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
- Conditions
- bowlecancercolorectal carcinoma10017991
- Registration Number
- NL-OMON49178
- Lead Sponsor
- Vall D'Hebron Institute of Oncology (VHIO)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 12
-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:
i Patients with documented liver metastases: AST and ALT < 5 x ULN
ii 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.
· Any treatment with investigational drugs within 28 d prior to Cycle 1, Day
1.· Previous cytotoxic agent within 14 d of planed treatment initiation.·
Active or untreated CNS metastases as determined by computed CT or MRI·
Radiotherapy within 14 d prior to Cycle 1, Day 1.· Uncontrolled pleural
effusion, pericardial effusion, or ascites requiring recurrent drainage
procedures.· Previous (within the last 5 y) 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 thebreast.· Life expectancy of
< 12 w.· History of severe allergic, anaphylactic, or other hypersensitivity
reactions to chimeric or humanized antibodies or fusion proteins.· Positive
test for HIV.· Active hepatitis B or hepatitis C.· Active tuberculosis.· Severe
infections within 4 w prior to Cycle 1, Day 1.· Infection within 2 w prior to
Cycle 1, Day 1.· Received therapeutic oral or IV antibiotics within 2 w prior
to Cycle 1, Day 1.· Significant cardiovascular or cerebrovascular disease·
Major surgical procedure within 28 d prior to cycle 1, day 1, 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 use of
dipyridamole, ticlopidine, clopidogrel, or cilostazol .· Unstable dose in the
last 2 w prior to the first study treatment of prophylactic or therapeutic low
molecular*weight heparin, direct thrombin inhibitors, or warfarin. Stable dose
is permitted where appropriate anticoagulation indices are stable.·
Inadequately controlled hypertension.· Prior history of hypertensive crisis or
hypertensive encephalopathy.· Significant vascular disease within 6 m 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.· Patients with history of pulmonary
hemorrhage/hemoptysis within 6 m prior to Cycle 1, Day 1.· Core biopsy or other
minor surgical procedure, excluding placement of a vascular access device,
within 7 calendar days prior to the first dose of bevacizumab.· History of
abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6
m prior to Cycle 1, Day 1.· Clinical signs or symptoms of gastrointestinal
obstruction or requirement for routine parenteral hydration, parenteral
nutrition, or tube feeding.· Evidence of abdominal free air not explained by
paracentesis or recent surgical procedure.· Serious, non-healing or dehiscing
wound, active ulcer, or untreated bone fracture.· History of autoimmune
disease, including but not limited to myasthenia gravis, myositis, autoimmune <br
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary endpoint is overall response rate (ORR) as measured by Response<br /><br>Evaluation Criteria in Solid Tumors (RECIST) version 1.1.</p><br>
- Secondary Outcome Measures
Name Time Method <p>The secondary endpoints for this study are as follows:<br /><br>• Duration of RECIST response.<br /><br>• Time to RECIST response.<br /><br>• Immune-related (ir) response rate as measured by irRC with the use of<br /><br>unidimensional measurement.<br /><br>• Progression free survival (PFS), defined as time from treatment initiation to<br /><br>progressive disease or death.<br /><br>• Overall survival (OS), defined as time from treatment initiation to death.<br /><br>• Safety and tolerability of atezolizumab plus bevacizumab as measured by<br /><br>Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.<br /><br>• Evaluation of predictive biomarkers correlating with response and resistance.</p><br>