Clinical trial NCT04543279: Fostamatinib as a Single Agent or in Combination With Ruxolitinib for Treatment of Patients With Myelofibrosis With Severe Thrombocytopenia
Official title: Fostamatinib as a Single Agent or in Combination With Ruxolitinib for Treatment of Patients With Myelofibrosis With Severe Thrombocytopenia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Myelofibrosis
Thrombocytopenia
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Rigel Pharmaceuticals
First posted: 2020-09-10
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With a Platelet Response (Part A)
timeFrame: Week 12
measure: Toxicity of Fostamatinib and Ruxolitinib Treatment (Part B)
timeFrame: From start of treatment through 30 days after last day of study treatment (estimated to be approximately 40 weeks)
Secondary outcomes:
measure: Number of Participants Eligible to Initiate Therapy With Ruxolitinib (Part A)
timeFrame: Through completion of fostamatinib treatment (12 weeks)
measure: Toxicity of Fostamatinib Treatment (Part A)
timeFrame: From start of treatment through 30 days after last day of study treatment (estimated to be approximately 16 weeks)
measure: Number of Participants Who Permanently Discontinue Fostamatinib Due to Fostamatinib Related Adverse Events (Part A)
timeFrame: Through 12 weeks
measure: Number of Participants Who Require Treatment Interruption of Fostamatinib Due to Adverse Events (Part A)
timeFrame: Through 12 weeks
measure: Number of Participants Who Was Dose Escalated and Tolerated Fostamatinib Dose Greater Than 100 mg BID (Part A)
timeFrame: Through 12 weeks
measure: Number of Participants Who Achieve 35% or Greater Reduction in Spleen Volume as Determined by Ultrasound at Week 12 of Fostamatinib Treatment (Part A)
timeFrame: Week 12
measure: Change in Mean Spleen Volume as Determined by Ultrasound at Week 12 of Fostamatinib Treatment (Part A)
timeFrame: Week 12
measure: Number of Participants With 50% or Greater Improvement in Myeloproliferative Neoplasm - Symptom Assessment Form Total Symptom Score (Part A) From Baseline to Week 12
timeFrame: Baseline and Week 12
measure: Number of Participants Who Achieve Platelet Transfusion Independence (Part A)
timeFrame: Through week 12
measure: Number of Participants With Anemia Who Achieve RBC Transfusion Independence (Part A)
timeFrame: Through week 12
measure: Number of Participants With Change in Marrow Fibrosis by WHO Grading (Part A)
timeFrame: Through week 12
measure: Number of Participants With 35% or Greater Reduction in Spleen Volume as Determined by Ultrasound After 12 Weeks of Combination Treatment (Part B)
timeFrame: 12 weeks
measure: Number of Participants With 35% or Greater Reduction in Spleen Volume as Determined by Ultrasound After 12 Weeks of Combination Treatment (Part B)
timeFrame: At completion of combination treatment (estimated to be 36 weeks)
measure: Mean Reduction in Spleen Volume as Determined by Ultrasound After 12 Weeks of Combination Treatment (Part B)
timeFrame: 12 weeks
measure: Mean Reduction in Spleen Volume as Determined by Ultrasound After 12 Weeks of Combination Treatment (Part B)
timeFrame: At completion of combination treatment (estimated to be 36 weeks)
measure: Number of Participants With 50% or Greater Improvement in Total Symptom Score (Part B)
timeFrame: 12 weeks
measure: Number of Participants With 50% or Greater Improvement in Total Symptom Score (Part B)
timeFrame: At completion of combination treatment (estimated to be 36 weeks)
measure: Duration of Uninterrupted Ruxolitinib Treatment (Part B)
timeFrame: Up to 36 weeks
measure: Change in Marrow Fibrosis by WHO Grading (Part B)
timeFrame: At completion of combination treatment (estimated to be 36 weeks)
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Amy Zhou, M.D.
role: PRINCIPAL_INVESTIGATOR
References: