Efficacy and Safety of Simtuzumab in Adults With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis

Study Overview
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Brief Summary
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This study is to evaluate the efficacy and safety of simtuzumab (GS-6624) on bone marrow fibrosis either alone or in combination with ruxolitinib in participants with primary myelofibrosis (PMF) and post polycythemia vera or post essential thrombocythemia myelofibrosis (ET/PV MF). The study is designed as a two-stage trial. In the stage 1, participants will be randomized into two cohorts to receive either 200 or 700 mg of study drug. In the stage 2, participants on ruxolitinib will be randomized to receive either 200 or 700 mg of study drug.

Official Title
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A Phase 2 Study to Evaluate the Efficacy and Safety of GS-6624 in Adult Subjects With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: Simtuzumab
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be diagnosed with PMF or post ET/PV MF with intermediate-1, intermediate-2 or high risk disease according to the international working group (IWG) prognostic scoring system, or if with low risk disease then with symptomatic splenomegaly that is ≥ 10 cm below left costal margin by physical exam. Must have adequate organ function as demonstrated by the following: Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5x upper limit of normal (ULN), or ≤ 4x ULN (if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis [EMH] related to MF); Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN (if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis [EMH] related to MF); Serum creatinine ≤ 2.5 mg/dL. In Stage 2, participants must be on ruxolitinib for at least 8 weeks and on a stable dose for at least 4 weeks. Eastern cooperative oncology group (ECOG) performance status (PS) ≤ 2 Treatment-related toxicities from prior therapies must have resolved to Grade ≤ 1 Women of childbearing potential and men must agree to using one medically approved (ie, mechanical or pharmacological) contraceptive measure and have their partners agree to an additional barrier method of contraception for the duration of the study and for 90 days after the last administration of study drug. Definition of female of child bearing potential and a list of acceptable contraceptive methods for this study applies per protocol. Exclusion Criteria: Any serious medical condition or psychiatric illness that would prevent, (as judged by the treating physician) the participant from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Pregnant or lactating. Known history of human immunodeficiency virus (HIV), hepatitis C, or hepatitis B. History or presence of any form of cancer within the 3 years prior to enrollment, with the exception of excised basal cell or squamous cell carcinoma of the skin, or cervical carcinoma in situ or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis. Participation in an investigational drug or device trial within 2 weeks prior to study Day 1 or within 5 times the half-life of the investigational agent in the other clinical study, if known. Use of any cytotoxic chemotherapeutic agents (eg, hydroxyurea), corticosteroids (prednisone ≤ 10 mg/day or corticosteroid equivalent is allowed), or immune modulators (eg, thalidomide) within 2 weeks and interferon use within 4 weeks prior to study Day 1. Symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or unstable cardiac arrhythmia requiring medication. History of surgery within 2 weeks prior to enrollment or anticipated surgery during the study period. Any other condition that might reduce the chance of obtaining data required by the protocol or that might compromise the ability to give truly informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simtuzumab 200 mg<br>Participants in Stage 1 of study will receive simtuzumab 200 mg for up to 24 weeks. Treatment could be continued if there is evidence of clinical benefit as judged by the treating physician. | Drug: Simtuzumab<br>* Simtuzumab administered intravenously over approximately 30 minutes every 2 weeks<br>* Other names: AB0024;|
| Experimental: Simtuzumab 700 mg<br>Participants in Stage 1 of study will receive simtuzumab 700 mg for up to 24 weeks. Treatment could be continued if there is evidence of clinical benefit as judged by the treating physician. | Drug: Simtuzumab<br>* Simtuzumab administered intravenously over approximately 30 minutes every 2 weeks<br>* Other names: AB0024;|
| Experimental: Simtuzumab 200 mg+Ruxolitinib<br>In Stage 2, participants on stable doses of ruxolitinib will receive simtuzumab 200 mg for at least 24 weeks. Treatment could be continued if there is evidence of clinical benefit as judged by the treating physician. | Drug: Simtuzumab<br>* Simtuzumab administered intravenously over approximately 30 minutes every 2 weeks<br>* Other names: AB0024;Drug: Ruxolitinib<br>* In Stage 2, participants will be on a stable dose of ruxolitinib<br>|
| Experimental: Simtuzumab 700 mg+Ruxolitinib<br>In Stage 2, participants on stable doses of ruxolitinib will receive simtuzumab 700 mg for at least 24 weeks. Treatment could be continued if there is evidence of clinical benefit as judged by the treating physician. | Drug: Simtuzumab<br>* Simtuzumab administered intravenously over approximately 30 minutes every 2 weeks<br>* Other names: AB0024;Drug: Ruxolitinib<br>* In Stage 2, participants will be on a stable dose of ruxolitinib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Clinical Response as Defined by the Percentage of Participants With Reduction at Week 24 From Baseline in the Bone Marrow Fibrosis Score | Overall response for the study drug is defined by the reduction in bone marrow fibrosis score which is on a scale of 0-3 where 0 indicates the scattered linear reticulin with no fiber intersections representing normal marrow and 3 indicates dense increase in reticulin fibrosis with fiber intersections, often with osteosclerosis. Reduction from baseline of score indicates improvement in clinical condition. | Baseline; Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC) | Overall response for the study drug was defined by the rate of clinical improvement in hemoglobin, platelet or ANC. Clinical improvement in hemoglobin was defined as a ≥ 2 g/dL increase from baseline in hemoglobin level and transfusion independent (absence of red blood cell (RBC) transfusions in prior 8 weeks and applicable only for participants with baseline hemoglobin level of < 10 g/dL); clinical improvement in platelets was defined as a ≥ 100% increase from baseline in platelet count and an absolute platelet count of ≥ 50 x 10^9/L (applicable only for participants with baseline platelet count < 50 x 10^9/L); clinical improvement in ANC is defined as a ≥ 100% increase from baseline in ANC and an ANC of ≥ 0.5 x 10^9/L (applicable only for participants with baseline ANC < 1 x 10^9/L). | Baseline; Weeks 12, 24 and any time post baseline (enrollment up to 94 weeks) | 
| Percentage of Participants With Adverse Events (AEs) |  | First dose date up to the last dose date (maximum: 94 weeks) plus 28 days | 
| Change From Baseline in Myelofibrosis Symptoms Assessment Score | Myelofibrosis symptom assessment was performed using myeloproliferative neoplasm symptoms assessment form (MPN-SAF) which is a 27-item questionnaire to address symptom burden and quality of life. The form consists of 27 questions which are scored on a scale of 0-10 by participants based on how symptoms are affecting them, where 0 indicates less symptoms while 10 indicated more severe symptoms and greater inactivity. The MPN-SAF score was calculated at each visit for each participant as an average of the scales for each question and all answered questions. If the number of questions not answered at 1 visit was > 10, then the MPN-SAF score for that visit was taken as missing. A negative change from Baseline indicated improvement. | Baseline; Days 43 and 85 of Cycles 1-7 (cycle=12 weeks) | 
| Change From Baseline in Cytokine Levels | Biomarker samples were collected to evaluate the effects of SIM treatment on markers of serum and plasma cytokines. | Baseline; Week 24 | 
| Percentage of Participants With Anti-Simtuzumab Antibody Formation | Blood samples were collected for the presence of anti-SIM antibodies which was determined using a validated electro-chemiluminescent (ECL) assay screening test. | Baseline; Day 85 of Cycles 1 to 5 (cycle=12 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematology, Myelofibrosis, Thrombocythemia Myelofibrosis, Bone Marrow Diseases, Hematologic Diseases, Blood Diseases, Leukemia, Blood Disorders