Treosulfan-TMI Conditioning and Rapamycin GvHD Prophylaxis Before Allo-HSCT

Study Overview
=================
Brief Summary
-----------------
TrRaMM-TMI is a phase I trial to evaluate the feasibility and efficacy of an original sequential TMI/TrRaMM (Total Marrow Irradiation/Treosulfan-Rapamycin-Mycophenolate Mofetil) schedule in patients with hematological malignancies in advanced stage of disease undergoing an allogenic Stem Cell Transplant (SCT). The aim is to determine the maximum tolerated dose of TMI when combined with conditioning chemotherapy to transplant according to TrRaMM schedule.

Official Title
-----------------
Treosulfan and Total-marrow Irradiation (TMI) Based Conditioning With Rapamycin Based Graft vs. Host Disease (GvHD) Prophylaxis for Allogenic Stem Cell Transplantation (Allo-HSCT) in Patients With High-risk Hematological Malignancies

Conditions
-----------------
Irradiated Bone Marrow, Transplant-Related Hematologic Malignancy, Leukemia, Acute, Multiple Myeloma, Graft Vs Host Disease

Intervention / Treatment
-----------------
* Drug: Conditioning treatment Treosulfan-TMI
* Procedure: SCT
* Drug: GvHD prophylaxis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with haematological malignancies such as any acute myeloid leukemia (AML) beyond Complete Remission (CR) 1 any acute lymphoblastic leukemia (ALL) beyond CR1 multiple myeloma (MM) at any relapse/progression, except refractory disease MM with unfavourable cytogenetic profile at diagnosis MM with less than a partial response (PR) after induction therapy Karnofsky Index ≥ 80 % Adequate contraception in female patients of child-bearing potential. Written informed consent Availability of one of the following: A matched related or unrelated donor (MRD or MUD) Exclusion Criteria: A hematopoietic cell transplantation-specific comorbidity index > 4 Active non-controlled infectious disease at the moment of inclusion Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection Impaired liver function (Bilirubin > 2.0 x upper normal limit; Transaminases > 3.0 x upper normal limit) Impaired renal function (Creatinine-clearance < 60 ml/min; Serum Creatinine > 1.5 x upper normal limit). Pleural effusion or ascites > 1.0 L Pregnancy or lactation Known hypersensitivity to treosulfan and/or fludarabine and/or rapamycin Non-co-operative behaviour or non-compliance Psychiatric diseases or conditions that might impair the ability to give informed consent Previous spinal cord radiotherapy with dose ≥ 45 Gy equivalent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm Treatment<br>Conditioning treatment Treosulfan+TMI; SCT; GvHD prophylaxis; | Drug: Conditioning treatment Treosulfan-TMI<br>* Treosulfan i.v.: 14 g/m²/d (day -6 to -4) Fludarabine i.v.: 30 mg/m²/d (day -6 to -2) Antithymocyte globulin (ATG)-Fresenius i.v.: 5/0 mg/kg (day -4 to -2) Mabthera i.v.: 200/0* mg/m2 (day -1) TMI: (10 Gy) 2 Gy bis in die (BID) (day -2 to -1) or TMI: (12 Gy) 2 Gy BID (day -3 to -1) or TMI: (14 Gy) 2 Gy BID (day -3 to -1)<br>Procedure: SCT<br>* Stem Cell Transplant<br>Drug: GvHD prophylaxis<br>* Rapamycin p.o.: 4 mg/d, (target 8-15 ng/ml) (starting day -7) Mycofenolate mofetile: 10 mg/kg tid, (Maximum dose 720 mg/tid) (starting from day 0)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the maximum tolerated dose of TMI (FEASIBILITY of TMI) | To determine the maximum tolerated dose of TMI when combined with conditioning chemotherapy to transplant according to TrRaMM schedule | From administration of TMI (-5) to transplant | 
| Rate of Survival post transplant | Evaluation of survival and engraftment | +30 days post transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - progression free survival (PFS) | PFS | End of total follow-up is 365 days after transplantation of the last patient included | 
| Efficacy - Overall survival (OS) | OS | End of total follow-up is 365 days after transplantation of the last patient included | 
| Efficacy - Relapse incidence (RI) | RI | End of total follow-up is 365 days after transplantation of the last patient included | 
| Evaluation of Transplant Safety - incidence of non-relapse mortality (NRM) | Evaluation of incidence of NRM | Eon day +28, day +100 and +360 | 
| Evaluation of Transplant Safety | Cumulative of incidence and cumulative severity of GvHD | End of total follow-up is 365 days after transplantation of the last patient included |