Phase 1-2 Study of Total Bone Marrow Irradiation With Helicoidal Tomotherapy in 1st Myeloma Relapse

Study Overview
=================
Brief Summary
-----------------
In Multiple Myeloma, an adult hematological malignancy, mainly located in the Bone Marrow (BM), dramatic recent progresses have been observed, thanks to new agents (proteasome inhibitors and IMIDs). However, at time of first relapse, high-dose therapy followed by Stem Cell Rescue (SCR) is frequently mandatory as a consolidation in minimal residual disease, to healthy patients under 65 yo, combining Melphalan (MPH) and/or Total Body Irradiation. Modern irradiation modalities are now available by the use of HI-ART Tomotherapy system to realize a Total Bone Marrow Irradiation (TBMI), in order both to limit the dose administered to Organ at Risk (lungs, oral cavity) and to focus efficacy on BM. In this phase-1 study, the conditioning regimen before SCR will combine a fixed high-dose MPH (140 mg/m²) and a dose escalated TBMI, so as to define its Maximal Tolerated Dose (MTD) and the Dose Limiting Toxicities (DLT). An extended cohort will further in a phase-2 setting.

Detailed Description
-----------------
Experimental : Total Bone Marrow Irradiation (TBMI) is delivered by the Tomotherapy HI-ART machine, in 2 fractions per day during 4 consecutive days from d -6 to d -3. The escalated dose levels are determined according to a 3x3 modified Fibonacci method and five dose levels will be explored. The doses per fraction are: 1gy, 1.25gy, 1.5gy, 1.75gy and 2gy, and consequently the cumulative TBMI doses are: 8gy, 10gy, 12gy, 14gy and 16gy. Drug : Melphalan is infused intravenously in 30 minutes on day -2 after IV anti-emetics. Autologous Peripheral Stem Cell Rescue : are re-infused in the central line on day 0 after adequate premedication. Despite the recent finding of new drugs (proteasome inhibitors and IMIDs), Multiple Myeloma still remain uncurable, especially after the first relapse, even in responding disease under conventional chemotherapy. In the healthy youngest patients (<65 yo), when peripheral stem cells collection is available, a high-dose therapy is often proposed in consolidation of complete or very good partial remission: the conditioning regimen usually includes high dose alkylating agent (mostly Melphalan) and/or Total Body Irradiation. The new Tomotherapy HI-ART technology allows irradiating on a 1.6m length field all the bone marrow sites together with optimal respect of the Organ at Risk (lungs, oral cavity, heart, liver, kidneys…). The proposed phase-1 study will explore the safety and efficacy of escalated dose of Total Bone-Marrow Irradiation in combination with a fixed dose of Melphalan (140mg/m²), followed by autologous SCR. To determine the MTD is the main objective of the study, then the toxicity profile (DLTs) and the RP2D in an extended cohort at the MTD dose.

Official Title
-----------------
Phase 1-2 Study of the Combination of Escalated Total Bone Marrow Irradiation (TBMI) by Helicoidal Tomotherapy and a Fixed High-dose Melphalan (140 mg/m²) Followed by Peripheral Stem Cell Rescue (PSC) in First Relapsed Multiple Myeloma.

Conditions
-----------------
Multiple Myeloma in Relapse

Intervention / Treatment
-----------------
* Drug: Melphalan
* Biological: Autologous Hematopoietic Stem cell


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Multiple Myeloma in first relapse. In Complete or very good partial remission Available Collected Autologous Peripheral Stem cells: 2.5x106 CD34+/Kg Exclusion Criteria: Uncontrolled visceral disease: kidney, heart, lung, diabetes mellitus Previous Total body irradiation Any previous radiation dose to the spinal cord which could reach to 45gy equivalent, including the proposed TBMI Amyloidosis Brain localizations

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 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: Total BM irradiation dose<br>Total Bone Marrow Irradiation (TBMI) is delivered by the Tomotherapy HI-ART machine, in 2 fractions per day during 4 consecutive days from d -6 to d -3. The escalated dose levels are determined according to a 3x3 modified Fibonacci method and five dose levels will be explored. The doses per fraction are: 1gy, 1.25gy, 1.5gy, 1.75gy and 2gy, and consequently the cumulative TBMI doses are: 8gy, 10gy, 12gy, 14gy and 16gy. For Every patients: Drug : Melphalan is infused intravenously in 30 minutes on day -2 after IV anti-emetics. Autologous Peripheral Stem Cell Rescue : are re-infused in the central line on day 0 after adequate premedication. | Drug: Melphalan<br>* Melphalan: 140 mg/m²is infused intravenously in 30 minutes on day -2 after IV anti-emetics (5-HT3 antagonists).<br>* Other names: Phenylalanin Mustard;Biological: Autologous Hematopoietic Stem cell<br>* Autologous Peripheral Stem Cell Rescue : 2.5 10^6 CD-34/Kg are re-infused in the central line on day 0 after adequate premedication.<br>* Other names: Hematopoietic stem cell;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Tolerated Dose, type of DLTs | Maximal Tolerated Dose Type of Dose-limiting Toxicities The escalated dose levels are determined according to a 3x3 modified Fibonacci method and five dose levels will be explored. The doses per fraction are: 1gy, 1.25gy, 1.5gy, 1.75gy and 2gy, and consequently the cumulative TBMI doses are: 8gy, 10gy, 12gy, 14gy and 16gy. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile Recommended Dose for Phase-2 (RDP2) | Safety profile: acute, short and middle term toxicities Recommended Dose for Phase-2 (RDP2) and Extended Cohort for 14 patients at this dose | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Multiple Myeloma, Relapse, Complete Remission, Very Good Partial Remission