Phase I studies of CBP501, a G2 checkpoint abrogator, as monotherapy and in combination with cisplatin in patients with advanced solid tumors

Geoffrey I. Shapiro, Raoul Tibes, Michael S. Gordon, Bryan Y. Wong, Joseph Paul Eder, Mitesh J. Borad, David S. Mendelson, Nicholas J. Vogelzang, Bruno R. Bastos, Glen J. Weiss, Cristian Fernandez, William Sutherland, Hitoshi Sato, William E. Pierceall, David Weaver, Scott Slough, Ernesto Wasserman, Donald W. Kufe, Daniel Von Hoff, Takumi KawabeSunil Sharma

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23 Scopus citations

Abstract

Purpose: Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G2 checkpoint abrogator CBP501, as a single agent and in combination with cisplatin. Experimental Design: Patients with advanced solid tumors were treated with CBP501 alone (D1/D8/ D15, q4w, from 0.9 mg/m2), or with cisplatin (both on D1, q3w, from 3.6 mg/m2 CBP501, 50 mg/m 2 cisplatin). Dose escalation proceeded if dose-limiting toxicity (DLT) was observed in 1 or less of 3 to 6 patients; CBP501 dose increments were implemented according to the incidence of toxicity. MTD was determined from DLTs occurring during the first two cycles. Results: In the combination study, the DLT was a histamine-release syndrome (HRS) occurring 10 to 60 minutes after initiating infusion that was attenuated by prophylaxis comprising dexamethasone, diphenhydramine, ranitidine, and loratadine. The MTD was 25 mg/m2 CBP501 and 75 mg/m2 cisplatin, with two patients at the highest dose (36.4 mg/m2 CBP501, 75 mg/m2 cisplatin) experiencing grade 3 HRS. The only DLT with monotherapy was transient G3 rise of troponin in one patient. Grade 3 to 4 treatment-related events were rare. Promising activity was observed with CBP501/cisplatin, mainly in ovarian and mesothelioma patients who had previously progressed on platinum-containing regimens. Among ovarian cancer patients, low expression of DNA repair proteins was associated with partial response or stable disease. Conclusions: CBP501 is well tolerated in patients as monotherapy and with cisplatin. At the recommended phase II dose (RP2D), the combination is feasible and HRS manageable with prophylaxis. Evidence of antitumor activity was observed in platinum-resistant patients.

Original languageEnglish (US)
Pages (from-to)3431-3442
Number of pages12
JournalClinical Cancer Research
Volume17
Issue number10
DOIs
StatePublished - May 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Shapiro, G. I., Tibes, R., Gordon, M. S., Wong, B. Y., Eder, J. P., Borad, M. J., Mendelson, D. S., Vogelzang, N. J., Bastos, B. R., Weiss, G. J., Fernandez, C., Sutherland, W., Sato, H., Pierceall, W. E., Weaver, D., Slough, S., Wasserman, E., Kufe, D. W., Von Hoff, D., ... Sharma, S. (2011). Phase I studies of CBP501, a G2 checkpoint abrogator, as monotherapy and in combination with cisplatin in patients with advanced solid tumors. Clinical Cancer Research, 17(10), 3431-3442. https://doi.org/10.1158/1078-0432.CCR-10-2345