Clinical trial NCT01242267
Conditions: Multiple Myeloma
Keywords: multiple myeloma transplant Multiple myeloma patients undergoing transplant
Sponsor: Hackensack Meridian Health
Start date: 2010-05-11; Completion date: 2016-01-20
Enrollment: 29 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to:

• Determine the maximum tolerated dose of thalidomide used in conjunction with dose-intense melphalan, bortezomib and autologous (syngeneic) HSC support in the salvage therapy of patients who failed a prior treatment with dose-intense melphalan

The secondary objectives of this study are to:

* Determine the toxicities resulting from administration of combinations of thalidomide, bortezomib and melphalan
* Determine the complete response (CR) and very good partial response (VgPR) rate in patients undergoing ASCT using thalidomide, bortezomib and melphalan
* Evaluate the treatment-free interval after treatment with the combination of thalidomide, bortezomib and melphalan

Detailed description:
VELCADE™ (bortezomib) for Injection is a small molecule proteasome inhibitor developed by Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies. VELCADE is currently approved by the United States Food and Drug Administration (US FDA) and it is registered in Europe for the treatment of multiple myeloma patients who have received at least one prior therapy.

By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling pathways. The anti-neoplastic effect of bortezomib likely involves several distinct mechanisms, including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition of expression of genes that control cellular adhesion, migration and angiogenesis. Thus, the mechanisms by which bortezomib elicits its antitumor activity may vary among tumor types, and the extent to which each affected pathway is critical to the inhibition of tumor growth could also differ. Bortezomib has a novel pattern of cytotoxicity in National Cancer Institute (NCI) in vitro and in vivo assays (Adams et al., 1999). In addition, bortezomib has cytotoxic activity in a variety of xenograft tumor models, both as a single agent and in combination with chemotherapy and radiation (Steiner et al., 2001; Teicher et al., 1999; Cusack et al., 2001; LeBlanc et al., 2002; Pink et al., 2002). Notably, bortezomib induces apoptosis in cells that over express bcl-2, a genetic trait that confers unregulated growth and resistance to conventional chemotherapeutics (McConkey et al., 1999).

Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear factor κB (NF-κB) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct apoptotic effect, and possibly anti-angiogenic and other effects.

Arms: arm 1: Phase 1 including Thalidomide Dose Levels of 600, 800, 1000 mg. Three patients will be entered at each dose level sequentially with a maximum of six patients enrolled at the highest dose level that defines dose-limiting toxicity. The starting dose will be 600mg/d x 5 days (dose level 1) given on days -5 to -1 before transplantation. Doses will be escalated in sequential order as listed below through cohorts of patients. arm 2: Phase 2 Thalidomide Dose Level of 1000 mg. The maximum dose to be tested is 1000mg. When the MTD is defined, an additional 40 patients will be enrolled at this level. The first 3 patients of this cohort of 40 patients will be assessed for DLT (2 of 6 patients experiencing DLT at this dose will require dose-de-escalation as described above, and the phase II portion of the study re-initiated at the newly defined MTD).
Interventions: intervention 1: Thalidomide+Melphalan +Bortezomib+stem cell transplant
Intervention descriptions: intervention 1: Five days prior to transplant, the patient starts thalidomide. Dose range will be from 600mg for 5 days, to 1000mg for 5 days. Thalidomide dose is increased after groups of 3 to 6 patients have been treated. 4 days before the transplant and again on the day before the transplant the patient will be given bortezomib (VELCADE) intravenously at a dose of 1.6 mg/m2 (mg/m2 means that the dose will be calculated based on the patient's height and weight). 2 days before transplant the patient will be given melphalan 200 mg/m2 intravenously. Dexamethasone is given before the VELCADE and the melphalan.

Protocol documents: