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Phase III Study of N, N-Diethyl-2-[4-(Phenylmethyl) Phenoxyl] Ethanamine (BMS-2173801-01) Combined With Doxorubicin Versus Doxorubicin Alone in Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA-19

Posted on: Friday, 22 October 2004, 03:00 CDT

Objectives:

This large randomized trial was performed by the National Cancer Institute of Canada Clinical Trials Croup (CICCTG) - MA19, to evaluate the combination of N, N-Diethyl-2-[4-(Phenylmethyl) Phenoxyl] Ethanamine (BMS-2173801-01) (DPPE) with doxorubicin versus single agent doxorubicin (Dox) in anthracycline nave women with metastatic breast cancer.

DPPE is a Tamoxifen analog that augments anthracycline cytotoxicity through various mechanisms including: being a potent substrate for CYP3A4 (an isoenzyme that metabolizes a number of cytotoxics); inhibition of the p-glycoprotein pump (which has been implicated in drug resistance); and depletion of adenosine triphosphate. As a result of Phase II data demonstrating responses of > 50%, a randomized trial was undertaken.

Methods:

This international multi-centre trial began, with planned accrual of 350 patients with a planned interim analysis after 3 months of follow-up of the first 150 patients. Patients who were anthracycline nave, with a performance score of 0-2 and metastatic or recurrent measurable breast cancer were included. Adjuvant therapy and/or one regimen for metastatic disease were permitted. Patients were required to have adequate hepatic, renal, hematologic and cardiac reserves. Patients were randomly assigned Dox 60 mg/m^sup 2^ Q3/52 alone or Dox combined with DPPE (5.3 mg/kg) during the last 20 min of an 80 min infusion. Predefined sedation was required to reduce the neurologic toxicity associated with DPPE. Patients were stratified by centre, visceral metastases, prior treatments and inclusion in MA16.

Statistical analysis:

Progression free survival (PFS) was the primary endpoint. secondary cndpoints included response rate (RR), overall survival (OS), Quality of life (QoL) and toxicity. An increase in PFS from 6- 9 months was considered clinically relevant. Greater than 5% RR superiority was required at the interim analysis to prevent early closure.

Results:

Between April 1998 and July 1999, 305 eligible patients were entered into the trial. Baseline patient characteristics were all well matched except for time from diagnosis to randomization (26 months for DPPE + Dox versus 20 Months for Dox alone). The interim analysis (of 150 patients) failed to detect a difference in RR of > 5% resulting in study closure. Despite this 305 patients were already enrolled due to the rapid accrual. All these patients were included in the Anal analysis. Treatment with Dox + DPPE was associated with more gastrointestinal and neurologic (hallucinations, ataxia, dizziness and extrapyramidal) symptoms than Dox alone. There was no significant difference in RR between the arms at 29%. The median response duration and PFS were 6.9 and 5.9 months and 6.4 and 6 months in the Dox + DPPE and Dox alone arms, respectively. There was a significant difference in median OS of 23.6 and 15.6 months in the Dox + DPPE and Dox alone arms, respectively (HR 0.66). Gox proportional hazards for various factors were performed. In the Anal model treatment effect remained significant. Performance status, longer duration from diagnosis to randomization and longer MA19 treatment were the only other variables related to improved OS. Further evaluations to establish a potential cause for improved OS without improved RR or PFS did not demonstrate differences in sites of progression or subsequent treatments.

Commentary:

This is an interesting study that highlights a potential survival advantage of a cytotoxic potentiating agent. Anthracyclines remain amongst the most active agents in the treatment of breast cancer. An understanding of the mechanisms of resistance and improving the therapeutic index of Dox is of significant interest. The mechanism by which DPPE has been shown to enhance the cytotoxicity of these agents has been shown in vivo and in vitro. How this translates to clinically relevant and meaningful results remains to be shown.

Despite not demonstrating a difference in PFS (primary endpoint) or RR, the study found a significant difference in overall survival. These results need to be interpreted with caution. The response rate was 29% in this study in both arms which was significantly lower than the promising results seen with this regimen in the phase II setting . Few studies in the management of metastatic breast cancer have actually demonstrated a survival advantage despite many showing improved RR and PFS2,3. The mechanism by which a survival advantage is seen without an associated improvement in response or PFS remains unclear from a biologic point of view. Sensitisation to subsequent therapies is an unlikely mechanism. This was evaluated by the authors and no difference in response or PFS with subsequent therapies was seen, but this study would not have been powered sufficiently to detect these differences. The authors evaluated a number of other potentially confounding factors which may have influenced the survival results. No specific factor was identified.

Our ultimate goal is to provide a survival benefit with the development of novel regimens. However, in the context of breast cancer management and the availability of several lines of treatment regimens, overall survival is likely to be influenced by a number of confounding factors. As such, RR and PFS remain more useful measures or surrogate markers in the evaluation of the efficacy and value of a particular regimens.

This is a potentially useful agent but the clinical relevance in the context of current management of metastatic breast cancer remains doubtful. This is further complicated by the integration of taxanes and other agents with well established activity, including Herceptin, capecitabine and vinorelbine in the treatment of metastatic breast cancer. Furthermore the toxicity profile and sedation required has logistical and resource implications.

This study was due to be stopped as per the early stopping rules defined by the protocol, due to the lack of difference in response rate at the interim analysis. A further 155 patients were enrolled while awaiting the results of the interim analysis. Although all of these patients were included in the final analysis, the value and role of the interim analysis was undermined.

The survival benefit seen is provocative. Whether or not further research using this agent is a priority remains controversial.

Reyno L, Seymour L, Tu D, Dent S, Gelmon K, Walley B, Pluzanska A, Gorbunova V, Garin A, Jassem J, Pienkowski T, Dancey J, Pearce L, MacNeil M, Mariin S, Lebwohl D, Voi M, Pritchard K; National Cancer Institute of Canada Clinical Trials Group Study MA-19. J Clin Oncol 2004;22:269-76

Selected references and further reading:

1. Khoo K, Brandes L, Reyno L, Arnold A, et al. Phase II trial of N,N-dicthyl-2-[4-(phenylmcthyl)phcnoxy]ethanamine.HCl and doxorubicin chemotherapy in metastatic breast cancer: A National Cancer Institute of Canada clinical trials group study. J Clin Oncol 1999;17:3431-7

2. O'Shaughiiessy J, Miles D, Vukelja S, Moiseyenko V, et al. Superior survival with capecitabine plus docetaxcl combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002;20:2812-23

3. Jassem J, Pienkowski T, Pluzanska A, Jelic S, et al. and the Central and Eastern Europe and Israel Pacitaxel Breast Cancer Study Group. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial, [see comment]. J Clin Oncol 2001:19:1707-15

Commentary by: Gavin M. Marx and Josie J. Rutovitz, Sydney Haematology and Oncology Clinics, Sydney, Australia

Copyright CRC Press Jun 2004

Source: Women's Oncology Review

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