Clinical trial NCT00867334
Conditions: Colorectal Neoplasm Colorectal Cancer
Keywords: colorectal neoplasm colorectal cancer imatinib mesylate Gleevec Physiological Effects of Drugs panitumumab Vectibix c-kit receptor Receptor Platelet-Derived Growth Factor alpha
Sponsor: Inova Health Care Services
Start date: 2009-06-01; Completion date: 2011-08-01
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of imatinib mesylate in combination with panitumumab for the treatment of stage IV colorectal cancer that has spread to the liver. It will also assess the whether imatinib mesylate, either alone or in combination with panitumumab, is effective in treating this type of cancer. In addition, the study will evaluate the feasibility of a predefined lab score and whether it can predict which patients will respond to treatment with imatinib mesylate.

Detailed description:
Recently, a series of clinical trial outcome reports have shown that KRAS mutations (and to a lesser extent KRAS mutations with BRAF V600E mutation) significantly negatively correlate with response to anti-epidermal growth factor (EGFR) mAbs, such as panitumumab, in metastatic colorectal cancer (mCRC) patients. WT KRAS status was shown to be required but not sufficient to confer sensitivity to panitumumab monotherapy. The molecular mechanisms underlying the response or lack of response to EGFR-directed therapies in CRC patients with WT RAS status are unknown. Potential mechanisms of response include activation of EGFR through receptor mutation or autocrine/paracrine ligand binding, activation while tumors that do not respond to EGFR-directed therapy may have activation of other distinct pathways such as VEGF, PDGF, and insulin-like growth factor 1 receptor; activating mutations of additional signaling proteins downstream of EGFR such as PI3K, and Src, or downstream of KRAS, such as RAF; and loss of function genes such as phosphatase and tensin homolog (PTEN). Identifying prognostic and predictive biomarkers to EGFR-directed therapy will prove important for the selection of therapeutic combinations to maximize clinical benefit. In addition to ascertaining resistance mechanisms other biomarkers such as EGFR gene copy number and expression levels of EGFR ligands in tumor cells may be useful to further refine responder population. The current approach applies to the panitumumab monotherapy and indicates that KRAS status should be considered when selecting mCRC patients as candidates for treatment. Thus, patients who are found to harbor KRAS mutation(s) as identified in the pre-treatment liver biopsy specimen will not be eligible for continuation on the trial, but following patient consent, the pre-treatment biopsy will be studied for pathway activation analysis by a CAP/CLIA compliant independent laboratory for research purposes only in the hopes for generating future hypothesis on pathway activation correlating with KRAS mutation status and help extend research into predictive pathway biomarkers for anti-EGFR therapy.

This is a two arm prospective non-randomized study that is designed to assess the safety and efficacy of Gleevec and Vectibix in the treatment of metastatic colorectal cancer to the liver. It also studies the change in phosphorylation levels of Gleevec® targets (PGDT) and tumor burden in patients treated with Gleevec® monotherapy followed by Gleevec® + Vectibix® combination therapy versus treatment with standard of care (panitumumab).

Arms: arm 1: Subjects whose initial liver biopsy samples meet certain lab values will be placed in Arm 1. Each participant assigned to Arm 1 will receive imatinib mesylate for 28 days, followed by a combination of imatinib mesylate and panitumumab. arm 2: Subjects whose initial liver biopsy samples meet certain lab values will be placed in Arm 2. Participants in Arm 2 will receive standard-of-care treatment with panitumumab.
Interventions: intervention 1: Imatinib mesylate and panitumumab intervention 2: Standard-of-care treatment with panitumumab
Intervention descriptions: intervention 1: Patients will be entered into sequential cohorts with escalating doses of imatinib mesylate. After approximately 28 days of monotherapy treatment with imatinib mesylate, patients will be asked to have a liver biopsy performed (this biopsy is voluntary and is not required for continued participation in the study). All patients in this group will then receive imatinib mesylate in combination with standard-of-care doses of panitumumab. After approximately 1-2 months of combination treatment, patients will asked to have an additional liver biopsy performed (this biopsy is voluntary and is not required for continued participation in the study). Combination treatment will continue for the remainder of the subject's time in the trial. intervention 2: Panitumumab as standard of care. After approximately 2-3 months of standard of care treatment, patients will asked to have a liver biopsy performed (this biopsy is voluntary and is not required for continued participation in the study).

Protocol documents: