A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies

David A. Rizzieri, Eric Feldman, John F. Dipersio, Nashat Gabrail, Wendy Stock, Roger Strair, Victor M. Rivera, Maher Albitar, Camille L. Bedrosian, Francis J. Giles

Research output: Contribution to journalArticle

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Abstract

Purpose: Deforolimus (AP23573), a novel non-prodrug rapamycin analogue, inhibits the mammalian target of rapamycin, a downstream effector of the phosphatidylinositol 3-kinase/Akt and nutrient-sensing pathways. A phase 2 trial was conducted to determine the efficacy and safety of single-agent deforolimus in patients with relapsed or refractory hematologic malignancies. Experimental Design: Eligible patients were assigned to one of five disease-specific, parallel cohorts and given 12.5 mg deforolimus as a 30-minute infusion once daily for 5 days every 2 weeks. A Simon two-stage design was used for each cohort. Safety, pharmacokinetics, pharmacodynamics, and antitumor response were assessed. Results: Fifty-five patients received deforolimus as follows: cohort 123 acute myelogenous leukemia, two myelodysplastic syndrome and one chronic myelogenous leukemia in nonlymphoid blast phase; cohort 2, one acute lymphocytic leukemia; cohort 3, nine agnogenic myeloid metaplasia; cohort 4, eight chronic lymphocytic leukemia; cohort 5, nine mantle cell lymphoma and two T-cell leukemia/lymphoma. Most patients were heavily pretreated. Of the 52 evaluable patients, partial responses were noted in five (10%), two of seven agnogenic myeloid metaplasia and three of nine mantle cell lymphoma. Hematologic improvement/stable disease was observed in 21 (40%). Common treatment-related adverse events, which were generally mild and reversible, were mouth sores, fatigue, nausea, and thrombocytopenia. Decreased levels of phosphorylated 4E-BP1 in 9 of 11 acute myelogenous leukemia/myelodysplastic syndrome patients after therapy showed mammalian target of rapamycin inhibition by deforolimus. Conclusions: Deforolimus was well-tolerated in patients with heavily pretreated hematologic malignancies, and antitumor activity was observed. Further investigation of deforolimus alone and in combination with other therapeutic agents is warranted in patients with selected hematologic malignancies.

Original languageEnglish (US)
Pages (from-to)2756-2762
Number of pages7
JournalClinical Cancer Research
Volume14
Issue number9
DOIs
StatePublished - May 1 2008

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Hematologic Neoplasms
Sirolimus
Clinical Trials
Mantle-Cell Lymphoma
Primary Myelofibrosis
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Phosphatidylinositol 3-Kinase
Blast Crisis
T-Cell Leukemia
Safety
ridaforolimus
T-Cell Lymphoma
B-Cell Chronic Lymphocytic Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Thrombocytopenia
Nausea
Fatigue
Mouth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Rizzieri, David A. ; Feldman, Eric ; Dipersio, John F. ; Gabrail, Nashat ; Stock, Wendy ; Strair, Roger ; Rivera, Victor M. ; Albitar, Maher ; Bedrosian, Camille L. ; Giles, Francis J. / A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 9. pp. 2756-2762.
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abstract = "Purpose: Deforolimus (AP23573), a novel non-prodrug rapamycin analogue, inhibits the mammalian target of rapamycin, a downstream effector of the phosphatidylinositol 3-kinase/Akt and nutrient-sensing pathways. A phase 2 trial was conducted to determine the efficacy and safety of single-agent deforolimus in patients with relapsed or refractory hematologic malignancies. Experimental Design: Eligible patients were assigned to one of five disease-specific, parallel cohorts and given 12.5 mg deforolimus as a 30-minute infusion once daily for 5 days every 2 weeks. A Simon two-stage design was used for each cohort. Safety, pharmacokinetics, pharmacodynamics, and antitumor response were assessed. Results: Fifty-five patients received deforolimus as follows: cohort 123 acute myelogenous leukemia, two myelodysplastic syndrome and one chronic myelogenous leukemia in nonlymphoid blast phase; cohort 2, one acute lymphocytic leukemia; cohort 3, nine agnogenic myeloid metaplasia; cohort 4, eight chronic lymphocytic leukemia; cohort 5, nine mantle cell lymphoma and two T-cell leukemia/lymphoma. Most patients were heavily pretreated. Of the 52 evaluable patients, partial responses were noted in five (10{\%}), two of seven agnogenic myeloid metaplasia and three of nine mantle cell lymphoma. Hematologic improvement/stable disease was observed in 21 (40{\%}). Common treatment-related adverse events, which were generally mild and reversible, were mouth sores, fatigue, nausea, and thrombocytopenia. Decreased levels of phosphorylated 4E-BP1 in 9 of 11 acute myelogenous leukemia/myelodysplastic syndrome patients after therapy showed mammalian target of rapamycin inhibition by deforolimus. Conclusions: Deforolimus was well-tolerated in patients with heavily pretreated hematologic malignancies, and antitumor activity was observed. Further investigation of deforolimus alone and in combination with other therapeutic agents is warranted in patients with selected hematologic malignancies.",
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A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. / Rizzieri, David A.; Feldman, Eric; Dipersio, John F.; Gabrail, Nashat; Stock, Wendy; Strair, Roger; Rivera, Victor M.; Albitar, Maher; Bedrosian, Camille L.; Giles, Francis J.

In: Clinical Cancer Research, Vol. 14, No. 9, 01.05.2008, p. 2756-2762.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies

AU - Rizzieri, David A.

AU - Feldman, Eric

AU - Dipersio, John F.

AU - Gabrail, Nashat

AU - Stock, Wendy

AU - Strair, Roger

AU - Rivera, Victor M.

AU - Albitar, Maher

AU - Bedrosian, Camille L.

AU - Giles, Francis J.

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