PRIMARY OBJECTIVE:
I. To determine whether atezolizumab combined with oxaliplatin, leucovorin calcium, and
fluorouracil (FOLFOX) and its continuation as monotherapy can significantly improve
disease-free survival (DFS) compared to FOLFOX alone in patients with stage III colon cancers
and deficient DNA mismatch repair (dMMR).
SECONDARY OBJECTIVES:
I. To determine whether atezolizumab combined with FOLFOX and its continuation as monotherapy
can significantly improve overall survival compared to FOLFOX alone in patients with stage
III colon cancers and dMMR.
II. To assess the adverse events (AE) profile and safety of each treatment arm, using the
Common Terminology Criteria for Adverse Events (CTCAE) and patient related outcomes
(PRO)-CTCAE (among patients aged >= 18 years).
QUALITY OF LIFE OBJECTIVE:
I. To determine the impact of the addition of atezolizumab to FOLFOX on patient-reported
neuropathy, health-related quality of life (QOL), and functional domains of health-related
QOL.
POTENTIAL CORRELATIVE SCIENCE OBJECTIVES:
I. To determine if the "immunoscore" can predict the efficacy of atezolizumab for
disease-free survival among patients with stage III colon cancer.
II. To assess whether circulating immune cell populations can predict the efficacy of
atezolizumab as adjuvant therapy for stage III colon cancer.
III. To explore the associations of genomic alterations identified in cell-free (cf)DNA with
DFS in patients treated with FOLFOX with or without atezolizumab.
IV. To assess whether soluble markers of systemic inflammation in blood can predict the
efficacy of atezolizumab as adjuvant therapy for stage III colon cancer.
V. To assess the relationship between baseline plasma 25(OH) D levels, change in 25(OH)D
levels, and DFS and overall survival (OS) in patients with stage III colon cancer receiving
FOLFOX +/- atezolizumab.
VI. To determine the ability of using fecal microbiota and their metabolic products to
predict survival benefit from anti-PD-L1 antibody therapy in dMMR colon cancer patients.
VII. To determine if hypermutation or hyper-indel status is associated with response to
atezolizumab.
VIII. To determine if unique messenger ribonucleic acid (mRNA) expression signatures are
predictive of disease-free survival among patients receiving adjuvant chemotherapy for stage
III colon cancer.
IX. To determine if the efficacy of atezolizumab differs among dMMR cancers due to germline
MMR mutation (MLH1, MSH2, MSH6, PMS2) versus those with MLH1 hypermethylation and CIMP in
patients with stage III colon cancer.
X. To identify overall mutational burden and number of putative tumor neoantigens in colon
carcinoma specimens.
XI. To determine changes in growth patterns compared to baseline (relative to age-specific
standards for height and weight). (Patients aged 12 to < 18 years to evaluate the impact of
atezolizumab on growth and development patterns in this population) XII. To determine changes
in development patterns compared to baseline (relative to onset of menarche [for females] and
pubertal changes). (Patients aged 12 to < 18 years to evaluate the impact of atezolizumab on
growth and development patterns in this population)
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours and leucovorin calcium IV
over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46
hours on days 1-3. Treatment repeats every 14 days for up to 12 cycles in the absence of
disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over
30-60 minutes starting on day 1 of cycle 1 or 2. Treatment repeats every 14 days for up to 25
cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours
on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days
1-3. Treatment repeats every 14 days for up to 12 cycles in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for recurrence every 6 months
for 2 years, then annually for 3 years. Patients are also followed up for survival every 6
months for up to 8 years.
Inclusion Criteria:
- Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4],
N1-2M0; includes N1C); tumors must be deemed to originate in the colon including
tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve)
- Presence of deficient (d) DNA mismatch repair (dMMR); MMR status must be assessed by
immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where
loss of one or more proteins indicates dMMR; dMMR may be determined either locally or
by site-selected reference lab; Note: loss of MLH1 and PMS2 commonly occur together;
formalin-fixed paraffin-embedded (FFPE) tumor tissue is required for subsequent
retrospective central confirmation of dMMR status
- Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to
participate; patients whose tumors show MSI-H by polymerase chain reaction (PCR)-based
assay are not eligible to participate unless they also have MMR testing by IHC and are
found to have dMMR (i.e. loss of one or more MMR proteins)
- Patients who are known to have Lynch syndrome, have been found to carry a specific
germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), and have been shown to be
dMMR by IHC are eligible to participate
- Tumors must have been completely resected; in patients with tumor adherent to adjacent
structures, en bloc R0 resection must be documented in the operative report or
otherwise confirmed by the surgeon; near or positive radial margins are acceptable so
long as en bloc resection was performed; proximal or distal margin positivity is not
permitted
- Entire tumor must be in the colon (rectal involvement is an exclusion); surgeon
confirmation that entire tumor was located in the colon is required only in cases
where it is important to establish if the tumor is a colon versus (vs.) rectal
primary; patients with more than one primary colon adenocarcinoma are eligible if the
qualifying stage III tumor is confined to the colon, and not rectum, and the other
cancers of lower stage are removed in the en bloc R0 resection
- Based upon the operative report and other source documentation, the location of the
primary tumor will be categorized as proximal or distal to the splenic flexure
(included with distal), and further categorization will be as follows:
cecum/ascending, transverse, descending, sigmoid colon, or rectosigmoid colon
- No evidence of residual involved lymph node disease or metastatic disease at the time
of registration based on clinician assessment of imaging; the treating physician will
determine if incidental lesions on imaging require workup to exclude metastatic
disease; if based on review of images, the treating physician determines the patient
to be stage III, then the patient is eligible
- No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy)
or radiation therapy for the current colon cancer except for one cycle of mFOLFOX6
- Performance Status:
- Patients < 16 years of age: Lansky >= 50%
- Patients 16 to < 18 years of age: Karnofsky >= 50%
- Patients >= 18 years of age: Eastern Cooperative Oncology Group (ECOG)
performance status =< 2
- This study involves: 1) an investigational agent whose genotoxic, mutagenic and
teratogenic effects on the developing fetus and newborn are unknown; and 2) an agent
that has known genotoxic, mutagenic, and teratogenic effects; therefore, for women of
childbearing potential only, a negative pregnancy test done =< 7 days prior to
registration is required; a female of childbearing potential is a sexually mature
female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has
not been naturally postmenopausal for at least 12 consecutive months (i.e. has had
menses at any time in the preceding 12 consecutive months)
- Absolute neutrophil count (ANC) >= 1500 mm^3
- Platelet count >= 100,000 mm^3; platelets >= 75,000 required for patients who received
cycle 1 of mFOLFOX6 prior to registration
- Creatinine =< 1.5 x upper limit of normal (ULN) or
- Calculated creatinine clearance >= 45 mL/min by Cockcroft-Gault equation
- Alternatively, for patients < 18 years of age, maximum serum creatinine =< the
below age-gender-specific norms:
- 12 years: 1.2 (male and female)
- 13 to < 16 years: 1.5 (male), 1.4 (female)
- 16 to < 18 years: 1.7 (male), 1.4 (female)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) except in the case of Gilbert
disease
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN)
- Thyroid-stimulating hormone (TSH) within normal limits (WNL); supplementation is
acceptable to achieve a TSH WNL; in patients with abnormal TSH, if free T4 is normal
and patient is clinically euthyroid, patient is eligible
- No active known autoimmune disease, including colitis, inflammatory bowel disease
(i.e. ulcerative colitis or Crohn's disease), rheumatoid arthritis,
panhypopituitarism, adrenal insufficiency
- No known active hepatitis B or C
- Active hepatitis B can be defined as:
- Hepatitis B virus surface antigen (HBsAg) detectable for > 6 months;
- Serum hepatitis B virus (HBV) DNA 20,000 IU/ml (105 copies/ml); lower values
2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e
antigen (HBeAg)-negative chronic hepatitis B
- Persistent or intermittent elevation in ALT/AST levels
- Liver biopsy showing chronic hepatitis with moderate or severe
necroinflammation
- Active hepatitis C can be defined as:
- Hepatitis C antibody (AB) positive AND
- Presence of hepatitis C virus (HCV) RNA
- Excluded if known active pulmonary disease with hypoxia defined as:
- Oxygen saturation < 85% on room air, or
- Oxygen saturation < 88% despite supplemental oxygen
- No grade >= 2 peripheral motor or sensory neuropathy
- Patients positive for human immunodeficiency virus (HIV) are eligible only if they
meet all of the following:
- A stable regimen of highly active anti-retroviral therapy (HAART)
- No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections
- A CD4 count above 250 cells/mcL, and an undetectable HIV viral load on standard
PCR-based tests
- No other planned concurrent investigational agents or other tumor directed therapy
(chemotherapy, radiation) while on study
- No systemic daily treatment with either corticosteroids (> 10 mg daily prednisone
equivalents) or other immunosuppressive medications within 7 days of registration
- No known history of severe allergic anaphylactic reactions to chimeric, human or
humanized antibodies, or fusion proteins
- No known hypersensitivity to Chinese hamster ovary (CHO) cell products or any
component of the atezolizumab formulation
- No known allergy to 5-fluorouracil, oxaliplatin, or leucovorin
