Multicenter, randomized, phase II trial of CI-1033, an irreversible pan-ERBB inhibitor, for previously treated advanced non small-cell lung cancer.

PURPOSE: To evaluate the efficacy of the pan-ERBB inhibitor, CI-1033, in platinum-refractory or recurrent advanced-stage non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This open-label, randomized phase II trial evaluated CI-1033 in patients with advanced-stage NSCLC who experienced treatment failure after or were refractory to platinum-based chemotherapy. Three oral CI-1033 doses were evaluated in 21-day dosing cycles: 50 mg daily for 21 consecutive days, 150 mg daily for 21 consecutive days, and 450 mg daily for 14 consecutive days followed by 7 days of no treatment. The primary efficacy end point was the 1-year survival rate. RESULTS: One hundred sixty-six patients were randomly assigned to treatment. Baseline patient demographics were well balanced. The most common drug-related adverse events were rash and diarrhea. The 450-mg arm (14 days on/7 days off) was closed early due to an excessive rate of adverse events. The 1-year survival rates were 29%, 26%, and 29%, respectively, in the three arms. The response rates were 2%, 2%, and 4%, and stable disease was confirmed in 16%, 23%, and 18% of patients, respectively, in the three study arms. Exploratory analyses demonstrated a prolonged survival in patients who developed a rash and in those with baseline tumor ERBB-2 expression. CONCLUSION: CI-1033 had modest activity in unselected NSCLC patients but did not meet its primary end point. Future studies should focus on identifying methods of patient selection.

Increased bioavailability of intravenous versus oral CI-1033, a pan erbB tyrosine kinase inhibitor: results of a phase I pharmacokinetic study.

PURPOSE: In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability. EXPERIMENTAL DESIGN: Fifty-three patients with advanced nonhematologic malignancies received i.v. CI-1033 via 30-minute infusions (10-500 mg) on a thrice-weekly schedule. Pharmacokinetic samples were collected on days 1 and 8 and evaluated using noncompartmental analysis. RESULTS: Dose levels evaluated were 10, 20, 30, 45, 67.5, 100, 150, 225, 337.5, and 500 mg. The maximum administered dose was 500 mg, whereas the maximum tolerated dose was 225 mg. The most common treatment-related grade 1 to 2 adverse events were rashes (38% of patients), nausea (17%), vomiting (17%), stomatitis (14%), and diarrhea (13%). Most common grade 3 adverse events were hypersensitivity reactions (7.5%), rashes (3.8%), and diarrhea (3.8%). No grade 4 toxicities were observed. Ten of the 53 (19%) patients had disease stabilization at their first efficacy evaluation visit (including two with minor responses). A 5- to 10-fold increase in i.v. C(max) was noted with a 3-fold increase in AUC compared with oral CI-1033 at equivalent doses. Treatment-related gastrointestinal adverse events were notably less frequent with this i.v. regimen. CONCLUSIONS: CI-1033 was safely given i.v. up to 225 mg/dose on a thrice-weekly schedule, with evidence of antitumor activity. At equivalent doses, the bioavailability of i.v. CI-1033 is thrice that of the oral formulation. Treatment with i.v. CI-1033 is feasible and may be warranted when increased drug exposures are desired.

A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors.

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. EXPERIMENTAL DESIGN: Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing. RESULTS: CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38% incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equivalent safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)], 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.

Administration of CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, is feasible on a 7-day on, 7-day off schedule: a phase I pharmacokinetic and food effect study.

PURPOSE: To determine the maximum tolerated dose of administrating CI-1033, an oral 4-anilinoquinazoline that irreversibly inhibits the tyrosine kinase domain of all erbB subfamilies, on an intermittent schedule, and assess the interaction of CI-1033 with food on the pharmacokinetic behavior. EXPERIMENTAL DESIGN: Escalating doses of CI-1033 from a dose level of 300 mg/day for 7 days every other week were administered to patients with advanced solid malignancies. Plasma concentration-time data sets from all evaluable patients were used to develop a population pharmacokinetic model. Noncompartmental methods were used to independently assess the effect of a high-fat meal on CI-1033 absorption and bioavailability. RESULTS: Twenty-four patients were treated with 69 twenty-eight day courses. The incidence of unacceptable toxicity, principally diarrhea and skin rash, was observed at the 300 mg/day dose level. At the 250 mg/day level, toxicity was manageable, and protracted administration was feasible. A one-compartment linear model with first-order absorption and elimination adequately described the pharmacokinetic disposition. CL/F, apparent volume of distribution (Vd/F), and ka (mean +/- relative SD) were 280 L/hour +/- 33%, 684 L +/- 20%, and 0.35 hour(-1)+/- 69%, respectively. Cmax values were achieved in 2 to 4 hours. Systemic CI-1033 exposure was largely unaffected by administration of a high-fat meal. At 250 mg, concentration values exceeded IC50 values required for prolonged pan-erbB tyrosine kinase inhibition in preclinical assays. CONCLUSIONS: The recommended dose on this schedule is 250 mg/day. Its tolerability and the biological relevance of concentrations achieved at the maximal tolerated dose warrant consideration of disease-directed evaluations. This intermittent treatment schedule can be used without regard to meals.

CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer.

The erbB family of cell surface receptor proteins consists of four members, all of which play a role in the development and growth of the normal breast. The activity of this signaling pathway is normally tightly controlled, and dysregulation has been shown to play a significant role in the pathogenesis and progression of breast and other cancers. The potent transforming potential of these receptors is further enhanced by the coexpression of multiple members of this receptor family, which worsens prognosis. Therapeutic blockade of erbB-2 receptor signaling has to date been shown to be effective in only a subset of chemotherapy-resistant breast cancer patients. CI-1033 is a highly potent and selective pan-erbB inhibitor that efficiently blocks signal transduction through all four members of the erbB receptor family. In addition, it covalently binds to these receptors, irreversibility inhibiting them, and thereby provides for prolonged suppression of erbB receptor-mediated signaling. Clinically, it has been shown to have an acceptable side effect profile at potentially therapeutic doses and schedules. Biomarker studies have shown target inhibition in patients, and evidence of antitumor activity has also been observed in phase I studies. Given the broad expression pattern of the erbB family of receptors in solid tumors, and the important proliferative effect of co-expression of multiple erbB receptors, CI-1033, as an irreversible, pan-erbB inhibitor, has the potential to have an important role in the future treatment of breast and other cancers.

Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer.

Transmembrane receptor tyrosine kinases have been shown to play an important role in the modulation of growth factor signaling and regulation of key cellular processes. The erbB receptor family is part of the receptor tyrosine kinase superfamily and consists of four members, erbB-1, erbB-2, erbB-3, and erbB-4. A majority of solid tumors express one or more members of this receptor family, and coexpression of multiple erbB receptors leads to an enhanced transforming potential and worsened prognosis. The erbB receptor family has been shown to play an important role in both the development of the normal breast and in the pathogenesis and progression of breast cancer. Receptor overexpression has also been shown to be a negative prognostic indicator and to correlate with both tumor invasiveness and a lack of responsiveness to standard treatment. Clinically, blockade of the erbB-2 receptor has recently been shown to provide benefit in a subset of chemotherapy-resistant breast cancer patients. CI-1033 is an orally available pan-erbB receptor tyrosine kinase inhibitor that, unlike the majority of receptor inhibitors, effectively blocks signal transduction through all four members of the erbB family. In addition, it blocks the highly tumorigenic, constitutively activated variant of erbB-1, EGFRvIII, and inhibits downstream signaling through both the Ras/MAP kinase, and PI-3 kinase/AKT pathways. CI-1033 is also unique in that it is an irreversible inhibitor, thereby providing prolonged suppression of erbB receptor-mediated signaling. Preclinical data have shown CI-1033 to be efficacious against a variety of human tumors in mouse xenograft models, including breast carcinomas. In a phase I study, CI-1033 has been shown to have an acceptable side effect profile at potentially therapeutic dose levels and demonstrates evidence of target biomarker modulation. Antitumor activity has also been observed in this study, including one partial clinical response and stable disease in over 30% of patients, including one patient with heavily pretreated breast cancer. By virtue of its pan-erbB receptor inhibition and potent interruption of downstream mitogenic signaling pathways, CI-1033 may have clinical activity for solid tumors that overexpress one erbB family member, coexpress multiple members of the erbB family, or express a constitutively activated, mutated form of these receptors. Given the important role of the erbB receptor family in the pathogenesis and progression of breast cancer, an irreversible pan-erbB inhibitor like CI-1033 could have an important role to play in the future treatment of breast cancer.