Oral CEP-701 in Solid Tumors--Phase I Study

Georgetown University, Washington DC

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Abstract

This is a Phase I, multi-center, open-label study of oral CEP-701 in patients with advanced, incurable solid tumors or lymphoma to assess the safety and tolerability as well as pharmacokinetic profile of CEP-701. Particular effort will be made to enroll patients with prostate tumors. Approximately 40 patients having met the admission criteria are expected to participate in the study. Preclinical pharmacology suggest that certain tumors may be selectively sensitive to the effects of CEP-701, and efforts will be made to enrich the patient population for these tumor types. Based on safety data obtained from a Phase I single-dose study of oral CEP-701 in normal volunteers as well as from two Phase I studies in patients with intravenous CEP-2563, administration of oral CEP-701 at a starting dose of 5mg BID for 28 days is expected to be well tolerated. Doses will be escalated at 100% increments until > Grade 1 probably or definitely related toxicities are observed. Doses will be escalated at 50% increments, thereafter, until > 2DLTs are observed per cohort. After a 7 day rest period, patients will be eligible to continue treatment with oral CEP-701 at the next higher dose level, in the absence of tumor progression or DLT. CEP-701, a novel indolocarbazole, is a potent inhibitor of neurotrophin receptor-linked tyrosine kinases (trkA, B and C) with antineoplastic activity in vivo. It also inhibits PKC and kinases linked to PDGFR and VEGFR (flk-1) to a lesser extent. A Phase I study was conducted to determine the maximum tolerated dose, dose limiting toxicity (DLT) and pharmacokinetic (PK) profile of CEP-701 when administered orally twice daily (BID) for 28 days to patients (pts) with advanced, incurable solid tumors. Pts without DLTs or disease progression were allowed to dose escalate in subsequent treatment cycles. Twenty-nine pts have been treated: 16M/13F, median age 58 (29-81), ECOG PS 0-2. Primary tumor sites were: prostate (5), pancreas (4), colorectal (3), renal (4), sarcoma (2), lung (3), melanoma (2) and others (6). The number of pts per dose level (mgBID) was (pts started de novo/pts escalated from lower dose levels): 5(3/10), 10 (3/2), 20 (3/2), 40 (12/4), 80 (7/4), 120 (1/0), 160 (0/3). Six pts underwent intra- Patient dose escalation (no. of escalations/no. of pts): 5/1, 4/1, 3/1, 1/3. The median duration of treatment was 5 weeks; 2 pts received treatment for >6 months. Preliminary data indicate the following drug-related toxicities to date: nausea (gr 1-3), vomiting (gr 1-2), diarrhea (gr 1-2), epigastric discomfort, gastro-esophageal reflux, increased fecal frequency and anorexia (gr 1-3). Other toxicities include moderate muscle cramps, parasthesias and mild fatigue. No myelosuppression was observed. All pts at 160mg BID discontinued treatment for gastrointestinal symptoms. Ten pts at 40mg BID dose have tolerated CEP-701 without grade 3 toxicities. PK analysis will be presented. Two pts (prostate cancer and sarcoma) had stabilization of disease for > 6 months while on treatment. The remaining pts continue on study or had disease progression after variable periods of treatment. Based on these preliminary data, CEP-701 at a dose of 40mg BID appears to be well-tolerated during chronic administration.