A Phase I/II Study of Paclitaxel, Carboplatin and YM155 (Survivin Suppressor) in Subjects With Solid Tumors (Phase I) and Advanced Non-Small Cell Lung Carcinoma (Phase II)
- Treatment with platinum-based doublet chemotherapy results in a median survival of 7 to
10 months in patients with locally advanced or metastatic non-small cell lung cancer
- Carboplatin-paclitaxel is a commonly used regimen in advanced NSCLC and other solid
tumors. In a randomized clinical trial carboplatin, paclitaxel plus bevacizumab
resulted in improved efficacy (response rate and survival) compared to carboplatin and
paclitaxel alone but only patients with non-squamous histology and who were considered
low risk of bleeding were treated. Improvement of survival was not confirmed in another
randomized study with a different chemotherapy backbone.
- Novel treatment strategies need to be developed for advanced NSCLC.
- YM155 is a transcriptional inhibitor of survivin, an inhibitor of apoptosis protein.
Pre-clinical activity of YM155 has been observed in several solid tumors, including
NSCLC models and synergy was observed in combination with chemotherapeutic drugs,
including carboplatin and paclitaxel.
- YM155 has been investigated in several phase I and phase II clinical trials and it has
been shown to be well tolerated with the most common toxicities reported as being
reversible and of grades 1 -2 in severity. In addition, as a monotherapy YM155 alone
has shown modest antitumor activity in a phase II trial in advanced NSCLC in patients
who had failed one or two prior chemotherapy lines.
- In the Phase I portion of the study the primary objective will be to determine a safe
and tolerable phase II dose of YM155 based upon dose limiting toxicities (DLTs) when
YM155 is administered over 72 hours by continuous intravenous infusion (CIVI) every 3
weeks in combination with paclitaxel and carboplatin.
- In the Phase II portion of the study the primary objective will be to determine the
objective response rate (ORR = partial response (PR)+ complete response (CR)) of YM155
in combination with carboplatin and paclitaxel in the first line treatment of patients
with advanced NSCLC.
- In the Phase I portion of the study the secondary objective will be to determine the
preliminary activity of the combination regimen based upon response rate as measured by
response evaluation criteria in solid tumors [RECIST].
- In the Phase II portion of the study the secondary objectives will be to determine the
median progression free survival (PFS), median overall survival (OS) and safety and
tolerability of this combination regimen in this patient population.
- To assess expression of particular genes on the pretreatment tumor and pre/post
treatment serum samples to evaluate the treatment effects and correlate them with
- The phase I portion of the trial will be open to all patients with recurrent or advanced
cancer (NSCLC and other solid tumors) for whom standard therapy offers no curative potential
and also in patients for whom the carboplatin / paclitaxel regimen is considered standard of
care. Patients should have received no more than one previous chemotherapy regimen.
- Pathologically confirmed stage IIIB (malignant pleural effusion) or intravenous (IV) or
- No previous chemotherapy for advanced lung cancer.
- Adequate organ and bone marrow function.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
- Open label phase I/II trial
- Following a Simon two-stage optimal design
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase 1 Safe and Tolerable Phase 2 Dose.
Phase I: Doses were given at different dose levels until the maximum tolerated dose (MTD) was reached. Dose level 1: 3.6 mg/m^2, dose level 2:5 mg/m^2 , dose level 3:6 mg/m^2, dose level 4:8 mg/m^2, dose level 5:10 mg/m^2 (MTD), dose level 6:12 mg/m^2. Doses were given by continuous intravenous infusion over 72 hours every 21 days.Three patients were enrolled at each dose level in the absence of dose limiting toxicity (DLT). A DLT is defined as adverse events occurring during the first cycle of therapy (e.g. every 21 days). Phase 2 dose is based upon dose limiting toxicities experienced during cycle 1.
Giuseppe Giaccone, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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