PMID- 19843663
OWN - NLM
STAT- MEDLINE
DCOM- 20091229
LR  - 20231120
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 15
IP  - 21
DP  - 2009 Nov 1
TI  - A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC 
      chemotherapy in relapsed and refractory acute myelogenous leukemia.
PG  - 6732-9
LID - 10.1158/1078-0432.CCR-09-0842 [doi]
AB  - PURPOSE: Inhibiting mammalian target of rapamycin (mTOR) signaling in acute 
      myelogenous leukemia (AML) blasts and leukemic stem cells may enhance their 
      sensitivity to cytotoxic agents. We sought to determine the safety and describe 
      the toxicity of this approach by adding the mTOR inhibitor, sirolimus 
      (rapamycin), to intensive AML induction chemotherapy. EXPERIMENTAL DESIGN: We 
      performed a phase I dose escalation study of sirolimus with the chemotherapy 
      regimen MEC (mitoxantrone, etoposide, and cytarabine) in patients with relapsed, 
      refractory, or untreated secondary AML. RESULTS: Twenty-nine subjects received 
      sirolimus and MEC across five dose levels. Dose-limiting toxicities were 
      irreversible marrow aplasia and multiorgan failure. The maximum tolerated dose 
      (MTD) of sirolimus was determined to be a 12 mg loading dose on day 1 followed by 
      4 mg/d on days 2 to 7, concurrent with MEC chemotherapy. Complete or partial 
      remissions occurred in 6 (22%) of the 27 subjects who completed chemotherapy, 
      including 3 (25%) of the 12 subjects treated at the MTD. At the MTD, measured 
      rapamycin trough levels were within the therapeutic range for solid organ 
      transplantation. However, direct measurement of the mTOR target p70 S6 kinase 
      phosphorylation in marrow blasts from these subjects only showed definite target 
      inhibition in one of five evaluable samples. CONCLUSIONS: Sirolimus and MEC is an 
      active and feasible regimen. However, as administered in this study, the synergy 
      between MEC and sirolimus was not confirmed. Future studies are planned with 
      different schedules to clarify the clinical and biochemical effects of sirolimus 
      in AML and to determine whether target inhibition predicts chemotherapy response.
FAU - Perl, Alexander E
AU  - Perl AE
AD  - Hematologic Malignancies Program, Abramson Cancer Center, University of 
      Pennsylvania, Philadelphia, Pennsylvania, USA. alexander.perl@uphs.upenn.edu
FAU - Kasner, Margaret T
AU  - Kasner MT
FAU - Tsai, Donald E
AU  - Tsai DE
FAU - Vogl, Dan T
AU  - Vogl DT
FAU - Loren, Alison W
AU  - Loren AW
FAU - Schuster, Stephen J
AU  - Schuster SJ
FAU - Porter, David L
AU  - Porter DL
FAU - Stadtmauer, Edward A
AU  - Stadtmauer EA
FAU - Goldstein, Steven C
AU  - Goldstein SC
FAU - Frey, Noelle V
AU  - Frey NV
FAU - Nasta, Sunita D
AU  - Nasta SD
FAU - Hexner, Elizabeth O
AU  - Hexner EO
FAU - Dierov, Jamil K
AU  - Dierov JK
FAU - Swider, Cezary R
AU  - Swider CR
FAU - Bagg, Adam
AU  - Bagg A
FAU - Gewirtz, Alan M
AU  - Gewirtz AM
FAU - Carroll, Martin
AU  - Carroll M
FAU - Luger, Selina M
AU  - Luger SM
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091020
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - BG3F62OND5 (Carboplatin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - Q41OR9510P (Melphalan)
RN  - W36ZG6FT64 (Sirolimus)
RN  - MEC regimen
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibiotics, Antineoplastic/*administration & dosage
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Carboplatin/therapeutic use
MH  - Drug Administration Schedule
MH  - Drug Resistance, Neoplasm
MH  - Etoposide/therapeutic use
MH  - Female
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*drug therapy
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Melphalan/therapeutic use
MH  - Middle Aged
MH  - Protein Kinases/metabolism
MH  - Recurrence
MH  - Signal Transduction
MH  - Sirolimus/*administration & dosage/adverse effects/metabolism
MH  - TOR Serine-Threonine Kinases
EDAT- 2009/10/22 06:00
MHDA- 2009/12/30 06:00
CRDT- 2009/10/22 06:00
PHST- 2009/10/22 06:00 [entrez]
PHST- 2009/10/22 06:00 [pubmed]
PHST- 2009/12/30 06:00 [medline]
AID - 1078-0432.CCR-09-0842 [pii]
AID - 10.1158/1078-0432.CCR-09-0842 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2009 Nov 1;15(21):6732-9. doi: 10.1158/1078-0432.CCR-09-0842. 
      Epub 2009 Oct 20.