Clinical Trials Register

Summary
EudraCT Number:	2013-005007-13
Sponsor's Protocol Code Number:	GS-US-352-1214
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-04-10
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2013-005007-13

A.3

Full title of the trial

A Phase 3, Randomized Study to Evaluate the Efficacy of Momelotinib Versus Best Available Therapy in Anemic or Thrombocytopenic Subjects with Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis who were Treated with Ruxolitinib

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Study to Compare the Efficacy of Momelotinib Versus Best Available Therapy in Anemic or Thrombocytopenic Subjects with Myelofibrosis who were Treated with Ruxolitinib

A.4.1

Sponsor's protocol code number

GS-US-352-1214

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Sierra Oncology, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Sierra Oncology, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sierra Oncology, Inc.
B.5.2	Functional name of contact point	Martha Bond
B.5.3	Address:
B.5.3.1	Street Address	46701 Commerce Center Drive
B.5.3.2	Town/ city	Plymouth
B.5.3.3	Post code	MI48170
B.5.3.4	Country	United States
B.5.4	Telephone number	+14165287431
B.5.5	Fax number	897284
B.5.6	E-mail	mbond@sierraoncology.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/888
D.3 Description of the IMP
D.3.1	Product name	Momelotinib 200mg
D.3.2	Product code	GS-0387
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	momelotinib dihydrochloride monohydrate
D.3.9.2	Current sponsor code	GS-0387-01 monohydrate
D.3.9.3	Other descriptive name	MOMELOTINIB
D.3.9.4	EV Substance Code	SUB126831
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/888
D.3 Description of the IMP
D.3.1	Product name	Momelotinib 100mg
D.3.2	Product code	GS-0387
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	momelotinib dihydrochloride monohydrate
D.3.9.2	Current sponsor code	GS-0387-01 monohydrate
D.3.9.3	Other descriptive name	MOMELOTINIB
D.3.9.4	EV Substance Code	SUB126831
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/888
D.3 Description of the IMP
D.3.1	Product name	Momelotinib 150mg
D.3.2	Product code	GS-0387
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	momelotinib dihydrochloride monohydrate
D.3.9.2	Current sponsor code	GS-0387-01 monohydrate
D.3.9.3	Other descriptive name	MOMELOTINIB
D.3.9.4	EV Substance Code	SUB126831
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis.

E.1.1.1

Medical condition in easily understood language

Blood disorder that means the body produces too many mature blood cells too quickly.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10028537
E.1.2	Term	Myelofibrosis
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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).

E.2.2

Secondary objectives of the trial

- To determine the effect of MMB compared with BAT on the improvement of total symptom score (TSS) on Week 24
- To determine the effect of MMB compared with BAT on rate of red blood cell (RBC) transfusion through Week 24
- To determine the effect of MMB compared with BAT on RBC transfusion independance rate at Week 24
- To determined the effect of MMB compared with BAT on RBC transfusion dependance rate at Week 24

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

MMB PK/Pharmacodynamic Substudy (optional; additional consent required)
The substudy will target enrollment of approximately 20 study subjects for additional PK and pharmacodynamic blood sampling.

MMB Biomarker substudy (optional; additional consent required)
Additional blood samples will be collected in a biomarker substudy from consenting subjects who also agree to storage of samples for future research. The samples will be used to conduct research related to drug activity such as JAK inhibition and disease persistence.

E.3

Principal inclusion criteria

1) Age ≥ 18 years old
2) Palpable splenomegaly at least 5 cm below left costal margin
3) Confirmed diagnosis of PMF in accordance with the World Health Organization (WHO) criteria, or Post-PV/ET MF in accordance with the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria
4) Currently or previously treated with ruxolitinib for PMF or Post-PV/ET MF for at least 28 days and characterized by:
- Requirement for red blood cell (RBC) transfusion while on ruxolitinib treatment, or
- Dose adjustment of ruxolitinib to < 20 mg twice-daily at start of or during ruxolitinib treatment AND at least one of the following while on ruxolitinib treatment:
* ≥ CTCAE Grade 3 thrombocytopenia, OR
* ≥ CTCAE Grade 3 anemia, OR
* ≥ CTCAE Grade 3 hematoma (bleed)
5) High risk OR intermediate-2 risk as defined by Dynamic International Prognostic Scoring System (DIPSS), OR intermediate-1 risk as defined by DIPSS and associated with symptomatic splenomegaly and/or hepatomegaly
6) If receiving myelofibrosis therapy, must be on a stable dose of the same regimen for at least 2 weeks prior to screen date and through the screening period
7) If not receiving therapy for myelofibrosis, must remain off therapy for at least 2 weeks prior to screen date and through the screening period
8) Acceptable laboratory assessment obtained within 14 days prior to randomization
- Absolute neutrophil count (ANC) > 0.75 x 10^9/L in the absence of growth factor in the prior 7 days
- Peripheral blood blast count < 10%
- AST/SGOT and ALT/SGPT ≤ 3 x ULN (≤ 5 x ULN if liver is involved by extramedullary hematopoiesis as judged by the investigator or if related to iron chelator therapy that was started within the prior 60 days)
- Calculated creatinine clearance of ≥ 45 mL/min
- Direct bilirubin ≤ 2.0 x ULN
9) Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
10) Life expectancy > 24 weeks
11) Negative serum pregnancy test for female subjects (unless surgically sterile or greater than 2 years post-menopausal)
12) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
13) Females who are nursing must agree to discontinue nursing before the first dose of MMB
14) Able to understand and willing to sign informed consent form (ICF)

E.4

Principal exclusion criteria

1) Prior splenectomy
2) Splenic irradiation within 3 months prior to randomization
3) Use of investigational agent within 28 days prior to randomization
4) Prior treatment with MMB
5) Hematopoietic growth factor (granulocyte growth factor, erythropoiesis stimulating agent, thrombopoietin mimetic) within 28 days prior to Day 1
6) Uncontrolled intercurrent illness including, but not limited to: active uncontrolled infection (subjects receiving outpatient antibacterial and/or antiviral treatments for infection that is under control or as infection prophylaxis may be included in the study); active or chronic bleeding event within 4 weeks prior to randomization; symptomatic congestive heart failure (CHF); unstable angina pectoris; uncontrolled cardiac arrhythmia; or psychiatric illness/social situation that would limit compliance with study requirements as judged by treating physician
7) QTc interval > 450 msec, unless attributed to bundle branch block
8) History of a concurrent or second malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to randomization, adequately treat Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 5 years
9) Known positive status for human immunodeficiency virus (HIV)
10) Chronic active or acute viral hepatitis A. B or C infection (testing required for hepatitis B and C), or hepatitis B or C carrier
11) Unresolved non-hematologic toxicities from prior therapies that are > CTCAE Grade 1
12) Use of CYP3A4 inducers within 1 week prior to randomization
13) Changes to dose of iron chelator therapy within 14 days prior to randomization
14) Presence of peripheral neuropathy ≥ CTCAE Grade 2
15) Unwilling or unable to undergo a MRI or CT Scan
16) Known hypersensitivity to MMB, the metabolites, or formulation excipients

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is SRR24 - defined as the proportion of subjects who achieves a ≥ 35 % reduction in spleen volume at Week 24 from baseline as measure by MRI or CT

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 24

E.5.2

Secondary end point(s)

- Response rate in total symptom score (TSS) from Baseline to Week 24 - defined as the proportion of subjects who achieves a ≥ 50 % reduction from Baseline in total symptom score to Week 24 as measured by the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF) TSS diary
- Rate of RBC transfusion - defined as the average number of RBC units per subject-month during the randomized treatment period (through Week 24)
- RBC transfusion independence rate at Week 24 - defined as the proportion of subjects who is transfusion independent at Week 24, where transfusion independence is defined as absence of RBC transfusion and no hemoglobin (Hgb) level below 8 g/dL in the prior 12 weeks
- RBC transfusion dependence rate at Week 24 - defined as the proportion of subjects who is transfusion dependent at Week 24, where transfusion dependence is defined as at least 4 units of RBS transfusions, or a Hgb level below 8 g/dL, in the prior 8 weeks

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 24

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Best Available Therapy

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

France

Germany

Israel

Italy

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

150

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After the patients have completed/terminated their study participation, long term care for the patient will remain the responsibility of their primary treating physician.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-05-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-04-25

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