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

2017-02-14 12:38:22 | BioPortfolio

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.

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.

Study Design

Conditions

Colorectal Cancer

Intervention

Avelumab, Ad-CEA vaccine, Bevacizumab, 5-FU, Leucovorin, Oxaliplatin, Capecitabine

Location

National Institutes of Health Clinical Center
Bethesda
Maryland
United States
20892

Status

Not yet recruiting

Source

National Institutes of Health Clinical Center (CC)

Results (where available)

View Results

Links

Published on BioPortfolio: 2017-02-14T12:38:22-0500

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Medical and Biotech [MESH] Definitions

A deoxycytidine derivative and fluorouracil PRODRUG that is used as an ANTINEOPLASTIC ANTIMETABOLITE in the treatment of COLON CANCER; BREAST CANCER and GASTRIC CANCER.

Tumors or cancer of the COLON or the RECTUM or both. Risk factors for colorectal cancer include chronic ULCERATIVE COLITIS; FAMILIAL POLYPOSIS COLI; exposure to ASBESTOS; and irradiation of the CERVIX UTERI.

Tumor suppressor genes located in the 5q21 region on the long arm of human chromosome 5. The mutation of these genes is associated with the formation of colorectal cancer (MCC stands for mutated in colorectal cancer).

Tumor suppressor genes located in the 18q21-qter region of human chromosome 18. The absence of these genes is associated with the formation of colorectal cancer (DCC stands for deleted in colorectal cancer). The products of these genes show significant homology to neural cell adhesion molecules and other related cell surface glycoproteins.

A group of autosomal-dominant inherited diseases in which COLON CANCER arises in discrete adenomas. Unlike FAMILIAL POLYPOSIS COLI with hundreds of polyps, hereditary nonpolyposis colorectal neoplasms occur much later, in the fourth and fifth decades. HNPCC has been associated with germline mutations in mismatch repair (MMR) genes. It has been subdivided into Lynch syndrome I or site-specific colonic cancer, and LYNCH SYNDROME II which includes extracolonic cancer.

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