Shorter Course Tacro After NMA, Related Donor PBSCT With High-dose Posttransplant Cy for Hard-to-Engraft Malignancies

Study Overview
=================
Brief Summary
-----------------
To see if it is possible to use short-duration tacrolimus after a peripheral blood stem cell transplant in certain malignancies that are considered difficult to engraft.

Detailed Description
-----------------
The main goal is to learn whether a drug called tacrolimus, which is an immune-lowering drug (an immunosuppressant) given after transplant to help prevent certain complications, can be given safely for a shorter period of time than it has been in the past. The experiences with immunosuppression duration with other allogeneic HSCT platforms cannot be directly extrapolated to the high-dose posttransplantation cyclophosphamide platform (another type of immunosuppressant given after transplant to help prevent GVHD). There are presently no published data on the minimum required duration of tacrolimus after nonmyeloablative HSCT that includes high-dose Cy as part of postgrafting immunosuppression. The effectiveness of high-dose posttransplantation Cy in GVHD prevention, however, permits the investigation of this question. At the present time there are few or no cures for diseases studied on this trial outside of a bone marrow or peripheral blood transplant. The peripheral blood for this transplant comes from a relative who is a half-match or haplo match to the participant. Possible donors include parents, siblings, and children. In order to help the bone marrow grow, or take, inside the body, participants will receive chemotherapy and radiation before the transplant. After the transplant participants will receive high doses of cyclophosphamide (Cytoxan®) along with other medications to lower the immune system, such as tacrolimus. These medications may lower the risk of graft versus host disease (GVHD) and of rejection of the peripheral blood graft.

Official Title
-----------------
Phase II Study of Shortened-duration Tacrolimus Following Nonmyeloablative Peripheral Blood Stem Cell Transplant With High-dose Posttransplantation Cyclophosphamide in Malignancies That Are Challenging to Engraft

Conditions
-----------------
Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Chronic Myeloid Leukemia, Chronic Myeloproliferative Disorders, Multiple Myeloma, Plasma Cell Neoplasm, Plasma Cell Dyscrasia, Myelofibrosis, Polycythemia Vera, Essential Thrombocythemia, Plasma Cell Leukemia

Intervention / Treatment
-----------------
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Radiation: Total body irradiation
* Drug: Tacrolimus
* Drug: Mycophenolate mofetil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Presence of a suitable related HLA-haploidentical or -matched stem cell donor, or a 10/10 matched unrelated donor Eligible diagnoses: myelodysplastic syndrome (MDS) with at least 1 poor-risk feature; small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) with 17p deletion or with progression < 6 months after a second or greater treatment regimen; T-cell prolymphocytic leukemia (PLL) in partial response or better; interferon- or tyrosine-kinase-refractory chronic myeloid leukemia (CML), or CML in second or subsequent chronic phase; Philadelphia chromosome negative (Ph-) myeloproliferative disease, including myelofibrosis; Multiple myeloma or plasma cell leukemia in partial response or better; Hematologic malignancy in complete remission with minimal residual disease (MRD) detectable by conventional cytogenetics, FISH, flow cytometry, or molecular testing Any previous autologous transplant must have occurred > 3 months ago Left ventricular ejection fraction (LVEF) >= 35%, or shortening fraction > 25% Bilirubin <= 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis) AST and ALT <= 5 x institutional upper limit of normal FEV1 and FVC >= 40% of predicted; if unable to perform pulmonary function testing, oxygen saturation > 92% on room air ECOG performance status <= 2, or Karnofsky/Lansky status >= 60 Exclusion Criteria: Pregnancy or active breastfeeding Uncontrolled active infection Previous allogeneic transplant Active extramedullary leukemia or active central nervous system (CNS) malignant disease
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PBSCT D90<br>Non-myeloablative peripheral blood stem cell transplant (PBSCT) with a fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis. Tacrolimus will be stopped at either Day 90 or Day 180 depending on GVHD status. | Drug: Fludarabine<br>* Days -6 through -2: 30 mg/m^2 IV daily<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Days -6 and -5: 14.5 mg/kg IV daily Days 3 and 4: 50 mg/kg IV daily<br>* Other names: CTX;Radiation: Total body irradiation<br>* Day -1: 200 cGy in a single fraction<br>* Other names: TBI;Drug: Tacrolimus<br>* Start on Day 5 through either Day 60 or Day 90 depending on cohort assignment. May be continued through Day 180 depending on GVHD status.<br>* Other names: FK-506;Drug: Mycophenolate mofetil<br>* Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day)<br>* Other names: CellCept;|
| Experimental: PBSCT D60<br>Non-myeloablative peripheral blood stem cell transplant (PBSCT) with a fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis. Tacrolimus will be stopped at either Day 60 or Day 180 depending on GVHD status. | Drug: Fludarabine<br>* Days -6 through -2: 30 mg/m^2 IV daily<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Days -6 and -5: 14.5 mg/kg IV daily Days 3 and 4: 50 mg/kg IV daily<br>* Other names: CTX;Radiation: Total body irradiation<br>* Day -1: 200 cGy in a single fraction<br>* Other names: TBI;Drug: Tacrolimus<br>* Start on Day 5 through either Day 60 or Day 90 depending on cohort assignment. May be continued through Day 180 depending on GVHD status.<br>* Other names: FK-506;Drug: Mycophenolate mofetil<br>* Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day)<br>* Other names: CellCept;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Are Able to Stop Prophylactic Tacrolimus (D90 Cohort) | This outcome measures the feasibility of stopping prophylactic tacrolimus at Day 90. | Day 90 | 
| Percentage of Participants Who Are Able to Stop Prophylactic Tacrolimus (D60 Cohort) | This outcome measures the feasibility of stopping prophylactic tacrolimus at Day 60. | Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grades III-IV Acute GVHD, Days 90-180 (D90) | Number of participants who experience grade III or IV acute GVHD between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable. | Between Day 90 and Day 180 | 
| Number of Participants With Grades III-IV Acute GVHD, Days 60-180 (D60) | Number of participants who experience grade III or IV acute GVHD between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable. | Between Day 60 and Day 180 | 
| Number of Participants With Chronic GVHD, Days 90-180 (D90) | Number of participants who experience chronic GVHD requiring additional immunosuppressive therapy between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable. | Between Day 90 and Day 180 | 
| Number of Participants With Chronic GVHD, Days 60-180 (D60) | Number of participants who experience chronic GVHD requiring additional immunosuppressive therapy between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable. | Between Day 60 and Day 180 | 
| Number of Participants Who Experience Graft Failure, Days 90-180 (D90) | Number of participants who experience graft failure between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable. | Between Day 90 and Day 180 | 
| Number of Participants Who Experience Graft Failure, Days 60-180 (D60) | Number of participants who experience graft failure between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable. | Between Day 60 and Day 180 | 
| Number of Participants Who Experience Disease Relapse, Days 90-180 (D90) | Number of participants who experience disease relapse between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable. | Between Day 90 and Day 180 | 
| Number of Participants Who Experience Disease Relapse, Days 60-180 (D60) | Number of participants who experience disease relapse between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable. | Between Day 60 and Day 180 | 
| Number of Participants Who Experience Non-relapse Mortality, Days 90-180 (D90) | Number of participants who die for any reason other than disease relapse between Day 90 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 90 are evaluable. | Between Day 90 and Day 180 | 
| Number of Participants Who Experience Non-relapse Mortality, Days 60-180 (D60) | Number of participants who die for any reason other than disease relapse between Day 60 and Day 180. Only participants who are able to stop prophylactic tacrolimus at Day 60 are evaluable. | Between Day 60 and Day 180 | 
| Number of Participants Who Experience Grades III-IV GVHD, Day 360 (D90) | Number of participants who experience grade III or IV GVHD by Day 360. All participants are evaluable. | Day 360 | 
| Number of Number of Participants Who Experience Grades III-IV GVHD, Day 360 (D60) | Number of participants who experience grade III or IV GVHD by Day 360. All participants are evaluable. | Day 360 | 
| Number of Number of Participants With Severe Chronic GVHD, Day 360 (D90) | Number of participants who experience severe chronic GVHD requiring additional immunosuppressive therapy by Day 360. All participants are evaluable. | Day 360 | 
| Number of Number of Participants With Severe Chronic GVHD, Day 360 (D60) | Number of participants who experience severe chronic GVHD requiring additional immunosuppressive therapy by Day 360. All participants are evaluable. | Day 360 | 
| Number of Number of Participants Who Experience Graft Failure, Day 360 (D90) | Number of participants who experience graft failure by Day 360. All participants are evaluable. | Day 360 | 
| Number of Number of Participants Who Experience Graft Failure, Day 360 (D60) | Number of participants who experience graft failure by Day 360. All participants are evaluable. | Day 360 | 
| Number of Participants Who Experience Relapse, Day 360 (D90) | Number of participants who experience disease relapse by Day 360. All participants are evaluable. | Day 360 | 
| Number of Participants Who Experience Relapse, Day 360 (D60) | Number of participants who experience disease relapse by Day 360. All participants are evaluable. | Day 360 | 
| Number of Participants Who Experience Non-relapse Mortality, Day 360 (D90) | Number of participants who die for any reason other than disease relapse by Day 360. All participants are evaluable. | Day 360 | 
| Number of Participants Who Experience Non-relapse Mortality, Day 360 (D60) | Number of participants who die for any reason other than disease relapse by Day 360. All participants are evaluable. | Day 360 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
immunosuppression, nonmyeloablative, non-myeloablative, allogeneic, tacrolimus, peripheral blood, cyclophosphamide, mycophenolate mofetil