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Randomized Phase I/II Evaluation of Neoadjuvant Administration of a Chemokine-Modulatory Regimen in Patients With Recurrent Resectable Colorectal Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Colorectal Cancer

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Trial Information

Randomized Phase I/II Evaluation of Neoadjuvant Administration of a Chemokine-Modulatory Regimen in Patients With Recurrent Resectable Colorectal Cancer

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
αDC1vaccine to a safe, tolerable and efficacious CKM regimen may hold promise for patients
with poor prognostic CRC.

Inclusion Criteria:

- Recurrent and/or metastatic resectable colorectal cancer, including disease within
the abdomen and pelvis with no evidence of extra-abdominal metastases.
Intra-abdominal disease includes: isolated hepatic metastasis / metastases (see next
inclusion criteria point), isolated peritoneal metastasis, or a combination of
hepatic and extrahepatic metastasis

- Patients with isolated hepatic metastasis must satisfy a Clinical Risk Score of 3 or

- 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

Exclusion Criteria:

- Patients currently treated with systemic immunosuppressive agents, including
steroids, are ineligible until 3 weeks after removal from immunosuppressive

- 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 and pelvis (such as lung,
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

- 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.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Primary - safety

Outcome Description:

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.

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Amer H Zureikat, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Pittsburgh


United States: Food and Drug Administration

Study ID:




Start Date:

October 2012

Completion Date:

December 2014

Related Keywords:

  • Colorectal Cancer
  • Colorectal Neoplasms



UPMC Hillman Cancer Center Pittsburgh, Pennsylvania  15232