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C.M.L. Herpen (Carla), F.A.L.M. Eskens (Ferry), M.J.A. de Jonge (Maja), I.M.E. Desar (Ingrid), L. Hooftman (Leon), E. Bone (Elisabeth), J.N.H. Timmerbonte (Johanna) and J. Verweij (Jaap)

2010-10-26

A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours

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Publication

British Journal of Cancer , Volume 103 - Issue 9 p. 1362- 1368

Background: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel. Methods: A total of 22 patients received paclitaxel (135-175 mg m 2) intravenously, administered once every three weeks for up to six cycles, with oral tosedostat (90-240 mg) daily. Results: One DLT (grade 3 dyspnoea) was observed in one patient with tosedostat 180 mg combined with paclitaxel 175 mg m 2. A high number of paclitaxel infusion reactions was noted during the second administration (59%) and this prompted interruption of tosedostat dosing for 5 days around every second and subsequent paclitaxel infusion. No formal MTD was determined because of the high frequency of paclitaxel infusion reactions that may have been influenced by tosedostat. Most frequently observed drug-related adverse events were alopecia, fatigue (95% each), peripheral sensory neuropathy (59%), paclitaxel hypersensitivity (59%) and rash (55%). One patient died because of eosinophilic myocarditis, possibly related to study medication. There was no PK interaction between tosedostat and paclitaxel. In all, 3 patients had a partial response and 12 patients had stable disease lasting 3 months. Conclusion: The combination of tosedostat with paclitaxel was well tolerated except for the high incidence of paclitaxel-related infusion reactions. © 2010 Cancer Research UK.

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Keywords CHR-2797, Phase I, adult, advanced cancer, aged, alopecia, aminopeptidase inhibitor, anemia, anorexia, antineoplastic activity, antineoplastic agent, area under the curve, arthralgia, article, backache, bilirubin blood level, bladder cancer, bronchitis, cancer pain, chr 2797, clinical article, clinical trial, colorectal cancer, compression, constipation, controlled study, coughing, cystitis, dehydration, diabetes mellitus, diarrhea, dizziness, drug blood level, drug dose escalation, drug eruption, drug fever, drug hypersensitivity, drug safety, drug tolerability, drug withdrawal, dry skin, dyspnea, edema, erythema, fatigue, female, fluid intake, human, hypercalcemia, hyperglycemia, hyperhidrosis, infusion reaction, injection site reaction, kidney failure, leukocyte, leukopenia, lung embolism, lung non small cell cancer, lymphocyte, lymphocyte count, malaise, male, maximum allowable concentration, maximum tolerated dose, mucosa inflammation, multiple cycle treatment, myalgia, myocarditis, nausea, neutropenia, neutrophil, paclitaxel, peripheral edema, phase 1 clinical trial, pollakisuria, priority journal, pruritus, rhinopharyngitis, sarcoma, sensory neuropathy, side effect, solid tumor, spinal cord, stomach cancer, stomach distension, thrombocyte, tosedostat, treatment response, unclassified drug, urinary tract infection, vomiting
Persistent URL doi.org/10.1038/sj.bjc.6605917, hdl.handle.net/1765/21643
Journal British Journal of Cancer
Organisation Erasmus MC: University Medical Center Rotterdam
Citation
Herpen, C., Eskens, F., de Jonge, M., Desar, I., Hooftman, L., Bone, E., … Verweij, J. (2010). A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours. British Journal of Cancer, 103(9), 1362–1368. doi:10.1038/sj.bjc.6605917
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