Escalating Doses of Thalidomide in Conjunction With Bortezomib and HIgh Dose Melphalan for BSCT
Escalating Doses of Thalidomide in Conjunction With Bortezomib and HIgh Dose Melphalan for BSCT
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
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.
Inclusion Criteria:

 -  Each patient must meet all of the following inclusion criteria to be enrolled in the
 study:

 -  Voluntary written informed consent before performance of any study-related procedure
 not part of normal medical care, with the understanding that consent may be withdrawn
 by the subject at any time without prejudice to future medical care

 -  Female subject is either post-menopausal or surgically sterilized or willing to use an
 acceptable method of birth control as described in the S.T.E.P.S program.
 Participation in the program is required.

 -  Male subject agrees to use an acceptable method for contraception for the duration of
 the study as described in the S.T.E.P.S program. Participation in the program is
 required.

 -  Confirmed diagnosis of multiple myeloma, or plasma cell leukemia.

 -  Show progression of disease after a previous dose-intense cycle of melphalan, or less
 than a complete response after a prior cycle of dose-intense melphalan. Patients may
 have received more than on prior autologous transplant with high-dose melphalan.

 -  May have received intervening therapies after disease progression after dose-intense
 melphalan and before enrollment in this protocol.

 -  Recovery from complications of salvage therapy, if administered.

 -  Age: ≥18 yrs but <76 yrs at the time of melphalan administration.

 -  Gender: There is no gender restriction.

 -  Availability of >2x106 autologous peripheral blood CD34+ cells/kg or a syngeneic donor
 meeting eligibility criteria for syngeneic donation.

 1. Syngeneic transplantation is preferred.

 Exclusion Criteria:

 -  Patients meeting any of the following exclusion criteria are not to be enrolled in the
 study.

 -  Cytotoxic chemotherapy or radiotherapy within 21 days of initiating treatment in this
 study.

 -  Prior dose-intense therapy within 56 days of initiating treatment in this study.

 -  Uncontrolled bacterial, viral, fungal or parasitic infections .

 -  Uncontrolled CNS metastases.

 -  Known amyloid deposition in heart.

 -  Organ dysfunction:

 LVEF <40% or cardiac failure not responsive to therapy. DLCO <50% of predicted and/or
 receiving supplementary continuous oxygen. Evidence of hepatic synthetic dysfunction, or
 total bilirubin >2x or AST >3x ULN.

 Measured creatinine clearance <20 ml/min. Sensory peripheral neuropathy grade 4 within 14
 days of enrollment.

 -  Karnofsky score <70% unless as a result of bone disease directly caused by myeloma.

 -  Life expectancy limited by another co-morbid illness.

 -  Diagnosed or treated for another malignancy within 2 years of enrollment, with the
 exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
 the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

 -  Female subject is pregnant or breast-feeding (women) or unwilling to use acceptable
 birth control methods (men or women) for twelve months after treatment or unwilling to
 participate in the S.T.E.P.S program.

 -  Documented hypersensitivity to melphalan, thalidomide or to bortezomib, boron or
 mannitol or any components of the formulation

 -  Patients unable or unwilling to provide consent

 -  Myocardial infarction within 6 months prior to enrollment or has New York Heart
 Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
 uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
 ischemia or active conduction system abnormalities. Prior to study entry, any ECG
 abnormality at screening has to be documented by the investigator as not medically
 relevant.

 -  Patient has received other investigational drugs with 14 days before enrollment

 -  Serious medical or psychiatric illness likely to interfere with participation in this
 clinical study.