion criteria to be eligible for enrollment in Arm B:)

• Histologically or cytologically confirmed locally advanced or metastatic adenocarcinoma of the stomach or GEJ in participants who have not received prior systemic therapy for metastatic disease

• Absence of HER2 expression documented as in situ hybridization (ISH) negative on previously collected and assessed tumor tissue upon initial diagnosis of disease

Inclusion criteria specific to metastatic pancreatic cancer (Arm C) (Patients must also meet all of the following specific inclusion criteria to be eligible for enrollment in Arm C:)

• Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas

• No previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease

Inclusion Criteria Specific to mEC (Arm E) (Patients must also meet all of the following specific inclusion criteria to be eligible for enrollment in Arm E:)

• Histologically or cytologically confirmed locally mEC or metastatic adenocarcinoma of the GEJ Siewert Classification Type I in participants who have not received prior systemic therapy for primary and metastatic disease or chemoradiation therapy for primary disease

• Absence of HER2 expression documented as ISH-negative on previously collected and assessed tumor tissue upon initial diagnosis of disease

• Willing to undergo biopsy if archival tissue is not available or if archival tissue was taken >6 months from Cycle 1 Day 1

Exclusion Criteria:

General Exclusion Criteria

• Uncontrolled pleural effusion, pericardial effusion, or ascites

• Uncontrolled tumor-related pain

• Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy

• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease (exception for participants in Arm A and Arm F)

• Known primary central nervous system (CNS) malignancy or untreated or active CNS metastases

• Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or other recombinant human antibodies

• Positive test for Human Immunodeficiency Virus (HIV)

• Active hepatitis B (chronic or acute), or hepatitis C (exception for participants in Arm A and Arm F)

• Active tuberculosis

• Severe infections within 4 weeks prior to Day 1

• Signs or symptoms of significant infection within 2 weeks prior to Day 1

• Received oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1

• Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to Day 1, unstable arrhythmias, or unstable angina

• History of stroke, reversible ischemic neurological defect or transient ischemic attack within 6 months prior to Day 1

• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study

• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's and/or Medical Monitor's judgment, precludes the participants safe participation in and completion of the study

• Malignancies other than pancreatic carcinoma within 2 years prior to study start, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)

Exclusion Criteria Related to Medications

• Prior treatment with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4), anti-programmed death-1 (anti-PD-1), or anti-programmed death ligand-1 (anti-PD-L1) therapeutic antibody

• Treatment with systemic immunostimulatory agents within 6 weeks or five half-lives of the drug, whichever is longer, prior to screening

• Treatment with systemic corticosteroids or other immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1

• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

• Participants with prior allogeneic bone marrow transplantation or prior solid organ transplantation

• Known allergies to oxaliplatin (or other platinum agents), leucovorin, 5-FU, nab-paclitaxel (or other taxanes) or gemcitabine

Exclusion Criteria Specific to Bevacizumab-Containign Arms (Arms A, B, and F) (Patients who meet any of the following criteria will be excluded from enrollment into bevacizumab-containing Arms A, B, and F:)

• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab or vanucizumab

• History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to Day 1

• History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction within 6 months prior to Day 1 of Cycle 1

• Clinical signs or symptoms of GI obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding

• Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure

• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture

• Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour urine collection

• Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses of large volume. HCC participants (Arm A and F) with vascular invasion of the portal or hepatic veins may be enrolled

• History of intra-abdominal inflammatory process within 6 months prior to Day 1 of Cycle 1

• Radiotherapy within 28 days and abdominal/pelvic radiotherapy within 60 days prior to Day 1 of Cycle 1

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 of Cycle 1

• Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID)

Exclusions specific to Arms A and F (HCC) (Patients who meet any of the following specific exclusion criteria will be excluded from enrollment in Arms A and F:)

• Participants with untreated or incompletely treated varices with bleeding or high-risk for bleeding

• Treatment with any HCV anti-viral therapy within 4 weeks prior to Cycle 1 Day 1

• Moderate or severe ascites

• Hepatic encephalopathy

Exclusion Criteria Specific to Arm B (Gastric Cancer) (Patients who meet any of the following specific exclusion criteria will be excluded from enrollment in Arm B:)

• HER2 expression as defined by ISH positive and/or 3+ by immunohistochemistry (IHC)

• Prior treatment with an oxaliplatin-containing regimen

• Previous antiangiogenic therapy

• Ongoing treatment for epilepsy

Exclusion Criteria Specific to Arm C (Metastatic Pancreatic Cancer) (Patients who meet any of the following specific exclusion criteria will be excluded from enrollment in Arm C:)

• Patients with only locally advanced disease

• Presence of islet cell neoplasms

Exclusions Specific to Arm E (Metastatic Esophageal Cancer) (Patients who meet any of the following specific exclusion criteria will be excluded from enrollment in Arm E:)

• HER2 expression as defined by ISH positive and/or 3+ by immunohistochemistry

• Prior chemotherapy treatment, including radio-sensitization in pre- and post-operative settings

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumor

Intervention

Drug:
• 5-FU
5-FU (400 mg/m^2) will be administered as an IV bolus, followed by 2400 mg/m^2 by continuous IV infusion over 46 (± 1) hours, q2w.
• Atezolizumab
Participants will receive atezolizumab in a flat dose of 1200 mg q3w (Arm A, Group E2, and Arm F) or 840 mg q2w (Arm B, Arm C, and Groups E1 and E3).
• Bevacizumab
Participants will receive bevacizumab at 15 mg/kg q3w (Arm A and Group F1) or 10 mg/kg q2w (Arm B).
• Gemcitabine
Gemcitabine will be administered according to the local prescribing information. The starting dose-level of gemcitabine (1000 mg/m^2) will be administered intravenously over 35 (± 5) minutes on Days 1, 8, and 15 of each 28-day cycle (3-weeks-on/1-week-off schedule).
• Leucovorin
Leucovorin 200 mg/m^2 L-isomer form or 400 mg/m^2 D,L-racemic form will be administered IV over 120 (± 15) minutes, q2w.
• Nab-Paclitaxel
Nab-Paclitaxel will be administered according to the local prescribing information. The starting dose-level of nab-paclitaxel (125 mg/m^2) will be administered intravenously over 35 (± 5) minutes on Days 1, 8, and 15 of each 28-day cycle (3-weeks-on/1-week-off schedule).
• Oxaliplatin
Oxaliplatin 85 mg/m^2 will be administered IV over 120 (± 5) minutes q2w.
• Capecitabine
Capecitabine may be administered after 6 months at the discretion of the investigator (range of 650-1000 mg/m^2) twice daily on Days 1-4 of a 21-day cycle.
• Cisplatin
Cisplatin will be administered as 80 mg/m^2 IV over 120 minutes q3w (Group E2).

Locations

Country	Name	City	State
Australia	Monash Medical Centre Clayton	Clayton	Victoria
Australia	Austin Hospital	Heidelberg	Victoria
China	The 81st Hospital of P.L.A.	Nanjing City
Japan	National Cancer Center Hospital East	Chiba
Japan	Kanagawa Cancer Center	Kanagawa
Japan	Yokohama City University Medical Center	Kanagawa
Japan	The Cancer Institute Hospital of JFCR	Tokyo
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
New Zealand	Auckland City Hospital	Auckland
Taiwan	China Medical University Hospital	North Dist.
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei City
Taiwan	Chang Gung Medical Foundation - LINKOU; Dept of Cardiology	Taoyuan County
United States	University of Colorado Hospital	Aurora	Colorado
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Duke Cancer Institute	Durham	North Carolina
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Sarah Cannon Research Inst.	Nashville	Tennessee
United States	Yale School of Medicine	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	Stanford Cancer Institute; Hematology	Palo Alto	California
United States	Mayo Clinic	Rochester	Minnesota
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  China,  Japan,  Korea, Republic of,  New Zealand,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With At Least One Adverse Event, with Severity Determined According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)		From screening to up to 90 days after the last dose of study drug (up to approximately 55 months)
Primary	Percentage of Participants with Objective Response as Determined By The Independent Review Facility (IRF) According To Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Arm A)		From screening to end of study (approximately 55 months)
Primary	Progression-Free Survival (PFS) as determined by the Independent Review Facility (IRF) according to RECIST v 1.1 (Arm F)		From randomization to the first occurrence of disease progression or death from any cause (whichever occurs first)
Secondary	Serum Concentrations of Atezolizumab (All Arms)		Predose (0 hour[h]), 30 minutes(min) postdose on Day 1 of Cycles(Cy) 1 and 3; Predose(0h) on Day 1 of Cy 2,4,8 and every 8 Cy until treatment discontinuation (up to 55 months); 120 days after last dose (Cy length=21-28 days; up to 55 months)
Secondary	Serum Concentrations of Bevacizumab (Arm A, Arm B and Group F1)		Predose (0 h) and 30 min postdose (infusion length=30-90 min) on Day 1 of Cy 1 and 3; at treatment discontinuation (up to 55 months); at 120 days after last dose (Cy length=21-28 days; up to 55 months)
Secondary	Plasma Concentration of Oxaliplatin (Arm B and Group E1)		Predose (0 h) and 5-10 min before the end of infusion (infusion length=120 min) on Day 1 of Cycles 1 and 3 (Cycle length=21-28 days; up to approximately 3 months)
Secondary	Plasma Concentration of 5-FU (Arm B and Arm E)		Predose (0 h), immediately following bolus administration and 2 hours post-bolus dose on Day 1 of Cycles 1 and 3 (Cycle length=21-28 days; up to approximately 3 months)
Secondary	Plasma Concentration of Cisplatin (Group E2)		Predose (0 h) and 5-10 minutes before the end of infusion (infusion length=120 min) on Day 1 of Cycles 1 and 3 (Cycle length=21 days; up to approximately 3 months)
Secondary	Plasma Concentration of nab-Paclitaxel (Arm C)		Predose (0 h), 5-10 minutes before the end of infusion and 1 hour after the end of the infusion (infusion length=35 min) on Day 1 of Cycles 1 and 3 (Cycle length=28 days; up to approximately 3 months)
Secondary	Plasma Concentration of Gemcitabine (Arm C)		Predose (0 h), 5-10 minutes before the end of infusion and 1 hour after the end of the infusion (infusion length=35 min) on Day 1 of Cycles 1 and 3 (Cycle length=28 days) (up to approximately 3 months)
Secondary	Percentage of Participants with Objective Response as Determined by the IRF according to RECIST v 1.1 (Arm F)		Baseline, every 8 weeks (± 1 week) for the first 12 months following Cycle 1 Day 1, and every 12 weeks (± 1 week) thereafter up to study completion (Cycle length=21-28 days; up to approximately 55 months)
Secondary	Percentage of Participants with Objective Response as Determined By The Investigator According To RECIST v 1.1 (Arm A and Arm F)		Baseline, every 8 weeks (± 1 week) for the first 12 months following Cycle 1 Day 1, and every 12 weeks (± 1 week) thereafter up to study completion (Cycle length=21-28 days; up to approximately 55 months)
Secondary	Percentage of Participants with Objective Response as Determined by the IRF according to HCC-Specific Modified RECIST (mRECIST) (Arm A and Arm F)		Baseline, every 8 weeks (± 1 week) for the first 12 months following Cycle 1 Day 1, and every 12 weeks (± 1 week) thereafter up to study completion (Cycle length=21-28 days; up to approximately 55 months)
Secondary	Duration of Objective Response as Determined by the IRF according to RECIST v1.1 (Arm A and Arm F)		From the first occurrence of a documented objective response to disease progression or death from any cause, whichever comes first (up to approximately 55 months)
Secondary	Duration of Objective Response as Determined by The Investigator According to RECIST v 1.1 (Arm A and Arm F)		From the first occurrence of a documented objective response to disease progression or death from any cause, whichever comes first (up to approximately 55 months)
Secondary	Duration of Objective Response as Determined by the IRF According to HCC-Specific mRECIST (Arm A and Arm F)		From the first occurrence of a documented objective response to disease progression or death from any cause, whichever comes first (up to approximately 55 months)
Secondary	PFS Duration as Determined by The IRF According to RECIST v1.1 (Arm A)		From the first dose of study treatment to the first occurrence of disease progression or death from any cause, whichever comes first (up to approximately 55 months)
Secondary	PFS Duration as Determined by the Investigator According To RECIST v 1.1 (Arm A and Arm F)		From the first dose of study treatment (Arm A) or randomization (Arm F) to the first occurrence of disease progression or death from any cause, whichever comes first (up to approximately 55 months)
Secondary	PFS Duration as Determined by the IRF Acording to HCC-Specific mRECIST (Arm A and Arm F)		From the first dose of study treatment (Arm A) or randomization (Arm F) to the first occurrence of disease progression or death from any cause, whichever comes first (up to approximately 55 months)
Secondary	Overall Survival (OS) Duration (Arm A and Arm F)		Baseline up to study completion or death, whichever occurs first (up to approximately 55 months)
Secondary	Time to Radiological Progression (TTRP) as Determined by the IRF According to RECIST v1.1 (Arm A and Arm F)		From the first dose of study treatment (Arm A) or randomization (Arm F) to the first occurrence of radiographic disease progression (up to approximately 55 months)
Secondary	TTRP as Determined by The Investigator According to RECIST (Arm A and Arm F)		From the first dose of study treatment (Arm A) or randomization (Arm F) to the first occurrence of radiographic disease progression (up to approximately 55 months)
Secondary	TTRP as Determined by The IRF According to HCC-Specific mRECIST (Arm A and Arm F)		From the first dose of study treatment (Arm A) or randomization (Arm F) to the first occurrence of radiographic disease progression (up to approximately 55 months)
Secondary	Percentage of Participants With Anti-Therapeutic Antibodies (ATAs)		Predose (0 h) on Day 1 of Cycles 1, 2, 3, 4, 8 and every 8 cycles until treatment discontinuation (up to 55 months); at 120 days after last dose (Cycle length =21-28 days; up to 55 months)