Clinical trial NCT04370301: Reduced Intensity Haploidentical Transplantation for the Treatment of Primary or Secondary Myelofibrosis
Official title: Pilot Study of JAK Inhibitor Therapy Followed by Reduced Intensity Haploidentical Transplantation for Patients With Myelofibrosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Primary Myelofibrosis
Secondary Myelofibrosis
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
First posted: 2020-04-30
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This initial cohort of this phase II trial studied the outcomes of using a JAK inhibitor prior to reduced intensity haploidentical (Haplo) transplantation for the treatment of primary or secondary myelofibrosis (MF). The primary risk of using Haplo HCT in patients with MF is graft failure. In the first cohort, all patients engrafted. There were no instances of graft failure. However, a large number of patients did have graft versus host disease as a complication of their transplant. JAK inhibitors have since been approved for the indication of graft versus host disease treatment. And we are also using them for graft versus host disease prevention in a study of MF patients with sibling and unrelated donors. Therefore, we are opening a new cohort of the current study using the JAK inhibitor prior to, during and after Haplo transplant. Our goal is to decrease graft versus host disease in patients receiving a Haplo MF transplant without increasing the risk of graft failure.

Detailed description: OUTLINE: Cohort 1 is now closed and all patients will be enrolled on Cohort 2.

COHORT I:

JAK INHIBITOR THERAPY: Patients receive a JAK inhibitor at least 8 weeks prior to the start of hematopoietic cell transplantation (HCT) conditioning through day -4 before transplantation.

CONDITIONING: Patients receive melphalan intravenously (IV) over 1 hour on day -5, fludarabine IV over 30-60 minutes on days -5 to -2, and undergo total-body irradiation (TBI) on day -1 or day -1 and day 0.

TRANSPLANT: Patients receive peripheral blood stem cell infusion on day 0.

GVHD PROPHYLAXIS: Patients then receive cyclophosphamide IV over 3 hours on days 3-4, tacrolimus IV beginning day 5 then orally (PO) for about 6 months, mycophenolate mofetil PO twice daily (BID) or three times daily (TID) beginning day 5 for 6 weeks, and granulocyte colony-stimulating factor (G-CSF) subcutaneously (SC) beginning day 7 until neutrophil recovery is \> 1,500/mm\^3.

COHORT II:

JAK INHIBITOR THERAPY: Patients receive a JAK inhibitor at least 8 weeks prior to the start of HCT conditioning through day -4 before transplantation. Additionally, patients receive a JAK inhibitor following transplantation beginning day +5 through 9-12 months after transplant.

CONDITIONING: Patients receive melphalan IV over 1 hour on day -5, fludarabine IV over 30-60 minutes on days -5 to -2, and undergo TBI on day -1 or day -1 and day 0.

TRANSPLANT: Patients receive peripheral blood stem cell infusion on day 0.

GVHD PROPHYLAXIS: Patients then receive cyclophosphamide IV over 3 hours on days 3-4, tacrolimus IV beginning day 5 then PO for about 6 months, mycophenolate mofetil PO BID or TID beginning day 5 for 6 weeks, and G-CSF SC beginning day 7 until neutrophil recovery is \> 1,500/mm\^3.

All patients undergo magnetic resonance imaging (MRI), computed tomography (CT), bone marrow biopsy and aspiration and blood sample collection throughout the trial. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) on the trial.

After completion of study treatment, patients are followed up between day 80-100, at 1 year, and then up to 5 years.

Eligibility criteria: Inclusion Criteria:

* PART 1: JAK INHIBITOR ADMINISTRATION INCLUSION CRITERIA
* Age \> 18 years
* Diagnosis of primary myelofibrosis (PMF) as defined by the 2016 World Health Organization classification system or diagnosis of secondary MF as defined by the International Working Group (IWG) for Myeloproliferative Neoplasms Research and Treatment criteria
* Patients meeting the criteria for intermediate-1, intermediate-2 or high-risk disease by the Dynamic International Prognostic Scoring System (DIPSS)-plus scoring system (DIPSS may be used if all data from DIPSS are not available)
* Ability to understand and the willingness to sign a written informed consent document (or legally authorized representative)
* Patient must be a potential hematopoietic stem cell transplant candidate
* PART 2: ALLOGENEIC STEM CELL TRANSPLANT INCLUSION CRITERIA
* Meeting criteria for 1st phase as above, at time of initiation of JAK inhibitor, including ability to understand and willingness to sign a written informed consent (or legally authorized representative). Patients arriving to our institution for transplant and not enrolled in Part 1 may still be enrolled in Part 2 if Part 1 criteria met. These patients will have Part 1 endpoints transcribed from medical records
* Received JAK inhibitor for at least 8 weeks immediately prior to conditioning and be willing to continue until 9-12 months post-transplant as tolerated
* Karnofsky performance status score \>= 70
* Calculated creatinine clearance using the Cockcroft-Gault formula or 24 hour (hr) urine creatinine clearance must be \> 60 ml/min
* Total serum bilirubin must be \< 3 mg/dL unless the elevation is thought to be due to Gilbert's disease or hemolysis
* Transaminases must be \< 3 x the upper limit of normal
* Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension. Patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3 mg/dL, and symptomatic biliary disease will be excluded
* Diffusion capacity of the lung for carbon monoxide (DLCO) corrected \> 60% normal; may not be on supplemental oxygen
* Left ventricular ejection fraction \> 40% OR shortening fraction \> 26%
* Comorbidity Index \< 5 at the time of pre-transplant evaluation
* DONOR: Patients must be screened prior to transplant for donor-specific anti-HLA antibodies (DSA). Patients with DSA will be reviewed by the principal investigator and considered for desensitization treatment
* DONOR: Children are preferred over siblings and parents
* DONOR: Younger donors are preferred over older donors
* DONOR: ABO matched donors are preferred over minor ABO mismatched and over major ABO mismatch donors

Exclusion Criteria:

* PART 1: JAK INHIBITOR ADMINISTRATION EXCLUSION CRITERIA
* Contraindication to receiving a JAK inhibitor including:

  * Patients who have known hypersensitivity to JAK inhibitors
  * Clinical or laboratory evidence of significant renal or hepatic impairment including cirrhosis
  * Active uncontrolled infection
  * Known human immunodeficiency virus (HIV) positivity
  * Women who are pregnant or trying to conceive
  * Caution should be used in patients with platelets \< 100 though adjustments in dose can be made to accommodate anyone with platelets \> 50
* History of prior allogeneic transplant
* Leukemic transformation (\> 20% blasts)
* PART 2: ALLOGENEIC STEM CELL TRANSPLANT EXCLUSION CRITERIA
* Uncontrolled viral or bacterial infection at the time of study enrollment
* Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval
* Known HIV positivity
* Pregnant or breastfeeding
* Availability of an human leukocyte antigen (HLA)-identical or 1-allele-mismatched related donor or an HLA 10 of 10 matched unrelated donor

Primary outcomes:
measure: Probability of primary and secondary graft failure
timeFrame: Up to 5 years
Secondary outcomes:
measure: Incidence of severe (grade 3 or 4) cytokine release syndrome
timeFrame: Up to 5 years
measure: Non-relapse mortality (NRM)
timeFrame: Day 100
measure: NRM
timeFrame: 1 year
measure: Overall survival
timeFrame: 1 year
measure: Overall survival
timeFrame: 3 years
measure: Incidence of grade II-IV acute graft versus host disease (GVHD)
timeFrame: Up to 5 years
measure: Incidence of grade III-IV acute GVHD
timeFrame: Up to 5 years
measure: Incidence of moderate-severe chronic GVHD
timeFrame: Up to 5 years
measure: Incidence of relapse
timeFrame: At 1 year
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutch/University of Washington Cancer Consortium
state: Washington
Study officials:
affiliation: Fred Hutch/University of Washington Cancer Consortium
name: Rachel B. Salit
role: PRINCIPAL_INVESTIGATOR
References: