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A Phase I/II Study of Escalating Doses of Thalidomide in Conjunction With Bortezomib and HIgh Dose Melphalan as a Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation in Patients With Advanced Multiple Myeloma


Phase 1/Phase 2
18 Years
75 Years
Open (Enrolling)
Both
Multiple Myeloma

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Trial Information

A Phase I/II Study of Escalating Doses of Thalidomide in Conjunction With Bortezomib and HIgh Dose Melphalan as a Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation in Patients With Advanced Multiple Myeloma


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.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Description:

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

Outcome Time Frame:

Dose escalation will be based on the assessment of tolerability determined after the last patient of each cohort reaches day +21.

Safety Issue:

Yes

Principal Investigator

Scott D Rowley, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

John Theurer Cancer Center at Hackensack Univ Medical Center

Authority:

United States: Food and Drug Administration

Study ID:

PRO-00001215

NCT ID:

NCT01242267

Start Date:

April 2010

Completion Date:

December 2014

Related Keywords:

  • Multiple Myeloma
  • multiple myeloma
  • transplant
  • Multiple myeloma patients undergoing transplant
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

John Theurer Cancer Center at Hackensack University Medical CenterHackensack, New Jersey  07601