|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology Parallel Phase I Studies of Daunorubicin Given With Cytarabine and Etoposide With or Without the Multidrug Resistance Modulator PSC-833 in Previously Untreated Patients 60 Years of Age or Older With Acute Myeloid Leukemia: Results of Cancer and Leukemia Group B Study 9420From the Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD; Duke University Comprehensive Cancer Center, Durham; Comprehensive Cancer Center of Wake Forest University School of Medicine, Winston-Salem, NC; Ohio State University School of Medicine, Columbus, OH; Cornell University School of Medicine, New York; State University of New York Health Science Center at Syracuse, Syracuse; Roswell Park Cancer Institute, Buffalo, NY; Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine, Detroit, MI; and the Cancer and Leukemia Group B, Chicago, IL. Address reprint requests to Charles A. Schiffer, MD, Division of Hematology/Oncology, Harper Hospital, 5 Hudson, 3990 John R, Detroit, MI 48201 emailschiffer{at}karmanos.org
PURPOSE: The Cancer and Leukemia Group B conducted parallel phase I trials of cytarabine, daunorubicin, and etoposide (ADE) with or without PSC-833 (P), a modulator of p-glycoprotein–mediated multidrug resistance.
PATIENTS AND METHODS: One hundred ten newly diagnosed patients RESULTS: There was no toxicity attributed to the PSC-833. Dose-limiting toxicity was primarily gastrointestinal (diarrhea, mucositis in the ADEP group). The estimated maximum-tolerated doses, calculated using a logistic regression model, were daunorubicin 40 mg/m2/d for 3 days with etoposide 60 mg/m2 for 3 days in the ADEP group and daunorubicin 60 mg/m2/d for 3 days and etoposide 100 mg/m2/d for 3 days in the ADE group. Twenty-one (48%) of 44 patients achieved complete remission with ADE, compared with 29 (44%) of 66 patients treated with ADEP. CONCLUSION: It is necessary to decrease the doses of daunorubicin and etoposide when they are administered with PSC-833, presumably because of the effect of the modulator on the pharmacokinetics of these agents. A phase III trial comparing the regimens derived from this phase I trial has recently begun.
ALTHOUGH THE understanding of the biology of neoplastic diseases has increased dramatically over the past few years, treatment advances have not occurred as rapidly. For diseases such as acute myeloid leukemia (AML), there has been only modest improvement in outcome since the development of the combination of daunorubicin and cytarabine (ara-C) in the 1970s. AML is a disease that affects older individuals, with a median age in adults of approximately 55 years. Although intensive postremission therapy has improved results in younger patients, complete remission (CR) rates remain at 45% to 55% in patients who are older than 60 years, with only 10% to 15% of patients surviving 4 years.1,2 Older patients with AML are more likely to have chromosome abnormalities associated with a poor outcome, such as loss of all or part of the long arms of chromosomes 5 or 7, or trisomy 8.3-5 Older patients commonly have trilineage dysplasia and more frequently are suspected of having preexisting myelodysplasia than younger individuals. Other biologic differences between younger and older patients have been shown as well, and those involving mechanisms by which leukemia cells may escape death after exposure tochemotherapy may be relevant. A series of membrane proteins, which transport large molecules of organic origin from the interior of cells to their exterior, have been identified. The best understood of these is the glycoprotein called p170 or p-glycoprotein (PGP).6,7 PGP has been identified in cells from newly diagnosed patients with AML using flow cytometric, immunohistochemical, Northern blotting, and functional drug transport assays.8-13 Rapid extrusion of anthracycline antibiotics and etoposide from leukemic cells is associated with resistance to these chemotherapeutic agents in vitro. Recent data suggest that PGP is more likely to be overexpressed at recurrence than at diagnosis and in patients with prior myelodysplasia.14,15 Furthermore, studies from the Southwest Oncology Group have shown that older patients with AML are more likely to express PGP, and that the presence of PGP is an independent prognostic indicator associated with lower rates of CR and shorter disease-free survival.15,16 Thus PGP is an appropriate target for therapeutic interventions. A number of agents inhibit the function of PGP, blocking efflux of daunorubicin and etoposide from the intracellular compartment.12,15,17-20 Although drugs such as verapamil, cyclosporine, or quinine are effective in vitro, their clinical utility is limited by side effects, such as hypotension with verapamil or the potential for immunosuppression and nephrotoxicity with cyclosporine. PSC-833 is a cyclosporine analog that is relatively free of side effects at doses that are adequate to block PGP function in vitro. It is also a more potent modulator of this multidrug-resistance (MDR) phenotype in vitro than cyclosporine.21-23 The Cancer and Leukemia Group B (CALGB), therefore, undertook a phase I study in older patients with newly diagnosed AML to define the appropriate doses of daunorubicin given together with ara-C and etoposide for a future randomized phase III trial of PGP blockade in patients with AML. In planning this trial, the traditional anthracycline/ara-C chemotherapy regimen was reconsidered. Studies using this induction regimen for this patient population by both the CALGB and others have shown remarkably consistent results,1,2,24 with CR rates of approximately 50% and similar mortality in the first month, despite using differing doses of daunorubicin of 30, 45, or 60 mg/m2 for 3 consecutive days. Optimal doses of anthracycline in this regimen have not been defined by contemporary phase I studies incorporating recent improvements in supportive care. In addition, we felt that it would be advisable to include another chemotherapeutic drug that could be modulated by PSC-833. Although etoposide did not have an effect on CR rate when added to anthracycline/ara-C induction therapy, a prolongation of relapse-free survival was noted in a recent study.25 It was hoped that using two drugs that are affected by PGP may, in the presence of an inhibitor of PGP, increase the fraction of leukemia cells killed by chemotherapy to a greater extent than could be seen with dose escalation alone. As a prelude to a phase III randomized trial of chemotherapy with or without PGP inhibition, parallel phase I studies were conducted by CALGB of the two regimens: ara-C, daunorubicin, and etoposide (ADE) and ara-C, daunorubicin, etoposide, and PSC-833 (ADEP).
Eligibility Criteria Patients were eligible if they were  60 years old and had AML with French-American-British (FAB) M0-M2 and M4-M7 as defined by standard morphologic and immunophenotypic criteria. Patients with acute promyelocytic leukemia (FAB M3) were not eligible and were treated with tretinoin-based protocols. It was required that there was no prior treatment for AML, with the exception of hydroxyurea and cranial irradiation if needed for management of hyperleukocytosis. History of prior chemotherapy exposure or myelodysplasia rendered the patient ineligible for entry onto the study. Patients were also required to have adequate renal and hepatic function. The protocol was reviewed and approved by local institutional review boards, and written informed consent was obtained from all patients.
Statistical Design and Methodology The traditional phase I design provides for dose escalation and identification and confirmation of excessive toxicity, followed by the assignment of the label of maximum-tolerated dose (MTD) to the dose level preceding the one that was associated with excessive toxicity.26 Historically, relatively small cohorts of patients have been entered, and there is little statistical confidence in the resultant estimate of the frequency of toxicity. Because we were planning a phase III study to follow the present study, it was important to estimate the doses of the two different regimens with more precision than is customary in a phase I study. For these reasons, the design departed from the traditional phase I design in terms of the number of patients treated and the use of a model-based approach to estimate the MTDs. The design was based on the following assumptions and considerations:
2. The frequency of mucosal toxicity (the most likely dose-limiting event) with traditional daunorubicin/ara-C regimens would be approximately 30% on the basis of results from previous CALGB studies (95% confidence interval [CI], 25% to 35%).1,2 3. A reliable method of establishing appropriate doses requires more patients to be entered at doses near the hypothetical appropriate dose. 4. Adequate time for assessment of toxicity must pass before dose escalation can occur. For this reason, patients were entered alternately on one cohort of one treatment regimen (ADE or ADEP) during 1 month, followed in the next month by a cohort of the other treatment regimen, with dose changes as indicated under Dose Escalation and Alternating Cohorts in the study design. 5. The target accrual was estimated to be 108 patients to ensure reasonable precision in the estimates of the regression model parameters and a reasonably small SE in the estimates of the rates of dose-limiting toxicity (DLT) at specific dose levels. This number of patients is much larger than that of typical phase I studies. Neither arm would be closed before the study ended, allowing additional information about dose and toxicity to be gathered.
Estimation of the MTD
Estimates of ßi were obtained in the usual fashion, using the Logistic procedure in SAS (SAS/STAT User's Guide, Version 6, Cary, NC, SAS Institute, 1990). Goodness of fit of the model was assessed with the Hosmer-Lemeshow test.27 However, our primary interest was not in these estimates, but in the value of x1 yielding P = .33. This value is, by definition, the MTD for daunorubicin. This value depends on both the use of PSC-833 (x2) and the etoposide dose (x3). Thus there are potentially four separate estimates of the MTD for daunorubicin, one for each of the four combinations of PSC-833 usage and etoposide dose (see below). One of these cases (no PSC, etoposide = 60 mg/m2/d) would have represented an extrapolation of the model, as no patients were treated with this combination; thus this estimate will not be reported. This analysis was repeated by including all early deaths (< 28 days from the start of therapy) with the DLTs to form a composite adverse event end point. That is, in this analysis, all early deaths, regardless of the reason and regardless of whether DLT could be determined, were counted along with the DLTs as adverse events. This will cause the estimated logistic regression curves to shift to the left. A model-based approach allows use of all the data to estimate the MTD. This differs from the simple nonparametric procedures traditionally used in phase I trials and is much more efficient, as long as the model is reasonable. In the standard phase I design, one typically halts dose escalation when two of six patients experience DLT, but this approach is known to have poor statistical properties because of the small sample size. The particular model used here is the most commonly used method for binary outcome data (ie, DLT or no DLT for each patient) in the biomedical setting. A difference between a model-based analysis and other approaches is that the estimate of the MTD need not be a dose that was actually tested. Another difference is that the data from patients at all dose levels are used in the estimates, so that the outcome for patients actually treated at or near the estimated MTD is not the only basis for estimation. As a corollary, it should be appreciated that the observed simple arithmetic percentage of DLTs at the MTD may be somewhat different than the trial goal of 33% estimated by the model.
Induction Therapy Etoposide was given at a dose of 100 mg/m2/d over 2 hours on days 1, 2, and 3 until the final dosage level in ADEP was reached, when the dose was reduced to 60 mg/m2/d for 3 days. The starting dose of daunorubicin was 30 mg/m2/d given by slow intravenous push on days 1, 2, and 3 with adjustments of 10 mg/m2/d in subsequent cohorts based on the escalation/de-escalation rules.
Reinduction Therapy
Dose Escalation and Alternating Cohorts
Postremission Therapy Thereafter, patients who had hematologic recovery and no evidence of AML were treated with interleukin-2. The initial dose was 1 x 106 units/m2/d by subcutaneous injection for 90 days.29 The results and toxicity of this program of treatment will not be reported here.
Supportive Care
Quality Control, Quality Assurance, and Auditing
Outcome Measures Toxicity was measured according to the CALGB expanded common toxicity criteria. For the purposes of this trial, early death was defined as death on or before day 28 of the induction course. Death may have occurred as a consequence of an event considered as DLT, after events that occurred prior to treatment, or as a consequence of infection or the leukemia itself. Death alone was not used to define the presence of DLT, defined clinically by the occurrence of a clinical event that was at least grade 3 and not hematologic or infectious in nature. Isolated elevations of bilirubin were not considered DLT, and the use of parenteral nutrition, which varies considerably from institution to institution, was not considered sufficient to define DLT.
This study opened in January 1995 and closed to accrual in July 1997. Of the 111 patients registered, one patient was never treated. Demographic information is presented in Table 1. The median age was 69 years (range, 60 to 84 years). Four patients with clinically de novo AML were reclassified as refractory anemia with excess blasts in transformation on central review. Previous CALGB studies have suggested that such patients have similar outcomes to other patients with de novo AML, and they were, therefore, included in the evaluation of this phase I study.32
Toxicity
The vast majority of events that were considered DLT were mucosal, with either severe stomatitis and oral pain or diarrhea. Although neurologic toxicities were described in some of these patients, the majority were mild and were difficult to attribute to any specific agent (such as PSC-833) because of the widespread use of antiemetics, lorazepam, and diphenhydramine in this group of older patients.
Statistical Analysis and Estimation of MTDs
Although we were interested primarily in the estimated MTDs, the full logistic curves for the DLT are shown in Fig 1. There was no statistically significant lack of fit for these models (P = .06 for DLT only, and P = .62 for DLT + ED [not shown] by the Hosmer-Lemeshow test27). Although the curves were somewhat shifted to the left when the EDs were included, there is no major effect on the estimated MTDs. The estimated probabilities of DLT for doses larger than the calculated MTDs are extrapolations and should be interpreted with caution. No patients were treated with more than 60 mg/m2/d of daunorubicin on the ADE arm, and no patients were treated with more than 40 mg/m2/d on the ADEP arm. Table 4 lists the results in the various patients groups based on the escalation/de-escalation scheme.
ADE
ADEP
Response
The goal of this study was to define the appropriate doses of ADE and ADEP to be compared in a phase III study to test whether inhibition of PGP results in higher CR rates and longer overall survival. The doses of ADE and ADEP (calculated using a logistic regression model) that produce relatively equal toxicity are as follows: daunorubicin 60 mg/m2/d and etoposide 100 mg/m2/d for ADE and daunorubicin 40 mg/m2/d and etoposide 60 mg/m2/d for ADEP. There were no detectable adverse events attributable to the PSC-833 infusions, except for transient hyperbilirubinemia. In particular, there were no significant or recurrent CNS symptoms ascribed to the PSC-833, indicating that this dose and schedule are clinically acceptable. Minor events did occur, but they were not attributed to PSC-833 and were reversible. As might be predicted from the known side effects of these drugs, the major DLT was mucositis. The final doses were identified by treatment of a larger number of patients than is usually included in traditional phase I studies. Additionally, the clinical observations obtained by calculation of toxicities at a single final dose level were corroborated by the use of statistical models that incorporate information from patients treated at all dose levels. The study was designed to escalate doses rapidly to those doses at which toxicity occurs and then to define the proper doses with greater precision. The strategy of alternating ADE/ADEP cohorts on a monthly basis accelerated the completion of the study, as there was no "down time" spent awaiting the results at specific dosage levels. Thus decisions about dose escalation or decreases could be made more rapidly. The doses selected are close to what might have been predicted on the basis of what is known about the pharmacodynamic effect of PSC-833 and other MDR modulators on etoposide and anthracyclines. The final doses were lower by approximately one third in the patients receiving PSC-833, but it is known that PSC-833 and cyclosporine increase the area under the curve of concentration versus time for etoposide and anthracyclines.20,28,34-38 Interestingly, a series of recent small phase I trials also suggested that the doses of etoposide and mitoxantrone should be reduced by approximately one third when administered with PSC-833.34-38 Another study suggested increased daunorubicin concentrations in leukemic blasts in vivo after administration of PSC-833.39 In all of these studies, the PSC-833 was given in a fashion similar to our regimen and was well tolerated, with the exception of the expected development of asymptomatic hyperbilirubinemia. PSC-833 levels were always greater than the desired 1,000 ng/mL and in most patients were greater than 2,000 ng/mL. There were more deaths among patients receiving PSC-833 than among those who did not receive PSC-833. Some of the deaths were within the first 1 to 2 weeks of treatment and were largely a consequence of comorbid illnesses with which the patients presented to the hospital, rather than direct effects of the treatment. It is not appropriate to compare death rates or CR rates in such small cohorts of patients, hence the need for a phase III study. The overall response rate in the ADEP cohorts is similar to response rates in earlier studies in patients of this age, and, therefore, there are no significant concerns in evaluating this regimen in a larger phase III study. It is of interest that the doses identified in the patients receiving ADE are higher than are customarily used in older patients with AML, who usually receive doses of 30 to 45 mg/m2 of daunorubicin in regimens that do not include etoposide. As noted earlier, formal phase I studies have not really been performed for AML induction regimens with more contemporary supportive care. It is likely that improvements in antiemetics, platelet transfusion, and earlier use of antifungal agents contribute substantially to the higher doses tolerated by the patients in this study. Whether dose increases in this range are of long-term benefit to such patients is unknown. In this cooperative group setting, we were not able to do pharmacokinetic studies for the various doses, nor did we attempt to systematically assay leukemia cells for the presence of PGP. We did systematically collect data for chromosomal analysis of the leukemia cells from these patients, but again, the numbers are too small and the treatments too varied to allow any meaningful analysis. A phase III study using these doses of ADE and ADEP in newly diagnosed, older patients with AML has recently been initiated by the CALGB. A concurrent protocol is examining leukemia cells from patients entered on that study for PGP expression using flow cytometry and by functional efflux assays. Other groups are testing this concept in patients with AML in relapse. We elected to evaluate MDR modulation in untreated patients because it is known that multiple mechanisms of resistance develop in patients with AML, and it is hoped that these other factors may be less critical before selective pressure from induction chemotherapy. There are also provocative in vitro data suggesting a decreased mutation rate leading to doxorubicin resistance and less mdr1 gene activation when cells are exposed concurrently to doxorubicin and PSC-833 compared with doxorubicin alone.40 Thus considerable preclinical rationale and clinical data supporting the concept of MDR modulation exist, and it is expected that these ongoing studies will determine whether inhibition of PGP can be accomplished in vivo and is important in the treatment of patients with AML.
The following institutions participated in the study: University of Alabama, Birmingham, AL, Robert Diasio, MD (CA47545); Bowman Gray School of Medicine, Winston-Salem, NC, M. Robert Cooper, MD (CA03927); University of North Carolina, Chapel Hill, NC, Thomas Shea, MD (CA47559); University of Chicago Medical Center, Chicago, IL, Nicholas J. Vogelzang, MD (CA41287); Dartmouth-Hitchcock Medical Center, Hanover, NH, L. Herbert Maurer, MD (CA04326); Duke University Medical Center, Durham, NC, Jeffrey Crawford, MD (CA47577); Dana-Farber Cancer Institute, Boston, MA, George P. Canellos, MD (CA32291); Long Island Jewish Medical Center, New Hyde Park, NY, Marc Citron, MD (CA11028); University of Maryland Cancer Center, Baltimore, MD, Ernest Borden, MD (CA31983); Massachusetts General Hospital, Boston, MA, Michael Grossbard, MD (CA12449); McGill Cancer Center, Montreal, Quebec, Canada, Brian Leyland-Jones, MD (CA31809); University of Minnesota, Minneapolis, MN, Bruce Peterson, MD (CA16450); University of Missouri/Ellis Fischel Cancer Center, Columbia, MO, Michael C. Perry, MD (CA12046); Mount Sinai Hospital, New York, NY, James Holland, MD (CA04457); North Shore University Hospital, Manhassat, NY, Daniel R. Budman, MD (CA35279); New York Hospital-Cornell Medical Center, New York, NY, Ted Szatrowski, MD (CA07968); Rhode Island Hospital, Providence, RI, Louis A. Leone, MD (CA08025); and State University of New York Health Science Center at Syracuse, Syracuse, NY, Stephen Graziano, MD (CA21060).
Supported in part by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, Chairman) and the CALGB Statistical Center (CA33601).
The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.
1. Mayer RF, Davis RB, Schiffer CA, et al: Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331:896-903, 1994
2.
Stone RM, Berg DT, George SL, et al: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med 332:1671-1677, 1995 3. Keating MJ, Smith TL, Kantarjian H, et al: Cytogenetic pattern in acute myelogenous leukemia: A major reproducible determinant of outcome. Leukemia 2:403-412, l988 4. Samuels BL, Larson RA, Le Beau MM, et al: Specific chromosomal abnormalities in acute nonlymphocytic leukemia correlate with drug susceptibility in vivo. Leukemia 2:79-83, 1988[Medline]
5.
Schiffer CA, Lee EJ, Tomiyasu T, et al: Prognostic impact of cytogenetic abnormalities in patients with de novo acute non-lymphocytic leukemia. Blood 73:263-270, 1989 6. Bell DR, Trent JM, Willard HF, et al: Chromosomal location of human P-glycoprotein gene sequences. Cancer Genet Cytogenet 25:141-148, 1987[Medline] 7. Bell DR, Gerlach JH, Kartner N, et al: Detection of P-glycoprotein in ovarian cancer: A molecular marker associated with multidrug resistance. J Clin Oncol 3:311-315, 1985[Abstract]
8.
Campos L, Guyotat D, Archimbaud E, et al: Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphocytic leukemia cells at diagnosis. Blood 79:473-476, 1992
9.
Pieters R, Huismans DR, Leyva A, et al: MDR1 gene expression and treatment outcome in acute myeloid leukemia. J Natl Cancer Inst 83:708-712, 1991 10. Sato H, Preisler H, Day R, et al: MDR1 transcript levels as an indication of resistant disease in acute myelogenous leukemia. Br J Haematol 75:340-345, 1990[Medline]
11.
Marie JP, Zittoun R, Sikic BI: Multidrug resistance (mdr1) gene expression in adult acute leukemias: Correlations with treatment outcome and in vitro drug sensitivity. Blood 78:586-592, 1991
12.
Ross DD, Wooten PJ, Sridhara R, et al: Enhancement of daunorubicin accumulation, retention, and cytotoxicity by verapamil or cyclosporin A in blast cells from patients with previously untreated acute myeloid leukemia. Blood 82:1288-1299, 1993 13. Pirker R, Wallner J, Greissler K, et al: MDR1 gene expression and treatment outcome in acute myeloid leukemia. J Natl Cancer Inst 83:708-712, 1991 14. List AF, Spier CM, Cline A, et al: Expression of the multidrug resistance gene product (p-glycoprotein) in myelodysplasia is associated with a stem cell phenotype. Br J Haematol 78:28-34, 1991[Medline]
15.
Leith CP, Chen I-M, Kopecky KJ, et al: Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: Identification of discordant MDR-/efflux+ and MDR1+/efflux- cases. Blood 86:2329-2342, 1995
16.
Leith CP, Kopecky KJ, Godwin J, et al: Acute myeloid leukemia in the elderly: Assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy—A Southwest Oncology Group study. Blood 89:3323-3329, 1997
17.
Solary E, Witz B, Caillot D, et al: Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: A randomized multicenter study. Blood 88:1198-1205, 1996
18.
Miller TP, Grogan TM, Dalton WS, et al: P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high dose verapamil. J Clin Oncol 9:17-24, 1991
19.
Ross DD, Wooten PJ, Tong Y, et al: Synergistic reversal of multidrug resistance phenotype in acute myeloid leukemia cells by cyclosporin A and cremophor EL. Blood 83:1337-1347, 1994
20.
List AF, Spier C, Greer J, et al: Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia. J Clin Oncol 11:1652-1660, 1993
21.
Boesch D, Gaveriaux C, Jachez B, et al: In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. Cancer Res 51:4226-4233, 1991 22. Pourtier-Manzanedo A, Didier AD, Muller CD, et al: SDZ PSC 833 and SDZ 280-446 are the most active of various resistance-modifying agents in restoring rhodamine-123 retention within multidrug resistant P388 cells. Anticancer Drugs 3:419-425, 1992[Medline] 23. Watanabe T, Tsuge H, Oh-Hara T, et al: Comparative study on reversal efficacy of SDZ PSC 833, cyclosporin A and verapamil on multidrug resistance in vitro and in vivo. Acta Oncol 34:235-241, 1995[Medline]
24.
Büchner Th, Urbanitz D, Hiddemann W, et al: Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): Two multicenter studies of the German AML cooperative group. J Clin Oncol 3:1583-1589, 1985
25.
Bishop JF, Lowenthal RM, Joshua DE, et al: A randomized trial of cytosine arabinoside, daunorubicin + VP 16-213 (73 VS 737) as initial induction in adults with acute non-lymphocytic leukemia. Blood 75:27-32, 1990 26. Carter SK, Selawry O, Slavik M: Phase I clinical trials. Natl Cancer Inst Monogr 45:75-80, 1977 27. Hosmer DW, Lemeshow S: Applied Logistic Regression. New York, NY, John Wiley and Sons, 1989
28.
Boote DJ, Dennis IF, Twentyman PR, et al: Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer. J Clin Oncol 14:610-618, 1996
29.
Bernstein ZP, Porter MM, Could M, et al: Prolonged administration of low-dose interleukin-2 in human immunodeficiency virus-associated malignancy results in selective expansion of innate immune effectors without significant clinical toxicity. Blood 86:3287-3294, 1995
30.
Weiss RB, Vogelzang NJ, Peterson BA, et al: A successful system of scientific data audits for clinical trials: A report from the Cancer and Leukemia Group B. JAMA 270:459-464, 1993 31. Cheson BD, Cassileth PA, Head DR, et al: Report of the NCI-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8:813-819, 1990[Abstract] 32. Bernstein SH, Brunetto VL, Davey FR, et al: Acute myeloid leukemia type chemotherapy for newly diagnosed patients without antecedent cytopenias having myelodysplastic syndrome as defined by French-American-British criteria: A Cancer and Leukemia Group B study. J Clin Oncol 14:2486-2494, 1996[Abstract] 33. Storer BE: Design and analysis of phase I clinical trials. Biometrics 45:925-937, 1989[Medline]
34.
Lum BL, Kaubisch S, Yahanda A, et al: Alternation of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate drug resistance. J Clin Oncol 10:1635-1642, 1992 35. Sonneveld P, Lowenberg B, Vossebeld P, et al: Dose finding study of PSC833, a novel MDR reversing agent, with daunorubicin and ara-c in untreated elderly patients with acute myeloid leukemia. Blood 90:566a, 1997 (suppl) 36. Visani G, Milligan D, Leoni F, et al: A phase I dose-finding study of PSC 833, a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor prognosis acute leukemia. Blood 90:566a, 1997 (suppl) (abstr)
37.
Advani R, Saba HI, Tallman MS, et al: Treatment of refractory and relapsed acute myelogenous with combination chemotherapy plus the multidrug modulator PSC-833 (Valdospar). Blood 93:787-795, 1999
38.
Kornblau SM, Estey E, Madden T, et al: Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia. J Clin Oncol 15:1796-1802, 1997 39. Paul C, Tidefelt U, Gruber A, et al: The P-glycoprotein inhibitor PSC 833 increases the intracellular concentrations of daunorubicin in vivo in patients with PgP-positive AML. Blood 90:182a, 1997 (suppl) (abstr)
40.
Beketic-Oreskovic L, Durán Chen G, et al: Decreased mutation rate for cellular resistance to doxorubicin and suppression of mdr1 gene activation by the cyclosporin analogue PSC 833. J Natl Cancer Inst 87:1593-1602, 1995 Submitted February 3, 1999; accepted May 26, 1999.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
