Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia

Robert T Dorr, C. Karanes, Catherine S Perry, T. Grogan, J. Greer, J. Moore, B. Weinberger, G. Schiller, T. Pearce, M. Litchman, W. Dalton, Denise Roe, A. F. List

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Abstract

Purpose: To determine the maximum-tolerated dose, pharmacokinetic interaction, and activity of PSC 833 compared with daunorubicin (DNR) and cytarabine in patients with poor-risk acute myeloid leukemia. Patients and Methods: Patients received ara-C 3 g/m2/d on 5 consecutive days, followed by an IV loading dose of PSC 833 (1.5 mg/kg) and an 84-hour continuous infusion escalating from 6, 9, or 10 mg/kg/d. Daunorubicin was administered as a 72-hour continuous infusion at 34 or 45 mg/kg/d. Responding patients received consolidation chemotherapy with DNR pharmacokinetics performed without PSC-833 on day 1, and with PSC-833 on day 4. Response was correlated with expression of P-glycoprotein and lung resistance protein (LRP), and in vitro sensitization of leukemia progenitors to DNR cytotoxicity by PSC 833. Results: All 43 patients are assessable for toxicity and response. Grade 3 or greater hyperbilirubinemia (70%) was the only dose-dependent toxicity. Four patients (9%) succumbed to treatment-related complications. Twentyone patients (49%) achieved a complete remission or restored chronic phase, including 10 of 20 patients treated at the maximum-tolerated dose of 10 mg/kg/d of PSC-833 and 45 mg/m2 of DNR. The 95% confidence interval for complete response was 33.9% to 63.7%. Administration of PSC 833 did not alter the mean area under the curve for DNR, although clearance decreased approximately two-fold (P = .04). Daunorubicinol clearance decreased 3.3-fold (P = .016). Remission rates were not effected by mdr-1 expression, but LRP overexpression was associated with chemotherapy resistance. Conclusion: Combined treatment with infused PSC 833 and DNR is well tolerated and has activity in patients with poor risk acute myeloid leukemia. Administration of PSC 833 delays elimination of daunorubicinol, but yields variable changes in DNR systemic exposure.

Original languageEnglish (US)
Pages (from-to)1589-1599
Number of pages11
JournalJournal of Clinical Oncology
Volume19
Issue number6
StatePublished - Mar 15 2001

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P-Glycoprotein
Daunorubicin
Acute Myeloid Leukemia
Maximum Tolerated Dose
Cytarabine
Pharmacokinetics
Consolidation Chemotherapy
valspodar
Hyperbilirubinemia
Area Under Curve
Leukemia
Confidence Intervals
Drug Therapy
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia. / Dorr, Robert T; Karanes, C.; Perry, Catherine S; Grogan, T.; Greer, J.; Moore, J.; Weinberger, B.; Schiller, G.; Pearce, T.; Litchman, M.; Dalton, W.; Roe, Denise; List, A. F.

In: Journal of Clinical Oncology, Vol. 19, No. 6, 15.03.2001, p. 1589-1599.

Research output: Contribution to journalArticle

Dorr, RT, Karanes, C, Perry, CS, Grogan, T, Greer, J, Moore, J, Weinberger, B, Schiller, G, Pearce, T, Litchman, M, Dalton, W, Roe, D & List, AF 2001, 'Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia', Journal of Clinical Oncology, vol. 19, no. 6, pp. 1589-1599.
Dorr, Robert T ; Karanes, C. ; Perry, Catherine S ; Grogan, T. ; Greer, J. ; Moore, J. ; Weinberger, B. ; Schiller, G. ; Pearce, T. ; Litchman, M. ; Dalton, W. ; Roe, Denise ; List, A. F. / Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia. In: Journal of Clinical Oncology. 2001 ; Vol. 19, No. 6. pp. 1589-1599.
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abstract = "Purpose: To determine the maximum-tolerated dose, pharmacokinetic interaction, and activity of PSC 833 compared with daunorubicin (DNR) and cytarabine in patients with poor-risk acute myeloid leukemia. Patients and Methods: Patients received ara-C 3 g/m2/d on 5 consecutive days, followed by an IV loading dose of PSC 833 (1.5 mg/kg) and an 84-hour continuous infusion escalating from 6, 9, or 10 mg/kg/d. Daunorubicin was administered as a 72-hour continuous infusion at 34 or 45 mg/kg/d. Responding patients received consolidation chemotherapy with DNR pharmacokinetics performed without PSC-833 on day 1, and with PSC-833 on day 4. Response was correlated with expression of P-glycoprotein and lung resistance protein (LRP), and in vitro sensitization of leukemia progenitors to DNR cytotoxicity by PSC 833. Results: All 43 patients are assessable for toxicity and response. Grade 3 or greater hyperbilirubinemia (70{\%}) was the only dose-dependent toxicity. Four patients (9{\%}) succumbed to treatment-related complications. Twentyone patients (49{\%}) achieved a complete remission or restored chronic phase, including 10 of 20 patients treated at the maximum-tolerated dose of 10 mg/kg/d of PSC-833 and 45 mg/m2 of DNR. The 95{\%} confidence interval for complete response was 33.9{\%} to 63.7{\%}. Administration of PSC 833 did not alter the mean area under the curve for DNR, although clearance decreased approximately two-fold (P = .04). Daunorubicinol clearance decreased 3.3-fold (P = .016). Remission rates were not effected by mdr-1 expression, but LRP overexpression was associated with chemotherapy resistance. Conclusion: Combined treatment with infused PSC 833 and DNR is well tolerated and has activity in patients with poor risk acute myeloid leukemia. Administration of PSC 833 delays elimination of daunorubicinol, but yields variable changes in DNR systemic exposure.",
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T1 - Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia

AU - Dorr, Robert T

AU - Karanes, C.

AU - Perry, Catherine S

AU - Grogan, T.

AU - Greer, J.

AU - Moore, J.

AU - Weinberger, B.

AU - Schiller, G.

AU - Pearce, T.

AU - Litchman, M.

AU - Dalton, W.

AU - Roe, Denise

AU - List, A. F.

PY - 2001/3/15

Y1 - 2001/3/15

N2 - Purpose: To determine the maximum-tolerated dose, pharmacokinetic interaction, and activity of PSC 833 compared with daunorubicin (DNR) and cytarabine in patients with poor-risk acute myeloid leukemia. Patients and Methods: Patients received ara-C 3 g/m2/d on 5 consecutive days, followed by an IV loading dose of PSC 833 (1.5 mg/kg) and an 84-hour continuous infusion escalating from 6, 9, or 10 mg/kg/d. Daunorubicin was administered as a 72-hour continuous infusion at 34 or 45 mg/kg/d. Responding patients received consolidation chemotherapy with DNR pharmacokinetics performed without PSC-833 on day 1, and with PSC-833 on day 4. Response was correlated with expression of P-glycoprotein and lung resistance protein (LRP), and in vitro sensitization of leukemia progenitors to DNR cytotoxicity by PSC 833. Results: All 43 patients are assessable for toxicity and response. Grade 3 or greater hyperbilirubinemia (70%) was the only dose-dependent toxicity. Four patients (9%) succumbed to treatment-related complications. Twentyone patients (49%) achieved a complete remission or restored chronic phase, including 10 of 20 patients treated at the maximum-tolerated dose of 10 mg/kg/d of PSC-833 and 45 mg/m2 of DNR. The 95% confidence interval for complete response was 33.9% to 63.7%. Administration of PSC 833 did not alter the mean area under the curve for DNR, although clearance decreased approximately two-fold (P = .04). Daunorubicinol clearance decreased 3.3-fold (P = .016). Remission rates were not effected by mdr-1 expression, but LRP overexpression was associated with chemotherapy resistance. Conclusion: Combined treatment with infused PSC 833 and DNR is well tolerated and has activity in patients with poor risk acute myeloid leukemia. Administration of PSC 833 delays elimination of daunorubicinol, but yields variable changes in DNR systemic exposure.

AB - Purpose: To determine the maximum-tolerated dose, pharmacokinetic interaction, and activity of PSC 833 compared with daunorubicin (DNR) and cytarabine in patients with poor-risk acute myeloid leukemia. Patients and Methods: Patients received ara-C 3 g/m2/d on 5 consecutive days, followed by an IV loading dose of PSC 833 (1.5 mg/kg) and an 84-hour continuous infusion escalating from 6, 9, or 10 mg/kg/d. Daunorubicin was administered as a 72-hour continuous infusion at 34 or 45 mg/kg/d. Responding patients received consolidation chemotherapy with DNR pharmacokinetics performed without PSC-833 on day 1, and with PSC-833 on day 4. Response was correlated with expression of P-glycoprotein and lung resistance protein (LRP), and in vitro sensitization of leukemia progenitors to DNR cytotoxicity by PSC 833. Results: All 43 patients are assessable for toxicity and response. Grade 3 or greater hyperbilirubinemia (70%) was the only dose-dependent toxicity. Four patients (9%) succumbed to treatment-related complications. Twentyone patients (49%) achieved a complete remission or restored chronic phase, including 10 of 20 patients treated at the maximum-tolerated dose of 10 mg/kg/d of PSC-833 and 45 mg/m2 of DNR. The 95% confidence interval for complete response was 33.9% to 63.7%. Administration of PSC 833 did not alter the mean area under the curve for DNR, although clearance decreased approximately two-fold (P = .04). Daunorubicinol clearance decreased 3.3-fold (P = .016). Remission rates were not effected by mdr-1 expression, but LRP overexpression was associated with chemotherapy resistance. Conclusion: Combined treatment with infused PSC 833 and DNR is well tolerated and has activity in patients with poor risk acute myeloid leukemia. Administration of PSC 833 delays elimination of daunorubicinol, but yields variable changes in DNR systemic exposure.

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