A phase 2, single agent study of CI-1033 administered at two doses in ovarian cancer patients who failed platinum therapy

Campos, S. M.; Seiden, Michael V.; Oza, A.; Plante, Marie; Potkul, Ronald K.; Hamid, Oday; Lenehan, Peter F.; Kaldjian, Eric P.; Jordan, Cheryl; Hirte, Hal W.

doi:10.1200/jco.2004.22.90140.5054

Cited by 10 publications

(4 citation statements)

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“…Phase II studies in progressive or recurrent locally advanced or metastatic nonsmall cell lung cancer and metastatic breast cancers are ongoing (http://www.clinicaltrials.gov/). In one phase II study in platinum refractory ovarian cancer patients, canertinib has shown minimal activity, i.e., stable disease with no objective responses (Campos et al, 2004). The most common adverse events associated with this agent were diarrhea, nausea, skin rash, vomiting, asthenia, and stomatitis (Rowinski et al, 2003).…”

Section: Canertinib (Ci-1033)mentioning

confidence: 99%

Role of Tyrosine Kinase Inhibitors in Cancer Therapy

Arora¹,

Scholar²

2005

J Pharmacol Exp Ther

876

595

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Section: Canertinib (Ci-1033)mentioning

confidence: 99%

Role of Tyrosine Kinase Inhibitors in Cancer Therapy

Arora¹,

Scholar²

2005

J Pharmacol Exp Ther

876

595

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“…CI-1033 has been evaluated in multiple phase I and II cancer clinical trials, with various treatment regimens, against a (Rinehart et al, 2002;Campos et al, 2004;Nemunaitis et al, 2005). The most common adverse events were emesis, nausea, diarrhea, stomatitis, asthenia, and acneiform rash (Allen et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Cutaneous Lesions in the Rat Following Administration of an Irreversible Inhibitor of erbB Receptors, Including the Epidermal Growth Factor Receptor

et al. 2008

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CI-1033 (canertinib) is an irreversible inhibitor of the erbB family of transmembrane tyrosine kinase receptors, including the epidermal growth factor (EGF) receptor. Various inhibitors of the EGF receptor, including CI-1033, have resulted in cutaneous toxicity in humans as a common adverse event. In a chronic toxicity study in rats, CI-1033 produced cutaneous lesions with morphologic characteristics similar to that reported in man. Here the authors describe in detail the dermal changes observed, along with other noteworthy findings of that study. Male and female Wistar rats (15/sex/group) were administered CI-1033 for 27 weeks at 2.5, 5, or 10 mg/kg (15, 30, or 60 mg/m 2 , respectively) by gavage. Control animals (15/sex) received vehicle alone (aqueous 0.5% methylcellulose) in a dose volume of 5 mL/kg. Six animals/sex/dose were included for toxicokinetic evaluations. Skin lesions were the primary drug-related toxicity and occurred at ≥2.5 mg/kg in a dose-dependent fashion. The major gross lesions were papules that evolved into crusts and scales that were first observed in weeks 1 and 3, respectively. Alopecia developed in conjunction with the papular eruptions. Skin changes were most pronounced in females, possibly due to higher drug levels. In week 13, CI-1033 plasma AUC(0-24) values were 527 to 1980 ng·h/mL in males and 844 to 2920 ng·h/mL in females at 2.5 to 10 mg/kg. Microscopic changes could be described as 3 patterns that affected the tail and body (haired skin). Pattern 1 consisted of epidermal changes that started as a superficial, perivascular spongiotic dermatitis with evolving epidermal hyperplasia, scale-crusts, and areas of ulceration. Areas of hyperplasia on the tail were often associated with the development of new hair follicles. Pattern 2 was characterized by a suppurative to pyogranulomatous infundibular folliculitis. Pattern 3 consisted of abnormally oriented hair follicles with malformed hair shafts that were associated with a deeper (isthmic) folliculitis; this correlated with alopecia. Elevations in bone marrow myeloid counts correlated with a peripheral leukocytosis, consistent with inflammatory changes in the dermis. In addition, hepatic cholestasis and epithelial atrophy in the gastrointestinal tract and vagina occurred at ≥2.5 mg/kg. In conclusion, CI-1033 produced cutaneous lesions involving the epidermis and hair follicle, and the morphologic characteristics were similar to that reported in clinical studies with various inhibitors of the EGF receptor. These changes are consistent with pharmacologic inhibition of the EGF receptor in these tissues and demonstrate that the rat can serve as an animal model for investigating the mechanisms for this toxicity.

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“…Campos et al (57) reported a phase II study of CI-1033 administered as a single agent in 105 ovarian cancer patients who had failed platinum therapy. Patients were randomized to either a 50-or a 200-mg dose of CI-1033 taken orally for 21 days of a 28-day cycle.…”

Section: Canertinib/ci-1033mentioning

confidence: 99%

The emerging role of epidermal growth factor receptor inhibitors in ovarian cancer

Palayekar

Herzog

2008

Int J Gynecol Cancer

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Epidermal growth factor receptor (EGFR) inhibitors are a new biologically targeted therapy, which may offer new hope in the treatment of patients with advanced or recurrent ovarian cancers. In this review, we summarize and discuss the results of research to date on EGFR inhibitors with particular emphasis on ovarian cancer. We reviewed data identified by searches of MEDLINE, PubMed, and abstracts from the proceedings of the American Society of Clinical Oncology meetings from 1998 to 2006, with the search terms "Ovarian Cancer,""EGFR,""gefitinib, ZD1839, Iressa,""erlotinib, OSI-774, Tarceva,""CI-1033,"" GW 572016, lapatinib,""PKI-166,""EKB 569,""anti-EGFR antibodies,""trastuzumab, Herceptin,""cetuximab, Erbitux, IMC-C225,""matuzumab, EMD 72000,""panitumamab, ABX-EGF,""pertuzumab," and "vandetanib, rINN, Zactima, ZD6474." Phase II trials of both small molecule inhibitors of EGFR- and antibody-based inhibitors are currently ongoing in ovarian cancer and emerging data suggest that their activity in unselected women with advanced or recurrent ovarian cancer is modest, when utilized as a single agent. It is possible that these agents will be highly effective in smaller subsets of patients whose tumors are dependent on EGFR signaling, perhaps through activating mutations in EGFR or its downstream pathway. Targeted therapy with EGFR inhibitors is an untapped potential resource in the treatment of advanced or recurrent ovarian cancer. Ongoing trials will elucidate the most effective strategies to use these agents individually or in combination with traditional chemotherapeutic agents.

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A phase 2, single agent study of CI-1033 administered at two doses in ovarian cancer patients who failed platinum therapy

Cited by 10 publications

References 0 publications

Role of Tyrosine Kinase Inhibitors in Cancer Therapy

Role of Tyrosine Kinase Inhibitors in Cancer Therapy

Cutaneous Lesions in the Rat Following Administration of an Irreversible Inhibitor of erbB Receptors, Including the Epidermal Growth Factor Receptor

The emerging role of epidermal growth factor receptor inhibitors in ovarian cancer

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