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

NCT02715531

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Carcinoma
  • Gastric Adenocarcinoma
  • Hepatocellular Carcinoma
  • Pancreatic Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

  • ORG STUDY ID: GO30140
  • NCT ID: NCT02715531

Conditions

  • Solid Tumor

Interventions

DrugSynonymsArms
5-FUArm B (Gastric Cancer)
AtezolizumabTecentriq; RO5541267Arm A (Hepatocellular Carcinoma [HCC], All subtypes)
BevacizumabArm A (Hepatocellular Carcinoma [HCC], All subtypes)
GemcitabineArm C (Metastatic Pancreatic Cancer)
LeucovorinArm B (Gastric Cancer)
Nab-PaclitaxelArm C (Metastatic Pancreatic Cancer)
OxaliplatinArm B (Gastric Cancer)
CapecitabineArm B (Gastric Cancer)
CisplatinArm E (Randomized Metastatic Esophageal Cancer)

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Arm A (Hepatocellular Carcinoma [HCC], All subtypes)ExperimentalParticipants with advanced or metastatic and/or unresectable HCC who have received no prior treatment are non-randomized and will receive atezolizumab and bevacizumab, every 3 weeks (q3w), each cycle of 21 days, as long as participants are experiencing clinical benefit in the opinion of the investigator.
  • Atezolizumab
  • Bevacizumab
Arm B (Gastric Cancer)ExperimentalParticipants with previously untreated human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the stomach or gastroesophageal junction (GEJ) are non-randomized and will receive atezolizumab, bevacizumab, and FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil [FU]), every 2 weeks (q2w), each cycle of 28 days, as long as participants are experiencing clinical benefit in the opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. After 6 months, at discretion of investigator, capecitabine may be administered as maintenance therapy without oxaliplatin instead of infusional 5-FU and leucovorin, and biologic therapy may be given every 3 weeks (q3w). In the event that a patient experiences unacceptable toxicity after replacement of infusional 5-FU and leucovorin with capecitabine, the patient may be allowed to switch back to 5-FU and leucovorin following investigator discussion with the Medical Monitor.
  • 5-FU
  • Atezolizumab
  • Bevacizumab
  • Leucovorin
  • Oxaliplatin
  • Capecitabine
Arm C (Metastatic Pancreatic Cancer)ExperimentalParticipants with previously untreated metastatic pancreatic cancer are non-randomized and will receive atezolizumab q2w starting on Day 1, Cycle 1 (each cycle of 28 days). Administration of nab-paclitaxel followed by gemcitabine will occur on Days 1, 8, and 15 of each cycle (3-weeks-on/1-week-off schedule). Treatment consisting of atezolizumab with gemcitabine and nab-paclitaxel may be continued as long as participants are experiencing clinical benefit in the opinion of the investigator.
  • Atezolizumab
  • Gemcitabine
  • Nab-Paclitaxel
Arm E (Randomized Metastatic Esophageal Cancer)ExperimentalParticipants with squamous metastatic esophageal cancer (mEC) will be randomized (1:1) into Group E1 and Group E2. All participants with metastatic adenocarcinoma of esophageal carcinoma or GEJ Siewert Classification Type I will be enrolled into Group E3. In Groups E1 and E3, participants will receive atezolizumab and FOLFOX, q2w, each cycle of 28 days, as long as participants are experiencing clinical benefit in opinion of the investigator. Oxaliplatin will be administered for up to 8 cycles. In Group E2, participants will receive atezolizumab followed by cisplatin and 5-FU q3w. Cisplatin will be administered for up to 6 cycles. Treatment with atezolizumab in combination with 5-FU may be continued as long as participants experience clinical benefit in opinion of the investigator.
  • 5-FU
  • Atezolizumab
  • Leucovorin
  • Oxaliplatin
  • Cisplatin
Arm F (Randomized HCC)ExperimentalParticipants with advanced or metastatic and/or unresectable HCC who have received no prior systemic treatment will be randomized (1:1) into Group F1 and Group F2. Participants will receive atezolizumab alone (Group F2) or combined with bevacizumab (Group F1) on a q3w schedule, with dosing on Day 1 of each 21 day Cycle. Treatment with atezolizumab with or without bevacizumab may be continued as long as participants are experiencing clinical benefit in the opinion of the investigator. Participants who are randomly assigned to Group F2 (atezolizumab monotherapy) and experience investigator-assessed unequivocal radiographic progression as per RECIST v1.1 will also be given the option to cross over to atezolizumab and bevacizumab combination therapy, provided they meet the criteria for crossover and Medical Monitor approval is obtained.
  • Atezolizumab
  • Bevacizumab

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Time Frame:From screening to up to 90 days after the last dose of study drug (up to approximately 55 months)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Serum Concentrations of Atezolizumab (All Arms)
Time Frame: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)
Safety Issue:
Description:
Measure:Serum Concentrations of Bevacizumab (Arm A, Arm B and Group F1)
Time Frame: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)
Safety Issue:
Description:
Measure:Plasma Concentration of Oxaliplatin (Arm B and Group E1)
Time Frame: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)
Safety Issue:
Description:
Measure:Plasma Concentration of 5-FU (Arm B and Arm E)
Time Frame: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)
Safety Issue:
Description:
Measure:Plasma Concentration of Cisplatin (Group E2)
Time Frame: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)
Safety Issue:
Description:
Measure:Plasma Concentration of nab-Paclitaxel (Arm C)
Time Frame: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)
Safety Issue:
Description:
Measure:Plasma Concentration of Gemcitabine (Arm C)
Time Frame: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)
Safety Issue:
Description:
Measure:Percentage of Participants with Objective Response as Determined by the IRF according to RECIST v 1.1 (Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:Percentage of Participants with Objective Response as Determined By The Investigator According To RECIST v 1.1 (Arm A and Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:Percentage of Participants with Objective Response as Determined by the IRF according to HCC-Specific Modified RECIST (mRECIST) (Arm A and Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:Duration of Objective Response as Determined by the IRF according to RECIST v1.1 (Arm A and Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:Duration of Objective Response as Determined by The Investigator According to RECIST v 1.1 (Arm A and Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:Duration of Objective Response as Determined by the IRF According to HCC-Specific mRECIST (Arm A and Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:PFS Duration as Determined by The IRF According to RECIST v1.1 (Arm A)
Time Frame: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)
Safety Issue:
Description:
Measure:PFS Duration as Determined by the Investigator According To RECIST v 1.1 (Arm A and Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:PFS Duration as Determined by the IRF Acording to HCC-Specific mRECIST (Arm A and Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:Overall Survival (OS) Duration (Arm A and Arm F)
Time Frame:Baseline up to study completion or death, whichever occurs first (up to approximately 55 months)
Safety Issue:
Description:
Measure:Time to Radiological Progression (TTRP) as Determined by the IRF According to RECIST v1.1 (Arm A and Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:TTRP as Determined by The Investigator According to RECIST (Arm A and Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:TTRP as Determined by The IRF According to HCC-Specific mRECIST (Arm A and Arm F)
Time Frame: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)
Safety Issue:
Description:
Measure:Percentage of Participants With Anti-Therapeutic Antibodies (ATAs)
Time Frame: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)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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