Chemokine-Modulatory Regimen for Recurrent Resectable Colorectal Cancer

Phase 1

Terminated

Conditions: Colorectal Cancer
Colorectal Tumors
Colorectal Carcinoma
Neoplasms, Colorectal

Interventions: Drug: Chemokin Modulatory Regimen (10 MU/m2)
Drug: Chemokin Modulatory Regimen (5 MU/m2)
Drug: Chemokin Modulatory Regimen (20 MU/m2)

Registration Number: NCT01545141

Lead Sponsor: Roswell Park Cancer Institute

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 15

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Chemokin Modulatory Regimen (10 MU/m2)	Chemokin Modulatory Regimen (10 MU/m2)	Chemokine Modulatory Regimen monday through Friday prior to surgery: 400 mg celecoxib for 5 days IFN by intravenous infusion (IV) (Phase 1 dose escalation of 10 MU/m2) for 5 days Rintatolimod 200 mg by IV infusion for 5 days
Chemokin Modulatory Regimen (5 MU/m2)	Chemokin Modulatory Regimen (5 MU/m2)	Chemokine Modulatory Regimen monday through Friday prior to surgery: 400 mg celecoxib for 5 days IFN by intravenous infusion (IV) (Phase 1 dose escalation of 5 MU/m2) for 5 days Rintatolimod 200 mg by IV infusion for 5 days
Chemokin Modulatory Regimen (20 MU/m2)	Chemokin Modulatory Regimen (20 MU/m2)	Chemokine Modulatory Regimen monday through Friday prior to surgery: 400 mg celecoxib for 5 days IFN by intravenous infusion (IV) (Phase 1 dose escalation of 20 MU/m2) for 5 days Rintatolimod 200 mg by IV infusion for 5 days

Primary Outcome Measures

Name	Time	Method
Change in the Number of Tumor-infiltrating CD8+ Cells.	Day of surgery: day 8-10	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

Name	Time	Method
Treatment Related Adverse Events	1 week	The number of adverse events experienced within 1 week of treatment. This was completed for the Phase II portion of the study.