Clinical trial NCT00637767: High-Dose Melphalan With or Without Radiolabeled Monoclonal Antibody in Treating Patients With Multiple Myeloma Undergoing an Autologous Stem Cell Transplant
Official title: A Randomised Phase II Clinical Trial Using Targeted Radiotherapy Delivered by an Yttrium-90 Radio-Labelled Anti-CD66 Monoclonal Antibody With High Dose Melphalan Compared to Melphalan Alone, Prior to Autologous Stem Cell Transplantation for Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Multiple Myeloma and Plasma Cell Neoplasm
Keywords: stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
Lead sponsor: University of Southampton
Sponsor class: OTHER
Collaborators: name: NIHR Clinical Research Facility, University Hospital Southampton NHS Foundation Trust
name: European Federation of Pharmaceutical Industries and Associations
name: Bill & Melinda Gates Foundation Visitor Center
name: The Periscope Consortium
name: Q-Biologicals NV
First posted: 2008-03-18
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiolabeled monoclonal antibodies can find cancer cells and carry cancer-killing substances to them without harming normal cells. A stem cell transplant using stem cells from the patient may be able to replace blood-forming cells that were destroyed by the chemotherapy and radiolabeled monoclonal antibody.

PURPOSE: This randomized phase II trial is studying how well high-dose melphalan works when given with or without radiolabeled monoclonal antibody in treating patients with multiple myeloma undergoing an autologous stem cell transplant.

Detailed description: OBJECTIVES:

Primary

* To determine the efficacy of high-dose melphalan (200mg/m²) in combination with targeted radiotherapy delivered by yttrium Y 90 anti-CD66 monoclonal antibody BW250/183, in terms of disease response (complete remission rate and change in serum free light chain level before and after treatment with yttrium Y 90 anti-CD66 monoclonal antibody BW250/183), in patients undergoing autologous hematopoietic stem cell transplantation for multiple myeloma.

Secondary

* To determine the toxicity profile of yttrium Y 90 anti-CD66 monoclonal antibody BW250/183 in the context of autologous hematopoietic stem cell transplantation.
* To determine the effect of targeted radiotherapy on other parameters of disease response, in terms of proportion of patients with partial remission, stable disease, and progressive disease, remission duration (time to disease progression), and overall survival.
* To determine the effect of targeted radiotherapy on engraftment when used in combination with high-dose melphalan in patients undergoing autologous hematopoietic stem cell transplantation for multiple myeloma.
* To investigate the pharmacokinetic behavior of indium In 111 anti-CD66 monoclonal antibody BW250/183 (used for dosimetry).
* To continue to develop a dosimetry model based on single-photon emission computed tomography (SPECT) and whole body gamma camera imaging following administration of the radiolabeled anti-CD66 monoclonal antibody (in a subset of patients at the Southampton site only).
* To assess the proportion of patients who form human anti-murine antibodies (HAMA) after treatment with targeted radiotherapy in the context of an autologous hematopoietic stem cell transplantation.

OUTLINE: This is a multicenter study. Patients are stratified according to disease risk group (low risk \[beta-2 microglobulin and C-reactive protein \< 6 or either beta-2 microglobulin or C-reactive protein ≥ 6\] vs high risk \[both beta-2 microglobulin and C-reactive protein ≥ 6\]). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive a dosimetry dose of indium In 111 anti-CD66 monoclonal antibody BW250/183 IV on day 1 and undergo gamma camera imaging and serial blood samples on days 1-5. Patients then receive a therapeutic dose of yttrium Y 90 anti-CD66 monoclonal antibody BW250/183 IV once between days 9 and 16 and high-dose melphalan IV on day 28. Patients then undergo autologous hematopoietic stem cell transplantation (HSCT) on day 30.
* Arm II: Patients receive high-dose melphalan IV on day 1. Patients then undergo autologous HSCT on day 3.

Patients in arm I undergo blood sample collection periodically for pharmacokinetic and pharmacodynamic studies and analysis of human anti-murine antibody (HAMA) status.

After completion of study treatment, patients are followed periodically.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically or cytologically proven multiple myeloma (MM)
* Scheduled to undergo autologous hematopoietic stem cell transplantation (HSCT) as consolidation treatment for MM

  * Must have sufficient CD34-positive stem cells (≥ 4 x 10\^6 cells per kg body weight) in cryo-storage for two autologous HSCTs
* In partial remission (PR) after prior chemotherapy but before priming therapy for stem cell mobilization

  * Patients in complete remission (CR) after prior chemotherapy are not eligible
* Bone marrow cellularity ≥ 20%

PATIENT CHARACTERISTICS:

* WHO performance status 0-1
* Life expectancy ≥ 24 weeks
* Hemoglobin ≥ 9.0 g/dL
* Neutrophils ≥ 1,500/mm³
* Platelets ≥ 50,000/mm³
* Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
* ALT and/or AST ≤ 2.5 times ULN
* Creatinine clearance ≥ 50 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile female patients must use effective contraception for 4 weeks prior to, during, and for 6 months after completion of study treatment
* Fertile male patients must use effective contraception during and for 6 months after completion of study treatment
* Able to cooperate with study treatment and follow up
* Human anti-mouse antibody (HAMA) negative
* No active uncontrolled infection
* No high-risk non-malignant systemic disease
* No other condition, that in the investigator's opinion, would make the patient an unsuitable candidate for the study
* No known HIV or hepatitis B or C seropositivity
* No history of allergy, including an allergy to rodents or rodent proteins
* No history of eczema or asthma
* No history of New York Heart Association (NYHA) class III or IV cardiac disease
* No congestive heart failure

PRIOR CONCURRENT THERAPY:

* Recovered from prior therapy

  * Alopecia or certain grade 1 toxicities allowed
* More than 4 weeks since prior radiotherapy (except for localized pain control), endocrine therapy, or immunotherapy
* More than 4 weeks since prior and no other concurrent chemotherapy for the underlying hematological condition, except for the following:

  * Cyclophosphamide as priming for stem cell harvest
  * Thalidomide
* More than 3 weeks since prior major thoracic and/or abdominal surgery and recovered
* No prior high-dose therapy and autologous HSCT
* Concurrent radiotherapy allowed for the control of bone pain

  * The irradiated lesions are not used for response evaluation
* No other concurrent anti-cancer therapy or investigational drugs during transplantation conditioning

Primary outcomes:
measure: Remission status pre- and post-transplantation, specifically the number of patients who achieve complete remission, as measured by the European Blood and Marrow Transplantation Organization Response Criteria
timeFrame: end of study
Secondary outcomes:
measure: Disease response, as measured by changes in serum free light chains (in those patients with serum free light chains that are informative)
timeFrame: end of study
measure: Disease response, including the proportion of patients with partial remission, stable disease, and progressive disease and remission duration (time to disease progression)
timeFrame: end of study
measure: Engraftment quality, as measured by time to recovery of peripheral blood neutrophils to > 500/mm³ and platelets > 50, 000/mm³ and duration of recovery for > 180 days post-transplantation
timeFrame: end of study
measure: Treatment-related mortality
timeFrame: end of study
measure: Overall survival
timeFrame: end of study
measure: Toxicity profile of yttrium Y 90 anti-CD66 monoclonal antibody BW250/183 in the context of autologous stem cell transplantation
timeFrame: end of study
measure: Pharmacokinetics of indium In 111 anti-CD66 monoclonal antibody BW250/183 as measured by serial blood samples and serial planar and single-photon emission computed tomography (SPECT) gamma camera imaging of selected organs
timeFrame: end of study
measure: Development of a dosimetry model based on SPECT and whole body gamma camera imaging
timeFrame: end of study
measure: Proportion of patients who form human anti-murine antibodies (HAMA) after treatment with targeted radiotherapy in the context of an autologous hematopoietic stem cell transplantation
timeFrame: end of study
Other outcomes:
Locations:
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
state: England
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
Study officials:
affiliation: University Hospital Southampton NHS Foundation Trust
name: Kim Orchard, MD
role: STUDY_CHAIR
References: