Evaluate the activity of Momelotinib versus Danazol in Anemic subjects with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post Essential Thrombocythemia Myelofibrosis who had recevied JAK Inhibitor Therapy

Phase 1

Conditions: Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis, or Post Essential Thrombocythemia Myelofibrosis
MedDRA version: 20.0Level: PTClassification code 10028537Term: MyelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: LLTClassification code 10028538Term: Myelofibrosis with myelometaplasiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.0Level: LLTClassification code 10074689Term: Post polycythemia vera myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.0Level: LLTClassification code 10074690Term: Post essential thrombocythemia myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1Level: LLTClassification code 10074691Term: Post polycythaemia vera myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.0Level: LLTClassification code 10074692Term: Post essential thrombocythaemia myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: PTClassification code 10077161Term: Primary myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2019-000583-18-AT

Lead Sponsor: Sierra Oncology, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 180

Inclusion Criteria

1. Age = 18 years
2. Confirmed diagnosis of PMF in accordance with the World Health Organization (WHO) 2016 criteria, or Post-PV/ET MF in accordance with the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria
3. Symptomatic, defined as a MFSAF TSS of = 10 units assessed by a single MFSAF v4.0 assessment during Screening prior to Day BL1
4. Anemic, defined as any of the following:
a. For any subject; having received a transfusion within 28 days prior to the first day of Baseline assessments (BL1), with pre-transfusion Hgb < 10 g/dL (if a subject receives a transfusion after Day BL1, but prior to Randomization, this pre-transfusion hemoglobin will be used for eligibility), or
b. For subjects without ongoing JAK inhibitor therapy at Screening; Hgb < 10 g/dL during the Baseline Period (Days BL1 to Day BL7), or
c. For subjects receiving ongoing JAK inhibitor therapy at Screening; Hgb < 10 g/dL during Screening, prior to the last day of Baseline assessments (Day BL7)
5. Previously treated, with an approved JAK inhibitor for PMF or Post- PV/ET MF for = 90 days, or = 28 days if JAK inhibitor therapy is complicated by RBC transfusion requirement of = 4 units in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma
a. Subjects who discontinued JAK inhibitor therapy prior to Screening require no additional non-treatment interval
b. For subjects with ongoing JAK inhibitor therapy at Screening, JAK inhibitor therapy must be tapered over a period of at least 1 week. Subjects receiving a low dose of JAK inhibitor, eg, 5 mg QD of RUX, may have a reduced taper period, or no taper, with the sponsor's approval. A non-treatment interval begins = 7 days prior to Day BL1 (the first of 7 consecutive days of baseline MFSAF assessments)
6. Baseline splenomegaly, defined as having a palpable spleen at = 5 cm, below the LCM, or with volume = 450 cm3 on imaging (ultrasound, MRI or CT are acceptable), assessed during Screening at any point prior to Randomization
7. High risk, intermediate-2, or intermediate-1 risk as defined by DIPSS, or DIPSS-plus (criteria provided in Appendix 1)
8. No allogeneic stem cell transplant planned
9. Acceptable laboratory assessments:
ANC = 0.75 × 10 (9)/L
PLT = 25 × 10( 9)/L (without requirement for platelet transfusion)
Peripheral blast count < 10%
AST/SGOT and ALT/SGPT = 3 × ULN (= 5 × 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 = 30 mL/min (According to Cockcroft-
Gault calculation provided in Section 4.1)
Direct bilirubin = 2.0 × ULN
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (criteria provided in Appendix 3)
11. Life expectancy > 24 weeks
12. Able to understand and willing to sign the ICF
13. Willing and able to complete PRO assessments using an ePRO device according to protocol Section 8.2.1
14. WOCBP, men with partners of childbearing potential, and subjects with pregnant or lactating partners must agree to follow the contraceptive requirements of the clinical trial protocol, effective from the first administration of MMB, throughout the trial and for 6 months
after the last dose of MMB (requirements provided in Appendix 4).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 36

Exclusion Criteria

1. Use of the following treatments within the time periods noted (criteria a-i), restricted therapies are further described in Section 5.3.3:
a. MMB at any time
b. Approved JAK inhibitor therapy (eg, fedratinib or ruxolitinib) within 1 week prior to Day BL1 (refer to inclusion criterion #5)
c. Active anti-MF therapy as defined in Section 5.3.3 within 1 week prior to Day BL1.
Supportive care including steroids for non-MF indications may be used as
defined in Section 5.3.3
d. Potent cytochrome P450 3A4 (CYP3A4) inducers within 1 week prior to Randomization (refer to Appendix 5)
e. Investigational agent (including investigational JAK inhibitors) within 4 weeks prior to Randomization
f. Erythropoiesis stimulating agent (ESA) within 4 weeks prior to Randomization
g. Danazol within 3 months prior to Randomization
h. Splenic irradiation within 3 months prior to Randomization
i. Current treatment with simvastatin, atorvastatin, lovastatin or rosuvastatin
2. History of prostate cancer, with the exception of localized prostate cancer that has been treated surgically or by radiotherapy with curative intent and presumed cured
3. Prostate specific antigen (PSA) > 4 ng/mL
4. Unsuitable for spleen volume measurements due to prior splenectomy or unwilling or unable to undergo an MRI or CT scan for spleen volume measurement per protocol requirements in Section 8.3
5. Any of the following (criteria a-k):
a. 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 trial)
b. Significant active or chronic bleeding event = Grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, within 4 weeks prior to Randomization
c. Unstable angina pectoris within 6 months prior to Randomization
d. Symptomatic congestive heart failure within 6 months prior to Randomization
e. Uncontrolled cardiac arrhythmia within 6 months prior to Randomization
f. QTcF interval > 500 msec, unless attributed to bundle branch block
g. Current progressive thrombosis despite treatment
h. History of porphyria
i. Child-Pugh score = 10 (criteria provided in Appendix 2)
j. Psychiatric illness, social situation, or any other condition that would limit compliance with trial requirements or may interfere with the interpretation of study results, as judged by investigator or sponsor
k. Inability or unwillingness to comply with the protocol restrictions on MF therapy and other medications prior to and during study treatment
6. Subjects with a prior or concurrent malignancy, whose natural history or treatment has a significant potential to interfere with the safety or efficacy assessment of the investigational regimen
7. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding, or thalassemia
8. Known positive status for HIV
9. Chronic active or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier (testing required for hepatitis B and C)
10. Unresolved non-hematologic toxicities from prior therapies that are > Grade 1 per CTCAE v5.0
11. Presence of peripheral neuropathy = Grade 2 per CTCAE v5.0
12. Women who are already pregnant or lactating
13. Known intolerance or hypersensitivity to MMB or DAN, their metabolites, or formulation excipients.
14. Patients with rare here

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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