GS-US-352-0101

Sierra Oncology, Inc.

46701 Commerce Center Drive, Plymouth, MI, United States, 48170

Martha Bond, Sierra Oncology, Inc., +1 4165287431, mbond@sierraoncology.com

Martha Bond, Sierra Oncology, Inc., +1 4165287431, mbond@sierraoncology.com

No

No

No

Final

01 Jul 2019

No

Yes

02 May 2019

No

To determine the efficacy of momelotinib compared with ruxolitinib as measured by splenic response rate at Week 24 (SRR24).

The protocol, protocol amendments, consent forms, and study subject information sheets were submitted by each investigator to a duly constituted independent ethics committee (IEC) or institutional review board (IRB) for review and approval before study initiation. Protocol amendments and all revisions to the consent form or study subject information sheet after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. Study GS-US-352-0101 was conducted under a United States (US) investigational new drug (IND) application and in accordance with recognized international scientific and ethical standards, including but not limited to the International Council for Harmonisation (ICH) guideline for Good Clinical Practice (GCP) and the original principles embodied in the Declaration of Helsinki. These standards are consistent with the requirements of the US Code of Federal Regulations (CFR) Title 21, Part 312 (21CFR312), and the European Community Directive 2001/20/EC, as well as other local legislation. Investigators (or designee[s]) were responsible for obtaining written informed consent from each individual who participated in this study after adequate explanation of the aims, methods, objectives, and potential hazards of the study and before undertaking any study related procedures. Subjects were informed that they were completely free to refuse to enter the study or to withdraw from it at any time for any reason.

06 Dec 2013

Yes

Yes

Netherlands: 13

Poland: 71

Romania: 11

Spain: 20

Sweden: 16

United Kingdom: 25

Austria: 2

Belgium: 18

Bulgaria: 22

Czechia: 21

Denmark: 4

France: 24

Germany: 14

Hungary: 31

United States: 45

Canada: 13

Australia: 39

Israel: 8

Japan: 15

Singapore: 8

Korea, Republic of: 7

Taiwan: 5

432

267

0

0

0

0

0

0

185

245

2

Baseline

Not applicable

Yes

Momelotinib

Tablet

Oral use

Momelotinib was available as 100 mg, 150 mg, and 200 mg strength (as free base equivalent) tablets. In addition to the drug substance, the tablets also contained the excipients microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, silicon dioxide, magnesium stearate, propyl gallate, polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, yellow iron oxide, and red iron oxide. Momelotinib 100-mg and 150-mg tablets were plain round, film-coated brown tablets, and MMB 200-mg tablets were plain capsule-shaped, film-coated brown tablets. Momelotinib placebo tablets were visually identical to the MMB tablets but contained no active ingredient. The starting dose of MMB for all subjects was 200 mg (or placebo equivalent) in a single tablet. Momelotinib was to be orally self-administered once daily in the morning, and thereafter at approximately the same time each day. Momelotinib was not administered in the baseline period.

Ruxolitinib

Tablet

Oral use

Ruxolitinib was orally self-administered twice daily as either 1 or 2 tablets per dose. The starting dose of RUX (or placebo equivalent) was determined based on screening laboratory values. Ruxolitinib doses may have been interrupted and/or reduced sequentially due to drug-related thrombocytopenia. Following improvement of platelet count to ≥ 50 × 10^9/L in the absence of platelet transfusion for at least 5 days, RUX may have been restarted. Dose adjustments and rule for withholding RUX are discussed in further detail in the protocol. Ruxolitinib was not administered during baseline.

Double-blind Phase

Randomised - controlled

During the double-blind (DB) phase, study drug was administered in a DB fashion. The identity of the study drug was concealed by central blinding of study drug assignments. DB treatment assignments remained blinded until all subjects had completed Week 24 and the study was unblinded for the purpose of the final efficacy analysis. Blinding was accomplished through use of placebos that were well-matched to the study drugs in appearance, packaging, labeling, and schedule of administration.

Yes

Momelotinib

Tablet

Oral use

Momelotinib was available as 100 mg, 150 mg, and 200 mg strength (as free base equivalent) tablets. In addition to the drug substance, the tablets also contained the excipients microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, silicon dioxide, magnesium stearate, propyl gallate, polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, yellow iron oxide, and red iron oxide. Momelotinib 100-mg and 150-mg tablets were plain round, film-coated brown tablets, and MMB 200-mg tablets were plain capsule-shaped, film-coated brown tablets. Momelotinib placebo tablets were visually identical to the MMB tablets but contained no active ingredient. The starting dose of MMB for all subjects was 200 mg (or placebo equivalent) in a single tablet. Momelotinib was to be orally self-administered once daily in the morning, and thereafter at approximately the same time each day.

Ruxolitinib

Tablet

Oral use

Ruxolitinib was orally self-administered twice daily as either 1 or 2 tablets per dose. The starting dose of RUX (or placebo equivalent) was determined based on screening laboratory values. Ruxolitinib doses may have been interrupted and/or reduced sequentially due to drug-related thrombocytopenia. Following improvement of platelet count to ≥ 50 × 10^9/L in the absence of platelet transfusion for at least 5 days, RUX may have been restarted. Dose adjustments and rule for withholding RUX are discussed in further detail in the protocol.

Open-label Phase

Not applicable

Yes

Momelotinib

Tablet

Oral use

Momelotinib was available as 100 mg, 150 mg, and 200 mg strength (as free base equivalent) tablets. In addition to the drug substance, the tablets also contained the excipients microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, silicon dioxide, magnesium stearate, propyl gallate, polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, yellow iron oxide, and red iron oxide. Momelotinib 100-mg and 150-mg tablets were plain round, film-coated brown tablets, and MMB 200-mg tablets were plain capsule-shaped, film-coated brown tablets. Momelotinib was to be orally self-administered once daily in the morning, and thereafter at approximately the same time each day.

Momelotinib

Tablet

Oral use

Momelotinib was available as 100 mg, 150 mg, and 200 mg strength (as free base equivalent) tablets. In addition to the drug substance, the tablets also contained the excipients microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, silicon dioxide, magnesium stearate, propyl gallate, polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, yellow iron oxide, and red iron oxide. Momelotinib 100-mg and 150-mg tablets were plain round, film-coated brown tablets, and MMB 200-mg tablets were plain capsule-shaped, film-coated brown tablets. Momelotinib was to be orally self-administered once daily in the morning, and thereafter at approximately the same time each day.

Momelotinib (MMB)

Ruxolitinib (RUX)

Intent-to-Treat Analysis Set

The ITT Analysis Set included all subjects who were randomized in the study. Subjects were grouped within the ITT Analysis Set by the treatment group to which they were randomized. This is the primary analysis set for efficacy analyses and for demographic and baseline characteristics. For the secondary efficacy endpoint of TSS response rate at Week 24, the analysis was performed on subjects in the ITT Analysis Set who had a baseline TSS > 0 or who had a baseline TSS = 0 but a nonzero or missing TSS at Week 24.

Momelotinib (MMB)

Ruxolitinib (RUX)

Momelotinib (MMB)

Ruxolitinib (RUX)

MMB to MMB

RUX to MMB

Intent-to-Treat Analysis Set

The ITT Analysis Set included all subjects who were randomized in the study. Subjects were grouped within the ITT Analysis Set by the treatment group to which they were randomized. This is the primary analysis set for efficacy analyses and for demographic and baseline characteristics. For the secondary efficacy endpoint of TSS response rate at Week 24, the analysis was performed on subjects in the ITT Analysis Set who had a baseline TSS > 0 or who had a baseline TSS = 0 but a nonzero or missing TSS at Week 24.

The primary endpoint of the study, splenic response rate at Week 24, was defined as the proportion of subjects who achieved a spleen volume reduction of ≥ 35% from baseline at the Week 24 assessment as measured by MRI or CT scans. A similar proportion of subjects achieved a response in the MMB group (57 of 215 subjects, 26.5%) as in the RUX group (64 of 217 subjects, 29.5%) in the ITT population. The non-inferiority proportion difference in response rates was statistically significant by stratified CMH method (0.09 [95% CI: 0.02, 0.16]; p = 0.014). Because the lower bound of the 2-sided 95% CI was greater than 0, the MMB group met the primary endpoint of noninferiority on splenic response rate over the RUX group. An additional 101 subjects (47.0%) in the MMB group and 112 subjects (51.6%) in the RUX group achieved a reduction of spleen volume that was insufficient to meet the response definition (< 35% spleen volume reduction and not more than a 0% spleen volume increase at Week 24).

Primary

Week 24

The primary endpoint was splenic response rate at Week 24, defined as the proportion of subjects who achieved a ≥ 35% reduction in spleen volume at Week 24 versus baseline as measured by MRI or CT. The primary hypothesis is that MMB is non-inferior to RUX in splenic response rate at Week 24. Noninferiority of MMB was evaluated by comparing the difference in response rate at Week 24 (Pa − 0.60 Pc) and 0 at a 2-sided 0.05 level, using the CMH approach to adjust for the stratification factors.

Momelotinib (MMB) v Ruxolitinib (RUX)

432

Pre-specified

0.09

2-sided

Response rate in TSS, a prespecified secondary endpoint, was defined as the proportion of subjects who achieved a ≥ 50% reduction in TSS at Week 24 versus baseline as measured by the modified MPN-SAF TSS v2.0 diary. Response rate was calculated using the average of the daily TSS from a consecutive 28-day period prior to Week 24, which had ≥ 20 daily TSS available. Response rate was evaluated for subjects in the ITT analysis set who had a baseline TSS > 0 or had a baseline TSS = 0 but nonzero or missing TSS at Week 24. In the MMB group, 60 (28.4%) of the 211 subjects at Week 24 had a TSS reduction of ≥ 50% from baseline compared to 89 (42.2%) of the 211 evaluable subjects in the RUX group. The noninferior proportion difference by stratified CMH method (95% CI) was 0.00 (-0.08, 0.08); this difference was not statistically significant (p = 0.98). Because the lower bound of the 2-sided 95% CI was not greater than 0, noninferiority of the MMB group to the RUX group was not met.

Secondary

Week 24

Response rate in TSS from baseline to Week 24 is defined as the proportion of subjects who achieved a ≥ 50% reduction from baseline in TSS at Week 24 as measured by the modified MPN SAF TSS v2.0 diary. Noninferiority of MMB was evaluated by comparing the difference in response rate of total symptom score at Week 24 (Pa − 0.67 Pc) and 0 at a 2-sided 0.05 level, using the CMH approach to adjust for the stratification factors.

Ruxolitinib (RUX) v Momelotinib (MMB)

422

Pre-specified

0

2-sided

The rate of RBC transfusions in the double-blind phase was a prespecified secondary endpoint, defined as the average number of RBC units transfused not associated with clinically overt bleeding per subject-month during the double-blind phase. For the ITT analysis set, the rate of RBC transfusion was nominally significantly lower in the MMB group with transfusion rate ratio of 0.28 (95% CI=0.19 to 0.43) and p-value < 0.001 per negative binomial model adjusted for strata. The median (Q1, Q3) rate of RBC transfusion was lower in the MMB group (0.0 [0.0, 0.2] units/month) compared with the RUX group (0.4 [0.0, 1.5] units/month) through Week 24. The median (Q1, Q3) total number of RBC transfusion units in the double-blind phase was lower in the MMB group (0.0 [0.0, 1.0]) compared with the RUX group (2.0 [0.0, 8.0]).

Secondary

Baseline to Week 24

Rate of RBC transfusion in the RT phase is defined as the average number of RBC units transfused that was not associated with clinically overt bleeding per subject month during the double-blind phase

Momelotinib (MMB) v Ruxolitinib (RUX)

432

Pre-specified

0.28

2-sided

Transfusion independent response at Week 24 was defined as the absence of RBC transfusion and no hemoglobin level < 8 g/dL in the 12 weeks prior to Week 24, excluding cases associated with clinically overt bleeding. A greater proportion of subjects in the MMB group was TI at Week 24: 66.5% (143 subjects) compared with the RUX group 49.3% (107 subjects). The difference was nominally statistically significant (p < 0.001).

Secondary

Week 24

Response rate for TI at Week 24 is defined as the proportion of subjects who were TI at Week 24, where TI was defined as absence of RBC transfusion and no hemoglobin level below 8 g/dL in the prior 12 weeks, excluding cases associated with clinically overt bleeding.

Momelotinib (MMB) v Ruxolitinib (RUX)

432

Pre-specified

0.18

2-sided

Red blood cell TD rate at Week 24 for the ITT population was a prespecified secondary endpoint, defined as having had at least 4 units of RBC transfusion or a hemoglobin level below 8 g/dL in the prior 8 weeks ending with Week 24 (excluding cases associated with clinically overt bleeding). Subjects with the last double-blind phase participation date prior to Day 162 (ie. missing at Week 24) were considered TD at Week 24. A smaller proportion of subjects in the MMB group were TD at Week 24 (30.2%, 65 subjects) compared with the RUX group (40.1%, 87 subjects). The difference was nominally statistically significant (p = 0.019).

Secondary

Week 24

Momelotinib (MMB) v Ruxolitinib (RUX)

432

Pre-specified

-0.1

2-sided

Adverse events were recorded that occurred from initiation of investigational product (IP) until 30 days after the last administration of IP regardless of cause or relationship.

All adverse events were recorded in the eCRF database. Serious adverse events needed to be reported within 24 hours of investigator being aware. Severity of AEs were graded using the CTCAE, Version 4.03, per AE (episode) the highest severity grade attained should be reported. All AEs were followed up until resolution when possible.

22.0

Momelotinib (MMB)

Ruxolitinib (RUX)

MMB to MMB

RUX to MMB