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PHASE II TRIAL TO TREAT MULTIPLE MYELOMA PATIENTS WITH CYTOXAN AND VINCRISTINE AFTER CYCLING MYELOMA CELLS WITH rHuGM­CSF


General Information:


The cells that cause the disease multiple myeloma (plasma cells) are slow dividing in nature. Chemotherapy and chemotherapeutic medications are usually most effective against fast dividing cells. This is thought to be the main reason that cures in multiple myeloma are exceedingly rare. rHuGM-CSF, which is a natural product known for stimulating the production of white blood cells which fight infection, has been noted to act in collaboration with IL-6 on the myeloma cells to increase the activity, resulting in a high proportion of the cells dividing at a fast rate. Theoretically this should make the myeloma cells more sensitive to chemotherapeutic drugs and if this holds true, response rates and possible cure should be improved upon.


Eligibility criteria

    Patients who have failed, or progressed after at least two chemotherapeutic or biologic regimens.

    Patients who are bone marrow transplant failure (Auto, Stem cell or Allo) will be eligible.

    Platelet count > 50 k/µl

    Absolute neutrophil count > 1000/µl

Ineligibility Criteria

    Patients with active infection requiring I.V. antibiotics.

    Patients who are HIV positive, as chemotherapy may further suppress their immune system and worsen chances for opportunistic infections.

    Pregnant women.

    Patients with SGOT, or SGPT 3X the upper limits of normal for the institution.

    Patients with bilirubin > 5.0 mg/dl

    Patients with creatinine > 2.0 mg/dl

Allowable Concomitant Therapy

    Standard radiation therapy to treat extra-skeletal and/or skeletal tumor sites is allowed. If radiation is needed during the study period, the investigator must document that there is no sign of progressive disease leading to radiation as a treatment. Comparisons of area to be radiated with baseline bone survey films must be provided to document lack of disease progression.

    Erythropoietin for anemia.

    rHuGM-CSF is the only granulocytic growth factor that will be allowed.

    Aredia and Immunoglobulin therapy will be allowed at any stage of the therapy.

SCIENTIFIC BACKGROUND:

MULTIPLE MYELOMA (1,2,3)

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, non­dividing, 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 (L­PAM) and Prednisone, introduced more than 30 years ago, has shown a 30­40% 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 murine­plasmacytoma already resistant to Melphalan were still sensitive to Cyclophosphamide. Subsequent studies were designed to add Vincristine, which is a S­phase 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.

Alkylating Agents (4)

Alkylating agents impair cell function by transferring alkyl groups to amino, carboxyl, sulfhydryl or phosphate groups. Nucleic acids (DNA and RNA) and proteins are alkylated. Guanine alkylation results in abnormal nucleotide sequences, miscoding of small mRNA cross­linked DNA strands that cannot replicate, resulting in breakage of DNA strands and other damage to the transcription and translocation of genetic material. These agents are cell cycle specific, but not phase­specific and kill at a fixed percentage of cells at a given dose. Most clinical neoplasm's are recognized at a stage of decelerating growth due to poor vascularity, hypoxia, competition for nutrients and other factors. These tumors contain a high fraction of slowly dividing or non­dividing cells (termed Go cells). Because many antineoplastic agents, particularly the antimetabolites and anti tumor antibiotics, are most effective against rapidly dividing cells and some are phase specific (i.e., most effective in killing cells in a specific phase of the cell cycle), the initial kinetic situation is unfavorable for treatment with most drugs. To review, there are five phases of cell growth:

. G0 Phase (Gap 0 or "resting" phase). Here, the cells are refractory to chemotherapy. The cells perform their specialized functions;

. Gl Phase (Gap 1 or inter phase) RNA and proteins are synthesized for the specialized functions of the cell. During the last G phase a burst of RNA synthesis occurs producing many enzymes for DNA synthesis;

. S Phase DNA synthesis occurs in this phase where the cellular content of DNA doubles;

.G2 Phase(Gap 2) DNA synthesis ceases. RNA and protein synthesis continues. The micro tubular precursors of the mitotic spindles are also produced; and,

. G2M Mitosis Proteins and RNA synthesis diminish and the genetic material is segregated into daughter cells.

Cyclophosphamide is the drug of choice of alkylating agents because the depth of leukocyte nadir is similar to that produced by other alkylators, however the return of the leukocyte count towards normal is more rapid and the platelet count is not depressed to clinically hazardous levels

Vinca Alkaloids (4)

Vincristine is a member of the Vinca Alkaloids family. Its mechanism of action is by binding to microtubule proteins. The inhibition of RNA synthesis is accomplished by affecting DNA dependent RNA polymerase. Vincristine is a cell cycle­phase specific drug, arresting cells at G2­M interface. Its dose limiting toxicity is mainly neurotoxicity with no major myelo­toxicity.

Interleukin­6 (IL­6) (5-8)

IL-6 is a potent growth factor for human myeloma cells. Spontaneous myeloma­cell proliferation is observed in about 50% of myeloma tumor cells when cultured with IL­6 for several days. Among the numerous Cytokines, produced during this brief period of in­vitro growth (IL­6, GM­CSF, G­CSF, IL­l, and TNF), IL­6 has been shown to be the major growth factor. In­vitro studies using anti­IL­6 monoclonal antibodies has demonstrated a virtual complete inhibition of the spontaneous myeloma­cells proliferation; moreover studies have confirmed this activity of IL­6 as a major malignant plasmablastic growth factor.

IL-6 and C-Reactive Protein (6)

It has been shown that IL­6 at the hepatic level stimulates the synthesis of acute phase proteins among which is the C­reactive protein (CRP). It has also been found that only IL­6 induces synthesis of C­reactive protein by hepatocytes in primary cultures. Bataille and coworkers have demonstrated that serum C­reactive protein concentration actually reflects the IL­6 activity in­vivo. Furthermore, serum C­reactive protein level was shown to be a highly significant prognostic factor and was independent of serum beta­2 micro globulin. Patients with active multiple myeloma treated with anti­interleukin­6 monoclonal antibodies measured C­reactive protein became undetectable and their inhibition of myeloma cell proliferation occurred. Available data suggest that C­reactive protein strongly correlates with patients survival and a strong prognostic indicator in multiple myeloma.

Labeling Index (9,10)

Plasma cells by definition contain cytoplasmic Immunoglobulin (CIg) which can be detected by using antibodies to kappa or lambda Immunoglobulin (Ig) light chains. Plasma cells which incorporate 5-bromo­2'­deoxyuridine) are in the DNA S­phase of the cell cycle and can be detected by using a monoclonal antibody to Brd Urd. With the use of antiIg and anti­Brd Urd antibody one can determine the percentages of monoclonal Ig­positive plasma cells that are in the S­phase of the cell cycle. The percentage is the plasma cell labeling index (PCLI). The PCLI has been shown to distinguish patients with stable monoclonal gammopathies from those with active multiple myeloma. Patients with PCLI of > 0.8% have been shown to have active multiple myeloma while patients with MGUS, SMM and Amyloidosis have PCLI < 0.8%. Furthermore, studies have also shown PCLI along with B­2 micro globulin were highly significant prognostic factors in the patients with multiple myeloma.

rHuGM­CSF and Multiple Myeloma (5)

    In-Vitro (5)

The role of rHuGM­CSF in the growth of multiple myeloma was investigated in 21 patients with the disease. In 17 patients rHuGM­CSF at concentrations clinically achievable, increased the endogenous IL­6 mediated myeloma cell proliferation occurring in 5 day cultures of tumor cells in­vitro.

It has been demonstrated that rHuGM­CSF has no direct growth factor activity on human myeloma cells, but it significantly increases the IL­6 responsiveness of myeloma cells. IL­6 has been shown to be a synergistic factor with rHuGM­CSF on normal hematopoietic stem cells and on leukemia myeloid cells. It acts early in the cell cycle by pushing hematopoietic stem cells from the Go into the Gl phase and rendering these cells responsive to rHuGM­CSF. (Concerning myeloma cells, present results obtained with the XG­1 cell line indicate a different sequence of action displayed by these factors, the actual myeloma cell growth factor being IL­6). To explain this phenomenon, several hypothesis are put forward:

1). rHuGM­CSF can increase the number of IL­6 receptors on myeloma cells and their sensitivity to IL­6.

2). It can also increase the self renewal of tumor stem cells and/or the proliferative potential of more differentiated tumor cells.

    In-Vivo (Results of CCF Pilot Study)

In view of the available data discussed above, we conducted a Phase I/II trial evaluating the in-vivo effect of different dose and schedule levels of rHuGM-CSF on the plasma cell labeling index, the toxicity profile of rHuGM-CSF in multiple myeloma patients and, if the rHuGM-CSF cycling effect would improve or reverse tumor response or resistance, respectively, to chemotherapy timed in a cycle specific fashion. Twenty-two patients were treated with rHuGM-CSF. Twenty patients were evaluable. Labeling index was measured on bone marrow specimens on day #1 and after 12-16 h from the last dose (day 5) of rHuGM-CSF. If the LI doubled and was 1.7%, patients proceeded with chemotherapy at least 48 h after discontinuing rHuGM-CSF. Patients received Cytoxan IV on day #1, rHuGM-CSF started on day #2 and continued for 10 days or neutrophil count >1000/ml. Vincristine was administered IV on day #8 and Prednisone oraly x 4 days beginning on day #1. Four patients achieved the necessary criteria to proceed to the chemo phase of the trial. Two were Stage II, one was Stage IIIa, and one was Stage IIIb, 2/4 were progressive nonresponders, and one failed several regimens.

    All four patients responded to treatment with 2/4 alive and well 16+ months, both are the progressive nonresponders to previous regimens.

    There was no advantage to any particular rHuGM-CSF dose or schedule in achieving the LI goal.

    There was no evidence of disease progression in any of the patients. rHuGM-CSF was well tolerated even at the high dose schedule without any significant exaggeration of Vincristine neurotoxicity.

    There was no correlation between LI, CRP, IL-6 levels or GM-CSF levels.

    It is not clear if the responses are related to the cell cycling effect or this would have occurred irrespective of the LI changes.

Labeling Index, Cell Cycling, and Advanced Disease

Plasma cells with high Labeling Index appear to be more responsive to the cycling abilities of different biologics and or growth factors. We therefore, are planning to treat patients who have failed at least two different chemotherapeutic or biologic regimens, including bone marrow transplant failures. This group of patients usually have aggressive disease and a high labeling index.

Cytopenias, Renal Failure and Therapy

Cytopenias

  • Cyclophosphamide and Cytopenia (4, 11, 12)

    In the treatment of myeloma patients, certain features of the hematologic toxicity and metabolism of the alkylating agents have a strong influence on how and when the agent is used. Cyclophosphamide, at the current dosages (dosage proposed for this study), has a low toxic profile on granulopoiesis and thrombopoiesis. Also, the hematologic toxicity following cyclophosphamide is not cumulative. For this reason, cyclophosphamide is used for the treatment of myeloma patients with neutropenia and thrombocytopenia.

  • Vincristine and Cytopenia (4)

    Vincristine does not have any significant effect on hematopoiesis.

Therapy and Renal Failure

  • Alkylating Agents and Renal Failure (4, 11)

    Melphalan is excreted largely by the kidney and causes greatly increased toxicity in patients with renal failure. In contrast, there is a large non-renal component to the elimination of alkylating activity following the adminstration of cyclophosphamide, and it is recommended that the dose administered to myeloma patients with moderate renal impairment should not be reduced.

  • Vincristine and Renal Failure (4)

    Vincristine does not have any negative influence on renal function and renal function does not have any significant importance on drug metabolism.

References

1. Jelinek DF, Lipsky PE. The role of B cell proliferation in the generation of immunoglobin secreting cells in man. J Immunol 130:2597, 1983.

2. Reidel DA, Pottern LM. The epidemiology of multiple myeloma. Hematology/Oncology Clinics of North America 6(2):225, 1992.

3. Boccadora M, Alessandro P. Standard chemotherapy for myelomatosis: An area of great controversy. Hematology/Oncology Clinica of North America, 6(2):371, 1992.

4. Colvin M, Chabner B. Alkylating agents. Cancer Chemotherapy Principles and Practice, JB Lippincott Company; Philadelphia: 1990.

5. Zhang X, Battaille R, Jourdan M, Saeland S, Banchereau J, Mannoni P, Klein B. Granulocyte-macrophage colony stimulating factor synergizes with interleukin-6 in supporting the proliferation of human myeloma cells. Blood 76(12):2599, 1990.

6. Bataille R, Boccadoro M, Klein B, Durie B, Pileri A. C-reactive protein and B-2 microglobulin produce a simple and powerful myeloma staging system. Blood 80(3):733, 1992.

7. Aglietta M, Piacibello W, Sanovio F, Stacchini A, Apra F, Schena M, Mossetti C, Carino F, Caligaris-Cappio F, Gavosto F. Kinetics of human hematopoietic cells after in vivo administration of granulocyte-macrophage colony stimulating factor. J Clinical Invest with the American Soc for Clin Investigation, Inc. 83:551, 1989.

8. Investigator's Brochure: Sargramostim (rHuGM-CSF), Section 5:13.

9. Durie BGM, Salmon SE, Moon TE. Pretreatment tumor mass, cell kinetics and prognosis in multiple myeloma. Blood, 59:43-51, 1982.

10. Greipp PR, Lust JA, O'Fallon WM, Katzmann JA, Witzig TTE, Kyle RA. Plasma cell labeling index and 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood, 81:3382-7, 1993.

11. Malpos JS, Bergsagel DE, Kyle RA. Myeloma "Biology and Management"; Chemotherapy of Myeloma, Oxford University Press: 271-306, 1995.

12. Bramwell V, Calvert RT, Edwards G, Scraffe H, Crowther D. The disposition of cyclophosphamide in a group of myeloma patients. Cancer Chemotherapy and Pharmacology, 3:253-259, 1979.
 
 
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