Patient case: 45-year-old female with colon cancer; genetic feature: PIK3CA (E545K)

Clinical trial: Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in Treating Patients With Deficient DNA Mismatch Repair Metastatic Colorectal Cancer

Summary: This randomized phase III trial studies how well combination chemotherapy, bevacizumab, and/or atezolizumab work in treating patients with deficient deoxyribonucleic acid (DNA) mismatch repair colorectal cancer that has spread to other places in the body. Drugs used in chemotherapy, such as fluorouracil, oxaliplatin, and leucovorin calcium, 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 bevacizumab and 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, bevacizumab, and atezolizumab may work better in treating patients with colorectal cancer.

Detailed description: PRIMARY OBJECTIVES:
  I. To determine the efficacy, based on progression-free survival (PFS), of fluorouracil, oxaliplatin, and leucovorin calcium (mFOLFOX6)/bevacizumab plus atezolizumab (combination) and atezolizumab (single agent) as compared to mFOLFOX6/bevacizumab (control).
  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 combination of mFOLFOX6/bevacizumab/atezolizumab and atezolizumab monotherapy in patients with mismatch-repair deficient (dMMR) metastatic colorectal cancer (mCRC).
  IV. To compare the surgical conversion rate. V. To determine the duration of response and stable disease. VI. To determine the progression-free survival (PFS) by retrospective central independent scan review.
  EXPLORATORY OBJECTIVES:
  I. To compare the health-related quality of life and patient-reported symptoms.
  TRANSLATIONAL OBJECTIVES:
  I. To bank tissue and blood samples for other future correlative studies from patients enrolled on the study.
  II. To compare disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) at 12 months.
  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.
  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.

Eligibility: 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; Note: microsatellite instability high (MSI-H) diagnosed by microsatellite instability (MSI) testing (either Bethesda markers or Pentaplex panel) or by next-generation sequencing (NGS) is not eligible unless dMMR is confirmed by CLIA-certified immunohistochemical (IHC) assay with a panel of all four IHC markers including MLH1, MSH2, PMS2 and MSH6
  -  An adequate amount of archived tumor tissue, either from primary colorectal cancer site or metastatic lesions, for central confirmation of dMMR status:
  -  Either whole or part of the formalin-fixed paraffin-embedded (FFPE) block containing tumor tissue; or
  -  At least 9 unstained slides containing tumor sections
  -  Documentation by positron emission tomography(PET)/computed tomography (CT) scan, CT scan, or magnetic resonance imaging (MRI) that the patient has untreated 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 or calculated creatinine clearance >= 30 mL/min (obtained within 28 days prior randomization)
  -  A urine sample tested for proteinuria by the dipstick method must indicate 0 -1+ protein; if dipstick reading is >= 2+, a 24-hour urine specimen 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
  -  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 and/or mFOLFOX6/bevacizumab 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 must agree to use adequate contraception (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; men with female partners of child-bearing potential must agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months after the last dose of bevacizumab and 6 months after the last dose of mFOLFOX6
  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:
  -  Radiographic demonstration of improvement upon the completion of CNS-directed therapy 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 or symptomatic peripheral ischemia
  -  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) in patients with no prior oxaliplatin therapy
  -  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
  -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
  -  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: pregnancy testing should be performed within 14 days prior to randomization according to institutional standards for women of childbearing potential)
  -  Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have:
  -  A stable regimen of highly active anti-retroviral therapy (HAART); and
  -  No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections; and
  -  A CD4 count above 250 cells/uL and an undetectable HIV viral load on standard PCR-based tests
  -  Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation

Relevance to patient case: not relevant