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Phase II Trial of Doxil, Vincristine and Decadron (DVD) in Multiple Myeloma, Newly Diagnosed and Refractory Disease

General Information

The purpose of this study is to evaluate the effectiveness of the investigational drug DOXIL in treating patients with Multiple Myeloma. DOXIL will be used in combination with vincristine and Decadron, where the DOXIL will replace the Adriamycin, which is the usual part of the standard Vincristine, Adriamycin, and Decadron treatment. Doxil is a special formulation of the approved anticancer drug, Doxorubicin hydrochloride (Adriamycin). In this formulation, the drug Doxorubicin is enclosed in tiny, fatty bubbles called liposomes. Tests conducted have shown that Doxorubicin enclosed in these liposomes appears to deliver drug more directly to the tumor and secondary tumor (metastases) sites, with lesser amounts going to normal areas, thus lessening side effects. This study will also evaluate the side effects caused by treatment with DOXIL. Approximately 30 patients will participate in this study.

Eligibility Criteria

Inclusion Criteria

Each patient must meet all these criteria to be considered for enrollment.

All newly diagnosed multiply myeloma patients will be eligible.

All patients that have failed or progressed after at least one treatment regimen, and no more than 4 treatment regimens. The total dose of Adriamycin should not exceed a total of 500mg/m

Patients with pancytopenia related to multiple myeloma will be eligible for treatment i.e. patients with > 50% plasma cells in the BM, or have splenomegaly, or have plasma cell leukemia.

Patients must have an Eastern Cooperative Group (ECOG) Performance Status of 0-2.

Organ function permitted:  

  • WBC > 2500/µl or Absolute Neutrophil Count > 1000/µl

  • Platelets > 75,000/µl

  • Bilirubin < institutional upper limits of normal

  • Liver enzymes (ALT or AST) < 2 x normal (unless >1/3 of liver is involved by tumor, in which case ALT or AST must be < 5 x normal)

  • Left Ventricular Ejection Fraction (LVEF) >50% by MUGA scan or echocardiogram

Prior Therapy allowed:

  • All patients that have failed or progressed after at least one regimen of chemotherapy, and no more than 4 chemotherapy regimens.

  • Prior Biologic Response Modifier treatment will be allowed.

  • Prior radiation therapy will be allowed. Radiation therapy to control pain or to prevent fractures will be allowed.

  • Prior surgery will be allowed provided that the patient has recovered from that surgery. 

  • All patients must give informed consent to participation in this trial.

Exclusion Criteria

A patient must not be enrolled if any of these criteria apply.

Patients with a life expectancy of less than 3 months will be ineligible.

Pregnant or lactating patients will be ineligible. Men or women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

No prior malignancy is allowed, except for adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, or other cancer from which the patient has been disease-free for at least 5 years.

Patients must not receive other chemotherapy while on this protocol.

Patients physically, mentally, or emotionally unable to give informed consent will be ineligible.

Patients who have a history of hypersensitivity reactions to Doxorubicin HCL are ineligible for this study.

Patients who have had previous hypersensitivity reactions to liposomal or PEGylated formulations of other drugs will be ineligible.

Patients who have cardiac disease of New York Heart Association Class II or greater are ineligible for this study.

Evidence of active infection requiring IV antibiotics.

Patients with solitary bone or solitary extramedullary plasmacytoma.

 

Scientific Background:

Introduction

The role of VAD in the management of Multiple Myeloma

Over the past 30 years there has been limited progress in controlling multiple myeloma. The combination of vincristine, doxorubicin by continuous infusion with intermittent Dexamethasone (VAD) reduced tumor mass rapidly and markedly in 50-80% of untreated multiple myeloma patients and in 50-60% of melphalan and prednisone failures (1,2,3).

The VAD regimen uses Vincristine and Doxorubicin given by 4 day continuous infusion rather than as bolus doses, with the rationale being that this is more likely to be effective against slowly dividing cells. Lengthier exposure to Doxorubicin could be possibly more effective, however, the toxicity to the drug and the logistics of administering it over a lengthier period hampers testing this therapy. DOXIL could be the formulation that will provide a solution to some of the difficulties.

Background and Rationale for the Use of DOXIL

Multiple myeloma, a plasma cell tumor arising in the bone marrow, is a slowly proliferating disease. This "malignant proliferation" is of early plasma cells that further differentiate into mature plasma cells. It is the accumulation of monoclonal plasma cells that secrete monoclonal immunoglobulins or fragments that indirectly cause renal failure in a segment of MM patients. This combined with suppression of normal synthesis of immunoglobulins results in the clinical features of multiple myeloma. Stable multiple myeloma is characterized by mature, non-dividing, plasmacytic cells. Some limitations of effective multiple myeloma therapy is associated with the low proliferation rate, multidrug resistance, the age of the patients at presentation (about 50% are greater than 65 years old), and other concurrent diseases which are present in these patients. Presently the mainstay of treatment, Melphalan (L-PAM) and Prednisone, introduced more than 30 years ago, has shown a 30-40% resistant rate and median survival not greater than 3 years. A cure, however, is exceedingly rare. Combination chemotherapy with cytoxan was introduced in the early 1970's, after observing that human and murine-plasmacytoma already resistant to Melphalan were still sensitive to Cyclophosphamide. Subsequent studies were designed to add Vincristine, which is an S-phase specific agent, to target actively proliferating plasma cells. Many clinical trials have investigated these combinations without any clear therapeutic advantage over Melphalan and Prednisone in that no differences in median survival time could be detected (4,5,6,7).

The anthracycline antibiotic Doxorubicin is a logical candidate for innovative reformulation, as it has a broad spectrum of antineoplastic action and a correspondingly widespread degree of clinical use. In addition to Hodgkin’s and non-Hodgkin’s lymphoma, Doxorubicin is indicated for Multiple Myeloma in combination regimens. Unfortunately, toxicity limits the therapeutic activity of Doxorubicin and may preclude adequate dosing. The conventional formulation of the drug is rapidly cleared from the bloodstream and has a very large volume of distribution; this may contribute to drug toxicity. High cumulative doses of Doxorubicin generally must be avoided because of the possibility of cardiotoxicity, while individual doses are often limited by myelosuppression. Alopecia typically develops and persists throughout treatment. Severe acute nausea and vomiting, stomatitis and esophagitis are additional adverse effects of Doxorubicin that may necessitate reducing doses or discontinuing dosing. A Doxorubicin formulation with improved toleration would increase the drug’s therapeutic ratio and thus enhance its efficacy.

Liposomal encapsulation of Doxorubicin may reduce the nonspecific drug delivery to normal tissues, and the high peak plasma levels of free drug that are responsible for toxicity. At the same time, a liposomal formulation may deliver Doxorubicin to tumors with improved specificity. DOXIL¨ is a Doxorubicin formulation in which the drug is encapsulated in liposomes (Stealth liposomes) that can avoid uptake by the reticuloendothelial system. As a result, the formulation has a long circulation time, and the liposomes can eventually become extravasated through the abnormally permeable vessels characteristic of many tumors. Once concentrated in tumors, the liposomes of DOXIL can deliver high levels of Doxorubicin to destroy malignant cells without affecting normal tissue.

References

  1. Alexanian R, Barlogie B, and Tucker S. VAD-Based regimens as primary treatment for multiple myeloma. Am J of Hemat 33:86-89,1990.
  2. Barlogie B, Smith L, and Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Eng J of Med 310(21);1353-1356,1984.
  3. Samson D, Newland A, Kearney J, Joyner M, Mitchell T, Barrett AJ, Gaminara E, Van de Pette J, McCArthy D, Aston L, Hamon M, and Evans M. Infusion of vincristine and Doxorubicin with oral Dexamethasone as first-line therapy for multiple myeloma. The Lancet, October 14, 1989:882-885.
  4. Jelinek DF, Lipsky PE. The role of B cell proliferation in the generation of immunoglobin secreting cells in man. J Immunol 130:2597, 1983.
  5. Reidel DA, Pottern LM. The epidemiology of multiple myeloma. Hematology/Oncology Clinics of North America 6(2):225, 1992.
  6. Boccadora M, Alessandro P. Standard chemotherapy for myelomatosis: An area of great controversy. Hematology/Oncology Clinic of North America, 6(2):371, 1992.
  7. Edmonson JH, Ryan LM, Blum RH, Brooks JSJ, Shiraki M, Frytak S, Parkinson DR. Randomized comparison of Doxorubicin alone versus ifosfamide plus Doxorubicin or mitomycin, Doxorubicin, and cisplatin against Multiple Myelomas. Journal of Clinical Oncology. 11:1269-75, 1993.

 

 
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