A Phase 1 Study of AZD6244 in Combination With Cetuximab in Refractory Solid Tumors
- AZD6244 is an oral highly selective and potent uncompetitive inhibitor of
mitogenactivated protein kinase 1/2 (MEK1/2).
- The presence of KRAS mutations predict resistance to EGFR-directed antibody therapy of
metastatic colorectal cancer. This appears secondary to KRAS activation of signaling
cascades downstream of the EGFR receptor, including the RAF/MEK/ERK pathway.
- Our hypothesis is that EGFR inhibition by cetuximab would be augmented in patients with
KRAS mutations if activation of the RAF/MEK/ERK cascade were to be inhibited.
- To determine the dose limiting toxicities and the maximum tolerated dose of AZD6244 in
combination with cetuximab in advanced, refractory solid tumors.
- To assess for evidence of anti-tumor activity with this combination, per tumor
measurements using RECIST criteria.
- To evaluate the pharmacokinetics of AZD6244 and cetuximab when administered
- To evaluate the safety and tolerability of the combination of AZD6244 and cetuximab in
patients with K-RAS mutated metastatic colorectal cancer.
- To assess the inhibition of the RAF/MEK/ERK pathway in peripheral blood mononuclear
cells secondary to treatment with AZD6244.
- To evaluate the pharmacokinetics of AZD6244 in combination with cetuximab and the
relation to treatment side effects.
- Patients must have histologically confirmed malignancy that is metastatic or
unresectable and for which standard curative or palliative measures do not exist or are
no longer effective. In the MTD expansion cohort: Patients must have biopsy proven
K-RAS mutant, metastatic colorectal cancer.
- Age greater than or equal to 18
- ECOG performance status less than or equal to 2
- This is a phase 1 dose escalation study of AZD6244 in combination with fixed-dose
cetuximab with an expanded cohort in K-RAS mutated metastatic colorectal cancer.
- Patients will be treated with AZD6244 orally twice daily continuously, and cetuximab
will be administered at standard doses on days 1, 8, 15 and 22. Dose escalations are
outlined per the schema in the parent protocol.
- The dose of AZD6244 will be escalated using a 3-patient cohort design based on first
cycle toxicities until dose limiting toxicities (DLT) and maximum tolerated dose (MTD)
are defined. Once the MTD/RP2D has been identified, an additional 12 patients with KRAS
mutant colorectal cancer will be enrolled at that dose level, in an effort to more
fully characterize pharmacokinetic characteristics of this combination. If at least an
8% response rate is observed in the expanded cohort, the combination will be
recommended for future analysis.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the dose limiting toxicities and the maximum tolerated dose of AZD6244 in combination with cetuximab in advanced, refractory solid tumors.
Austin G Duffy, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|