A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours

Abstract

The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6 -12 mg m À2 ) and docetaxel (50 -75 mg m À2 ). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m À2 with docetaxel 60 mg m À2 . Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (X18 weeks). One patient with HRPC had a confirmed 450% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.

MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma

“…An explanation for the clinical failure of mitosis-specific suppressors is the much smaller proportion of mitotic cells in human tumors compared with the animal xenograft models (26). Because of the insufficient antitumor effect of monotherapy, several ongoing clinical studies have incorporated KIF inhibitors with chemotherapeutic agents including carboplatin, capecitabine, and docetaxel to explore potential synergistic effects (27). In addition, drug resistance continues to be a major challenge in HCC chemotherapy (8).…”

Increased KIF15 Expression Predicts a Poor Prognosis in Patients with Lung Adenocarcinoma

“…The first kinesin inhibitor to be developed was monastrol, which targets KIF11 [31], and several new inhibitors are currently under development [32][33][34][35][36]. For example, HR22C16, which is also a KIF11 inhibitor, targets taxol-sensitive and -resistant ovarian cancer cells [37].…”

Oncogenic role of kinesin proteins and targeting kinesin therapy

“…(61) Presently, this quinazolinone derivative represents the most studied Eg5 inhibitor and is now in a phase II clinical trial. (62)(63)(64)(65) The phase I studies for solid tumors indicated ispinesib is well tolerated with an acceptable safety profile and no indications of neurotoxicity. (62) However, recent results from the phase II trial in 15 patients with metastatic hepatocellular carcinoma showed no conclusive evidence of benefit with ispinesib monotherapy.…”

“…(62)(63)(64)(65) The phase I studies for solid tumors indicated ispinesib is well tolerated with an acceptable safety profile and no indications of neurotoxicity. (62) However, recent results from the phase II trial in 15 patients with metastatic hepatocellular carcinoma showed no conclusive evidence of benefit with ispinesib monotherapy. (63) Other results of ispinesib from recurrent or metastatic squamous cell carcinoma of the head and neck, melanoma, colorectal cancer, ovarian cancer and renal cell carcinoma are similar in suggesting a lack of clinical efficacy.…”