Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair

Not Recruiting

Trial ID: NCT02912559


This phase III trial studies combination chemotherapy and atezolizumab to see how well it works compared with combination chemotherapy alone in treating patients with stage III colon cancer and deficient deoxyribonucleic acid (DNA) mismatch repair. Drugs used in combination chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy with atezolizumab may work better than combination chemotherapy alone in treating patients with colon cancer.

Official Title

Randomized Trial of Standard Chemotherapy Alone or Combined With Atezolizumab as Adjuvant Therapy for Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair

Stanford Investigator(s)

George A. Fisher Jr.
George A. Fisher Jr.

Colleen Haas Chair in the School of Medicine


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 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

   - 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

   - Age >= 12 years

   - 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

   - 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

      - Active hepatitis C can be defined as:

         - Hepatitis C antibody (AB) positive AND

         - Presence of hepatitis C virus (HCV) RNA

   - 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
      polymerase chain reaction (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

Exclusion Criteria:

   - Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to
   participate; patients whose tumors show MSI-H by 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)

   - Excluded if known active pulmonary disease with hypoxia defined as:

      - Oxygen saturation < 85% on room air, or

      - Oxygen saturation < 88% despite supplemental oxygen


drug: Atezolizumab

drug: Fluorouracil

drug: Leucovorin Calcium

drug: Oxaliplatin

other: Quality-of-Life Assessment

procedure: Biospecimen Collection

procedure: Computed Tomography

procedure: Magnetic Resonance Imaging

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Lisa Y Zhou

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