GS-US-352-1214

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

25 Jun 2019

No

Yes

25 Apr 2019

No

To determine the efficacy of momelotinib (MMB) versus best available therapy (BAT) in anemic or thrombocytopenic subjects with primary myelofibrosis (PMF), or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (Post-PV/EF MF) who were treated 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-352-1214 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.

19 Jun 2014

Yes

Yes

Spain: 16

United Kingdom: 10

France: 23

Germany: 16

Italy: 29

Canada: 10

United States: 33

Israel: 19

156

84

0

0

0

0

0

0

55

101

0

Baseline

Not applicable

Yes

Momelotinib

Tablet

Oral use

Subjects self-administered MMB tablets at 100 mg, 150 mg or 200 mg orally once daily.

No investigational medicinal product assigned in this arm

Randomized Treatment Phase

Randomised - controlled

Yes

Momelotinib

Tablet

Oral use

Subjects self-administered MMB tablets at 100 mg, 150 mg or 200 mg orally once daily.

Best Available Therapy

Tablet

Oral use

The reference therapy in this study was BAT. Regimens for BAT could include but were not limited to chemotherapy (eg, hydroxyurea), anagrelide, a corticosteroid, hematopoietic growth factor, an immunomodulating agent, androgen, or interferon and may include no MF treatment, as well as more than 1 treatment.

Extension Treatment Phase

Not applicable

Yes

Momelotinib

Tablet

Oral use

Subjects self-administered MMB tablets at 100 mg, 150 mg or 200 mg orally once daily.

Momelotinib

Tablet

Oral use

Subjects self-administered MMB tablets at 100 mg, 150 mg or 200 mg orally once daily.

Momelotinib (MMB)

Best Available Therapy (BAT)

Intent-to-Treat Analysis Set

For the RT phase, the ITT Analysis Set included all subjects who were randomized in the study. Subjects were grouped within the ITT 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)

Best Available Therapy (BAT)

Momelotinib (MMB)

Best Available Therapy (BAT)

MMB to MMB

BAT to MMB

Intent-to-Treat Analysis Set

For the RT phase, the ITT Analysis Set included all subjects who were randomized in the study. Subjects were grouped within the ITT 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 (6.7%, 7 of 104 subjects) as in the BAT group (5.8%, 3 of 52 subjects) in the ITT population. The difference in response rates was not statistically significant (proportion difference by stratified CMH method [95% CI]: 0.01 [−0.09, 0.10]; p = 0.90). Of the 3 responders in the BAT group, 1 subject received 5 mg ruxolitinib twice daily, increased to 10 mg twice daily, and prednisone/prednisolone; 1 subject received 5 mg ruxolitinib twice daily, prednisone/prednisolone, and hydroxyurea; and 1 subject received 20 mg ruxolitinib twice daily.

Primary

Week 24

The primary endpoint was splenic response rate at Week 24 is defined as the proportion of subjects who achieved a ≥ 35% reduction in spleen volume at Week 24 versus baseline measured by MRI or CT.

Momelotinib (MMB) v Best Available Therapy (BAT)

156

Pre-specified

0.01

2-sided

Response rate in TSS from baseline at Week 24, a prespecified secondary endpoint, was defined as the proportion of subjects who achieved a ≥ 50% reduction in TSS from baseline at Week 24 as measured by the modified MPN-SAF TSS v2.0 diary. Response rate in TSS at Week 24 was analyzed for subjects in the ITT who had a baseline TSS > 0 or subjects who had a baseline TSS = 0 but nonzero or missing TSS at Week 24. In the MMB group, 27 (26.2%) of the 103 evaluable patients had a TSS reduction of ≥ 50% from baseline compared to 3 (5.9%) of the 51 evaluable subjects in the BAT group, indicating a 4- to 5 fold greater symptomatic response improvement in subjects who received MMB compared to BAT. The proportion difference by stratified CMH method (95% CI) was 0.20 (0.09, 0.32); this difference was nominally significant (p < 0.001).

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

Momelotinib (MMB) v Best Available Therapy (BAT)

154

Pre-specified

0.2

2-sided

The rate of RBC transfusions in the RT phase was a prespecified secondary endpoint, defined as the average number of RBC units not associated with clinically overt bleeding per subject-month during the RT Phase. For the ITT analysis set, the median (Q1, Q3) rate of RBC transfusion was lower in the MMB group (0.5 [0.0, 2.4] units/month) compared with the BAT group (1.2 [0.0, 2.8] units/month) through Week 24. The median (Q1, Q3) total number of RBC transfusion units through Week 24 was lower in the MMB group (2.0 [0.0, 11.0]) compared with the BAT group (6.0 [0.0, 10.5]).

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 RT phase

Momelotinib (MMB) v Best Available Therapy (BAT)

156

Pre-specified

0.8

2-sided

Red blood cell TI at Week 24 is defined as the absence of RBC transfusion and no hemoglobin level < 8 g/dL in the prior 12 weeks, excluding cases associated with clinically overt bleeding. A nominally greater proportion of subjects in the MMB group was TI at Week 24 (43.3%, 45 subjects) compared with the BAT group (21.2%, 11 subjects) despite containing a lower proportion of TI subjects in the MMB group at baseline (MMB: 30.8%; BAT: 36.5%). The difference was nominally significant (p = 0.001). Overall, the proportion of subjects with TI status increased by 12.5% in the MMB group and decreased by 15.3% in the BAT group at Week 24 compared to baseline.

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 Best Available Therapy (BAT)

156

Pre-specified

0.23

2-sided

Red blood cell TD rate at Week 24 for the ITT population was a prespecified secondary endpoint, and was 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 RT phase participation date prior to Day 162 (ie. missing at Week 24) were considered TD at Week 24. A smaller proportion of the MMB group was TD at Week 24 (50.0%, 52 subjects) compared with the BAT group (63.5%, 33 subjects). The difference was not statistically significant.

Secondary

Week 24

Response rate for TD at Week 24 is defined as the proportion of subjects who were transfusion dependent at Week 24, where TD was defined as at least 4 units of RBC transfusion or a hemoglobin level below 8 g/dL in the prior 8 weeks excluding cases associated with clinically overt bleeding

Momelotinib (MMB) v Best Available Therapy (BAT)

156

Pre-specified

-0.13

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)

Best Available Therapy (BAT)

MMB to MMB

BAT to MMB