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

Multiple Myeloma in Relapse Clinical Trial

— TOMMY  

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01794572
• Other study ID #: ICO-2012-04
• Secondary ID: 2012-001473-91
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: April 24, 2013
• Est. completion date: January 7, 2020

Study information

• Verified date: January 2021
• Source: Institut Cancerologie de l'Ouest
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 13
• Est. completion date: January 7, 2020
• Est. primary completion date: January 7, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Multiple Myeloma in Relapse
• Neoplasms, Plasma Cell
• Recurrence

Intervention

Drug:
• Melphalan
Melphalan: 140 mg/m²is infused intravenously in 30 minutes on day -2 after IV anti-emetics (5-HT3 antagonists).

Biological:
• Autologous Hematopoietic Stem cell
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.

Locations

Country	Name	City	State
France	CHU Haut-Leveque, service d'Hématologie	Bordeaux
France	CLCC Bergonie, service de radiotherapie	Bordeaux
France	CHU Claude Huriez, service d'hématologie	Lille
France	CLCC Oscar Lambret, service de radiothérapie	Lille
France	CHU Hotel-Dieu, service d'hématologie	Nantes
France	CLCC ICO, service de radiothérapie	Saint-Herblain
France	CHU Hautepierre, service d'hématologie	Strasbourg
France	CLCC Paul Strauss, service de radiothérapie	Strasbourg

Sponsors (1)

Lead Sponsor	Collaborator
Institut Cancerologie de l'Ouest

Country where clinical trial is conducted

France, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Efficacy expressed as the rate (%) of Complete Response and Very Good Partial Response	osteo-medullary PET fixations evaluation by FDG PET-Scan Disease-free survival at 1 year and Overall Survival	1 and 2 years
Primary	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	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