Abstract 1496:
Phase 1 study to determine tolerability and pharmacokinetics (PK) of D0/NDR/02, a novel nanoparticle paclitaxel in patients with locally advanced or metastatic breast cancer (MBC)
Citation: European Journal of Cancer Supplements Volume 3, No. 2, October 2005, Page 433
P.P. Bapsy1, D. Raghunadharao2, A. Majumdar3, S. Ganguly3, D. Khattar4, R. Mukherjee5, S.K. Mishra3
1Kidwai Memorial Institute of Oncology, Medical Oncology, Bangalore, India
2Nizams Institute of Medical Sciences, Medical Oncology, Hyderabad, India
3Dabur Research Foundation, Clinical Research and Medical Services, Ghaziabad, India
4Dabur Research Foundation, Novel Drug Delivery Systems, Ghaziabad, India
5Dabur Research Foundation, Research and Development, Ghaziabad, India
Background:
Conventional paclitaxel is formulated in cremophor, which is known to be associated with hypersensitivity reactions and non-linear pharmacokinetics [PK]. DO/NDR/02 is a novel, cremophor free, polymeric, nanoparticle formulation of paclitaxel.
A phase I dose escalation study was designed to determine the maximum tolerated dose (MTD) and the safety profile of the formulation in patients with locally advanced or metastatic [MBC] who had failed on anthracyclines or taxanes.
The secondary objectives included evaluation of PK and preliminary assessment of efficacy.
Method:
DO/NDR/02 was administered in 3-weekly cycles as a one-hour infusion, without premedication, in doses ranging from 135 to 375 mg/m2, for a maximum of six cycles.
Serial blood samples were collected for PK analysis during cycles 1 and 2 and paclitaxel concentrations were determined using a validated HPLC method. The toxicities were graded using NCI CTC version 2.0.
Results:
Twenty-five patients who had received prior therapy with either anthracyclines or Taxanes were treated at various dose levels up to 375 mg/m2. Hypersensitivity reactions were not observed in any patient.
The major hematological toxicities have been grade 4 neutropenia (3 out of 123 cycles) two of which occurred at the highest dose of 375 mg/m2. There was only one incidence of febrile neutropenia at the highest dose. The major non-hematological toxicities were grade 3 infection without neutropenia (n = 1) seen at 135 mg/m2 and grade 3 diarrhea (n = 2) at 300 and 375 mg/m2 respectively and grade 3 neuropathy (n = 1 at 300 mg/m2). The maximum tolerated dose (MTD) was determined to be 375 mg/m2 and the dose one level below that (300 mg/m2) was selected as the recommended phase II dose.
Objective responses (OR) were seen in 5 out of 25 (24%) patients. There was no response noted in taxane failed patients. PK analysis showed a linear correlation between the mean AUC and dose, up to 375 mg/m2.
Conclusions:
DO/NDR/02 may be safely administered without any premedications, to a higher dose than cremophor paclitaxel.
It has also shown a linear PK profile and encouraging clinical activity in advanced breast cancers.
A phase II study to further establish its safety and efficacy is presently being conducted in patients with anthracycline failed MBC.
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