Abstract

Background

Momelotinib (MMB, previously CYT387) is a selective small molecule inhibitor of JAK 1 and JAK 2 currently under investigation for the treatment of myelofibrosis (MF). Study CCL09101 is a Phase I/II, open-label, dose-escalation study of oral MMB in MF subjects. Following an initial dose escalation phase, subjects were assigned to 150 mg once-daily (QD), 300 mg QD or 150 mg twice-daily (BID) MMB capsules, in a 9 month (mos) dose expansion phase. The safety and tolerability of MMB, based on assigned dose, was previously reported with a maximum tolerated dose of 300 mg QD and dose limiting toxicities of elevated lipase and headache at 400 mg QD. Clinical efficacy included spleen response rate of 37% based on IWG criteria and suggested improvement in anemia related endpoints. As the study allowed intra-subject dose adjustments for tolerability, additional analyses based on average daily dose administered were performed. In a subset of patients, pharmacokinetics (PK) was assessed.

Methods

Dose-efficacy analyses were conducted using the average daily dose received over 6 mos for spleen response and 9 mos for transfusion (txn) independence response. Subjects were grouped based on tertiles of average daily dose < 200 mg, 200 to < 300 mg, > 300 mg. Spleen response at 6 mos required a ≥ 50% reduction in palpable splenomegaly. Txn response required maintaining transfusion independence for ≥12 weeks (wks) for subjects who were txn dependent at baseline and completed ≥ 12 wks on study.

The incidence of hgb and platelet (plt) decline was also analyzed as a function of average daily dose received over 6 mos. Subjects evaluated for hgb decline were txn independent with hgb ≥ 8 g/dL at baseline. Hgb decline was defined as the incidence of hgb < 8 g/dL and at least a 1 g/dL decrease compared to baseline. Subjects evaluated for plt decline had baseline platelet count ≥ 100 x 109/L. Plt count decline was defined as the incidence of plt count < 100 x 109 /L and ≥ 50 x 109/L decrease compared to baseline at any point during the 6 mos. In the PK subset, dose-exposure relationship was explored.

Results

Spleen response rates were comparable across MMB average daily dose tertiles, indicating a relatively flat dose-efficacy relationship. A trend towards a higher txn response was observed at the highest MMB average daily dose. No dose dependent increase in hgb or plt decline was noted across average daily dose tertiles. 60 subjects (41%) reported peripheral neuropathy as an adverse event during the 9 mos study; 92% grade 1, 8% grade 2. Incidence was comparable across average daily dose tertiles (see table).

MMB Average Daily Dose (mg/day)< 200200 to < 300≥ 300
Spleen response, % at 6 mos (n = 148; spleen > 5 cm at baseline) 30% (14/47) 28% (12/43) 31% (18/58) 
Transfusion response, % over 9 mos (n = 68; transfusion dependent at baseline and completed 12 wks) 41% (9/22) 63% (20/32) 86% (12/14) 
Hgb < 8 g/dL and ≥ 1 g/dL decline compared to baseline, % over 6 mos (n = 93; transfusion independent and hgb ≥ 8 g/dL at baseline) 17% (4/24) 7% (2/27) 2% (1/42) 
Plt count < 100 x 109/L and ≥ 50 x 109/L decline compared to baseline, % over 6 mos (n = 126; plt ≥ 100 x 109/L at baseline) 28% (11/40) 28% (11/40) 13% (6/46) 
Neuropathy, % over 9 mos (n = 166)    
Grade 1 22% (9/41) 40% (32/81) 32% (14/44) 
Grade 2 2% (1/41) 4% (3/81) 2% (1/44) 
MMB Average Daily Dose (mg/day)< 200200 to < 300≥ 300
Spleen response, % at 6 mos (n = 148; spleen > 5 cm at baseline) 30% (14/47) 28% (12/43) 31% (18/58) 
Transfusion response, % over 9 mos (n = 68; transfusion dependent at baseline and completed 12 wks) 41% (9/22) 63% (20/32) 86% (12/14) 
Hgb < 8 g/dL and ≥ 1 g/dL decline compared to baseline, % over 6 mos (n = 93; transfusion independent and hgb ≥ 8 g/dL at baseline) 17% (4/24) 7% (2/27) 2% (1/42) 
Plt count < 100 x 109/L and ≥ 50 x 109/L decline compared to baseline, % over 6 mos (n = 126; plt ≥ 100 x 109/L at baseline) 28% (11/40) 28% (11/40) 13% (6/46) 
Neuropathy, % over 9 mos (n = 166)    
Grade 1 22% (9/41) 40% (32/81) 32% (14/44) 
Grade 2 2% (1/41) 4% (3/81) 2% (1/44) 

In the PK subset of subjects, MMB exposures were generally dose proportional between 150 mg QD and 300 mg QD (mean AUCtau: 2114 and 4424 h×ng/ml, respectively; steady state Cmax: 339 and 660 ng/ml, respectively) with limited data from the other dose levels (n ≤ 5).

Of subjects receiving 300 mg total daily starting dose, > 60% of subjects maintained this dose level throughout the study; > 75% of subjects had an average daily dose of ∼250 mg to 280 mg (following 300 mg QD or 150 mg BID dosing, respectively), and the median average daily dose was 300 mg, suggesting 300 mg QD was well tolerated.

Conclusion

No relationships were observed between average daily doses of MMB vs clinically relevant endpoints of spleen response rate or plt count decline compared to baseline. There was a suggested trend, albeit with limited sample size, towards improved anemia-related endpoints at MMB dose ≥ 300 mg QD. Analyses suggest no need to adjust dose based on baseline plt count. In conjunction with the previously reported primary endpoints of safety and efficacy, these analyses support selection of the 300 mg QD capsule formulation as the starting dose for all subjects in the planned Phase 3 study.

Disclosures:

Xin:Gilead Sciences: Employment, Equity Ownership. Shao:Gilead Sciences: Employment, Equity Ownership. Deng:Gilead Sciences: Employment, Equity Ownership. Niforos:Gilead Sciences: Employment. Kowalski:Gilead Sciences: Employment. Bavisotto:YM Biosciences: Consultancy. Kawashima:Gilead Sciences: Employment. Jun:Gilead Sciences: Employment. Collins:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

Author notes

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Asterisk with author names denotes non-ASH members.