Clinical trial NCT01794572: Phase 1-2 Study of Total Bone Marrow Irradiation With Helicoidal Tomotherapy in 1st Myeloma Relapse
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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma in Relapse
Keywords: Multiple Myeloma
Relapse
Complete Remission
Very Good Partial Remission
Lead sponsor: Institut Cancerologie de l'Ouest
Sponsor class: OTHER
First posted: 2013-02-20
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Maximal Tolerated Dose, type of DLTs
timeFrame: 1 year
Secondary outcomes:
measure: Safety profile Recommended Dose for Phase-2 (RDP2)
timeFrame: 1 year
Other outcomes:
measure: Efficacy expressed as the rate (%) of Complete Response and Very Good Partial Response
timeFrame: 1 and 2 years
Locations:
city: Bordeaux
country: France
facility: CLCC Bergonie, service de radiotherapie
city: Bordeaux
country: France
facility: CHU Haut-Leveque, service d'Hématologie
city: Lille
country: France
facility: CLCC Oscar Lambret, service de radiothérapie
city: Lille
country: France
facility: CHU Claude Huriez, service d'hématologie
city: Nantes
country: France
facility: CHU Hotel-Dieu, service d'hématologie
city: Saint-Herblain
country: France
facility: CLCC ICO, service de radiothérapie
city: Strasbourg
country: France
facility: CLCC Paul Strauss, service de radiothérapie
city: Strasbourg
country: France
facility: CHU Hautepierre, service d'hématologie
Study officials:
affiliation: Institut de Cancerologie de l'Ouest
name: Stéphane A SUPIOT, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, CHU de NANTES
name: Philippe MOREAU, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wong JY, Rosenthal J, Liu A, Schultheiss T, Forman S, Somlo G. Image-guided total-marrow irradiation using helical tomotherapy in patients with multiple myeloma and acute leukemia undergoing hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys. 2009 Jan 1;73(1):273-9. doi: 10.1016/j.ijrobp.2008.04.071. Epub 2008 Sep 9.
citation: Somlo G, Spielberger R, Frankel P, Karanes C, Krishnan A, Parker P, Popplewell L, Sahebi F, Kogut N, Snyder D, Liu A, Schultheiss T, Forman S, Wong JY. Total marrow irradiation: a new ablative regimen as part of tandem autologous stem cell transplantation for patients with multiple myeloma. Clin Cancer Res. 2011 Jan 1;17(1):174-82. doi: 10.1158/1078-0432.CCR-10-1912. Epub 2010 Nov 3.