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…
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Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is overall response rate (ORR) as measured by Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Secondary outcome
The secondary endpoints for this study are as follows:
• Duration of RECIST response.
• Time to RECIST response.
• Immune-related (ir) response rate as measured by irRC with the use of
unidimensional measurement.
• Progression free survival (PFS), defined as time from treatment initiation to
progressive disease or death.
• Overall survival (OS), defined as time from treatment initiation to death.
• Safety and tolerability of atezolizumab plus bevacizumab as measured by
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
• Evaluation of predictive biomarkers correlating with response and resistance.
Background summary
Approximately 4% of patients with Stage IV CRC have tumors with deficiencies in
the DNA mismatch repair system. A defining molecular feature of these tumors is
high MSI. Agendia has developed a gene expression signature that identifies MSI
CRC. Remarkably, this gene signature also identifies a subset of patients as
MSI-like phenotypically, but these tumors are microsatellite stable (MSS) by
the standard clinical diagnostic assays. Important for this application is the
observation that the MSI-like tumors also have high mutation load, emphasizing
the similarity between the MSI and MSI-like cancers. With the highly sensitive
MSI-like signature developed by Agendia we are able to identify a population of
patients with hypermutated tumors (20-25% of all CRC) more frequent than
standard MSI testing.
The MSI phenotype is also associated with mutations in specific oncogenes
including BRAF (Vilar and Gruber 2010). MSI tumors and other hypermutated
tumors may therefore exhibit higher immunogenicity in comparison to MSS tumors.
One possible correlate of higher immunogenicity MSI and other hypermutator
phenotypes is the presence of high numbers of tumor-infiltrating lymphocytes
(Greenson et al. 2003) and a potential role of PDL-1/PD-1 signaling in
restraining a pre-existing anti-tumor immune response in the tumor
microenvironment.
Anti-tumor activity, including RECIST-based responses (i.e., RECIST 1.1
responses), have been observed in patients with different tumor types,
including non-small cell lung cancer, renal cell carcinoma, melanoma, gastric
cancer, and colorectal cancer, treated with atezolizumab, an anti-PD-L1
antibody, in Study PCD4989g (IB). Preliminary results suggest that PD-L1
expression in tumor tissue is likely to be associated with response to
atezolizumab.
Preliminary clinical data are available for 144 patients who have received at
least one study treatment dose in the dose-escalating GP28328 study evaluating
the safety and pharmacology of atezolizumab combined with bevacizumab, a VEGF
inhibitor, or with bevacizumab plus FOLFOX. Efficacy data are available for 44
efficacy evaluable patients with colorectal cancer. (efficacy cutoff 29 Sep
2014). The treatment combinations have been generally well tolerated with the
incidence of AEs in the combination arms consistent with the known safety
profiles of the individual drugs. No dose limiting toxicities have been
reported in this study or any other atezolizumab trial to date (IB, cutoff for
safety data 10 May 2015).
Our primary hypothesis is that the addition of bevacizumab to atezolizumab will
expand the efficacy of immunotherapeutics from a *real MSI* CRC population to
an *MSI-like* CRC population. This potential synergistic effect of immune
checkpoint inhibitors and antiangiogenic drugs is in part explained by
microenvironment changes, such as neutralization of vascular barriers
preventing T-cell homing, in tumors known to have immune cell infiltration
linked to a hypermutated phenotype.
Study objective
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.
Study design
This is an international, open-label single arm (non-randomized), one-stage
phase II trial. Patients potentially eligible for the protocol will have tumor
sample pre-screened by Agendia for the MSI-like signature, among others, as
part of the MoTriColor project, during first-line standard chemotherapy. If
positive for the MSI-like signature, patients will be offered the trial,
provided the inclusion criteria are met. The goal is to register 50 MSI-like
CRC patients to complete efficacy assessment. Treatment will be administered on
Day 1 of each 21 days-cycle (Figure 2) until disease progression as defined by
either RECIST 1.1 or irRECIST criteria (see details later), unacceptable
toxicity or withdrawal of consent.
Intervention
Treatment with atezolizumab in combination with bevacizumab
Study burden and risks
- Blood will be drawn for pharmacokinetic, pharmacodynamic and pharmacogenetic
research
Pg Vall Hebron 119-129
Barcelona 08035
ES
Pg Vall Hebron 119-129
Barcelona 08035
ES
Listed location countries
Age
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:
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.
Exclusion criteria
· 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
hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory
bowel disease, vascular thrombosis associated with antiphospholipid
syndrome,Wegener*s granulomatosis, Sjögren*s syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis:· Prior allogeneic bone
marrow transplantation or prior solid organ transplantation.· History of
idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis,
idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT
scan.· Administration of a live, attenuated vaccine within 4 w before Cycle 1,
day 1· Treatment with systemic immunostimulatory agents within 4 w or five
half-lives of the drug, whichever is longer, prior to study treatment.·
Treatment with systemic corticosteroids or other systemic immunosuppressive
medications within 2 w prior to start of study maintenance treatment, or
requirement for systemic immunosuppressive medications during the trial. The
use of inhaled corticosteroids and mineralocorticoids is allowed.· If receiving
a RANKL inhibitor, unwilling to adopt alternativetreatment such as
bisphosphonates, while receiving atezolizumab.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002001-19-NL |
| ClinicalTrials.gov | NCT02982694 |
| CCMO | NL59204.031.17 |