| General information |
| Database: | DB00706 |
| Objective: | UCN01 (7hydroxystaurosporine) is a novel antineoplastic agent targeting cyclindependent kinases, which shows potent in vitro and in vivo activity against a broad range of tumor types. Their group has previously shown that UCN01 potentiates the apoptotic response of agents such as cisplatin in vitro by preventing sequencespecific abrogation of G2 arrest caused by DNAdamaging chemotherapies. |
| Authors: | Lara PN Jr, et al |
| Title: | The cyclindependent kinase inhibitor UCN01 plus cisplatin in advanced solid tumors: a California cancer consortiumphase I pharmacokinetic and molecular correlative trial. |
| Journal: | Clin Cancer Res. |
| Year: | 2005 |
| PMID: | 15958629 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | UCN01
|
| Target: | Serine/threonineprotein kinase Chk1
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | UCN01 plus cisplatin |
| Study Type: | Phase IPharmacokinetic and Molecular Correlative Trial |
| Key Patients Feature: | Patients with advanced, recurrent, or metastaticmalignant tumors, deemed incurable or refractory to therapy, wereeligible. Measurable disease was not required. Fresh tumor tissue, paraffin tumor tissue, or unstained slides were requested at protocolentry for the proposed correlative studies. |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | Cisplatin was infused over 1 hour before UCN01 (45 mg/m2/d) given as a 72hour continuous infusion. Escalation of cisplatin was planned through five dose levels at 20, 30, 45, 60, and 75 mg/m2. |
| Primary End Point: | safety, maximum tolerated dose, and pharmacokinetics of escalating doses |
| Secondary End Point: | NA |
| Patients Number: | 10 |
| Trial Results |
| DLT_MTD: | a given patient wasdefined as any grade 3 or 4 nonhematologic toxicity (except nausea, vomiting, and alopecia), grade 3 or 4 thrombocytopenia, grade 4neutropenia, or neutropenic fever.maximum tolerated dose was defined as the highest dose level inwhich six patients have been evaluated for toxicity with no more thanone patient experiencing doselimiting toxicities attributable to thestudy drugs, during the first course of therapy |
| Objective Response Rate: | Onepatient with metastatic adenocarcinoma of unknown primaryhad a partial response.Sixpatients had progressive disease as the best response. Threepatients were not assessable for response |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | No further doselimiting toxicities were observed in the five remaining patients treated in this expanded cohort. Dose level 2 was then opened with the nearly simultaneous enrollment of three patients. Doselimiting toxicities consisting of grade 5 sepsis with respiratory failure associated with grade 3 creatinine (one patient) and grade 3 atrial fibrillation (one other patient) were observed at this dose level. |
| Conclusions: | This phase I trial failed to achieve targeted therapeutic dose levels of cisplatin when combined with prolonged infusion UCN01. Hotheyver, because preclinical data indicate that UCN01 potentiates response to platinum, further studies with alternative dose schedules of the combination, or with other platinum analogues, are warranted. |