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Study Comparing STR (Skeletal Targeted Radiotherapy) Plus Melphalan to Melphalan Alone, With Stem Cell Transplant in Multiple Myeloma

This study has been terminated.
(For business reasons)
Sponsor:
Information provided by:
Poniard Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00083564
First received: May 25, 2004
Last updated: March 30, 2009
Last verified: March 2009
  Purpose

STR (Skeletal Targeted Radiotherapy, 166Ho-DOTMP) is an investigational radiopharmaceutical that delivers radiation directly to cancer cells in the bone and bone marrow. Conventional methods of delivering radiation therapy, such as total body irradiation, expose non-target tissues to radiation and cause serious side effects. In contrast, STR's targeted approach to delivering radiotherapy concentrates the radiation where it is needed, and minimizes exposure of normal tissues.

STR is composed of a bone-targeting molecule, DOTMP, in a stable complex with the radionuclide holmium-166. When injected into a patient's bloodstream, STR rapidly binds to bone mineral, delivering a brief, intense dose of radiation to destroy cancer cells in the bone and marrow. The high-energy and long path-length of holmium-166 beta particles provide optimal penetration and uniform irradiation of disease sites in the marrow and bone. STR that does not bind to bone is rapidly eliminated through the urinary tract. STR treatment is followed by autologous stem cell transplantation. The short half-life of holmium-166 allows treatment on an out-patient basis, and minimizes the time required between STR administration and transplantation.

The phase III study of STR is a multi-center, randomized, controlled study, designed to evaluate the safety and efficacy of STR in patients with primary refractory multiple myeloma. These are patients who have failed to achieve at least a partial response to conventional therapy and have been undergoing treatment for less than 18 months. The trial is expected to enroll approximately 240 evaluable patients, half on the experimental arm and half on the control arm. Patients on the experimental arm will receive STR at a dose of 750 mCi/m2 plus the chemotherapy drug melphalan at 200 mg/m2, followed by autologous stem cell transplantation. Patients on the control arm will receive melphalan only, followed by transplantation. Patients on both study arms will be evaluated for response to treatment six months after transplantation, using an immunofixation assay to detect myeloma protein in patient samples. Analysis of patient samples will be conducted at a central laboratory, and blinded results will be reviewed by an independent panel of experts. The study's primary endpoint is complete response, as determined by the complete disappearance of myeloma protein at six months post-transplant.


Condition Intervention Phase
Multiple Myeloma
Drug: STR(TM) (Skeletal Targeted Radiotherapy, Holmium-166-DOTMP)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Multicenter Study to Compare the Safety and Efficacy of 166Ho-DOTMP Plus Melphalan to Melphalan Alone as Conditioning for Autologous Peripheral Blood Stem Cell Transplant in Subjects With Primary Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Poniard Pharmaceuticals:

Estimated Enrollment: 240
Study Start Date: March 2004
Detailed Description:

PRIMARY OBJECTIVE:

1.To determine the efficacy of STR (166Ho-DOTMP). The primary endpoint of this study is to compare the CR rate at 6 months post-transplant (in the absence of further therapy) in subjects with primary refractory multiple myeloma after treatment with 750 mCi/m2 166Ho-DOTMP plus 200 mg/m2 melphalan followed by autologous PBSCT to treatment with 200 mg/m2 melphalan alone followed by autologous PBSCT.

SECONDARY OBJECTIVES:

  1. To compare the treatment groups with respect to survival and progression-free survival.
  2. To compare treatment groups with respect to overall response rate (CR+VGPR+PR), best response within 6 months, and duration of response.
  3. To compare the safety profile of the treatment groups.
  4. To assess the biodistribution and estimated radiation absorbed dose to kidney in the first 20 subjects.

METHODOLOGY: Informed consent for participation in the study will be obtained, eligibility determined, and the subject registered. All subjects will receive a tracer dose of 30 mCi 166Ho-DOTMP to determine skeletal uptake and biodistribution of 166Ho-DOTMP therapy. Subjects may receive a therapy dose only if 1) the tracer dose shows no aberrant distribution, and 2) if the skeletal residence time is at least 5.8 hours (equivalent to F x Te > 4 hr). Subjects with adequate skeletal uptake and no aberrant distribution will be stratified based on the length of time since first induction therapy, and on response to prior therapy, and will undergo randomization to determine whether they will receive 166Ho DOTMP plus melphalan (Arm A) or melphalan alone (Arm B) as the conditioning regimen prior to autologous PBSCT.

Subjects randomized to Arm A will be treated with 750 mCi/m2 166Ho DOTMP intravenously 4 to 12 days after the tracer dose, with a total dosage not to exceed 1500 mCi. Five to 9 days after the 166Ho-DOTMP therapy dose, subjects will receive 200 mg/m2 melphalan IV.

Subjects randomized to Arm B will receive 200 mg/m2 melphalan at least 10 days and no more than 3 weeks after the tracer dose.

For all patients, cryopreserved hematopoietic stem cells will be infused 24 to 48 hours after melphalan. Subjects will be followed for safety assessments for 10 years or until death. Efficacy will be evaluated for up to 3 years in responding subjects, and disease relapse or progression and survival will be documented until Year 10.

An analysis to estimate radiation dose to the kidney will be performed in the first 20 patients. Additionally, after 6 months of follow-up have been completed on the first 20 subjects in each arm, an analysis of the CR rate will be conducted to rule out lack of efficacy of 166Ho-DOTMP. A planned interim analysis to determine the efficacy of the treatment will be performed when 60 patients on each arm have completed 6 months of follow-up. Enrollment on trial will continue while these interim analyses are performed.

NUMBER OF SUBJECTS: Two hundred and forty subjects who meet the eligibility criteria and receive study treatment will be followed on this protocol.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A subject must meet all of the following criteria to be eligible for the study. These will be evaluated within four weeks prior to enrollment.

  • Subject must have primary refractory multiple myeloma defined as having failed to achieve an objective response (CR or PR using EBMT/IBMTR/ABMTR criteria) to any therapy since the initiation of induction therapy. At least one previous therapy must be a qualifying therapy that includes high dose pulsed steroids.
  • There must be < 18 months from the beginning of induction therapy to time of enrollment on study.
  • Subject must meet institutional guidelines for autologous PBSCT.
  • Subject must have a minimum of 2 x 106 unmanipulated CD34+ cells/kg cryopreserved and available for transplant.
  • Age 18 and 70 years.
  • Adequate pulmonary function defined by FEV1, FVC and DLCO > or = 50% of predicted.
  • Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) of > or = 45%, with no evidence of cardiac amyloidosis.
  • Adequate liver function, defined as serum total bilirubin < or = 2x institutional laboratory upper limit of normal and ALT/SGPT < or = 3x institutional laboratory upper limit of normal.
  • Adequate renal function, defined as 24 hour measured creatinine clearance of > or = 50 mL/min/1.73 m2 BSA and serum creatinine < or = 1.8 mg/dL.
  • ECOG performance score (PS) of 0, 1, or 2.
  • Women of childbearing potential must have a negative pregnancy test (serum or urine beta HCG) and be using appropriate birth control methods.
  • Ability to understand the study and provide informed consent.

Exclusion Criteria:

A subject meeting any of the following criteria is not eligible for participation in the study:

  • Non-secretory multiple myeloma.
  • Asymptomatic MGUS, smoldering multiple myeloma, or indolent multiple myeloma.
  • Solitary bone or extramedullary plasmacytoma.
  • Waldenstrom's macroglobulinemia (IgM myeloma).
  • Evidence of disease progression (such as new bone lesions) in the setting of a greater than 50% reduction in M-protein.
  • Absence of previous therapy with pulsed corticosteroids for multiple myeloma.
  • Previous high-dose therapy with stem cell or bone marrow transplant, including autologous, allogeneic, and reduced-intensity or non-myeloablative allogeneic transplants.
  • Life expectancy severely limited by concomitant illness (less than 6 months).
  • Evidence of symptomatic spinal cord compression or pathological fracture within 3 months.
  • Cumulative external beam radiation to > 20% of marrow volume or > 40 Gy to any single region of the spinal cord.
  • Prior radiation to the bladder or kidney, defined as radiation portals that directly include any volume of either kidney or the bladder.
  • Uncontrolled arrhythmia or symptomatic cardiac disease.
  • Clinical evidence of amyloidosis involving the heart, lungs, liver, kidney, autonomic nervous system, or GI tract.
  • History of hemorrhagic cystitis.
  • Current microscopic or gross hematuria in the absence of vaginal bleeding.
  • Obstructive uropathy.
  • Inability to have bladder catheter placed.
  • Evidence of HIV-seropositivity.
  • Recent history of alcohol or drug abuse.
  • History of non-compliance in other studies.
  • Use of bisphosphonates within 14 days preceding enrollment.
  • Use of any other therapy for multiple myeloma (including standard, induction, investigational, and alternative therapies) within 4 weeks prior to enrollment.
  • Experimental therapies for any other conditions in the four weeks prior to enrollment.
  • Pregnant or lactating women.
  • Known allergy to vitamin C or bisphosphonates.
  • Other prior malignancy except for: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or any other cancer from which the subject has been disease-free for 5 years.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00083564

  Hide Study Locations
Locations
United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35249
United States, California
Chao Family Comprehensive Cancer Center, University of California, Irvine
Orange, California, United States, 92868
United States, Colorado
Rocky Mountain Cancer Centers
Denver, Colorado, United States, 80218
United States, Florida
University of Miami
Miami, Florida, United States, 33136
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, Iowa
University of Iowa Hospital and Clinics
Iowa City, Iowa, United States, 52242
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Michigan
Wayne State University, Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Nebraska
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10467
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Case Western Reserve University
Cleveland, Ohio, United States, 44106
Miami Valley Hospital
Dayton, Ohio, United States, 45409
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
United States, Texas
Baylor University Medical Center
Dallas, Texas, United States, 75246
MD Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
United States, Wisconsin
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53208
Canada, Ontario
Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
Poniard Pharmaceuticals
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00083564     History of Changes
Other Study ID Numbers: STR 0303
Study First Received: May 25, 2004
Last Updated: March 30, 2009
Health Authority: United States: Food and Drug Administration

Keywords provided by Poniard Pharmaceuticals:
Multiple myeloma
Primary refractory multiple myeloma
STR
Skeletal Targeted Radiotherapy
Holmium-166
166-Ho-DOTMP

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
Melphalan
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014