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Journal of Clinical Oncology, Vol 22, No 2 (January 15), 2004: pp. 269-276 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2003.04.075 Phase III Study of N,N-Diethyl-2-[4-(Phenylmethyl) Phenoxy]Ethanamine (BMS-217380-01) Combined With Doxorubicin Versus Doxorubicin Alone in Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19From the National Cancer Institute of Canada Clinical Trials Group, Ontario, Canada; Bristol-Myers Squibb International Corp, Wallingford, CT Address reprint requests to Lesley Seymour, MD, National Cancer Institute of Canada Clinical Trials Group, Cancer Research Institute, Queens University, 10 Stuart St, Kingston, Ontario, Canada K7L3N6; e-mail: lseymour{at}ctg.queensu.ca.
PURPOSE: N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is a novel agent that augments chemotherapy cytotoxicity in vitro and in vivo. A phase II trial combining DPPE and doxorubicin (DOX) in metastatic breast carcinoma showed increased response over that expected with DOX. We report a phase III trial comparing DOX with DPPE plus DOX in metastatic or recurrent breast cancer. PATIENTS AND METHODS: Anthracycline-naive women with measurable metastatic disease were randomly assigned to receive, every 21 days, either DOX 60 mg/m2 intravenously or DOX during the last 20 minutes of an 80-minute infusion of DPPE (5.3 mg/kg), in both cases to cumulative DOX doses of 450 mg/m2. Patients receiving DPPE were aggressively premedicated to ameliorate toxicity. End points included progression-free survival (PFS), response rate (RR), and response duration (RD), quality of life (QOL), toxicity, and overall survival (OS). RESULTS: A planned interim analysis failed to detect an RR difference more than 5%. The study was closed to additional accrual and all DPPE was discontinued. The final analysis was conducted as planned after 256 progression events (median follow-up, 20.5 months). There was no significant difference in RR, RD, or PFS between arms. DPPE plus DOX was statistically superior to DOX in OS (hazard ratio, 0.66; 95% CI, 0.48 to 0.91; P = .021). DPPE plus DOX was associated with more gastrointestinal and CNS toxicity. No consistent influence on QOL was detected. CONCLUSION: This study demonstrated no advantage in RR, RD, or PFS but significantly superior OS for DPPE plus DOX. Additional studies of DPPE are warranted.
Doxorubicin (DOX) is active in metastatic breast cancer, with response rates (RR) of approximately 35% [1]. Improving the therapeutic index of such cytotoxics is clearly of interest. N,N-diethyl-2-[4-(phenylmethyl-6)phenoxy]ethanamine (DPPE; tesmilifene), a tamoxifen analog with novel antihistaminic properties, is a potent substrate for, and inhibits histamine binding to CYP 3A4 [2], a P450 isozyme that metabolizes several classes of antineoplastic agents. DPPE also inhibits the p-glycoprotein pump, the overexpression of which is implicated in drug resistance, and depletes cellular adenosine triphosphate [3]. Possibly correlating with these actions, DPPE potentiates the cytotoxicity of a variety of chemotherapy drugs in vitro and in vivo [4,5]. Between 1996 and 1998, 42 women with metastatic or locally advanced, measurable breast carcinoma [6], who had not previously received anthracyclines but may have received prior adjuvant chemotherapy, adjuvant or metastatic hormone therapy, and up to one non–anthracycline-containing metastatic regimen [6], were treated with DPPE plus DOX in a phase II trial conducted at four National Cancer Institute of Cancer Clinical Trials Group (NCIC-CTG) institutions. RR was 52.5% (95% CI, 36.4% to 68%), with four (9.5%) complete responses (CRs) and 18 (43%) partial responses (PR). There were four episodes of febrile neutropenia but no treatment-related deaths. Toxicities included nausea, vomiting, lethargy, stomatitis, mild to moderate anorexia, slurred speech, muscle incoordination, and hallucinations during DPPE administration, especially in cycle 1, all of which were considered manageable. With these promising RRs, we undertook and now report an international multicenter randomized trial comparing DOX 60 mg/m2 with DPPE plus DOX.
Eligible women had inoperable metastatic or recurrent breast cancer, with an Eastern Cooperative Oncology Group score of 0 to 2. Prior hormonal therapy (discontinued at least 6 weeks before random assignment unless disease progression was documented), one adjuvant chemotherapy regimen, and/or one regimen for metastatic disease (completed at least 4 weeks before random assignment and without prior anthracycline or anthracenedione therapy) were permissible. Immunotherapy, experimental therapy, and radiation therapy (unless nonmyelosuppressive) must have been discontinued at least 4 weeks before random assignment. All Canadian patients were required to have first been considered for the contemporaneous NCIC-CTG randomized MA.16 trial assessing high-dose chemotherapy followed by autologous stem-cell transplant. Consenting patients could participate in both trials.
All patients were required to have at least one assessable and measurable lesion; if only one lesion was measurable, no prior radiation was permissible to that lesion unless subsequent disease progression was documented. Minimum lesion size for computed tomography scan or ultrasound was
Absolute granulocyte counts Patients were not eligible if they had previous malignancies within 5 years of study entry (excluding curatively treated basal or squamous cell skin and in situ cervical cancer), brain or meningeal metastatic disease, bone-only disease, seizure disorders or other serious uncontrolled illness, or if pregnant or breast feeding. Patients were required to discontinue H1 antagonists for the duration of the study and to be able to suspend usage of prostaglandin inhibitors (eg, acetylsalicyclic acid) for 48 hours at the time of their chemotherapy infusion.
Treatment Plan All patients receiving DPPE received intensive medication as listed in Table 1 to control anticipated gastrointestinal and neurologic toxicity, and were nursed in a quiet, dimmed environment during the infusion.
Schedule of Evaluations Before random assignment, all patients had history; physical examination; tumor measurements; performance status; CBC with platelet count and differential; AST, ALT, bilirubin, creatinine, albumin, alkaline phosphatase, lactate dehydrogenase, calcium, protein, and electrolyte level measurements; chest x-ray; abdominal ultrasound or computed tomography; bone scan; ECG; MUGA scan; and pregnancy test (if the patient was of childbearing potential). If bone scans were positive, x-rays of abnormal areas were required. Physical examination, performance status, and blood chemistry were repeated with each treatment cycle. CBC was reported weekly during the first cycle and thereafter at every cycle. If initially positive, chest x-ray was repeated every 3 weeks and other imaging studies were repeated every 6 weeks. Bone scans and/or plain films of baseline bone lesions were repeated at the time of a CR or PR in measurable lesions. MUGA scans were repeated between cycles 3 and 4. Toxicities were graded using NCIC-CTG Expanded Common Toxicity Criteria. Quality of life (QOL) was measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 [7] and QLQ-BR23 [8] instruments. A trial-specific checklist assessing short-term neurologic toxicity was also incorporated. QOL was assessed at the end of each treatment cycle, 4 weeks after treatment ended, and then every 3 months until disease progression. The EORTC QLQ-C30 and trial-specific checklist were also administered on day 8 of cycles 1 and 2 to assess acute toxicity.
Statistical Design, Randomization, and Analyses Patients were stratified by center, presence of visceral disease, prior chemotherapy for metastatic disease, and registration to MA.16. All randomly assigned patients were to be included in the efficacy analyses, irrespective of eligibility or whether they actually received protocol therapy. Patients participating in both MA.19 and MA.16 were registered to MA.16 at the time of their random assignment to MA.19, but were only randomly assigned to MA.16 if they achieved PR or CR after four cycles of chemotherapy; patients randomly assigned to the high-dose chemotherapy plus stem-cell transplant arm of MA.16 received only four cycles of DPPE plus DOX or DOX, whereas patients assigned to the control arm of MA.16 received DPPE plus DOX or DOX according to the MA.19 protocol. Patients registered to MA.16 were censored for response and PFS after completion of four cycles of DPPE plus DOX or DOX if they had not experienced disease progression at that stage; these patients were not censored in the overall survival (OS) analyses. PFS, the primary end point of this study, was defined as time from random assignment to progression or death for patients who died without progression. PFS and OS were described by the Kaplan-Meier method. A stratified log-rank statistic was used to compare PFS adjusted for defined stratification factors excluding center. Cox proportional hazards model was used to adjust the observed treatment effect for the influence of prognostic factors at study entry and to identify factors related to PFS and OS. RR included PR or CR. A Cochrane-Mantel-Haenszel test was used to compare RR. Exploratory PFS analyses were also performed without censoring patients registered to MA.16.
QOL data were analyzed according to the Guidelines of the Quality of Life Committee of NCIC-CTG. Change scores (ie, differences from baseline) were calculated at each time point for each domain or symptom and groups. The proportion of patients showing improvement from baseline was calculated for each domain or symptom as follows. A change score of at least 10 points from baseline was defined as clinically relevant [11]. For each domain, patients were considered improved if they reported a score All patients receiving at least one dose of DPPE or DOX were included in the safety analysis. Adverse events were graded using the NCIC-CTG Expanded Common Toxicity Criteria. The incidence of adverse events was summarized by type, severity, and relationship to study drug. Fisher's exact test was used to compare toxicities between arms.
Study Population Between April 1998 and July 1999, 305 (all eligible) patients were entered onto the study from 38 centers in Eastern Europe (n = 192), Canada (n = 46), South Africa (n = 34), Western Europe (n = 24), and Australia (n = 9). Two patients, both randomly assigned to receive DOX, did not receive study drug: one experienced disease progression before starting protocol therapy and one did not arrive for treatment. Both patients are included in the efficacy analyses, but not in exposure and toxicity analyses. Baseline patient characteristics were well balanced between treatment groups (Table 2), except for time from diagnosis to random assignment (26 months for DPPE plus DOX v 20 months for DOX).
Interim Analysis The interim analysis was performed in June 1999, and failed to detect a difference in RR of more than 5% (RR was 35.5% for the DPPE plus DOX arm and 36.5% for the DOX arm). Thirty-three patients in each arm had experienced disease progression at this analysis. More DPPE plus DOX patients had neurologic toxicities, nausea, and vomiting. The study was closed to additional accrual, but because of rapid accrual there were already 305 patients enrolled onto the study. DPPE was discontinued, but patients continued to receive DOX and/or other therapy at the discretion of the treating physician.
Final Analysis
Toxicity Table 5 summarizes drug-related adverse events, which occurred in  10% of patients in either arm. As expected, patients who received DPPE plus DOX had more vomiting, ataxia, dizziness, extrapyramidal effects, and hallucinations; interestingly, they also had less stomatitis. There was no difference in grade 3 or 4 neutropenia (68% v 63%) or febrile neutropenia (7% v 8%) between DPPE plus DOX and DOX arms, respectively. There were no clinically significant adverse effects on liver or renal function. The use of blood transfusions (8% v 4%), growth factors (6% v 4%), and prophylactic antibiotics (2% v 1%) was similar for DPPE plus DOX and DOX arms, respectively. There were seven deaths within 30 days of protocol therapy. These included three patients receiving DPPE plus DOX in whom death was considered related to drug (febrile neutropenia, myelosuppression, and hypertension with possible pulmonary embolism). One patient receiving DOX died as a result of febrile neutropenia after receiving a subsequent salvage regimen of chemotherapy (Table 6). Two patients receiving DOX had clinical evidence of cardiomyopathy, four patients receiving DPPE plus DOX had at least one report of cardiac failure, and 18 patients in each arm had at least one documented decrease in left ventricular ejection fraction (by 20% of baseline value or to a value of < 40%).
Efficacy There was no significant difference in RR between treatment arms (29% for each; Table 7). There was no difference in CR, PR, stable disease, or disease progression. Median response duration was not statistically different between treatment arms (patients receiving DPPE plus DOX, 6.9 months [range, 5 to 11.7 months]; patients receiving DOX, 6.4 months [range, 4.8 to 7.6 months]; P = .09). There was no significant difference in PFS between arms (hazard ratio, 0.85; 95% CI, 0.67 to 1.09; Fig 1). Median PFS for patients receiving DPPE plus DOX was 5.9 months (95% CI, 4.9 to 6.7 months) and for patients receiving DOX alone, median PFS was 6.0 months (95% CI, 4.9 to 7.5 months); the results were similar for the exploratory analyses conducted without censoring of MA.16 patients. There was, however, a statistically significant difference in OS (Fig 2). Median OS for patients receiving DPPE plus DOX was 23.6 months (95% CI, 7.4 to infinity) and for patients receiving DOX, median OS was 15.6 months (95% CI, 12.2 to 18.5 months); the hazard ratio was 0.66 (95% CI, 0.48 to 0.91). The stratified log-rank test for OS was 0.021, with an unstratified log test of 0.008.
A stratified Cox proportional hazards model for survival was constructed. The following variables were included in the stepwise model building: age (< 65 v 65 years), baseline hemoglobin ( 11 v < 11 g/dL), performance status (2 or 0 v 1), liver function (normal v abnormal), prior radiation (no v yes), estrogen receptor status (positive v not positive, unknown v not unknown), progesterone receptor status (positive v not positive, unknown v not unknown), logarithm of time from diagnosis to randomization (continuous variable), logarithm of time from diagnosis to recurrence of disease (continuous variable), and logarithm of MA.19 treatment duration (continuous time-dependent variable). In the final model, treatment effect remained significant (hazard ratio, 0.66; 95% CI, 0.45 to 0.97; P = .03). Performance status (P < .0001), longer time from first diagnosis to random assignment (P  .0004), and longer MA.19 treatment duration were the only other variables significantly related to improved OS. Because of the observation of OS benefit without differences in RR or PFS, other parameters were evaluated for possible relationships to OS. There was, however, no difference in sites of progression or in subsequent treatment between arms.
QOL
DOX remains one of the most active single agents for metastatic breast cancer. There are few randomized trials comparing DOX with DOX-containing combinations in metastatic disease. The NCIC-CTG previously reported a study comparing vinorelbine plus DOX with DOX alone in metastatic breast cancer [12]. Single-agent DOX was associated with an RR of 31% compared with 38% for the combination (not significant). CRs were only 4% and 5% and median RDs were 6.9 and 7.2 months, respectively. There was no OS difference, with a median OS of 14.4 months for DOX and 13.8 months for the combination, comparable to the results obtained for DOX alone in MA.19. Doxorubicin has also been compared with taxanes in metastatic disease [13-15], with similar overall and complete RRs [16]. Thus, DOX remains an appropriate comparator in metastatic breast cancer. Improving its therapeutic index has proven difficult. Therefore, the results of this study are particularly provocative. This phase III study was designed after a promising phase II trial of the combination of DPPE plus DOX. The present study confirmed the feasibility of administering DPPE plus DOX in a multicenter multinational trial. Although study accrual closed early after no difference in RR was observed at the planned interim analysis, the number of patients accrued was close to the planned total sample size. All patients were observed for toxicity, PFS, and OS. The final analysis was conducted as planned. For the primary outcome measure, PFS, there was no statistically significant difference, although a trend toward a positive hazard ratio (0.85; 95% CI, 0.67 to 1.09) was observed, with an apparent separation of PFS curves after 10 months of follow-up (Fig 1); however, because there were only 73 patients still at risk in both arms, this observation should be interpreted cautiously. Censoring of patients registered to MA.16 had no influence on these results. There was a significant prolongation in OS (hazard ratio, 0.66; 95% CI, 0.48 to 0.91; Fig 2). DPPE has an unusual toxicity profile. Although the neurologic side effects are manageable, prolonged patient sedation is required. In this trial, most patients were sedated for at least 6 hours on the day of treatment. Thus, although this therapy is acceptable and can be given on an outpatient basis, the resource implications are significant. Interestingly, although the reported incidence of nausea and vomiting was higher (and more severe) with DPPE plus DOX, this did not translate into worse QOL scores for nausea and vomiting, presumably reflecting the retrograde amnesia from the antiemetic benzodiazepine regimen used for DPPE, and demonstrating the sensitivity of QOL tools. Chemotherapy in metastatic breast cancer is effective for disease palliation. Improvements in RR and QOL are often demonstrated for one regimen compared with another, but relatively few studies have demonstrated significantly improved survival. When improved OS is observed it is usually associated with differential RR [17,18]. In this study, we have demonstrated a significant improvement in OS for patients receiving DPPE plus DOX versus DOX alone, with no difference in RR or significant difference in PFS. We were unable to demonstrate differences in potential confounding factors, such as salvage therapies or death as a result of other causes. We conducted multiple exploratory analyses in an attempt to explain the observed differences, but ultimately concluded that the OS advantage likely was due to the experimental therapy. One could hypothesize that DPPE in some way sensitized tumor to subsequent treatments, although there were no discernible differences in RR to salvage therapies. There is no known preclinical mechanism of DPPE action that would explain such an effect, however. This novel compound clearly warrants additional clinical and laboratory evaluation to elucidate further its apparent effect on prolongation of survival in the absence of any significant effect on response or progression. Additional studies, both phase II and III, are planned. In conclusion, this study demonstrates that our phase II observations with respect to an enhanced RR for DPPE plus DOX were not realized in a randomized multicenter trial. No significant differences in the primary end point, PFS, were detected. However, a clinically meaningful survival advantage was demonstrated. This observation requires additional study because the magnitude of the benefit is of significant clinical interest to both patients and oncologists.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Maurizio Voi, Bristol-Myers Squibb; David Lebwohl, Bristol-Myers Squibb. Acted as a consultant within the last 2 years: Jacek Jassem, Bristol-Myers Squibb; Leonard Reyno, YM Biosciences, Bristol-Myers Squibb; Karen Gelmon, YM Biosciences; Kathleen Pritchard, YM Biosciences; Lesley Seymour, YM Biosciences. Performed contract work within the last 2 years: Kathleen Pritchard, Bristol-Myers Squibb. Received more than $2,000 a year from a company for either of the last 2 years: Maurizio Voi, Bristol-Myers Squibb; Jacek Jassem, Bristol-Myers Squibb; David Lebwohl, Bristol-Myers Squibb.
Supported by the National Cancer Institute of Canada Clinical Trials Group and Bristol-Myers Squibb. Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to test whether the two study arms had the same underlying multinomial distribution of the QOL response. 
