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Treosulfan-TMI Conditioning and Rapamycin GvHD Prophylaxis Before Allo-HSCT (TrRaMM-TMI)

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ClinicalTrials.gov Identifier: NCT03963024
Recruitment Status : Terminated (low rate of enrolment)
First Posted : May 24, 2019
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
Ciceri Fabio, IRCCS San Raffaele

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.


Condition or disease Intervention/treatment Phase
Irradiated Bone Marrow Transplant-Related Hematologic Malignancy Leukemia, Acute Multiple Myeloma Graft Vs Host Disease Drug: Conditioning treatment "Treosulfan-TMI" Procedure: SCT Drug: GvHD prophylaxis Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 12, 2014
Actual Primary Completion Date : January 31, 2019
Actual Study Completion Date : January 31, 2019


Arm Intervention/treatment
Experimental: Single Arm Treatment
Conditioning treatment "Treosulfan+TMI"; SCT; GvHD prophylaxis;
Drug: Conditioning treatment "Treosulfan-TMI"
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)

Procedure: SCT
Stem Cell Transplant

Drug: GvHD prophylaxis
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)




Primary Outcome Measures :
  1. Evaluation of the maximum tolerated dose of TMI (FEASIBILITY of TMI) [ Time Frame: From administration of TMI (-5) to transplant ]
    To determine the maximum tolerated dose of TMI when combined with conditioning chemotherapy to transplant according to TrRaMM schedule

  2. Rate of Survival post transplant [ Time Frame: +30 days post transplantation ]
    Evaluation of survival and engraftment


Secondary Outcome Measures :
  1. Efficacy - progression free survival (PFS) [ Time Frame: End of total follow-up is 365 days after transplantation of the last patient included ]
    PFS

  2. Efficacy - Overall survival (OS) [ Time Frame: End of total follow-up is 365 days after transplantation of the last patient included ]
    OS

  3. Efficacy - Relapse incidence (RI) [ Time Frame: End of total follow-up is 365 days after transplantation of the last patient included ]
    RI

  4. Evaluation of Transplant Safety - incidence of non-relapse mortality (NRM) [ Time Frame: Eon day +28, day +100 and +360 ]
    Evaluation of incidence of NRM

  5. Evaluation of Transplant Safety [ Time Frame: End of total follow-up is 365 days after transplantation of the last patient included ]
    Cumulative of incidence and cumulative severity of GvHD



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03963024


Locations
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Italy
Ospedale San Raffaele
Milano, Lombardia, Italy, 20132
Sponsors and Collaborators
IRCCS San Raffaele
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Responsible Party: Ciceri Fabio, Professor, IRCCS San Raffaele
ClinicalTrials.gov Identifier: NCT03963024    
Other Study ID Numbers: 2013-002479-16
First Posted: May 24, 2019    Key Record Dates
Last Update Posted: October 19, 2020
Last Verified: October 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms
Hematologic Neoplasms
Graft vs Host Disease
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Neoplasms by Site
Treosulfan
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents