Type-1-polarized Dendritic Cell Vaccine, Interferon Alpha-2b, Rintatolimod, and Celecoxib in Treating Patients with Chemo-refractory Metastatic Colorectal Cancer

This phase II trial studies how well type-1-polarized dendritic cell vaccine, interferon alpha-2b, rintatolimod, and celecoxib work in treating patients with colorectal cancer that does not respond to chemotherapy and has spread to other places in the body. Vaccines, such as type-1-polarized dendritic cell vaccine may help the body build an effective immune response to kill tumor cells. Interferon alpha-2b may improve the body’s natural response to infections and other diseases and interfere with the division of tumor cells and slow tumor growth. Rintatolimod may stimulate the immune system. Celecoxib may reduce pain and swelling. Giving alpha type-1-polarized dendritic cell vaccine, interferon alpha-2b, rintatolimod, and celecoxib may work better in treating patients with colorectal cancer that does not respond to chemotherapy and has spread to other places in the body.

Inclusion Criteria

• Be able to understand and be willing to sign a written informed consent document
• Be HLA-A2 positive
• Have mCRC that has been treated with currently approved standard therapies, including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) therapy, and, if Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type, an anti-epidermal growth factor receptor (EGFR) therapy
• Have at least 1 of the tumor sites that must be amenable to core needle biopsy and this may not be the site of disease used to measure antitumor response
• Have measurable disease based on immune-related response criteria (irRC)
• Performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1
• Platelet >= 75,000/µL
• Hemoglobin >= 9.0 g/dL
• Absolute neutrophil count (ANC) >= 1500/µL
• Creatinine < 1.5 x institutional upper limit of normal (ULN) OR creatinine clearance (CrCl) >= 50 mL/min/1.73 m^2 for subjects with creatinine levels greater than 1.5 x ULN
• Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (ULN) OR =< 5 x ULN for subjects with liver metastases
• Serum amylase and lipase within normal limits

Exclusion Criteria

• Is currently treated with systemic immunosuppressive agents, including steroids, are ineligible until 3 weeks after removal from immunosuppressive treatment
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has active autoimmune disease or history of transplantation
• Is a woman of child bearing potential (WOCBP) who are pregnant or nursing
• Has a history of cardiac event(s) (acute coronary syndrome, myocardial infarction, or ischemia) within 3 months of signing consent; subjects with a New York Heart Association classification of III or IV
• Has a history of upper gastrointestinal ulceration, upper gastrointestinal bleeding, or upper gastrointestinal perforation within the past 3 years; subjects with ulceration, bleeding or perforation in the lower bowel are not excluded
• Has prior allergic reaction or hypersensitivity to celecoxib, or nonsteroidal anti-inflammatory drugs (NSAIDs)
• Has an active infection requiring systemic therapy
• Has significant ascites or pleural effusion requiring drainage for symptom relief
• Has known active hepatitis B or hepatitis C infection
• Has history of asthma, or other allergic-type reactions after taking aspirin or other NSAIDs
• Has known serious hypersensitivity reactions to peg-interferon alfa-2b or interferon alfa-2b
• Has autoimmune hepatitis
• Has hepatic decompensation (Child-Pugh score > 6; = class B and C)

PRIMARY OBJECTIVES:

I. To establish whether the combination of peptide-loaded autologous alpha dendritic cell (DC)1 vaccines and tumor-selective chemokine modulation with interferon (IFN) alpha, rintatolimod, and celecoxib improves the overall survival (OS) in histocompatibility antigen (HLA)-A2+ subjects with chemo-refractory metastatic colorectal cancer (mCRC) compared to the historical control of the best supportive care.

SECONDARY OBJECTIVES:

I. To estimate the immune-related objective response rate (irORR) and the immune-related progression-free survival (irPFS) in HLA-A2+ subjects with chemo-refractory mCRC treated with the combination of peptide-loaded autologous alpha DC1 vaccines and tumor-selective chemokine modulation with celecoxib, IFN alpha and rintatolimod.

II. To estimate the changes of cluster of differentiation (CD)8+ tumor infiltrating lymphocytes (CTLs) in paired tumor tissues collected at pre- and post-treatment.

III. To estimate the changes of tumor microenvironment in paired tumor tissues collected at pre- and post-treatment.

OUTLINE:

Patients receive celecoxib orally (PO) once daily (QD), recombinant interferon alfa-2b (IFN alpha-2b) intravenously (IV) over 20 minutes, and rintatolimod IV over 120 to 150 minutes on days 1-3. Beginning course 2, patients also receive alpha-type-1-polarized dendritic cell vaccine (alpha DC1) intranodally (IN) and intradermally (ID) on day 1. Courses repeat every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 3 years.

Lead Organization
University of Pittsburgh Cancer Institute (UPCI)

Principal Investigator
James Jinhak Lee

Primary ID UPCI 15-023
Secondary IDs NCI-2016-00923
Clinicaltrials.gov ID NCT02615574