MYELOPROLIFERATIVE SYNDROMES: MYELOPROLIFERATIVE NEOPLASMS - CLINICAL FEATURES AND THERAPEUTICS
A Phase I Evaluation of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis: Clinical Response Is Accompanied by Significant Reduction in JAK2V617F Allele Burden.
Animesh D. Pardanani, MBBS, PhD1,
Jason R Gotlib, MD, MS*,2,
Catriona Jamieson, MD, PhD3,
Jorge Cortes, MD4,
Moshe Talpaz, MD5,
Richard Stone, MD*,6,
Michael H Silverman, MD, FACP*,7,
D. Gary Gilliland, MD, PhD9 and
Ayalew Tefferi, MD1
1 Hematology, Mayo Clinic, Rochester, MN, USA, 2 Stanford University, Palo Alto, CA, USA, 3 Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA, 4 Leukemia Dept., The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, 5 Comprehensive Cancer Ctr., University of Michigan, Ann Arbor, MI, USA, 6 Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA, 7 Biostrategics Consulting Ltd., Marblehead, MA, 8 TargeGen Inc., San Diego, CA, USA, 9 Merck Research Laboratories, Boston, MA, USA
Background: TG101348 is a potent, orally bioavailable, JAK2-selective smallmolecule inhibitor, that is currently being evaluated in a PhaseI study for the treatment of myelofibrosis. Data from the doseescalation cohort (n=28; 30-800mg administered as a single dailydose) showed dose-linear plasma exposure, with mean eliminationT1/2 at steady state ranging from 20 to 52 hours. The dose-limitingtoxicity was asymptomatic grade 3 or 4 amylasemia/lipasemiathat was reversible, and the maximum tolerated dose (MTD) was680mg. The most frequent non-hematological toxicities were mildnausea, vomiting, and/or diarrhea that were easily controlledor resolved spontaneously. Grade 3/4 neutropenia and thrombocytopeniawere observed in 14% and 25% of patients, respectively. TG101348 had activity in reducing spleen size, leukocyte count, andJAK2V617F (VF) allele burden. Here, we present updated resultswith a focus on data from the dose confirmation cohort who initiatedtreatment at a dose of 680mg/day.
Results: Fifty nine patients (median age=66 years; range 43-86) havebeen treated – 28 in the dose escalation phase, and 31in the dose confirmation phase. Overall, 44 patients had PMF,12 post-PV MF, and 3 post-ET MF; 86% were VF-positive. Medianpalpable spleen size was 18cm and 22 patients were RBC transfusion-requiringat study enrollment. After a median follow-up of 12 weeks (range<1-76), 18 (31%) patients have discontinued treatment dueto toxicity (n=7; thrombocytopenia=3, neutropenia=1), comorbidities(n=5), withdrawal of consent (n=4), or non-compliance/lack ofresponse (1 each). The remaining 41 patients are currently atthe following dose levels: 680mg (n=14), 520-600mg (n=16), 360-440mg(n=10), and 240mg (n=1). The cumulative drug exposure to dateis 362 patient-months; exposure at or above MTD (680mg) is 154patient-months. Forty patients (68%) started treatment at 680mg.
Toxicity: TG101348 is well tolerated. Of the patients who started at 680mg,Gr3/4 neutropenia was observed in 15/0% and Gr3/4 thrombocytopeniain 20/10%. Twenty four (60%) patients did not require RBC transfusionsat baseline (median Hgb=9.6g/dL; range 7.4-13.1); of these,42% and 8% of patients developed Gr3 and Gr4 anemia, respectively.The majority of patients who started at 680mg developed mildnausea (1 Gr3), vomiting (1 Gr3), and/or diarrhea (3 Gr3) thatwere self-limited or easily controlled. Other non-hematologicaltoxicities included Gr1/2 transaminitis (38%), Gr1/2 serum creatinineelevation (38%), and asymptomatic hyperlipasemia (33%).
Efficacy: Thirty three patients who started at 680mg have completed atleast 3 cycles of treatment; at 3 months, reduction in palpablespleen size (baseline median=18cms; range 6-32) was at least50% in 22 (67%) patients; the spleen became non-palpable in9 (27%) patients. All 21 patients with leukocytosis at baseline(WBC range 11 to 203 x109/L) who started at 680mg have experienceda marked reduction in their WBC count (range 4 to 90); 70% hada normal WBC count at their last follow-up visit. Overall, 48of the 51 VF-positive patients completed at least 1 cycle andwere evaluable for response in VF allele burden; at last availablefollow-up, the median decrease in granulocyte mutant alleleburden was 48%; 21 (44%) patients have had a 50% reduction,and in the group who started treatment at 680mg, 48% have hada 50% reduction. Of those evaluable, there was clinically significantbenefit or resolution of constitutional symptoms, includingearly satiety, fatigue, cough, pruritus, and night sweats.
Conclusions: TG101348 continues to be well tolerated in patients with myelofibrosis.Spleen and leukocyte responses are frequent, observed early,and produce substantial clinical benefit for patients. Theseresponses are associated with significant decrease in VF alleleburden and point to activity of TG101348 against the malignantclone in myelofibrosis.
Disclosures:Pardanani:TargeGen: Research Funding; Cytopia: Research Funding.Off Label Use: Data from ongoing clinical trial will be presented.Gotlib:TargeGen: Research Funding. Jamieson:Merck: ResearchFunding; Pfizer: Research Funding; Wintherix: Consultancy; TargeGen:Research Funding; Celgene: Research Funding. Cortes:Targegen:Research Funding. Stone:Cephalon: ad hoc advisory board. Silverman:TargeGen: Consultancy. Shorr:TargeGen: Employment, Equity Ownership.Gilliland:Merck: Employment. Tefferi:TargeGen: Research Funding.
* Asterisk with author names denotes non-ASH members.