Fostamatinib as a Single Agent or in Combination With Ruxolitinib for Treatment of Patients With Myelofibrosis With Severe Thrombocytopenia

Study Overview
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Brief Summary
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Fostamatinib may improve thrombocytopenia in myelofibrosis patients with severe thrombocytopenia (platelet <50,000/microL) and allow them to initiate treatment with a JAK2 inhibitor, ruxolitinib. Additionally, fostamatinib monotherapy may also improve myelofibrosis related symptoms and splenomegaly.

Official Title
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Fostamatinib as a Single Agent or in Combination With Ruxolitinib for Treatment of Patients With Myelofibrosis With Severe Thrombocytopenia

Conditions
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Myelofibrosis, Thrombocytopenia

Intervention / Treatment
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* Drug: Fostamatinib
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of primary myelofibrosis or post-polycythemia vera/essential thrombocythemia myelofibrosis classified as high risk, intermediate-2 risk, or intermediate 1 risk by IPSS. Severe thrombocytopenia defined as platelet count < 50,000/microL (confirmed on at least two measurements over an 8-week period prior to start of study). At least 18 years of age. ECOG performance status ≤ 2 Able to swallow pills Adequate bone marrow and organ function as defined below: ANC ≥ 1000/microL Peripheral blood blasts ≤ 10% Albumin > 2.7 g/dL Total bilirubin ≤ 1.5 x IULN; patients with Gilbert's syndrome may enroll if direct bilirubin ≤ 1.5 x IULN AST(SGOT)/ALT(SGPT) ≤ 1.5 x IULN Creatinine clearance > 30 mL/min by Cockcroft-Gault Female subjects must be either post-menopausal for at least 1 year or surgically sterile; or, if of childbearing potential, must not be pregnant or lactating and must agree to use a highly effective method of birth control throughout the duration of the trial and for 30 days following the last dose. Acceptable methods of birth control are defined as: hormonal contraception (pill, injection or implant) used consistently for at least 30 days prior to screening, an intrauterine device (IUD), or intrauterine hormone-releasing system (IUS), or true abstinence (i.e. abstinence is in line with the preferred and usual lifestyle of the subject.). Male subjects do not need to use contraception for fostamatinib because human studies showed minimal R406 in sperm. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: History of allogeneic stem cell transplant. Any solid tumor or hematologic malignancy (other than myelofibrosis) requiring active treatment at the time of study entry Currently receiving any other investigational agents. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to fostamatinib, ruxolitinib, or other agents used in the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, or cardiac arrhythmia. Subject has uncontrolled or poorly controlled hypertension, defined as systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg, whether or not the subject is receiving anti-hypertensive treatment. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry and prior to the first dose of fostamatinib. Known positive status for human immunodeficiency virus (HIV) Chronic, active, or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier. Treatment with strong CYP3A inhibitors or inducers within 14 days before the first dose of study drug. Strong CYP3A inhibitors and CYP3A inducers are not permitted during the study. Ongoing gastrointestinal medical condition such as Crohn's disease, inflammatory bowel disease, or chronic diarrhea that is not well controlled and could interfere with absorption of oral medication or be exacerbated by study medication Known hepatic cirrhosis or severe pre-existing hepatic impairment. Uncontrolled coagulopathy or bleeding disorder. Female patients who intend to donate eggs and male patients who intend to donate sperm during the course of this study or for 4 months after receiving the last dose of study treatment.

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: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Fostamatinib<br>The starting dose of fostamatinib is 100 mg twice daily (BID). After the first cycle, if no major dose related safety issue is observed and the platelet count is less than 50K/microL, then the fostamatinib dose will be increased to 150 mg BID for the next 2 cycles; otherwise the dose may be continued at 100 mg BID. | Drug: Fostamatinib<br>* Fostamatinib will be supplied by Rigel Pharmaceuticals.<br>* Other names: Tavalisse;|
| Experimental: Part B: Fostamatinib + Ruxolitinib<br>After 3 cycles of fostamatinib monotherapy, all patients with a sustained platelet count ≥ 50K/microL, will continue on the current fostamatinib dose plus ruxolitinib at the recommended dose per standard prescribing guidelines for an additional 9 cycles. Patients who do not reach platelet count of at least 50K/microL but who achieve clinical benefit per the treating provider may continue on single agent fostamatinib for up to 12 total treatment cycles. If these patients achieve a sustained platelet count of ≥ 50K/microL at any point prior to Cycle 10 Day 1, then they may be eligible to enroll in Part B of the study and continue treatment with fostamatinib and ruxolitinib for the remainder of the study. | Drug: Fostamatinib<br>* Fostamatinib will be supplied by Rigel Pharmaceuticals.<br>* Other names: Tavalisse;Drug: Ruxolitinib<br>* Ruxolitinib is commercially available.<br>* Other names: Jakafi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Platelet Response (Part A) | -Defined as an increase in platelet count ≥ 50K/microL with at least one more confirmatory platelet count separated by at least 2 weeks (in the absence of platelet transfusion) within the first 12 weeks of fostamatinib treatment | Week 12 | 
| Toxicity of Fostamatinib and Ruxolitinib Treatment (Part B) | -Measured by number of adverse events, serious adverse events, and laboratory abnormalities | From start of treatment through 30 days after last day of study treatment (estimated to be approximately 40 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Eligible to Initiate Therapy With Ruxolitinib (Part A) |  | Through completion of fostamatinib treatment (12 weeks) | 
| Toxicity of Fostamatinib Treatment (Part A) | -Measured by number of adverse events, serious adverse events, and laboratory abnormalities | From start of treatment through 30 days after last day of study treatment (estimated to be approximately 16 weeks) | 
| Number of Participants Who Permanently Discontinue Fostamatinib Due to Fostamatinib Related Adverse Events (Part A) |  | Through 12 weeks | 
| Number of Participants Who Require Treatment Interruption of Fostamatinib Due to Adverse Events (Part A) |  | Through 12 weeks | 
| Number of Participants Who Was Dose Escalated and Tolerated Fostamatinib Dose Greater Than 100 mg BID (Part A) |  | Through 12 weeks | 
| Number of Participants Who Achieve 35% or Greater Reduction in Spleen Volume as Determined by Ultrasound at Week 12 of Fostamatinib Treatment (Part A) |  | Week 12 | 
| Change in Mean Spleen Volume as Determined by Ultrasound at Week 12 of Fostamatinib Treatment (Part A) |  | Week 12 | 
| Number of Participants With 50% or Greater Improvement in Myeloproliferative Neoplasm - Symptom Assessment Form Total Symptom Score (Part A) From Baseline to Week 12 | -The Myeloproliferative Neoplasm - Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) has 10 questions for participants to rate their symptoms. The answers range from 0-absent to 10-worst imaginable. The total score for the questionnaire is 100. A higher score indicates worse symptoms. | Baseline and Week 12 | 
| Number of Participants Who Achieve Platelet Transfusion Independence (Part A) |  | Through week 12 | 
| Number of Participants With Anemia Who Achieve RBC Transfusion Independence (Part A) |  | Through week 12 | 
| Number of Participants With Change in Marrow Fibrosis by WHO Grading (Part A) |  | Through week 12 | 
| Number of Participants With 35% or Greater Reduction in Spleen Volume as Determined by Ultrasound After 12 Weeks of Combination Treatment (Part B) |  | 12 weeks | 
| Number of Participants With 35% or Greater Reduction in Spleen Volume as Determined by Ultrasound After 12 Weeks of Combination Treatment (Part B) |  | At completion of combination treatment (estimated to be 36 weeks) | 
| Mean Reduction in Spleen Volume as Determined by Ultrasound After 12 Weeks of Combination Treatment (Part B) |  | 12 weeks | 
| Mean Reduction in Spleen Volume as Determined by Ultrasound After 12 Weeks of Combination Treatment (Part B) |  | At completion of combination treatment (estimated to be 36 weeks) | 
| Number of Participants With 50% or Greater Improvement in Total Symptom Score (Part B) |  | 12 weeks | 
| Number of Participants With 50% or Greater Improvement in Total Symptom Score (Part B) |  | At completion of combination treatment (estimated to be 36 weeks) | 
| Duration of Uninterrupted Ruxolitinib Treatment (Part B) |  | Up to 36 weeks | 
| Change in Marrow Fibrosis by WHO Grading (Part B) |  | At completion of combination treatment (estimated to be 36 weeks) |