Administration of CI-1033, an Irreversible Pan-erbB Tyrosine Kinase Inhibitor, Is Feasible on a 7-Day On, 7-Day Off Schedule

Calvo, Emiliano; Tolcher, Anthony W.; Hammond, Lisa A.; Patnaik, Amita; Bono, Johann S. de; Eiseman, Irene A.; Olson, Stephen C.; Lenehan, Peter F.; McCreery, Heather; LoRusso, Patricia; Rowinsky, Eric K.

doi:10.1158/1078-0432.ccr-04-1187

Cited by 72 publications

(41 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the current study, skin rash was noted in 50% of patients, although the majority of rashes were mild (grade 1), with no grade 3 or 4 rash noted. Grade 3 skin rash has been reported as a treatment-related event in other studies using doses of CI-1033 of z250 mg/d (20,21).…”

Section: Discussionmentioning

confidence: 85%

“…However, it is unlikely that CI-1033 alone contributed to the high incidence of neutropenia seen in this trial as no leukopenia, neutropenia, or febrile neutropenia has been reported in preclinical and phase I studies of single-agent CI-1033 (13,20) nor in trials using the EGFR TKIs gefitinib and erlotinib (31 -34) and lapatinib, a dual erbB-1/erbB-2 TKI (35).…”

Section: Discussionmentioning

confidence: 89%

See 1 more Smart Citation

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

Garland

Hidalgo

Mendelson

et al. 2006

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

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,

show abstract

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 89%

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

Garland

Hidalgo

Mendelson

et al. 2006

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…This result is consistent with the clinical efficacy of the compound (Pharmaprojects database, www.pjbpubs.com͞pharmaprojects͞index.htm), but the direct interaction has not been demonstrated to our knowledge. Finally, we find that EKB-569 and CI-1033, EGFR inhibitors that have completed phase I clinical trials (26,27) Abbreviations: EGFR, EGF receptor; GIST, gastrointestinal stromal tumor. database), potently inhibit the erlotinib-and gefitinib-resistant EGFR(L858R͞T790M) variant.…”

mentioning

confidence: 94%

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

Carter

Wodicka

Shah

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

519

390

View full text Add to dashboard Cite

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved ''gatekeeper'' threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib-and BMS-354825-resistant ABL(T315I) kinase. The KIT͞FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D͞T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitiniband erlotinib-resistant EGFR(L858R͞T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib͞ erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of nextgeneration drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy. drug resistance ͉ gatekeeper mutation ͉ kinase inhibitor

show abstract

“…Increased erbB expression was shown to be a negative prognostic factor (3,4) in non-small cell lung cancer (NSCLC; ref. 5), breast (6,7), prostate (8,9), head and neck (10), brain (11), ovary (12,13), and stomach cancers (14,15), providing the rationale for development of compounds inhibiting erbB signaling (7).…”

mentioning

confidence: 99%

Increased Bioavailability of Intravenous Versus Oral CI-1033, a Pan erbB Tyrosine Kinase Inhibitor: Results of a Phase I Pharmacokinetic Study

Simon

Garrett

Olson

et al. 2006

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

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. Cmax 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.

show abstract

Administration of CI-1033, an Irreversible Pan-erbB Tyrosine Kinase Inhibitor, Is Feasible on a 7-Day On, 7-Day Off Schedule

Cited by 72 publications

References 31 publications

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

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

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

Increased Bioavailability of Intravenous Versus Oral CI-1033, a Pan erbB Tyrosine Kinase Inhibitor: Results of a Phase I Pharmacokinetic Study

Contact Info

Product

Resources

About