Clinical Trials /

Study With Atezolizumab Plus Bevacizumab in Patients With Chemotherapy Resistant, MSI-like, Colorectal Cancer

NCT02982694

Description:

The primary objective of this study is to determine the anti-tumor activity, as measured by overall response rate (ORR) of atezolizumab in combination with bevacizumab in patients with chemotherapy resistant CRC and positivity for MSI-like molecular signature. This is an international, open-label single arm (non-randomized), one-stage phase II trial.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study With Atezolizumab Plus Bevacizumab in Patients With Chemotherapy Resistant, MSI-like, Colorectal Cancer
  • Official Title: A Phase II Open-label Study With the Anti-PD-L1 Atezolizumab Monoclonal Antibody in Combination With Bevacizumab in Patients With Advanced Chemotherapy Resistant Colorectal Cancer and MSI-like Molecular Signature

Clinical Trial IDs

  • ORG STUDY ID: VHIO16001 - EORTC 1604
  • SECONDARY ID: 2016-002001-19
  • NCT ID: NCT02982694

Conditions

  • MSI
  • ColoRectal Cancer
  • Chemotherapy
  • Resistance, APC

Interventions

DrugSynonymsArms
AtezolizumabTECENTRIQAtezolizumab and Bevacizumab
BevacizumabAvastinAtezolizumab and Bevacizumab

Purpose

The primary objective of this study is to determine the anti-tumor activity, as measured by overall response rate (ORR) of atezolizumab in combination with bevacizumab in patients with chemotherapy resistant CRC and positivity for MSI-like molecular signature. This is an international, open-label single arm (non-randomized), one-stage phase II trial.

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab and BevacizumabExperimentalAtezolizumab will be administered intravenously at 1200 mg on Day 1 every 3 weeks. The dose of bevacizumab in this study is 7.5 mg/kg administered by IV infusion every 3 weeks on Day 1 of each 21 days cycle. Atezolizumab will be administered first, followed by Bevacizumab, with a minimum of 5 minutes between dosing. The interval between cycle infusions must not be < 10 days.
  • Atezolizumab
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent must be given according to ICH/GCP and national/local
             regulations.

          -  Histological or cytological proof of metastatic CRC.

          -  Disease progression or relapse after at least one line of treatment for advanced CRC
             with a fluoropyrimidine containing chemotherapy as single agent or in combination
             (combinations with oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab
             are allowed).

          -  Written documentation of positivity for MSI-like gene signature as determined by
             Agendia test.

          -  Unresectable disease, with at least one measurable lesion according to RECIST 1.1.

          -  Age ≥ 18 years.

          -  WHO performance status of 0-1.

          -  Ability and capacity to comply with study and follow-up procedures.

          -  Adequate hematologic and end-organ function, defined by the following laboratory
             results obtained within 28 calendar days prior to the first study treatment:

          -  ANC > 1.5 x 109/L (without granulocyte colony-stimulating factor support within 2
             weeks prior to Cycle 1, Day 1)

          -  WBC counts > 2500/μL

          -  Platelet count > 100,000/ μL (without transfusion within 2 weeks prior to Cycle 1, Day
             1)

          -  Hemoglobin > 9.0 g/dL

          -  AST, ALT, and alkaline phosphatase < 2.5 x ULN, with the following exceptions:

               -  Patients with documented liver metastases: AST and ALT < 5 x ULN

               -  Patients with documented liver or bone metastases: alkaline phosphatase < 5 x ULN
                  Bilirubin <1.5 x ULN. Patients with known Gilbert disease who have serum
                  bilirubin level < 3 x ULN may be enrolled.

          -  PT and PTT <1.5 x ULN, unless on a stable dose of warfarin

          -  Serum albumin > 2.5 g/dL

          -  Creatinine clearance > 30 mL/min (Cockcroft-Gault formula or based on 24-hour urine
             collection)

          -  Protein < 2+ on dipstick urinalysis or ≤ 1.0 g in a 24-hour urine collection. All
             patients with ≥2+ protein on dipstick urinalysis at baseline must undergo a 24-hour
             urine collection for protein.

          -  Women of child bearing potential (WOCBP) must have a negative serum pregnancy test
             before registration.

          -  Patients of childbearing / reproductive potential should use adequate birth control
             measures, as defined by the investigator, during the study treatment period and for at
             least 6 months after the last bevacizumab treatment (for women and men) and 5 months
             after the last atezolizumab treatment (for women). A highly effective method of birth
             control is defined as those which result in low failure rate (i.e. less than 1% per
             year) when used consistently and correctly.

          -  Female subjects who are breast feeding should discontinue nursing before trial
             registration and until 6 months after the last bevacizumab treatment and 5 months
             after the last atezolizumab treatment.

        Exclusion Criteria:

          -  Any treatment with investigational drugs (bevacizumab is not considered
             investigational drug in CRC) within 28 days prior to Cycle 1, Day 1.

          -  Previous cytotoxic agent within 14 days of planed treatment initiation.

          -  Active or untreated CNS metastases as determined by computed tomography (CT) or
             magnetic resonance imaging (MRI)

               -  Note: Patients with treated asymptomatic CNS metastases are eligible, provided
                  they meet all of the following criteria:

                    -  Evaluable or measurable disease outside the CNS

                    -  No metastases to midbrain, pons, medulla, cerebellum, or within 10 mm of the
                       optic apparatus (optic nerves and chiasm)

                    -  No history of intracranial or spinal cord haemorrhage

                    -  No ongoing requirement for dexamethasone as therapy for CNS disease;
                       anticonvulsants at a stable dose are allowed.

                    -  No evidence of significant vasogenic edema.

                    -  No stereotactic radiation, whole-brain radiation or neurosurgical resection
                       within 4 weeks prior to Cycle 1, Day 1.

                    -  Radiographic demonstration of interim stability (i.e., no progression)
                       between the completion of CNS-directed therapy and the screening
                       radiographic study.

                    -  Screening CNS radiographic study > 4 weeks since completion of radiotherapy
                       or surgical resection and > 2 weeks since discontinuation of
                       corticosteroids.

          -  Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or
             metastases causing nerve impingement) should be treated at least 14 days prior to
             Cycle 1, Day 1.

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures (once monthly or more frequently).

          -  Previous (within the last 5 years) or concurrent malignancies, with the exception of
             those treated with expected curative outcome as cone-biopsied in situ carcinoma of the
             cervix, basal cell carcinoma of the skin, localized prostate cancer or ductal
             carcinoma in situ of the breast.

          -  Life expectancy of < 12 weeks.

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

          -  Positive test for human immunodeficiency virus (HIV).

          -  Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]
             test prior to randomization) or hepatitis C.

               -  Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV
                  infection (defined as having a negative HBsAg test and a positive antibody to
                  hepatitis B core antigen [anti-HBc] antibody test) are eligible.

          -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase
             chain reaction (PCR) is negative for HCV RNA.

          -  Active tuberculosis.

          -  Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
             hospitalization for complications of infection, bacteremia, or severe pneumonia.

          -  Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1.

          -  Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1.

               -  Note: Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic
                  obstructive pulmonary disease exacerbation or for dental extraction) are
                  eligible.

          -  Significant cardiovascular or cerebrovascular disease, such as New York Heart
             Association cardiac disease (Class II or greater), unstable angina, history of stroke,
             transient ischemic attack, myocardial infarction or cerebrovascular events within the
             previous 6 months or unstable arrhythmias within the previous 3 months:

          -  Patients with known coronary artery disease, arrhythmias, congestive heart failure not
             meeting the above criteria must be on a stable medical regimen that is optimized in
             the opinion of the treating physician, in consultation with a cardiologist if
             appropriate. Baseline evaluation of left ventricular ejection fraction should be
             considered for all patients, especially in those with cardiac risk factors and/or
             history of coronary artery disease.

          -  Patients with known left ventricular ejection fraction <50%.

          -  Major surgical procedure within 28 days prior to cycle 1, day 1 (or until the surgical
             wound is fully healed), or planned procedure or surgery during the study.

          -  Prior allogeneic stem cell or solid organ transplant.

          -  Any other 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 patient at high risk from treatment
             complications.

          -  Prior treatment with CD137 agonists, anti−CTLA-4, anti−PD-1, or anti−PD-L1 therapeutic
             antibody or immune-related pathway-targeting agents.

          -  Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of
             dipyridamole, ticlopidine, clopidogrel, or cilostazol.

          -  Prophylactic or therapeutic use of low molecular−weight heparin (e.g., enoxaparin),
             direct thrombin inhibitors, or warfarin are permitted, provided, where appropriate
             anticoagulation indices are stable. Patients should have been on a stable dose (for
             therapeutic use) for at least two weeks (or until reaching steady state level of the
             drug) prior to the first study treatment.

          -  Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg
             and/or diastolic blood pressure >100 mmHg) (Anti-hypertensive therapy to achieve these
             parameters is allowable).

          -  Prior history of hypertensive crisis or hypertensive encephalopathy.

          -  Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1.

          -  Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or any component of the bevacizumab or atezolizumab formulation.

          -  Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence
             of therapeutic anticoagulation).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:36 months from first patient in
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Immune-related tumor response
Time Frame:36 months from first patient in
Safety Issue:
Description:the measurement that will be used is ir-RECIST (Immune-Related Response Criteria).
Measure:Progression Free Survival
Time Frame:36 months from first patient in
Safety Issue:
Description:
Measure:Overall Survival
Time Frame:36 months from first patient in
Safety Issue:
Description:
Measure:Safety and tolerability (adverse event assessment according to CTCAE v 4.0)
Time Frame:36 months from first patient in
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vall d'Hebron Institute of Oncology

Trial Keywords

  • MSI
  • colorectal
  • chemotherapy
  • Bevacizumab
  • Atezolizumab

Last Updated

January 30, 2018