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Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret
S J Hotte1, A Oza, E W Winquist
1Princess Margaret Hospital Phase II Consortium, Cancer Therapy Evaluation Program, and National Cancer Institute, Bethesda, MD, USA. sebastien.hotte@hrcc.on.ca
Background:
7-Hydroxystaurosporine (UCN-01) inhibits serine-threonine kinases including the Ca2+ and phospholipid-dependent protein kinase C (PKC), CDKs 2, 4, 6, Chk-1 and PDK1. UCN-01 mediates distinct effects in vitro/in vivo: cell cycle arrest in G1, abrogation of G2 arrest by inhibiting chk1, induction of apoptosis and potentiation of cytotoxicity of S-phase-active chemotherapeutics including the topoisomerase 1 inhibitor topotecan (T). This phase I study was designed to determine the maximal tolerated dose (MTD), recommended phase 2 dose (RPTD), toxicity profile, pharmacokinetics and antitumor activity of T and UCN-01 in patients with refractory solid tumors.
Design:
Both agents were administered every 21 days intravenously through central venous access in escalating doses to eligible patients. On day 1, following antiemetic prophylaxis with dexamethasone and a serotonin type 3(A) receptor (5HT3) inhibitor, UCN-01 was infused over 3 h, followed by T infused over 30 min. On days 2-5, patients received T only. UCN-01 doses were reduced by 50% in cycles 2 and beyond because of its prolonged half-life.
Results:
Thirty-three patients were entered in three cohorts: Dose Level (DL) 1 (UCN-01 70 mg/m2, T 0.75 mg/m2), three patients; DL 2 (UCN-01 70 mg/m2, T 1.0 mg/m2), 24 patients; DL 3 (UCN-01 90 mg/m2, T 1.0 mg/m2), six patients. All but three patients were PS 0 or 1, median age was 54 years (range, 29-72), 91% were female. Primary tumor types: ovary/peritoneal (23 patients), colon (three patients), salivary gland (two patients), others (five patients). All patients were eligible for adverse event (AE) analysis and 22 patients were eligible for survival and tumor response analysis. Two of six patients had dose limiting toxicity (DLT) at DL 3 (grade 3 N/V; grade 4 neutropenia with infection). One DLT was seen in one patient at DL 2, consisting of grade 4 leukopenia. This cohort was expanded and no further DLTs were observed. Most common drug-related AEs were mild (grade 1-2). Non-hematological grade 3-4 AEs consisted of transient hyperglycemia (4), infection (3), coagulation, fatigue, hypotension, nausea (2), hypomagnesemia, vomiting, headache (1). Hematologic toxicities occurred in 100% of patients. Grade 3-4 hematologic abnormalities included neutropenia (16, including three with infection), leukopenia (11), lymphopenia (7), thrombocytopenia (5). Best response for 22 evaluable patients was PD (8), SD for at least six cycles (12), PR (1: carcinoma of ovary, dose level 2) and one not assessable. Pharmacokinetic analysis confirmed the prolonged half-life of UCN-01 of approximately 15 days.
Conclusions:
DLT was observed at DL 3 and RPTD was determined to be DL 2. To date, this combination has been relatively well tolerated with some preliminary evidence of efficacy. A phase II study of this combination in patients with ovarian cancer is underway.
Insights
The combination of topotecan and 7-hydroxystaurosporine (UCN-01) showed preliminary efficacy in refractory solid tumors. The recommended phase 2 dose was determined to be dose level 2, with manageable toxicity.
Area of Science:
- Pharmacology and Oncology
- Clinical Trial Design and Analysis
Background:
- 7-Hydroxystaurosporine (UCN-01) is a potent inhibitor of serine-threonine kinases, including PKC, CDKs, Chk-1, and PDK1.
- UCN-01 exhibits anti-cancer effects such as cell cycle arrest, apoptosis induction, and potentiation of chemotherapy cytotoxicity.
- This study investigates the combination of UCN-01 with topotecan (T), a topoisomerase 1 inhibitor, in patients with refractory solid tumors.
Purpose of the Study:
- To determine the maximal tolerated dose (MTD) and recommended phase 2 dose (RPTD) of UCN-01 and T combination therapy.
- To evaluate the toxicity profile, pharmacokinetics, and preliminary antitumor activity of this combination.
- To establish a safe and effective dosing regimen for further clinical investigation.
Main Methods:
- A Phase I clinical trial involving escalating doses of intravenous UCN-01 and T administered every 21 days.
- Patients received antiemetic prophylaxis; UCN-01 was infused first, followed by T. UCN-01 doses were halved in subsequent cycles due to its long half-life.
- Thirty-three patients with refractory solid tumors were enrolled in three dose cohorts.
Main Results:
- Dose-limiting toxicities (DLTs) were observed at Dose Level 3 (90 mg/m2 UCN-01, 1.0 mg/m2 T), including nausea, vomiting, and neutropenia with infection.
- The RPTD was determined to be Dose Level 2 (70 mg/m2 UCN-01, 1.0 mg/m2 T), which was well-tolerated after expansion.
- Common adverse events were mild; grade 3-4 non-hematological toxicities included hyperglycemia and infection. Hematologic toxicities were frequent, with neutropenia being most common.
- One partial response (ovarian cancer) and 12 patients with stable disease for at least six cycles were observed among 22 evaluable patients.
Conclusions:
- The combination of UCN-01 and topotecan is relatively well-tolerated at the RPTD (DL 2) with preliminary evidence of efficacy.
- Dose Level 3 was associated with dose-limiting toxicities, establishing DL 2 as the recommended dose for further studies.
- A Phase II study of this combination in ovarian cancer patients is currently ongoing.
