Patient case: 35-year-old female with Colorectal cancer. Genetic variant: FGFR1 Amplification. Other conditions: None.

Clinical trial: Standard of Care Alone or in Combination With Ad-CEA Vaccine and Avelumab in People With Previously Untreated Metastatic Colorectal Cancer QUILT-2.004

Summary: Background:
  Colorectal cancer is a common cancer in the U.S. It causes the second most cancer-related deaths. The drug avelumab and vaccine Ad-CEA together help the immune system fight cancer.
  Objective:
  To test if avelumab and Ad-CEA plus standard therapy treats colorectal cancer that has spread to other sites better than standard therapy alone.
  Eligibility:
  People ages 18 and older with untreated colorectal cancer that has spread in the body
  Design:
  Participants will be screened with:
  Test to see if their cancer has a certain deficiency
  Blood, urine, and heart tests
  Scans
  Medical history
  Physical exam
  Tumor sample. This can be from a previous procedure.
  A small group of participants will get Ad-CEA and avelumab plus standard therapy. This is FOLFOX plus bevacizumab for up to 24 weeks then capecitabine plus bevacizumab.
  The others will have treatment in 2-week cycles. They will be Arm A or B:
  Arm A: FOLFOX and bevacizumab by IV days 1 and 2 for 12 cycles. After that, capecitabine by mouth twice a day and bevacizumab by IV on day 1.
  Arm B: Ad-CEA injection every 2 12 weeks. Avelumab by IV on day 1 of each cycle. FOLFOX and bevacizumab by IV days 2 and 3 for 12 cycles. Then, capecitabine by mouth twice a day and bevacizumab through IV on day 2.
  Participants will repeat screening tests during the study.
  Participants will be treated until their disease gets worse or they have bad side effects. Arm A participants can join Arm B. They will have a visit 4 5 weeks after they stop therapy.

Detailed description: Background
  -  Colorectal cancer (CRC) is the fourth most common cancer diagnosis in the United States and accounts for the second most cancer-related deaths.
  -  Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified for its role in the maintenance of self-tolerance and prevention of autoimmunity. Blockade of the interaction between PD-L1 on tumor cells and PD-1 on T cells is expected to reverse T cell suppression within tumors. These agents are dependent on underlying T cell activation against the tumor cell to be effective.
  -  Avelumab is a fully human IgG1 anti-PDL1 antibody that selectively binds to PD-L1 and competitively blocks its interaction with PD-1.
  -  In ongoing phase 1 trials of avelumab, the agent has been well tolerated and has shown clinical activity. Clinical trials with anti-PD-1/L1 agents in colorectal cancer have resulted in minimal activity in patients who do not have mismatch repair deficiency (MMR-D)
  -  Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to activate T cells against tumors.
  -  A novel adenovirus based, CEA-targeting vaccine has demonstrated cytolytic T cell responses in patients with metastatic colorectal cancer.
  -  Standard of care agents in first line metastatic CRC have properties been associated with improved immune response via immunologic cell death and immunogenic modulation.
  Objectives
  -To determine if there is an improvement progression free survival among patients with metastatic colorectal cancer lacking a mismatch repair deficiency who are treated with standard of care + anti- PDL1 monoclonal antibody + Ad-CEA therapeutic cancer vaccine compared with standard of care alone.
  Eligibility
  -  Subjects age 18 and older with previously untreated pathologically confirmed metastatic colorectal cancer; prior adjuvant therapy is acceptable
  -  ECOG performance status < 1
  -  Normal organ and bone marrow function
  -  Subjects with active autoimmune diseases requiring treatment and subjects requiring system steroids (except for physiologic doses for steroid replacement) are not allowed
  -  Tumor tissue (block) sample and whole blood sample must be available for proteomics, genomics and transcriptomics analyses. Archival FFPE tumor tissue block (< 24 weeks prior to coming on study) with a minimum tissue surface area of 25 mm2, 75 micro meters thick, and at least 30% malignant tissue must be available; leftover material from fresh biopsy if collected for diagnosis at screening may also be utilized.
  -  Subjects with metastatic colorectal cancer with mismatch repair deficiency (MMR-D or MSI-High) will
  not be eligible
  Design
  -  This is a randomized, multicenter phase II clinical trial designed to evaluate the potential improvement in progression free survival (PFS) when Avelumab and Ad-CEA vaccine are used in combination with standard of care therapy in metastatic colorectal cancer when compared with standard of care alone (FOLFOX-B).
  -  A lead in cohort, comprising the first 6 evaluable subjects enrolled, will be treated with avelumab + Ad- CEA vaccine + standard of care in order to assess the safety of the combination.
  -  If no more than 1 subject in the lead in cohort experiences a dose limiting toxicity attributable to the IND agents, 70 evaluable subjects will be randomized on a 1:1 basis to receive either Avelumab + Ad-CEA vaccine + standard of care (Arm B) or standard of care alone (Arm A).
  -  Standard of care therapy consists of 6 12 two week cycles of bevacizumab + FOLFOX (5-FU, leucovorin, oxaliplatin) followed by two week cycles of bevacizumab + capecitabine until disease progression.
  -  Subjects assigned Arm A that have progressive disease will be offered Avelumab + Ad-CEA vaccine in combination with a standard chemotherapy regimen.
  -  Kaplan-Meier curves and a two-tailed log-rank test will be the primary analysis methods.
  -  The accrual ceiling for the study is set at 81.

Eligibility: -  INCLUSION CRITERIA:
  -  Subjects must have previously untreated metastatic colorectal cancer and have no contraindications to treatment with the standard of care regimen as determined by the investigator. Prior adjuvant therapy is acceptable (including immunotherapy), but must have been completed at least 6 months prior to metastatic disease diagnosis.
  -  Patients should not be eligible for potentially curative surgical intervention in the case of oligometastic disease at the time of enrollment or must have actively refused after explicit discussion of potential benefit of this intervention with multidisciplinary team.
  -  Metastatic disease must be histologically confirmed by tumor sample with pathologic diagnosis confirmed at the enrolling institution. Tumor block of FFPE tumor tissue attained within the prior 6 months with no treatment between sample and enrollment must be available; otherwise, a fresh tumor biopsy will be collected.
  -  Tumor tissue (block) sample and whole blood sample must be available for proteomics, genomics and transcriptomics analyses. Archival FFPE tumor tissue block (<24 weeks prior to coming on study) with a minimum tissue surface area of 25 mm2, 75 micrometers thick,
  and at least 30% malignant tissue must be available; leftover sample from a fresh tumor
  biopsy collected for diagnostic/clinical purposes at screening may also be utilized to be
  formalin-fixed and paraffin-embedded.
  -  Patients must have measurable disease by RECIST criteria.
  -  Age greater than or equal to18 years. Because safety data is not known with this agent in patients less than 18 years old, children are excluded from this study.
  -  ECOG performance status less than or equal to 1.
  -  Patients must have normal organ and marrow function as defined below:
  -  Creatinine clearance (Cockroft-Gault calculated or 24-hour urine) greater than or equal to 30 mL/min.
  -  Adequate hepatic function defined by a total bilirubin level less than or equal to 1.5 (SqrRoot) the upper limit of normal range (ULN), an aspartate aminotransferase (AST), level less than or equal to 2.5 (SqrRoot) ULN, and an alanine aminotransferase (ALT) level less than or equal to 2.5 (SqrRoot) ULN or, for subjects with documented metastatic disease to the liver, AST and ALT levels less than or equal to 5 (SqrRoot) ULN.
  -  Hematological eligibility parameters (within16 days of enrollment):
  -  Granulocyte count greater than or equal to 1,500/mm3
  -  Platelet count greater than or equal to 100,000/mm3
  -  Hemoglobin greater than or equal to 9 g/dL
  -  The effects of Ad-CEA vaccine and Avelumab on the developing human fetus are unknown. For this reason and because Ad-CEA vaccine and Avelumab as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for a period of 4 months after the last treatment with avelumab or 6 months after the last administration of bevacizumab, whichever occurs later. 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.
  -  Ability of subject to understand and the willingness to sign a written informed consent document.
  EXCLUSION CRITERIA:
  -  Metastatic colorectal cancer with mismatch repair deficiency (MMR-D or MSI-High).
  -  Concurrent treatment for cancer except agents specified within the treatment protocol.
  -  Prior surgery or gastrointestinal perforation within 28 days of enrollment.
  -  Systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg. Subjects may take antihypertensive agents to fall within the required range, but this must be done prior to enrollment on study.
  Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade > 1); however alopecia, sensory neuropathy Grade <=2, or other Grade <=2 AEs not constituting a safety risk based on investigator's judgment are acceptable.
  -  Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
  -  Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
  -  Any significant disease that, in the opinion of the investigator, may impair the patient s tolerance of study treatment.
  -  Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
  -  Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses less than or equal to 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
  -  Patients who are receiving any other investigational agents within 28 days before start of study treatment.
  -  Prior organ transplantation including allogenic stem-cell transplantation.
  -  Patients with known central nervous system metastases.
  -  Active infection, requiring systemic therapy,
  -  Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (greater than or equal to New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
  -  Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
  -  Pregnant women and breastfeeding mothers are excluded due to unknown impact on embryos or infants.
  -  Known alcohol or drug abuse.
  -  Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade greater than or equal to 3).
  -  Patients with a known hypersensitivity/allergy to any of the standard of care agents used in this study or related compounds (e.g. platinum compounds) are excluded
  -  Prior history of hypertensive crisis or hypertensive encephalopathy.
  -  Proteinuria, as demonstrated by a 24 hour protein of 2000 mg.
  -  Urine protein should be screened by urine analysis.
  -  If urine dipstick is greater than or equal to 2.0+, then a 24 hour urine collection for total protein will need to be obtained and the level should be < 2000mg for patient enrollment.
  -  Serious, non-healing wound, active ulcer, or untreated bone fracture, including tumorrelated pathological fracture.
  -  Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
  -  Patients being treated with medications with drug-drug interactions with study agents will require evaluation by to determine if full doses of all study treatments can be given safely. Significant drug-drug interactions will need to be addressed prior to enrollment. Alternatively, the patient will not be eligible.
  -  Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited
  except for administration of inactivated vaccines

Relevance to patient case: not relevant