[111] A Phase I, Multi-Center,
Dose Escalation Study of Atiprimod in Patients with
Refractory or Relapsed Multiple Myeloma (MM).
Session Type: Oral Session
Michael Wang, Moshe Talpaz, Sundar Jagannath,
Asher Alban Chanan-Khan, Raymond Alexanian,
Donna M. Weber, Maria Gavino, Zeev Estrov,
Pamela J. Harris, Donald Picker,
Robert L. Schlossman, Pierfrancesco Tassone,
Kenneth C. Anderson, Nikhil C. Munshi
Lymphoma/Myeloma, U.T. M.D. Anderson Cancer Center, Houston, TX;
Myeloma, Sant Vincent's Comprehensive Cancer Center,
New York, NY; Hematologic Malignancies,
Roswell Park Cancer Institute, Buffalo, NY;
Callisto Pharmaceuticals, New York, NY; Medical
Oncology, Dana Farber Cancer Institute, Boston, MA
Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4,5]
decane-2-propanamine) is an orally bioavailable cationic amphilic compound that inhibited STAT 3 activation in MM cells.
It effectively blocked the signaling pathway of
interleukin-6, resulting in activation of caspase 3 and
apoptosis (Amit-Vazina et al, Br J Cancer, 2005).
Atiprimod has also induced cytotoxicity in
dexamethasone, doxorubicin, and melphalan resistant
MM cell lines (Hamasaki et al, Blood, 2005).
Based on these encouraging in vitro data, we initiated a
multi-center, phase I trial of atiprimod for patients (pts)
with refractory or relapsed MM who had 2 prior lines of
therapy and serum creatinine less than 2 mg/dl.
Primary objectives were to evaluate the safety of atiprimod
in MM pts and to identify the maximum tolerated dose (MTD).
Each cycle of treatment consisted of 14 consecutive days of
oral atiprimod followed by 14 consecutive days
without treatment.
A standard phase I dose escalation was used to determine MTD
with atiprimod dose levels
at 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg.
To date, 14 pts from 4 centers have been enrolled with evaluable data in 12 patients.
Median age was 60 (range 44-64);
median prior lines of therapy were 4 (range 3-7);
median duration from initial treatment to registration to this trial was 36 months (range 19-76).
Cohorts of 3 patients have been treated at
30, 60, 90,120 mg/day
and 2 patients have been enrolled at the 180 mg/day level;
no cohorts have been expanded because of dose-limiting toxicity.
Median number of cycles received by MM pts was 2 (range 1-5).
Common Grade 1 toxicity events included diarrhea, liver enzyme elevation and dyspepsia.
There were two Grade 2 toxicity events with 1 neutropenia
at the 90 mg/day level and 1 diarrhea at the 120 mg/day level.
One pt had Grade 3 transaminase elevation (peak AST 402,
ALT 469 units/L, bilirubin 0.5 mg/dl) during the second cycle
that resolved on its own during the 14 day period off treatment.
Two patients with rapidly rising serum M proteins prior to
enrollment had a transient but clear reduction of their M proteins (30% and 80%) after the first 14 days of atiprimod.
Two pts at higher dose levels noted subjective improvement
in their bone pain.
Atiprimod was generally well tolerated in this heavily treated group of MM pts.
The MTD has not been reached.
Although there has been no response to date,
clinical activity is not expected until higher dose levels are evaluated (240 mg/day, 300 mg/day, and 360 mg/day).
After the MTD has been established, the study of atiprimod
combinations should be considered based on the in vitro assessment of synergy with other active agents.
Abstract #111 appears in Blood, Volume 106, issue 11, November 16, 2005
Keywords: Multiple myeloma|Atiprimod|Phase I
Sunday, December 11, 2005 5:00 PM
Simultaneous Session: Multiple Myeloma: Novel Therapeutic Approaches
(4:30 PM-6:00 PM) |
