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

Primary Purpose

Irradiated Bone Marrow, Transplant-Related Hematologic Malignancy, Leukemia, Acute

Status

Terminated

Phase

Phase 1

Locations

Italy

Study Type

Interventional

Intervention

Conditioning treatment "Treosulfan-TMI"

SCT

GvHD prophylaxis

About this trial

This is an interventional treatment trial for Irradiated Bone Marrow

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Ospedale San Raffaele

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single Arm Treatment

Arm Description

Conditioning treatment "Treosulfan+TMI"; SCT; GvHD prophylaxis;

Outcomes

Primary Outcome Measures

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

Rate of Survival post transplant

Evaluation of survival and engraftment

Secondary Outcome Measures

Efficacy - progression free survival (PFS)

PFS

Efficacy - Overall survival (OS)

Efficacy - Relapse incidence (RI)

Evaluation of Transplant Safety - incidence of non-relapse mortality (NRM)

Evaluation of incidence of NRM

Evaluation of Transplant Safety

Cumulative of incidence and cumulative severity of GvHD

Full Information

NCT ID

NCT03963024

First Posted

May 21, 2019

Last Updated

October 13, 2020

Sponsor

IRCCS San Raffaele

1. Study Identification

Unique Protocol Identification Number

NCT03963024

Brief Title

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

Acronym

TrRaMM-TMI

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2020

Overall Recruitment Status

Terminated

Why Stopped

low rate of enrolment

Study Start Date

February 12, 2014 (Actual)

Primary Completion Date

January 31, 2019 (Actual)

Study Completion Date

January 31, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

IRCCS San Raffaele

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

9 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Single Arm Treatment

Arm Type

Experimental

Arm Description

Conditioning treatment "Treosulfan+TMI"; SCT; GvHD prophylaxis;

Intervention Type

Drug

Intervention Name(s)

Conditioning treatment "Treosulfan-TMI"

Intervention Description

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)

Intervention Type

Procedure

Intervention Name(s)

SCT

Intervention Description

Stem Cell Transplant

Intervention Type

Drug

Intervention Name(s)

GvHD prophylaxis

Intervention Description

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 Measure Information:

Title

Evaluation of the maximum tolerated dose of TMI (FEASIBILITY of TMI)

Description

To determine the maximum tolerated dose of TMI when combined with conditioning chemotherapy to transplant according to TrRaMM schedule

Time Frame

From administration of TMI (-5) to transplant

Title

Rate of Survival post transplant

Description

Evaluation of survival and engraftment

Time Frame

+30 days post transplantation

Secondary Outcome Measure Information:

Title

Efficacy - progression free survival (PFS)

Description

PFS

Time Frame

End of total follow-up is 365 days after transplantation of the last patient included

Title

Efficacy - Overall survival (OS)

Description

Time Frame

End of total follow-up is 365 days after transplantation of the last patient included

Title

Efficacy - Relapse incidence (RI)

Description

Time Frame

End of total follow-up is 365 days after transplantation of the last patient included

Title

Evaluation of Transplant Safety - incidence of non-relapse mortality (NRM)

Description

Evaluation of incidence of NRM

Time Frame

Eon day +28, day +100 and +360

Title

Evaluation of Transplant Safety

Description

Cumulative of incidence and cumulative severity of GvHD

Time Frame

End of total follow-up is 365 days after transplantation of the last patient included

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

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

Facility Information:

Facility Name

Ospedale San Raffaele

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20132

Country

Italy

12. IPD Sharing Statement

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

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