A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia.
OBJECTIVE
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.


METHODS
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.
Perl
Alexander E
AE
Hematologic Malignancies Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA. alexander.perl@uphs.upenn.edu
Kasner
Margaret T
MT
Tsai
Donald E
DE
Vogl
Dan T
DT
Loren
Alison W
AW
Schuster
Stephen J
SJ
Porter
David L
DL
Stadtmauer
Edward A
EA
Goldstein
Steven C
SC
Frey
Noelle V
NV
Nasta
Sunita D
SD
Hexner
Elizabeth O
EO
Dierov
Jamil K
JK
Swider
Cezary R
CR
Bagg
Adam
A
Gewirtz
Alan M
AM
Carroll
Martin
M
Luger
Selina M
SM
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008558:Melphalan / Q000627:therapeutic use; D008875:Middle Aged; D011494:Protein Kinases / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D005047:Etoposide; D016190:Carboplatin; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D008558:Melphalan; D020123:Sirolimus