A Phase I Study of PS-341 (Velcade, Bortezomib) in Combination With 17-allylamino-17-demethoxygeldanamycin (17-AAG) in Patients With Relapsed or Refractory Hematologic Malignancies
I. To determine the maximum tolerated dose (MTD) of PS-341 (Velcade, Bortezomib) in
combination with 17-allyamino-17-demethoxygeldanamycin (17-AAG) in patients with relapsed or
refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).
II. To determine the MTD of PS-341 in combination with 17-AAG in patients with relapsed or
refractory chronic lymphocytic leukemia (CLL), and non-Hodgkin's lymphoma (NHL).
III. To define the specific toxicities and the dose limiting toxicity (DLT) of PS-341 in
combination with 17-AAG in the treatment of patients with relapsed or refractory hematologic
I. To determine the pharmacokinetics of 17-AAG alone and in combination with PS-341 in
patients with AML, ALL, CLL, and NHL.
II. To evaluate 20S proteasome inhibition following combination therapy with 17-AAG and
PS-341 in patients with AML, ALL, CLL, and NHL.
III. To assess the relationship between FLT3 mutational status and leukemic cell response to
PS-341 and 17-AAG in patients with AML.
IV. To assess the relationship between Bcl-2 over-expression and response to 17-AAG and
PS-341 in patients with AML and NHL.
V. To evaluate the effects of the combination of PS-341 and 17-AAG on Hsp90 and NF-kappaB
and their downstream targets including Hsp70, Akt, phosphorylated Akt, p21, and caspases 3
and 9 in patient-derived primary AML and NHL cells.
OUTLINE: This is a dose-escalation study. Patients are stratified according to diagnosis
(acute myeloid leukemia [AML] or acute lymphoblastic leukemia vs chronic lymphoctyic
leukemia or non-Hodgkin's lymphoma [NHL]).
Patients receive 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) intravenously (IV) over
1-6 hours on days 1, 4, 8, and 11 and bortezomib IV over 3-5 seconds on days 4, 8, and 11 of
course 1 and on days 1, 4, 8, and 11 of all subsequent courses.
Treatment repeats every 21 days for 3-12 courses provided patient is receiving clinical
benefit. Patients achieving objective response may discontinue therapy to undergo stem cell
transplantation.Cohorts of 3-6 patients with receive escalating doses of 17-AAG and
bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the
dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
After the MTD is determined, an additional 20 patients (10 per stratum with AML or
follicular NHL) are enrolled and receive 17-AAG and bortezomib as above at the MTD.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) of bortezomib) in combination with 17-AAG)
Defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Ohio State University
United States: Food and Drug Administration
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