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Phase II Trial of N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl and Doxorubicin Chemotherapy in Metastatic Breast Cancer: A National Cancer Institute of Canada Clinical Trials Group Study

From The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), Queen's University, Kingston, ON; Manitoba Cancer Treatment and Research Foundation, Winnipeg, MB; Hamilton Regional Cancer Center, Hamilton, ON; Northwestern Ontario Regional Cancer Center, Thunder Bay, ON; and London Regional Cancer Center, London, ON, Canada; and Bristol-Myers Squibb, Wallingford, CT.

Address reprint requests to Kong Khoo, MD, Department of Medical Oncology, Cancer Center for the Southern Interior, BC Cancer Agency, 399 Royal Ave, Kelowna, British Columbia, Canada V1Y 5L3; email kkhoo{at}bccancer.bc.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: This multicenter phase II trial investigated the efficacy and toxicity of a combination of the novel intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl (DPPE), and doxorubicin in patients with anthracycline-naïve metastatic breast cancer. Preclinical models and early single institutional studies suggested DPPE could potentiate the cytotoxicity of doxorubicin.

PATIENTS AND METHODS: Forty-two women, 32 to 77 years old (median, 59 years), with anthracycline-naïve metastatic breast cancer were treated. Patients may have had one previous regimen of nonanthracycline chemotherapy, either in the adjuvant or metastatic disease treatment setting. DPPE (6 mg/kg) was administered as an 80 minute intravenous infusion with doxorubicin (60 mg/m²) given intravenously over the last 20 minutes of the DPPE infusion. Patients were premedicated with an antiemetic and sedating regimen. The DPPE/doxorubicin treatment was given every 21 days for a maximum of seven cycles.

RESULTS: All 42 patients were assessable. Overall, toxicity was comparable to that expected with doxorubicin alone, with the exception of DPPE-related motion sickness, mild hallucinations, and cerebellar signs at the time of the infusion. These CNS side effects were manageable in an ambulatory care setting, improved with subsequent cycles of treatment, and did not usually require hospitalization. Four patients developed febrile neutropenia. Thirty-five patients received four or more cycles of chemotherapy. The overall response rate was 52.5% (95% confidence interval, 36% to 68%), with 9.5% complete responses (n = 4), 43% partial responses (n = 18), and 38% of patients with stable disease (n = 16).

CONCLUSION: The antitumour effects of DPPE/doxorubicin the 52.5% response rate seems encouraging, particularly in consideration of the fact that a recently reported randomized National Cancer Institute of Canada Clinical Trials Group trial using single-agent doxorubicin 60 mg/m² in one of the treatment arms achieved a 31% response rate. Thus, a randomized phase III trial of doxorubicin versus doxorubicin plus DPPE is being conducted in this clinical setting.

	INTRODUCTION

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IN 1960, KAHLSON and Rosengren^1,2 first postulated that intracellular histamine mediates cell proliferation. The antiestrogen binding site ligand, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl (DPPE)³ is a diphenylmethane-derivative arylalkylamine similar in structure to various H₁-antihistamines and tamoxifen.⁴ Correlating with its potency to antagonize histamine binding in rat liver microsomes and nuclei, DPPE modulates tumor growth; in the MCF-7 breast cancer cell line, stimulation of in vitro DNA synthesis was observed at lower DPPE concentrations, whereas inhibition/cytotoxicity was observed at higher DPPE concentrations.^5,6 A major proportion of the microsomal histamine binding sites with which DPPE interacts represents cytochrome P450 monooxygenases that metabolize endogenous lipids and prostanoids as well as xenobiotics.⁷ Preclinical studies of DPPE indicate a wide variety of biologic effects, including inhibition of concanavalin A–induced mitogenesis in normal mouse spleen cells⁸ and interleukin-3–induced proliferation of normal myeloid progenitors⁹ and protection of rodent bone marrow from toxic doses of doxorubicin and fluorouracil⁶ and rodent gut endothelium from various noxious stimuli.^10,11 Cytoprotection of the gut by DPPE is linked to its stimulation of endogenous prostacyclin synthesis.¹¹

DPPE also has been observed in vitro and in vivo to potentiate the cytotoxicity of several classes of chemotherapeutic agents, including doxorubicin, to malignant cells.⁶ In vitro, DPPE potentiation of the cytotoxicity of doxorubicin, paclitaxel, and vinblastine in human (HCT116/mdr1+) colon cancer cells has been linked to its acting as a substrate for the P-glycoprotein (P-gp) pump at concentrations that also decrease mitochondrial membrane potential and deplete cellular adenosine triphosphate levels.¹² However, P-gp/multidrug resistance–related mechanisms could not fully explain the ability of DPPE to potentiate cytotoxicity of drugs such as cisplatin or fluorouracil, whose efflux is not mediated by the P-gp pump. In vivo, when combined with anthracyclines, DPPE increased the cure rate of experimental tumors in mice.⁶ DPPE enhanced cisplatin antitumor activity in human ovarian cancer cell lines in vitro and in vivo¹³ and in human melanoma cell lines in vitro.^14,15 In early phase I and II clinical trials in patients with a variety of malignancies refractory to treatment,^16,17 DPPE combined with single chemotherapeutic agents, including doxorubicin, showed some evidence of activity (objective responses) in heavily pretreated patients. DPPE in combination with cyclophosphamide produced a high rate of objective tumor and PSA responses in patients with hormone-refractory prostate cancer.¹⁸ A single institutional study of DPPE with doxorubicin in 23 patients with metastatic breast cancer who were anthracycline-naïve showed overall and complete responses rates of 69% and 30%, respectively, with manageable toxicity.¹⁹ On the basis of these findings, the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) conducted a multicenter phase II trial of the DPPE/doxorubicin combination in women with metastatic breast cancer who had had no previous exposure to anthracyclines.

	PATIENTS AND METHODS

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Eligibility
Patients must have had a histologic diagnosis of metastatic breast cancer with metastatic or locally advanced (inoperable) disease. Patients may have had nonanthracycline-containing adjuvant chemotherapy and up to one nonanthracycline-containing regimen for metastatic disease. Previous hormonal therapy was permitted, but a 6-week discontinuation before entry onto this study was required to rule out a withdrawal response. Patients were required to have at least one site of bidimensionally measurable disease; an Eastern Cooperative Oncology Group performance status of 0 to 2; a life expectancy 12 weeks; an absolute neutrophil count (ANC) greater than 1.5 x 10⁹/L; a platelet count 100 x 10⁹/L; normal bilirubin levels; AST or ALT less than three times the upper limit of normal (five times if documented liver metastasis present); and creatinine less than one and a half times the upper limit of normal.

Exclusion criteria were previous malignancies other than curatively treated basal or squamous cell skin carcinoma or cervical cancer; pregnancy or lactation; presence of brain or meningeal metastases; active or uncontrolled infection; clinical evidence of congestive heart failure, myocardial infarction within 6 months, or left ventricular ejection fraction (LVEF) less than 50%; concurrent treatment with other experimental or anticancer drugs including hormones; measurable disease in bone only; serious illnesses or medical conditions that would not permit management according to protocol; use of H₁ antagonists, including tricyclic antidepressants, that could not be discontinued during the period on study; and history of seizure disorder. Patients of childbearing age were required to have a pregnancy test and to use effective contraception. Written informed consent in accordance with institutional guidelines was mandatory for all patients.

Treatment
Patients were registered at the NCIC CTG central office in Kingston (Ontario, Canada) for this study. Treatment was given in an ambulatory care setting beginning in the morning and ending in mid to late afternoon. Treatment was administered in quiet surroundings to minimize visual and auditory stimulation. All patients were pre- and postmedicated (see below) to minimize side effects associated with DPPE administration.

Doxorubicin was commercially available. DPPE, supplied as a sterile bulk powder from a laboratory (L.B.) at the Manitoba Institute of Cell Biology, University of Manitoba (Manitoba, Canada), was weighed, dissolved in a final volume of 250 mL sterile normal saline, and administered as an 80-minute intravenous (IV) infusion at its maximum-tolerated dose of 6 mg/kg. Doxorubicin (60 mg/m²) was administered IV over the last 20 minutes of the DPPE infusion. Chemotherapy was given in 21-day cycles for a maximum of seven cycles.

The first 32 patients on study (group A) were premedicated with an antiemetic regimen consisting of ondansetron 8 mg, administered IV 30 minutes before the DPPE infusion, lorazepam 2 mg, administered IV over the first 60 minutes of the DPPE infusion, and metoclopramide 20 mg, administered IV at the end of the DPPE/doxorubicin infusion. As the study proceeded, some patients were noted to have nausea and/or emesis that persisted. Therefore, a subsequent cohort of 10 patients (group B) received a modification of the antiemetic regimen consisting of ondansetron 8 mg IV, dexamethasone 8 mg IV, and lorazepam 2 mg IV, all administered 30 minutes before the DPPE/doxorubicin infusion, followed by oral ondansetron 8 mg every 8 hours and oral dexamethasone 4 mg daily for 4 days after treatment. Patients who still experienced posttreatment emesis on this regimen received scopolamine 0.2 mg subcutaneously at the time of treatment.

Dose Modifications
There was no dose modification for DPPE. Doxorubicin doses were modified for hematologic and other toxicities. Treatment was delayed until ANC was 1.5 x 10⁹/L and platelet count was 100 x 10⁹/L. Doxorubicin dosage in subsequent cycles was reduced by 10 mg/m² if patients developed any one of the following: febrile neutropenia, ANC less than 0.5 x 10⁹/L for more than 7 days, platelet count less than 50 x 10⁹/L, or grade 3 mucositis. Patients were taken off the study if any of the following occurred: delay of more than 2 weeks in bone marrow recovery, a decrease in LVEF 20% from baseline, congestive heart failure, or other grade 3 major organ toxicities. There were no dosage modifications for nausea, emesis, CNS side effects, and alopecia.

Patient Evaluation and Response Assessment
At the time of study entry, patients were evaluated by a complete history and physical examination, weight, height, vital signs, chest x-ray, CBC with platelet count and differential, serum chemistry, bone scan, electrocardiogram, multiple gated aquisition (MUGA) scan, clinical tumor measurements, and imaging studies (ultrasound or computed tomography scan) of all measurable lesions. During treatment, physical examination, performance status, clinical tumor measurements, chest x-ray, biochemistry, and toxicity assessments were performed every 21 days before each cycle of treatment. CBC with platelet counts and differential were performed weekly. Radiologic studies of all measurable disease were performed every 6 weeks (every other cycle). MUGA scans were performed at baseline and when patients came off study. Toxicities were recorded and graded according to the NCIC CTG expanded common toxicity criteria.

Patients were assessable for response after they received at least one cycle of therapy. Complete response was defined as the disappearance of all clinical evidence of tumor for a minimum of at least 4 weeks. Assessable disease such as bone metastasis required the normalization of both x-ray and bone scan abnormalities. Partial response was defined as a 50% decrease in the sum of the products of the measured lesions for at least 4 weeks duration. No simultaneous increase in the size of an existing lesion or appearance of a new lesion could occur. Progressive disease was defined as an unequivocal increase of at least 25% in the overall sum of measurable lesion as compared with baseline or the appearance of new lesions. Stable disease was defined as the steady state of disease with less than a 50% decrease in the overall sum of measurable lesions and less than a 25% increase in the overall sum of measurable lesions lasting at least 6 weeks. Response duration was measured from the time measurement criteria were first met until disease progression occurred. Stable disease was measured from the start of therapy until disease progression.

Statistical Analysis
The primary end points of the study were complete and overall response rates. Secondary end points were toxicity, response duration, and survival. The response rate was determined for all assessable patients, and the 95% confidence interval was calculated. Progression-free and overall survival were analyzed by the Kaplan-Meier method.

A two-stage design was used for patient accrual.²⁰ The study was designed to detect a true complete response rate of 20% and to reject the DPPE/doxorubicin treatment combination if the complete response rate was less than 5%. If at least one complete response was seen in the first 15 assessable patients, an additional 15 assessable patients would be accrued. If four or more complete responses were observed in the final set of 30 assessable patients, the regimen was to be considered of promising activity for further study. After its initial design, the study was expanded to 42 patients to assess a modified antiemetic regimen, as discussed previously.

	RESULTS

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Patients
A total of 42 patients (32 in group A and 10 in group B) were entered onto the study from May 1996 to January 1998 from four participating NCIC centers. All patients were assessable for toxicity and response. Patient characteristics are outlined in Table 1. As of September 1998, all patients had either completed treatment or come off the study.

Drug Delivery
Details of dose reductions and delays are outlined in Table 2. Thirty-five of the 42 patients received four or more courses of treatment. A total of 209 cycles of DPPE/doxorubicin were given. Only four cycles required doxorubicin dose reduction, and there were no dose reductions for DPPE. Treatment was delayed for 7 days or more in 32 of the 209 cycles. DPPE and doxorubicin were given at 90% of planned dose intensity in approximately three quarters of the patients (Table 3).

Response
The response rates and response durations are shown in Table 4. The overall response rate for the DPPE/doxorubicin combination was 52.5%, with four (9.5%) of 42 patients with complete responses, 18 (43%) of 42 with partial responses, and 16 (38%) of 42 with stable disease. The remaining four patients (9.5%) had progressive disease. Responses were seen in all sites of disease including visceral metastasis. The median response duration for complete response was 4.7 months (range, 4.1 to 5.1 months) and 7.7 months for partial response (range, 2.1 to 13.6 months). The median time to progression for all 42 patients was 6.4 months.

Toxicity
The toxicities observed with the DPPE/doxorubicin combination were, for the most part, those expected with doxorubicin alone. The most common toxic effects are listed in Table 5. Alopecia was universal. Hematologic toxicity was similar in severity to that seen with doxorubicin 60 mg/m² given alone in a previous large NCIC CTG study.²¹ In that study, 67% of patients experienced grade 4 neutropenia. In this DPPE/doxorubicin trial, 62% experienced grade 4 neutropenia. Five patients developed either febrile neutropenia (four patients) or severe documented infection (one patient). In addition to these five patients, three others also required hospital admission for treatment-related complications (hallucinations, vomiting, and dyspnea), for a total of 11 admission events in eight patients. Six patients came off the study because of toxicity or possible toxicity. Two patients had persistent grade 2 nausea, vomiting, and stomatitis. One patient had mild congestive heart failure after five cycles of therapy (cumulative doxorubicin dose, 297 mg/m²); one developed febrile neutropenia, pneumonia, grade 4 thrombocytopenia, and a drop in LVEF by 20% to a value of 52% after only one cycle; one had hallucinations, grade 3 dizziness and headaches; and, finally, one patient developed grade 3 dyspnea of unknown etiology.

At the dosage used (6 mg/kg), DPPE produced CNS toxicity, consisting of cerebellar effects (dizziness and ataxia), mild hallucinations, and motion sickness, similar to many H₁-type arylalkylamine antihistamines. These side effects were generally observed during the time of the infusion and for a few hours afterward. Auditory or visual hallucinations were not distressing and occurred rarely after the first treatment. In some patients, nausea and emesis continued for several days after treatment and seemed more prolonged than usually noted with doxorubicin alone. In the group receiving the original antiemetic regimen (group A), 81% of patients had nausea and 69% vomiting (13% grade 3). In the 10 patients who were treated with a modified antiemetic regimen (group B), 80% had nausea and 80% vomiting (40% grade 3). Although these were nonrandomized cohorts, there did not seem to be a striking improvement in nausea or vomiting with the alteration in antiemetic protocol. In one patient, the nausea responded well to a single dose of scopolamine given with each course of treatment. Overall, the majority of patients had only grade 1 or 2 nausea and vomiting, which was easily managed in an outpatient setting; only two patients came off treatment because of DPPE-related nausea or emesis. There were no treatment-related deaths.

The median baseline pretreatment LVEF was 62% (range, 50% to 73%), decreasing to a median of 56% (range, 30% to 69%) in the 33 patients who had available follow-up data. The median cumulative doxorubicin dose was 294 mg/m² (range, 60 to 420 mg/m²), and nine patients received doses of doxorubicin in excess of 400 mg/m². Cardiac toxicity, defined as a 20% decrease in LVEF from baseline or a drop in LVEF to less than 50%, was seen in eight patients (19%). Details are provided in Table 6. Three of the eight patients (A,B, and C) had a 20% drop in LVEF, but with the lowest LVEF value still in the normal range. The remaining five patients (D,E,F,G, and H) had a drop in LVEF to less than 50% and, of these, three patients (D, G, and H) had clinical symptoms of congestive heart failure developing after five, six, and seven cycles of therapy (corresponding to cumulative doxorubicin doses of 297 mg/m², 351 mg/m², and 419 mg/m²). HIV infection may have contributed to the cardiomyopathy in one patient (G) who was found during treatment to be human immunodeficiency virus–positive.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this phase II study, the combination of DPPE and doxorubicin produced an overall response rate of 52.5%, with a complete response rate of 9.5%. In a recently reported randomized NCIC CTG study that had identical eligibility criteria (zero to one previous chemotherapy regimens for metastatic disease), 289 patients were randomized to receive a combination regimen versus the same dose/schedule of single-agent doxorubicin that was used in this phase II trial. For the 144 patients receiving doxorubicin, there was an overall response rate of only 31%, with 3% complete responses.²¹ The patients in the recently reported NCIC CTG trial were similar to those enrolled onto the phase II trial reported here, with respect to the amount of prior therapy (24.8% v 19%, respectively, with previous metastatic chemotherapy), age (median, 55.6 v 59 years, respectively), extent of metastatic tumor (56% v 60%, respectively, with three or more disease sites), but were somewhat more likely to have had liver involvement (44% v 29%, respectively). Moreover, the patients in our study were not heavily pretreated; less than half had received one prior chemotherapy regimen, and there were more patients with disease sites in bone and/or soft tissue than with visceral disease, factors that might contribute to the relatively high response rate. Thus, although the response rate observed in the current study seemed promising and was consistent with the hypothesis that DPPE may potentiate the antitumor activity of chemotherapy drugs, patient selection may have played a role in our favorable results.

Most of the toxicities noted were those anticipated with doxorubicin-containing regimens, although the CNS toxicities observed at the time of treatment were attributable to DPPE alone or in combination with agents in the antiemetic regimens, such as lorazepam. The main troublesome toxicity for some patients was prolonged nausea and vomiting. Two different antiemetic regimens were used in sequential cohorts of patients in an effort to ameliorate this, but, as described earlier, no major differences in gastrointestinal toxicity were seen between the two groups. Nursing and physician staff gained more confidence in dealing with these DPPE effects over the course of the study so that the protocol was successfully carried out in a multicenter setting. Few patients required admission to hospital for treatment-related complications. Although the incidence (19%) of cardiac toxicity was high, it is difficult to say whether it was increased above the expected incidence with doxorubicin alone because only three patients developed clinical congestive heart failure, and one patient had a relevant risk factor.

This study could have important implications for the use of DPPE in the potentiation of chemotherapy outside the metastatic breast cancer setting. How DPPE might increase the therapeutic index of doxorubicin and other cytotoxic agents^17,18 remains unclear. A similar ability to potentiate the cytotoxicity of several classes of cytotoxic drugs was reported for L-histidinol, a precursor of both histidine and histamine, by Warrington et al^22-26 and Edelstein.²⁷ Moreover, L-histidinol and DPPE have similar pharmacologic profiles.⁶ L-histidinol has been shown to antagonize intracellular histamine binding in microsomes and nuclei but with significantly lower potency than DPPE.⁶ Thus, two unrelated compounds have been found separately to possess similar activity and to be linked to the same putative mechanism of action.

The pharmacokinetics of doxorubicin were not assessed in this study. It could be postulated that one mechanism by which DPPE may increase tumor response is by altering doxorubicin pharmacokinetics. This would be consistent with the observation that DPPE antagonizes histamine binding to microsomal cytochrome P450 mono-oxygenases.⁷ A clinical study exploring a potential pharmacologic interaction between DPPE and doxorubicin is planned to begin soon. The finding that hematologic toxicity with DPPE/doxorubicin (62% of patients with grade 4 neutropenia) did not seem to differ from our observations with the same dose/schedule of single-agent doxorubicin (67% of patients with grade 4 neutropenia) suggests that a significant pharmacokinetic interaction is unlikely and that other cellular mechanisms may be important. As noted earlier, DPPE potentiation of in vitro cytotoxicity of doxorubicin, paclitaxel, and vinblastine in human (HCT116/mdr1+) colon cancer cells has been linked to its acting as a substrate for the P-gp pump.¹² However, P-gp/multidrug resistant–related mechanisms could not fully explain the ability of DPPE to potentiate cytotoxicity of drugs such as cisplatin or fluorouracil, whose efflux is not mediated by the P-gp pump.

The results of this study are of sufficient interest to pursue additional phase III studies to explore the potentiation by DPPE of cytotoxic drugs. A prospectively randomized international study has been initiated by the NCIC CTG to compare doxorubicin 60 mg/m² with DPPE 6 mg/kg plus doxorubicin 60 mg/m² in patients with metastatic breast cancer. The results of this study will be needed before definitive conclusions about the effect of DPPE on the therapeutic index of doxorubicin can be made.

	ACKNOWLEDGMENTS

 
Supported in part by research grants from the National Cancer Institute of Canada and Bristol-Myers Squibb.

We thank Susan Bracken, RN for her invaluable assistance in the accomplishment of this study. We also thank the following investigators who, in addition to the authors, contributed patients to this study: Charles Olweny, MD; Tsiporah Shore, MD; and David Bowman, MD, Winnipeg MB; H.S. Dhaliwal, MD, Thunder Bay, ON; and Richard Tozer, MD, Hamilton, ON, Canada.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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14. McClay E, Albright K, Jones J, et al: N, N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine.HCl (DPPE) is synergistic with cisplatin (DDP) in human melanoma cell lines. Proc Annu Meet Am Assoc Cancer Res34:402, 1993 (abstr 2398)

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17. Brandes LJ, Simons KJ, Bracken SP, et al: Results of a clinical trial in humans with refractory cancer of the intracellular histamine antagonist, N, N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl in combination with various single antineoplastic agents. J Clin Oncol12:1281-1290, 1994[Abstract/Free Full Text]

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Submitted February 3, 1999; accepted July 9, 1999.

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