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Chemokine-Modulatory Regimen for Recurrent Resectable Colorectal Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by University of Pittsburgh
Sponsor:
Collaborator:
Hemispherx Biopharma
Information provided by (Responsible Party):
Pawel Kalinski, University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01545141
First received: February 29, 2012
Last updated: April 25, 2014
Last verified: April 2014
  Purpose

Determine the safety of a combination of IFN, celecoxib, and rintatolimod for patients with recurrent colorectal cancer. This will also test whether the above combination can help the immune system to fight the tumors. The results will allow the investigators to determine the "preferred" combination for subsequent extended studies.


Condition Intervention Phase
Colorectal Cancer
Procedure: Surgical resection of recurrent colorectal cancer
Drug: Chemokine-modulatory (CKM) regimen
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase 1/2 Evaluation of Neoadjuvant Administration of a Chemokine-Modulatory Regimen in Patients With Recurrent Resectable Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • Primary - safety [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Safety: This will be assessed by adaptive evaluation of RLTs associated with each dose and selecting a dose with a maximum 33% RLT rate. Further continuous monitoring of safety will occur during the efficacy phase.

  • Primary - efficacy [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Immunologic efficacy: This will be assessed by the increase in the total number of tumor-infiltrating CD8+ T cells in the resected, recurrent CRC lesions (measured as the ratio between the CD8 mRNA message and the expression of the housekeeping gene HPRT), comparing Arm A and Arm B.


Secondary Outcome Measures:
  • Regimen limiting toxicities [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    To define the regimen-limiting toxicity and other toxicities associated with this combination.

  • Anti-tumor activity [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    To obtain preliminary evidence of anti-tumor activity in subjects receiving this combination.


Estimated Enrollment: 50
Study Start Date: October 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Control
Surgical resection only, performed as standard of care for the disease
Procedure: Surgical resection of recurrent colorectal cancer
Surgical resection of recurrent colorectal cancer performed as the standard of care for their condition
Experimental: Chemoking-modulating regimen plus surgery
Chemokine Modulatory Regimen (celecoxib, IFN, and rintatolimod) prior to surgical resection
Drug: Chemokine-modulatory (CKM) regimen

Celecoxib: 200 mg twice/day M-F of the week prior to scheduled surgery rintatolimod: 200 mg i.v. administration M-F of the week prior to scheduled surgery IFN: i.v. administration, M-F of the week prior to scheduled surgery. Dose escalation evaluating 5, 10, and 20 MU/m2.

Standard of care surgery on days 8, 9, or 10.

Other Names:
  • Celebrex
  • INTRON A
  • Interferon-alpha 2b
  • IFN-alpha
  • Ampligen

Detailed Description:

A previously-demonstrated correlation between the density of CRC-infiltrating effector T cells and long-term outcomes (Galon et al., 2006; Pages et al., 2005) has been established. In preclinical ex vivo studies performed using explants of resected metastatic CRC, the combination of IFNα with nonselective or COX2-selective inhibitors of prostaglandin synthesis resulted in elevated production of the effector T cell-attracting chemokines CXCL10 and CCL5. This was associated with concomitant suppression of the intratumoral expression of CCL22, a Treg-attracting chemokine (Muthuswamy et al 2008 Canc Res, and Muthuswamy et al, submitted to Canc Res 2011). However, in a subset of patients, the optimal results, particularly with regard to CCL5 induction, required additional stimulation by a third agent, poly-I:C (a toll-like receptor -TLR Ligand).

Therefore, the investigators seek to establish the safety profile of a novel chemokine regimen consisting of IFN, celecoxib and poly-I:C. The investigators also hypothesize that the proposed neoadjuvant chemokine modulation treatment in recurrent CRC patients undergoing tumor resection may increase the density of tumor infiltrating lymphocytes (TILS).

In addition, treatment in the neoadjuvant setting will allow a comparative analysis of the effect of chemokine modulation on the local recruitment of effector-type T cells and the de-recruitment of Treg within resected tumor tissues; helping to determine the "preferred" chemokine-modulating regimen for subsequent extended studies. Such prospective studies will focus on using combinations of chemokine modulation and cancer vaccines in patients with CRC. The investigators have, for example, recently observed that αDC1, a new type of DC vaccine (Kalinski and Okada, 2010; Mailliard et al., 2004) is particularly effective in inducing the effector pathway of T cells differentiation. This was manifested by the induction of tumor-killing function and the induction of effector-type chemokine receptors (CXCR3 and CCR5) (Kalinski and Okada, 2010; Watchmaker et al., 2010). Combining the αDC1 vaccine to a safe, tolerable and efficacious CKM regimen may hold promise for patients with poor prognostic CRC.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • Recurrent and/or metastatic resectable colorectal cancer, including disease within the abdomen and pelvis with no evidence of extra-abdominal metastases. Isolated resectable pulmonary metastasis are allowable in the absence of intra-abdominal metastasis. Intra-abdominal disease includes: isolated hepatic metastasis/metastases (see next inclusion criteria point), isolated peritoneal metastasis, peritoneal carcinomatosis (including patients undergoing cytoreductive surgery alone or in combination with hyperthermic intraperitoneal chemoperfusion - HIPEC), or a combination of hepatic and extrahepatic metastasis.
  • Patients with isolated hepatic metastasis must satisfy a Clinical Risk Score of 3 or higher (see Appendix C)
  • Eligible patients are expected to have a complete resection based on preoperative imaging. Any patient not found to be able to have complete resection will not be eligible for this study.
  • No chemotherapy, radiotherapy, major surgery, or biologic therapy within 3 weeks of protocol treatment
  • An ECOG performance status of 0, 1, or 2.
  • Age equal to 18 years or older.
  • Must have normal organ and marrow function as defined below:

    • Platelet ≥ 75,000/µL
    • Hemoglobin ≥ 9.0 g/dL
    • Hematocrit ≥ 27.0%
    • Absolute Neutrophil Count (ANC) ≥ 1500/µL
    • Creatinine < institutional upper limit of normal (ULN) OR
    • Creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels greater than ULN
    • Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN)
    • AST(SGOT) and ALT(SGPT) ≤ 2.5 X institutional upper limit of normal (ULN)
    • Serum amylase and lipase within normal limits.
  • Patient must be able to understand and be willing to sign a written informed consent document.

6.2 Exclusion criteria

  • Patients currently treated with systemic immunosuppressive agents, including steroids, are ineligible until 3 weeks after removal from immunosuppressive treatment.
  • Patients with active autoimmune disease or history of transplantation.
  • Patients who are pregnant or nursing. Women of childbearing potential (WOCBP) will have to undergo a urine pregnancy test as part of screening.
  • Patients with comorbid medical conditions that render them unfit for surgery.
  • Metastatic or recurrent disease that is deemed partially resectable or unresectable based on preoperative imaging.
  • Metastatic disease outside the confines of the abdomen, pelvis and thorax (e.g bone, brain)
  • Cardiac risk factors including:

    • Patients experiencing cardiac event(s) (acute coronary syndrome, myocardial infarction, or ischemia) within 3 months of signing consent
    • Patients with a New York Heart Association classification of III or IV (Appendix A)
  • History of upper gastrointestinal ulceration, upper gastrointestinal bleeding, or upper gastrointestinal perforation within the past 3 years. Patients with ulceration, bleeding or perforation in the lower bowel are not excluded.
  • Prior allergic reaction or hypersensitivity to sulfonamides, celecoxib, or NSAIDs.
  • Patients are ineligible if they plan on regular use of NSAIDs at any dose more than 2 times per week (on average) or aspirin at more than 325 mg at least three times per week, on average. Low-dose aspirin not exceeding 100 mg/day is permitted. Patients who agree to stop regular NSAIDs or higher dose aspirin are eligible and no wash out period is required.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01545141

Contacts
Contact: Amer H Zureikat, MD 412-623-7931 zureikatah@upmc.edu
Contact: Gail Tribble, RN, BSN, OCN 412-647-8205 tribbleg@upmc.edu

Locations
United States, Pennsylvania
UPMC Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
Pawel Kalinski
Hemispherx Biopharma
Investigators
Principal Investigator: Amer H Zureikat, MD University of Pittsburgh
  More Information

No publications provided

Responsible Party: Pawel Kalinski, Professor of Surgery, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01545141     History of Changes
Other Study ID Numbers: 10-131, 10-131
Study First Received: February 29, 2012
Last Updated: April 25, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Pittsburgh:
Colorectal cancer
metastatic
recurrent
peritoneal metastasis
peritoneal carcinomatosis
cytoreductive surgery
hyperthermic intraperitoneal chemoperfusion
HIPEC
hepatic metastasis
extrahepatic metastasis

Additional relevant MeSH terms:
Colorectal Neoplasms
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases

ClinicalTrials.gov processed this record on November 27, 2014