De-escalated Cyclophosphamide (PTCy) and Ruxolitinib for Graft-versus-Host Disease (GVHD) Prophylaxis

Study Overview
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Brief Summary
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This is an open-label phase 2 study designed to explore the efficacy and safety of low-dose PTCy-ruxolitinib GVHD prophylaxis in older adults undergoing allogeneic HCT with a matched sibling or unrelated donor with a peripheral blood stem cell graft.

Detailed Description
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Following reduced intensity conditioning and 8/8-matched peripheral blood transplant on Day 0, all patients will receive a GVHD prophylaxis post-transplant composed of the following: (i) cyclophosphamide administered at 25 mg/kg on Day +3 and +4, (ii) tacrolimus beginning on Day +5 and through Day +180 and administered with a trough target of 5-10 ng/ml through Day +90 and tapered thereafter; (iii) mycophenolate mofetil (MMF) administered at 15 mg/kg thrice daily beginning on Day +5 through Day +35; and (iv) ruxolitinib administered at 5 mg twice daily starting after engraftment (between Days +30 and +60) and continuing through one year post transplant.

Official Title
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A Phase II Trial of De-escalated PTCy and Ruxolitinib for GVHD Prophylaxis in Patients Undergoing Reduced Intensity Conditioning Allogeneic HCT

Conditions
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Graft-versus-host Disease

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of hematologic malignancy. Must be in remission: Acute Leukemia, chronic leukemia, or myelodysplasia/myeloproliferative neoplasm (excluding primary myelofibrosis): No circulating blasts and <5% blasts in the bone marrow. Hodgkin and non-Hodgkin lymphomas: Chemo-sensitive disease at time of transplant Patients must have a related or unrelated peripheral blood stem cell donor that is an 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donors must be willing to donate peripheral blood stem cells and meet NMDP criteria for donation. Planned reduced intensity conditioning therapy with fludarabine/melphalan, with total dose of melphalan of 100-140 mg/m^2 IV or fludarabine/busulfan with total dose of busulfan of 6.4 mg/kg IV. Karnofsky Performance Scale of 60 or greater. Male participants must agree to abstinence or to use of barrier contraception during the entire study period. Female participants of childbearing potential will require a negative pregnancy test and should agree to practice two effective methods of contraception during the entire study period. Ability to understand a written informed consent document, and the willingness to sign it. Exclusion Criteria: Prior allogeneic HCT or Chimeric antigen receptor (CAR) -T cell therapy. Patients with liver dysfunction evidenced by bilirubin ≥2x upper limit normal (ULN), except for a history of Gilbert syndrome. Patients with renal impairment defined by creatinine<2mg/dL. Patients with cardiac dysfunction defined by a left ventricular ejection fraction ≤45%. Patients with pulmonary dysfunction defined by a forced expiratory volume in the first second (FEV1) or diffusing capacity for carbon monoxide (DLCO) (corrected for hemoglobin) ≤50% of predicted. Patients with a chronic or active infection requiring systemic treatment during and after transplant. Presence of other active malignant disease diagnosed within 12 months, except for adequately treated non-melanoma skin cancer, adequately treated melanoma grade 2 or less, or cervical intraepithelial neoplasia. Active malignancy is malignancy receiving treatment. Pregnant or lactating subjects.

Ages Eligible for Study
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Minimum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Graft-versus-host disease prophylaxis<br>Following reduced intensity conditioning and 8/8-matched peripheral blood transplant on Day 0, all patients will receive a GVHD prophylaxis post-transplant composed of the following: (i) cyclophosphamide administered at 25 mg/kg on Day +3 and +4, (ii) tacrolimus beginning on Day +5 and through Day +180 and administered with a trough target of 5-10 ng/ml through Day +90 and tapered thereafter; (iii) mycophenolate mofetil (MMF) administered at 15 mg/kg thrice daily beginning on Day +5 through Day +35; and (iv) ruxolitinib administered at 5 mg twice daily starting after engraftment (between Days +30 and +60) and continuing through one year post transplant. | Drug: Cyclophosphamide<br>* 25 mg/kg by IV on Days +3 and +4.<br>* Other names: Cytoxan;Drug: Tacrolimus<br>* Target level 5-10 ng/mL (If the subject experiences nausea and vomiting that prevents the oral intake of tacrolimus anytime during treatment, tacrolimus is to be given by IV at the appropriate dose that was used to obtain the therapeutic level [IV:PO ratio = 1:4]). Administered Days +5 through +90. Taper after Day +90 and discontinue on Day +180.<br>* Other names: Prograf;Drug: Mycophenolate Mofetil<br>* 15 mg/kg tablet thrice daily Days +5 through +35 every eight hours.<br>* Other names: CellCept;Drug: Ruxolitinib<br>* 5 mg tablet twice daily after engraftment through Day +365. Taper after Day +365.<br>* Other names: Jakafi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of subjects who experience GVHD-free survival. | This measure is defined as being alive without having experienced grade III/IV acute GVHD, or chronic GVHD requiring systemic immune suppression. | One year (365 Days) after hematopoietic cell transplantation (HCT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of subjects with acute GVHD at Day +100. | The staging and grading of acute GVHD will be done according to Consensus GVHD grading criteria. | Day +100 after HCT | 
| The number of subjects with acute GVHD at Day +180. | The staging and grading of acute GVHD will be done according to Consensus GVHD grading criteria. | Day +180 after HCT | 
| The number of subjects with chronic GVHD at one year. | Chronic GVHD will be graded as mild, moderate, or severe according to the NIH consensus criteria. | One year after HCT | 
| The number of subjects with non-relapse mortality at Day +100. | This is defined as death before day +100 after transplant that was not preceded by recurrent or progressive malignancy. | Day +100 after HCT | 
| The number of subjects with non-relapse mortality at one year. | This is defined as death before day +100 after transplant that was not preceded by recurrent or progressive malignancy. | One year after HCT | 
| Overall survival at one year. | This is defined as the number of subjects alive one year after HCT. | One year after HCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft-versus-host disease, Ruxolitinib, Graft-versus-host disease prophylaxis