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.
- Written informed consent must be given according to ICH/GCP and national/local
- 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
- Written documentation of positivity for MSI-like gene signature as determined by
- 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
- 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
- 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
- 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.
- 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
- Screening CNS radiographic study > 4 weeks since completion of radiotherapy
or surgical resection and > 2 weeks since discontinuation of
- 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
- 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
- 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).