A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors

Abstract

Purpose: CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4.We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose. )], the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics. Conclusions: It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.Aberrant signaling through the erbB family of receptors, which includes erbB-1 [epidermal growth factor receptor (EGFR)], erbB-2, erbB-3, and erbB-4, plays an important role in the development and progression of a wide range of cancers. The majority of solid tumors express one or more members of the erbB receptor family, especially EGFR and erbB-2 (1, 2); tumor types include breast, ovarian, prostate, gastric, head and neck carcinoma, non -small cell lung carcinoma (NSCLC), and glioblastoma (3 -10). Tumors that overexpress these receptors generally have a more aggressive phenotype and a worse clinical prognosis (11,12).CI-1033 (canertinib dihydrochloride; Fig. 1) is a 4-anilinoquinazoline derivative that acts as a highly selective, irreversible ATP binding site -directed inhibitor of erB-1, erB-2, and erB-4 tyrosine kinases with IC 50 values in the low nanomolar/liter concentrations (13). Treatment with CI-1033 completely inhibited EGFR autophosphorylation in A431 human epidermoid carcinoma and MDA-MB-468 human breast cancer cells. Concentration-dependent inhibition of in vitro clone formation has been seen for a wide array of human tumors, including breast, ovary, kidney, liver, pancreas, and prostate. Oral administration of CI-1033 to animals bearing human tumor xenografts delayed growth of H125 (NSCLC) and ref. 14). Moreover, long-term administration (daily gavage, days 1-5 for 10 weeks over a 12-week period) of CI-1033 to mice bearing A431 xenografts caused long-term tumor regression (>9 weeks) without emergence of a drug-resistant population of tumor cells (15). Preclinical studies support an oral continuous daily dosing schedule. The predominant dose-limiting toxicity (DLT) noted in animal toxicology studies is gastrointestinal (diarrhea,

Epidermal growth factor receptor inhibitors in the treatment of lung cancer: reality and hopes

“…It is administered orally, although an intravenous formulation has also been tested, demonstrating increased bioavailability and less diarrhea [105]. It is safe in combination with docetaxel [106], and in NSCLC patients, with carboplatin/paclitaxel [107].…”

Combination of radiotherapy with EGFR antagonists for head and neck carcinoma

“…104 In phase I-II trials, it was shown to have activity as a single agent [105][106][107] and also to have activity in combination with chemotherapy. 108 An additional advantage of CI-1033 is its capacity to block EGFRvIII (see below) and to inhibit downstream signaling through both the Ras/MAP kinase and PI3K/AKT pathways. 104 Type II TKIs, such as lapatinib (GW572016), bind to EGFR in an inactive conformation of its tyrosine kinase.…”

The Potential of panHER Inhibition in Cancer

“…CI-1033 has undergone a phase I trial in combination with docetaxel in advanced solid tumor patients. It appeared to be safe with acceptable side effects following an intermittent administration schedule ( 109 ). CI-1033 has also been examined in combination with paclitaxel and carboplatin in advanced NSCLC patients ( 110 ).…”