Clinical Trials /

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

NCT03050814

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Standard of Care Alone or in Combination With Ad-CEA Vaccine and Avelumab in People With Previously Untreated Metastatic Colorectal Cancer QUILT-2.004
  • Official Title: A Randomized Phase II Trial of Standard of Care Alone or in Combination With Ad-CEA Vaccine and Avelumab in Patients With Previously Untreated Metastatic or Unresectable Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 170057
  • SECONDARY ID: 17-C-0057
  • NCT ID: NCT03050814

Conditions

  • Colorectal Tumors
  • Colorectal Neoplasms
  • Colorectal Carcinoma
  • Colorectal Adenocarcinoma
  • Colorectal Cancer

Interventions

DrugSynonymsArms
AvelumabB/Lead in, FOLFOX-A + Avelumab + Ad-CEA
Ad-CEA vaccineB/Lead in, FOLFOX-A + Avelumab + Ad-CEA
BevacizumabA /FOLFOX-A alone
5-FUA /FOLFOX-A alone
LeucovorinA /FOLFOX-A alone
OxaliplatinA /FOLFOX-A alone
CapecitabineA /FOLFOX-A alone
5-FUB/Lead in, FOLFOX-A + Avelumab + Ad-CEA

Purpose

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.

      Primary Objective

      -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
           or unresectable colorectal cancer; prior adjuvant therapy is acceptable

        -  ECOG performance status less than or equal to 2

        -  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 sample and whole blood sample must be available for proteomics, genomics and
           transcriptomics analyses.

        -  Subjects with metastatic or unresectable 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 or
           unresectable /5-FUcolorectal cancer when compared with standard of care alone
           (FOLFOX-A).

        -  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 to 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 97.
    

Trial Arms

NameTypeDescriptionInterventions
A /FOLFOX-A aloneActive ComparatorSuubjects will receive FOLFOX + bevacizumab + for up to 12 2-week cycles followed by maintenance therapy with bevacizumab + capecitabine until disease progression.
  • Bevacizumab
  • 5-FU
  • Leucovorin
  • Oxaliplatin
  • Capecitabine
  • 5-FU
B/Lead in, FOLFOX-A + Avelumab + Ad-CEAExperimentalSubjects will receive FOLFOX + bevacizumab + avelumab + Ad-CEA vaccine (given weeks 0,2,4,8,12,16 and then every 12 weeks) for up to 12 2-week cycles followed by maintenance therapy with bevacizumab + capecitabine + avelumab + Ad-CEA vaccine (following the every 12 week dosing schedule) until disease progression.
  • Avelumab
  • Ad-CEA vaccine
  • Bevacizumab
  • 5-FU
  • Leucovorin
  • Oxaliplatin
  • Capecitabine
  • 5-FU

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Subjects must have previously untreated metastatic or unresectable 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.

          -  Histologically confirmed colorectal cancer

          -  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/mm^3

               -  Platelet count greater than or equal to 100,000/mm^3

               -  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 or unresectable 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.

          -  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.

          -  Subjects with active central nervous system (CNS) metastases causing clinical symptoms
             or metastases that require therapeutic intervention are excluded. Subjects with a
             history of treated CNS metastases (by surgery or radiation therapy) are not eligible
             unless they have fully recovered from treatment, demonstrated no progression for at
             least 2 months, and do not require continued steroid therapy. Subjects with CNS
             metastases incidentally detected during Screening which do not cause clinical symptoms
             and for which standard of care suggests no therapeutic intervention is needed are
             eligible.

          -  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 immune colitis,
             inflammatory bowel disease, immune 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.

          -  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
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival.
Time Frame:18 months after first dose
Safety Issue:
Description:Proportion of patients that have progressive disease after 18 months

Secondary Outcome Measures

Measure:Safety
Time Frame:30 days after treatment discontinuation
Safety Issue:
Description:list of adverse event frequency
Measure:Immunologic analysis of samples from peripheral blood
Time Frame:3-4 years
Safety Issue:
Description:Immunologic analysis of samples from peripheral blood
Measure:Immunologic analysis of samples from tumor
Time Frame:3-4 years
Safety Issue:
Description:Immunologic analysis of samles from tumor
Measure:Overall response rate
Time Frame:every 2 months until disease progression
Safety Issue:
Description:Proportion of patients whose tumors shrunk after therapy
Measure:Correlative analysis of immune endpoints with clinical outcomes
Time Frame:Progression
Safety Issue:
Description:Correlation between immune endpoints and median amount of time it takes disease to worsen after treatment
Measure:Overall survival
Time Frame:death
Safety Issue:
Description:Median amount of time subject survives after therapy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Anti-PDL1 Antibody
  • Therapeutic Cancer Vaccine
  • Mismatch Repair Deficiency
  • Progression Free Survival
  • Adenovirus Based, CEA-Targeting Vaccine

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