1) Subcutaneous omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia
(CML) patients (Pts) with the T315I mutation: Data from an ongoing phase II/III trial.
2009 ASCO Annual Meeting
Abstract No:
7008
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 7008)
Author(s):
J. E. Cortes, H. J. Khoury, S. Corm, F. Nicolini, T. Schenk, D. Jones, A. Hochhaus, A. R. Craig, E. Humphriss, H.
Kantarjian, Omacetaxine 202 Study Group; UT M. D. Anderson Cancer Center, Houston, TX; Emory University,
Atlanta, GA; CHU Lille, Lille, France; Hôpital Edouard Herriot, Lyon, France; Universtatsmedizin Mannheim,
Mannheim, Germany; ChemGenex Pharmaceuticals, Menlo Park, CA
Abstract:
Background: Omacetaxine (OM), a first-in-class cetaxine shows clinical activity against Ph+ CML with a
mechanism independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have
no activity against T315I. Methods: Adult Pts with T315I+ CML following TKI failure received OM induction at
1.25 mg/m2 subcutaneous (SC) twice daily (BID) for 14 days every 28 days followed by maintenance at 1.25
mg/m2 SC BID for 7 days every 28 days (maintenance after at least one induction cycle and achievement of
hematologic response). Results: 66 pts (39 chronic [CP], 16 accelerated [AP] and 11 blast phase [BP]) have
been enrolled. All had failed prior imatinib and 80% failed ≥2 prior TKIs. Median age is 58 yrs. Median disease
duration is 58 mos. OM is well tolerated with transient myelosuppression as the primary toxicity. Grade 3/4 non-
hematologic events are diarrhea (2%) and fatigue (4%). Efficacy data are available for 44 Pts. In CP Pts, the
median number of cycles is 4 (1-22) with 39% having received ≥ 6 cycles of therapy; 64% of Pts have had the
T315I clone reduced to below detection limits; the 2-year progression free survival is 70%. Conclusions:
Omacetaxine in T315I+ CML Pts results in de-selection of the T315I clone and induces hematologic and
cytogenetic responses.
________________________________________
Hematologic and Cytogenetic Responses
________________________________________
Response; Median Duration Number (%); Median in Mos
________________________________________
CP N=25 AP N=11 BP N=8
________________________________________
Hematologic - Overall 20 (80) 4 (36) 1 (13)
CHR 20 (80);11.5+ 2 (18);9.6+ -
RCP NA 2 (18);2.0+ 1 (13);3.4
Cytogenetic - Overall 7 (28) 1 (9) -
Major 5 (20) - -
Complete 4 (16);4.8+ - -
Partial 1 (4);4.2 - -
Minor 2 (8);4.0+ 1 (9);2.3
________________________________________
Hematologic and Cytogenetic Responses
________________________________________
Response; Median Duration Number (%); Median in Mos
________________________________________
CP N=25 AP N=11 BP N=8
________________________________________
Hematologic - Overall 20 (80) 4 (36) 1 (13)
CHR 20 (80);11.5+ 2 (18);9.6+ -
RCP NA 2 (18);2.0+ 1 (13);3.4
Cytogenetic - Overall 7 (28) 1 (9) -
Major 5 (20) - -
Complete 4 (16);4.8+ - -
Partial 1 (4);4.2 - -
Minor 2 (8);4.0+ 1 (9);2.3
________________________________________
2) Nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP) with imatinib (IM)
resistance or intolerance: Longer follow-up results of a phase II study.
Meeting:
2009 ASCO Annual Meeting
Abstract No:
7029
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 7029)
Author(s):
H. Kantarjian, F. Giles, K. Bhalla, J. Pinilla, R. A. Larson, N. Gattermann, O. G. Ottmann, N. J. Gallagher, M.
Baccarani, P. leCoutre; University of Texas M. D. Anderson Cancer Center, Houston, TX; Institute for Drug
Development, CTRC, San Antonio, TX; Medical College of Georgia Cancer Center, Augusta, GA; H. Lee Moffitt
Cancer Center & Research Institute, Tampa, FL; University of Chicago, Chicago, IL; Heinrich-Heine University,
Düsseldorf, Germany; University Hospital of Frankfurt, Frankfurt, Germany; Novartis Pharma AG, Basel,
Switzerland; University of Bologna, Bologna, Italy; Charité - Humboldt-Universitat, Campus Virchow, Berlin,
Germany
Abstract:
Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML
patients (pts) in CP or accelerated phase who are resistant or intolerant to prior therapy including IM. This study
evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-CP pts resistant or intolerant to IM. Methods:
Primary endpoint was major cytogenetic response (MCyR). Secondary endpoints included complete cytogenetic
response (CCyR), complete hematological response (CHR), MCyR duration, overall survival (OS), and safety.
Results: CML-CP pts (n = 321, 70% IM-resistant, 30% IM-intolerant with resistance) with a minimum follow-up of
19 months (mos) were evaluated; 72% were treated with ≥600 mg/day IM prior to enrollment. Median duration of
prior IM treatment was 32 (<1-94) mos. Median dose intensity of nilotinib (790 mg/day; range 151-1,110 mg/day)
closely approximated the planned dose. Nilotinib led to rapid and durable CHR and MCyR. CHR was observed in
94% of pts. 59% achieved an MCyR (2.8 mos median time to MCyR; 56% in IM-resistant, and 65% in IM-
intolerant pts), including 73% of pts with a baseline CHR and 44% achieved a CCyR (41% in IM-resistant; 51% in
IM-intolerant pts). Responses were durable, with 78% pts maintaining MCyR at 24 mos. Estimated OS rate was
88% at 24 mos. Safety profile did not change with longer follow-up. Most frequent grade (gr) 3/4 biochemical
laboratory abnormalities were elevated lipase (17%), hypophosphataemia (16%), hyperglycemia (12%), and
total bilirubin (8%) which were transient and clinically asymptomatic. Gr 3/4 non-hematologic AEs were
infrequent: rash, headache, and diarrhea occurred in 2% of pts. Most common gr 3/4 hematological laboratory
abnormalities were neutropenia (31%), thrombocytopenia (31%), and anemia (10%). Brief dose interruptions
were successful in management of most AEs. Pleural or pericardial effusions (gr 3/4) were uncommon (< 1%).
Conclusions: These results demonstrate that nilotinib was highly effective, with rapid and durable responses in
CML-CP pts failing prior therapy due to resistance or intolerance. Nilotinib was well tolerated with favorable
risk/benefit.
3) Effect of the proton pump inhibitor esomeprazole on the oral absorption and
pharmacokinetics of nilotinib.
Sub-category:
Leukemia
Category:
Leukemia, Myelodysplasia, and Transplantation
Meeting:
2009 ASCO Annual Meeting
Abstract No:
7053
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 7053)
Author(s):
N. J. Gallagher, D. Fischer, E. Demirhan, W. Zhou, G. Golor, H. Schran, O. Yin; Novartis Pharma AG, Basel,
Switzerland; Novartis, Florham Park, NJ; Novartis, East Hanover, NJ; Parexel International GmbH, Berlin,
Germany
Abstract:
Background: Nilotinib, a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the
treatment of CML-CP and CML-AP patients resistant or intolerant to prior therapy including imatinib. The
solubility of nilotinib is pH dependent, with lower solubility at higher pH. We evaluated whether esomeprazole, a
potent proton pump inhibitor (PPI) that can significantly increase gastric pH, could affect the oral absorption and
pharmacokinetics of nilotinib in healthy subjects. Methods: Twenty-two subjects (6 F, 16M, age range 18-64
years) were enrolled to receive nilotinib alone or in the presence of steady-state esomeprazole during two
treatment periods. Nilotinib was given as a single oral 400 mg dose on days 1 and 13, and esomeprazole 40 mg
once-daily on day 8 through day 13. Serial blood samples were collected up to 72 hours after nilotinib dosing for
determination of nilotinib serum concentrations by a validated liquid chromatography-tandem mass spectrometry
assay. Gastric pH was monitored in all subjects at baseline (prior to nilotinib and esomeprazole dosing), before
and during the first 4 hrs of esomeprazole steady state dosing (fifth dose on Day 12). Results: When
coadministered with esomeprazole, nilotinib Cmax was decreased by 27% (397±89 vs 303±157ng/mL) and
AUC0-∞ decreased by 34% (11515±6140 vs 7164±3752ng*hr/mL) respectively. The median time to reach
nilotinib Cmax was slightly prolonged from 4.0 hrs to 6.0 hrs, but its elimination half-life was not altered (17.3±10.
7 vs 15.9±6.6 hrs). Median gastric pH was increased from 0.8 at baseline to 2.0 at pre-dose, and to 3.9, 5.8,
5.5, and 5.7 at 1, 2, 3, and 4 hrs after esomeprazole dosing. Administration of nilotinib alone or in combination
with esomeprazole was generally well tolerated in the study subjects. Conclusions: The study results
demonstrate a modest reduction in the rate and extent of nilotinib absorption when co-administered with
esomeprazole. Such an effect is unlikely to cause a significant clinical consequence for nilotinib therapy, and
thus nilotinib can be used with esomeprazole or other PPIs without the risk of substantial decrease in nilotinib
systemic exposure.
4) Inference of imatinib (IM) effects on leukemic stem cell (SC) compartment via mathematical
modeling of IRIS treatment response data.
Sub-category:
Leukemia
Category:
Leukemia, Myelodysplasia, and Transplantation
Meeting:
2009 ASCO Annual Meeting
Abstract No:
7056
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 7056)
Author(s):
D. Bottino, Y. Chia, A. Stein, A. Georgieva, J. Yu, J. Kahn, G. Helmlinger, T. Kalebic; Novartis Pharmaceuticals,
East Hanover, NJ; University of Minnesota, Minneapolis, MN; Novartis Pharmaceuticals, Cambridge, MA; Novartis
Pharmaceuticals, Florham Park, NJ
Abstract:
Background: Continuous treatment of chronic phase CML (CML-CP) patients with imatinib (IM) induces durable
responses in majority of patients with a decreasing rate of relapse (Hochhaus et al, Blood. 2007;110). We
present a mechanistic mathematical model which uses 6-year follow up data from the International Randomized
Study of Interferon Versus STI571 (IRIS) trial (O'Brien et al, N Engl J Med. 2003;348:994) to explore IM effects
on leukemic stem cells (SCs) across the patient population. Methods: The model approximates hemopoiesis as
a 4-stage process in which only the first stage, corresponding to the SC compartment, is capable of self-
renewal. Leukemic SCs, early and late progenitors were assumed to have higher self-renewal and
expansion/differentiation rates than their normal counterparts. Model parameters describing the patient
population distributions of leukemic/total SC ratio at diagnosis and sensitivity of leukemic cells to IM, were then
fitted to individual cytogenetic and molecular response (CR/MR) data from 200 randomly selected newly-
diagnosed CML-CP patients with 6-year follow-up. Results: Based on our analysis, successful characterization
of the wide range of clinically observed treatment responses requires the inhibition of the leukemic SC
compartment by IM. The median predicted inhibition of the leukemic SC proliferation rate was 79%. The model
further predicted that after 6 years of IM treatment, 45% of patients would achieve a leukemic/total SC ratio
below 0.1. Conclusions: We have developed a mathematical model of IM effects on CML-CP based on 6-year
CR and MR data from the IRIS trial. In contrast to prior reports (Michor et al, Nature. 2005;435), our modeling
predicts that IM reduces the leukemic SC compartment in most CML-CP patients, which could provide a
mechanistic rationale for the decreasing rate of relapse observed in the study population.
5) Effect of nilotinib on the pharmacokinetics and pharmacodynamics of warfarin.
2009 ASCO Annual Meeting
Abstract No:
7063
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 7063)
Author(s):
O. Yin, N. J. Gallagher, D. Fischer, L. Zhao, W. Zhou, G. Golor, H. Schran; Novartis Pharmaceuticals
Corporation, Florham Park, NJ; Novartis Pharma AG, Basel, Switzerland; Novartis Pharmaceuticals Corporation,
East Hanover, NJ; Parexel International GmbH, Berlin, Germany
Abstract:
Background: Nilotinib, a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the
treatment of CML-CP and CML-AP in patients resistant or intolerant to prior therapy including imatinib. Nilotinib
has shown competitive inhibition of CYP2C9 in vitro, but its effect on CYP2C9 activity in human is unknown. This
study evaluated the effects of nilotinib on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin, a
sensitive CYP2C9 substrate, in healthy subjects. Methods: Twenty-four subjects (6F, 18M, age 21-65 years)
were enrolled to receive a single oral 25 mg warfarin with either 800 mg nilotinib or matching placebo
(administered 30 minutes after consumption of a high-fat meal) in a cross-over design. Serial blood samples
were collected post-dose for determining nilotinib, S- and R-warfarin concentrations. Prothrombin time (PT) and
international normalized ratio (INR) were determined as PD measures for warfarin. CYP2C9 genotyping was
performed in all subjects using TaqMan assay. Results: Sixteen subjects were identified as CYP2C9 extensive
metabolizers (EM) and 8 as intermediate metabolizers (IM), but none was poor metabolizer. PK parameters of S-
and R-warfarin were found to be similar between two treatments (warfarin + nilotinib versus warfarin alone) for
both EM and IM groups. The geometric mean ratios (90% CIs) for the Cmax and AUC0-∞ of S-warfarin in all
subjects were 0.98 (0.95-1.02) and 1.03 (0.99-1.07), respectively, and for R-warfarin were 1.00 (0.96-1.04) and
1.02 (0.99-1.06) respectively. Mean ratios for the maximum value and AUC of PT were 1.00 (0.96-1.04) and
1.00 (0.98-1.02), respectively, and for INR were 1.00 (0.97-1.01) and 1.00 (0.99-1.01), respectively. Nilotinib
Cmax was 1872±560 ng/mL, which is comparable to the mean steady-state Cmax in CML and GIST patients
receiving 400 mg BID doses. Adverse effects observed following either treatment were generally consistent with
the known safety profiles of both drugs, and there were no new safety issues observed. Conclusion: The study
results demonstrate a lack of effect of nilotinib on the PK and PD of warfarin, suggesting nilotinib does not inhibit
CYP2C9 activity in human subjects. These findings suggest that warfarin can be used with nilotinib concurrently
without the risk of bleeding.
7) Imatinib mesylate experience of young patients with chronic myeloid leukemia in chronic
phase—Care to cure.
2009 ASCO Annual Meeting
Abstract No:
7072
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 7072)
Author(s):
D. Biswajit, R. Rejiv, N. Manjunath, G. Prasad, S. Lakshmi, P. Devika, K. Geetha, T. G. Sagar; Cancer Institute
(WIA), Chennai, India
Abstract:
Background: Chronic myeloid leukemia (CML) with introduction of imatinib has been transformed into a chronic
illness. The options of treatment in a patient less than 35 years include imatinib or allogenic stem cell
transplantation. Hence we studied this unique subset to look at the response rates, adverse effects, progression
free survival, and overall survival with imatinib mesylate. Methods: 477 patients with Philadelphia positive CML in
chronic phase were retrospectively analyzed from January 2002 to December 2007 at Cancer Institute (WIA),
Chennai, India. Standard criteria were used for response evaluation and adverse effects. Results: A total of 248
young CML patients with age less than 35 years (51.9%) were diagnosed in chronic phase. The median age of
study population was 27 years (4-35). The male to female ratio was 1.9: 1. Risk stratification was done using
Sokal index and were classified into low (32.3%), intermediate (50.4%), and high (17.3%). All patients received
imatinib 400 mg as the initial dose. Complete hematological remission (CHR) was seen in 96.7%.Cytogenetic
(FISH) and molecular (RTPCR) monitoring was possible in 53.2% and 17.3%, respectively. 72% of the patients
had major cytogenetic response. Major molecular response was seen in 34.8% while complete molecular
response occurred in 23.2% of the patients. Primary and secondary imatinib failure was seen in 3.1% and
16.9%, respectively. 6.7% had grade 3 and grade 4 hematological toxicities. The other common non
hematological toxicities included pedal edema (13.7%), hypo or hyper pigmentation (60.0%), hyalgia (14.5%),
diarrhea (1.6%), and liver dysfunction (1.6%). None of the patients discontinued imatinib due to toxicities. The 3-
year DFS and OS was 86.2% and 89.5%, respectively. Patients with male sex (p = 0.04), spleen > 8 cm (p =
0.02), high sokal index (p = 0.02), and loss of CHR (p < 0.001) were associated with poor outcome. Conclusions:
Imatinib in young patients have an excellent tolerance and response. A small subset does not respond to
therapy or develop resistance during treatment. Hence it is essential to identify these poor responders and to
offer stem cell transplantation at the earliest.