Fostamatinib Alone or in Combination with Ruxolitinib for Treatment of Patients with Intermediate- or High-Risk Myelofibrosis with Severe Thrombocytopenia
This phase II trial studies the effects of fostamatinib alone or in combination with ruxolitinib in treating patients with intermediate- or high-risk myelofibrosis with severe thrombocytopenia (low platelet count). Fostamatinib may help treat severe thrombocytopenia by blocking a certain enzyme. Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving fostamatinib in combination with ruxolitinib may work better in treating myelofibrosis.
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 International Prognostic Scoring System (IPSS)
- Severe thrombocytopenia defined as platelet count < 50,000/microL (confirmed on at least two measurements over an 8-week period prior to date of consent)
- At least 18 years of age
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Able to swallow pills
- Absolute neutrophil count (ANC) >= 1000/microL
- Peripheral blood blasts =< 10%
- Albumin > 2.7 g/dL
- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN); patients with Gilbert’s syndrome may enroll if direct bilirubin =< 1.5 x IULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [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 Institutional Review Board (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, 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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04543279.
PRIMARY OBJECTIVES:
I. To evaluate the impact of fostamatinib disodium (fostamatinib) on platelet counts in patients with myelofibrosis and severe thrombocytopenia. (Part A)
II. To evaluate the safety and tolerability of the combination of fostamatinib and ruxolitinib phosphate (ruxolitinib) in myelofibrosis (MF) patients. (Part B)
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of single agent fostamatinib in patients with MF and thrombocytopenia. (Part A)
II. To evaluate spleen response in patients with MF receiving fostamatinib. (Part A)
III. To evaluate anemia response in patients with MF receiving fostamatinib. (Part A)
IV. To evaluate the impact of fostamatinib on constitutional symptoms in patients with MF. (Part A)
V. To evaluate the impact of fostamatinib on transfusion requirements. (Part A)
VI. To evaluate the impact of fostamatinib on marrow fibrosis. (Part A)
VII. To evaluate the spleen response in patients with MF receiving fostamatinib in combination with ruxolitinib. (Part B)
VIII. To evaluate the impact of fostamatinib in combination with ruxolitinib on constitutional symptoms in patients with MF. (Part B)
IX. Evaluate the ability of fostamatinib to enable sustained treatment with ruxolitinib. (Part B)
X. To evaluate the impact of fostamatinib and ruxolitinib on marrow fibrosis. (Part B)
OUTLINE:
PART A: Patients receive fostamatinib disodium orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a sustained platelet count of >= 50,000/microL receive fostamatinib disodium for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
PART B: Patients who tolerate fostamatinib disodium and achieve a sustained platelet count of >= 50,000/microL by day 1 of cycle 10 in part A receive fostamatinib disodium PO BID and ruxolitinib phosphate PO BID on days 1-28. Treatment repeats every 28 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorAmy Zhou
- Primary ID202011080
- Secondary IDsNCI-2020-13895
- ClinicalTrials.gov IDNCT04543279