PRIMARY OBJECTIVE:
I. To determine the efficacy, based on progression-free survival (PFS), of fluorouracil,
oxaliplatin, and leucovorin calcium (modified [m]FOLFOX6)/bevacizumab plus atezolizumab
(combination) as compared to single agent atezolizumab.
SECONDARY OBJECTIVES:
I. To compare the overall survival. II. To compare the objective response rates (ORR) per
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
III. To determine the safety profiles of the single agent atezolizumab and the combination of
mFOLFOX6/bevacizumab/atezolizumab in patients with mismatch-repair deficient
(dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC).
IV. To determine the duration of response. V. To determine the duration of stable disease.
VI. To determine the progression-free survival (PFS) at 12 months. VII. To compare disease
control rate (complete response [CR] + partial response [PR] + stable disease [SD]) at 12
months.
EXPLORATORY OBJECTIVE:
I. To compare the health-related quality of life and patient-reported symptoms.
TRANSLATIONAL OBJECTIVE:
I. To bank tissue and blood samples for other future correlative studies from patients
enrolled on the study.
OUTLINE: Patients are randomized to 1 of 3 arms.
ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1,
oxaliplatin IV over 2 hours on day 1 of cycles 1-10, leucovorin calcium IV over 2 hours on
day 1, and fluorouracil IV over 46-48 hours on days 1 and 2. Treatment with oxaliplatin
repeats every 2 weeks for up to 10 cycles in the absence of disease progression or
unacceptable toxicity. Cycles of bevacizumab, leucovorin calcium, and fluorouracil repeat
every 2 weeks in the absence of disease progression or unacceptable toxicity. (CLOSED TO
ACCRUAL)
ARM II: Patients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats every
2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity.
ARM III: Patients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats
every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable
toxicity. Patients also receive bevacizumab IV over 30-90 minutes on day 1, oxaliplatin IV
over 2 hours on day 1 cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and
fluorouracil IV over 46-48 hours on day 1. Treatment with oxaliplatin repeats every 2 weeks
for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Cycles of
bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 8 weeks for 18 months,
and then every 12 weeks for up to 5 years.
Inclusion Criteria:
- The patient must have signed and dated an Institutional Review Board (IRB)-approved
consent form that conforms to federal and institutional guidelines
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- Diagnosis of metastatic adenocarcinoma of colon or rectum without previous
chemotherapy or any other systemic therapy for metastatic colorectal cancer
- Tumor determined to be mismatch-repair deficient (dMMR) by Clinical Laboratory
Improvement Act (CLIA)-certified immunohistochemical (IHC) assay with a panel of all
four IHC markers, including MLH1, MSH2, PMS2, and MSH6; alternatively, MSI-H diagnosed
by polymerase chain reaction (PCR)-based assessment of microsatellite alterations
(either Bethesda markers or Pentaplex panel) or by next-generation sequencing (NGS)
are eligible
- Documentation by positron emission tomography(PET)/computed tomography (CT) scan, CT
scan, or magnetic resonance imaging (MRI) that the patient has measurable metastatic
disease per RECIST 1.1
- No immediate need for surgical intervention for the primary tumor or palliative
diversion/bypass
- Absolute neutrophil count (ANC) must be >= 1500/mm^3 (obtained within 28 days prior
randomization)
- Platelet count must be >= 100,000/mm^3 (obtained within 28 days prior randomization)
- Hemoglobin must be >= 8 g/dL (obtained within 28 days prior randomization)
- Total bilirubin must be =< 1.5 x ULN (upper limit of normal) for the lab unless the
patient has a bilirubin elevation > 1.5 x ULN to 3 x ULN due to Gilbert's disease or
similar syndrome involving slow conjugation of bilirubin (obtained within 28 days
prior randomization); and
- Alkaline phosphatase must be =< 2.5 x ULN for the lab with the following exception:
patients with documented liver metastases or bone involvement - alkaline phosphatase
must be =< 5 x ULN (obtained within 28 days prior randomization); and
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 3 x ULN
for the lab with the following exception: for patients with documented liver
metastases, AST and ALT must be =< 5 x ULN (obtained within 28 days prior
randomization)
- Serum creatinine =< 1.5 x ULN for the lab or measured (24 hour urine collection) or
calculated creatinine clearance >= 30 mL/min (obtained within 28 days prior
randomization)
- A urine sample tested for proteinuria by either the dipstick method, urinalysis (UA),
or a urine protein creatinine (UPC) ratio:
- The dipstick method must indicate 0-1+ protein; if dipstick reading is >= 2+, a
24-hour urine must be done and it must demonstrate < 1.0 g of protein per 24
hours
- A urine protein creatinine (UPC) ratio must be < 1.0; if the UPC ratio is >= 1.0
a 24-hour urine must be done and it must demonstrate < 1.0 g of protein per 24
hours
- Urinalysis must indicate < 30 mg/dl. If urinalysis >= 30 mg/dl, a 24-hour urine
must be done and it must demonstrate < 1.0 g of protein per 24 hours
- International normalized ratio of prothrombin time (INR) and prothrombin time (PT)
must be =< 1.5 x ULN for the lab within 28 days before randomization; patients who are
therapeutically treated with an agent such as warfarin may participate if they are on
a stable dose and no underlying abnormality in coagulation parameters exists per
medical history, regardless of PT/INR results
- Pregnancy test done within 14 days prior randomization must be negative (for women of
childbearing potential only); pregnancy testing should be performed according to
institutional standards; administration of atezolizumab or
mFOLFOX6/bevacizumab/atezolizumab may have an adverse effect on pregnancy and poses a
risk to the human fetus, including embryo-lethality; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately
- Women of child-bearing potential and men must agree to use adequate contraception
methods that result in a failure rate of < 1% per year during the treatment period
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 5 months (150 days) after the last dose
of atezolizumab, 6 months after the last dose of bevacizumab, and 6 months after the
last dose of mFOLFOX6; a woman is considered to be of childbearing potential if she is
not postmenopausal, has not reached a postmenopausal state (>= 12 continuous months of
amenorrhea with no identified cause other than menopause), and has not undergone
surgical sterilization (removal of ovaries and/or uterus); examples of contraceptive
methods with a failure rate of < 1% per year include: bilateral tubal ligation; male
partner sterilization; intrauterine devices; the reliability of sexual abstinence
should be evaluated in relation to the duration of the clinical study and the
preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar,
ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable
methods of contraception; men must refrain from donating sperm during this same period
Exclusion Criteria:
- Patients with central nervous system (CNS) metastases are excluded, with the following
exceptions:
- Patients with asymptomatic untreated CNS metastases may be enrolled, provided all
eligibility criteria are met, as well as the following:
- Evaluable or measurable disease outside the CNS
- No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within
10 mm of the optic apparatus (optic nerves and chiasm)
- No history of intracranial hemorrhage or spinal cord hemorrhage
- No ongoing requirement for dexamethasone for CNS disease; patients on a
stable dose of anticonvulsants are permitted.
- No neurosurgical resection or brain biopsy within 28 days prior to
randomization
- Patients with asymptomatic treated CNS metastases may be enrolled, provided all
eligibility criteria are met, as well as the following:
- No radiographic demonstration and no evidence of interim progression between
the completion of CNS-directed therapy and the screening radiographic study
- No stereotactic radiation or whole-brain radiation within 28 days prior to
randomization
- Screening CNS radiographic study >= 28 days from completion of radiotherapy
and >= 14 days from discontinuation of corticosteroids
- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies, fluoropyrimidines, folic acid derivatives or oxaliplatin
- Uncontrolled high blood pressure defined as systolic blood pressure (BP) > 150 mmHg or
diastolic BP 90 mmHg with or without anti-hypertensive medication; patients with
initial BP elevations are eligible if initiation or adjustment of BP medication lowers
pressure to meet entry criteria
- Any of the following cardiac conditions:
- Documented New York Heart Association (NYHA) class III or IV congestive heart
failure
- Myocardial infarction within 6 months prior to randomization
- Unstable angina within 6 months prior to randomization
- Symptomatic arrhythmia
- Serious or non-healing wound, skin ulcer, or bone fracture
- History of transient ischemic attack (TIA), cerebrovascular accident (CVA),
gastrointestinal (GI) perforation or arterial thrombotic event within 6 months prior
to randomization, symptomatic peripheral ischemia, or other medical condition in the
opinion of the treating oncologist that makes the risk of cardiovascular or bleeding
complications with bevacizumab use unacceptably high
- Other malignancies are excluded unless the patient has completed therapy for the
malignancy >= 12 months prior to randomization and is considered disease-free;
patients with the following cancers are eligible if diagnosed and treated within the
past 12 months: in situ carcinomas or basal cell and squamous cell carcinoma of the
skin
- Known DPD (dihydro pyrimidine dehydrogenase) deficiency
- Symptomatic peripheral sensory neuropathy >= grade 2 (Common Terminology Criteria for
Adverse Events [CTCAE] version [v] 5.0)
- Prior treatment with oxaliplatin chemotherapy within 6 months prior to randomization
- Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or
pathway-targeting agents; patients who have received prior treatment with anti-CTLA-4
may be enrolled provided the following requirements are met:
- Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the
last dose to randomization
- No history of severe immune-related adverse effects (CTCAE Grade 3 and 4) from
anti-CTLA-4
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (other than alopecia) due to agents administered more
than 4 weeks earlier are excluded; however, the following therapies are allowed:
- Hormone-replacement therapy or oral contraception
- Herbal therapy > 7 days prior to randomization (herbal therapy intended as
anticancer therapy must be discontinued at least 1 week prior to randomization)
- Palliative radiotherapy for bone metastases > 14 days prior to randomization
- Treatment with systemic immunostimulatory medications (including, but not limited to
interferon [IFN]-alpha or interleukin [IL]-2 within 42 days prior to randomization
- Treatment with systemic immunosuppressive medications (including, but not limited to,
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 14 days prior to randomization; however,
- Patients who have received acute, low dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea; or chronic daily
treatment with corticosteroids with a dose of =< 10 mg/day methylprednisolone
equivalent) may be enrolled
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
for patients with orthostatic hypotension or adrenocortical insufficiency is
allowed
- Patients taking bisphosphonate therapy for symptomatic hypercalcemia; use of
bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is
allowed
- Patients requiring treatment with a receptor activator of nuclear factor kappa-B
ligand (RANKL) inhibitor (e.g., denosumab) who cannot discontinue it before treatment
with atezolizumab
- Treatment with any other investigational agent within 4 weeks prior to randomization
- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease; however,
- Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible if polymerase
chain reaction (PCR) for HBV RNA is negative per local guidelines
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA) per
local guidelines
- History or risk of autoimmune disease, including, but not limited to, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis; however,
- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone may be eligible
- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
be eligible
- Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:
- Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations
- Rash must cover less than 10% of body surface area (BSA)
- Disease is well controlled at baseline and only requiring low potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
- No acute exacerbations of underlying condition within the last 12 months
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors; high potency or
oral steroids)
- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan; history of radiation pneumonitis in the radiation field
(fibrosis) is permitted
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
- Patients with known active tuberculosis (TB) are excluded
- Severe infections within 28 days prior to randomization, including but not limited to,
hospitalization for complications of infection, bacteremia, or severe pneumonia
- Signs or symptoms of infection within 14 days prior to randomization
- Received oral or intravenous (IV) antibiotics within 14 days prior to randomization;
patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
infection or chronic obstructive pulmonary disease) are eligible
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to randomization or anticipation of need for a major surgical procedure during
the course of the study
- Administration of a live, attenuated vaccine within 28 days prior to randomization or
anticipation that such a live, attenuated vaccine will be required during the study
and up to 5 months after the last dose of atezolizumab; Note: influenza vaccination
should be given during influenza season only (approximately October to March);
patients must not receive live, attenuated influenza vaccine within 28 days prior to
randomization or at any time during the study
- Psychiatric illness/social situations that would limit compliance with study
requirements
- Pregnant women are excluded from this study because atezolizumab is an agent with the
potential for teratogenic or abortifacient effects; because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with atezolizumab, breastfeeding should be discontinued if the mother is
treated with atezolizumab; these potential risks may also apply to other agents used
in this study; (Note: pre
