What is a Clinical Trial?
A clinical trial is a study to evaluate the effectiveness of a new drug or treatment. Through initial clinical trials, researchers are able to understand which approaches are successful or likely to be successful in fighting hematological diseases, such as cancer. All of today's standard treatments were first shown to be effective through clinical trials. The continued support of patients participating in clinical trials allows us to create new, and more effective treatments for cancer and other diseases.
The Hadassah University Hospital Department of Hematology takes great care to insure both scientific integrity and ethical conduct throughout all clinical trials. The trials must first be approved by the Hadassah Hospital Helsinki Committee. The patient will be advised of the possible risks and benefits and will sign informed consent before being enrolled on a clinical trial. No patient can ever be enrolled in a clinical trial without his/her informed consent.
Below we will outline some of the clinical trials in which we have participated recently or which are now ongoing. These trials are subdivided into those related to coagulation, treatment for malignancies, and other miscellaneous trials. We will give a short summary of the drug(s) being used, as well as the indications for use of the drug. In addition, we will note the researcher in charge of enrolling new patients.
*Please note that in clinical trials, the inclusion criteria for new patients may be very strict, and the researcher may not have discretionary power to give a new drug to a patient who does not meet the criteria for enrollment in the trial.
1. Clinical Coagulation Trials
We are involved in several clinical trials in the field of thrombosis and hemostasis. The head researcher for most of these trials is Prof. David Varon. Patients who wish to participate in a trial related to their disorder are requested to contact him by making an appointment to meet with him in his clinic. There are many studies which focus on hypercoagulability: studying the effect of low molecular weight heparin (Clexane), preventing spontaneous abortions among thrombophilic patients, and the application of new anti-thrombotic agents (pentasaccharide and oral anti-thrombin) during treatment of deep venous thrombosis and pulmonary embolism. We are also involved in a study on the application of new IVIG (intravenous gamma globulin) preparation in the treatment of ITP (idiopathic thrombocytopenic purpura).
A. THRIVE III - This is a randomized double-blind multicenter study comparing the new antithrombotic agent megalatran with placebo in the prevention of recurrence of venous thromboembolic disease in patients completing 6 months of standard antithrombotic therapy. This trial is scheduled to last 18 months, and if successful it will pave the way for the next step - comparing megalatran and warfarin as treatment for deep venous thrombosis (after an initial course of heparin).
B. LIVENOX (low molecular weight heparin) - this is a randomized open-labeled multicenter study comparing 2 doses of enoxaparin in the prevention of spontaneous abortions in pregnant women with thrombophilia who've previously suffered pregnancy loss. It is now clear that hypercoagulable states account for a considerable proportion of recurrent abortions. This study, a first of its kind, will provide data that will enable us to recommend the optimal dose of anticoagulation for these pregnant women.
C. MATISSE - an open labeled, randomized multicenter study comparing intravenous heparin with intravenous pentasaccharide in the initial treatment of deep venous thrombosis and pulmonary embolism. Since the pentasaccharide is the active site of heparin, this smaller molecule holds much promise in the treatment of thromboembolic disease. This study exposes us to an exciting new agent, and will allow us to gain experience using it.
2. Trials and New Drugs for Malignancies
2.A. Drugs for Myeloid Malignancies
2.A.i. GEMTUZUMAB (MYLOTARG)
Gemtuzumab ozogamicin, a monoclonal antibody bound to a cytotoxic antibiotic, is a new drug used for the treatment of patients with CD33-positive acute myeloid leukemia (AML) in first relapse, who are more than 60 years old and may not be able to tolerate cytotoxic chemotherapy.
AML Treatment - Conventional treatment of AML consists of combination chemotherapy with cytarabine and an anthracycline antibiotic. About 60% to 80% of patients will have a complete remission after chemotherapy, but most relapse. Only 40% achieve a second remission with further chemotherapy, and second remissions average only 3 to 6 months in duration. Older adults generally have a less favorable prognosis and less tolerance for conventional chemotherapy. In large studies, the median survival of AML patients older than 60 was 6 to 9 months, and their five-year survival ranged from 5% to 8%.
Mechanism of Action - Gemtuzumab is a recombinant humanized antibody that acts against the CD33 antigen and linked to a derivative of calicheamicin, a potent enediyne antibiotic. CD33 is a surface antigen expressed on leukemic blasts in 80% to 90% of patients with AML. It is also expressed on immature myeloid cells and megakaryocytes, and to a lesser degree on mature myeloid cells, but not on pluripotent hematopoietic stem cells. Gemtuzumab binds to the CD33 antigen and is then internalized; once inside the cell, calicheamicin is released and converted to a reactive intermediate that damages DNA, causing cell death.
Pharmacokinetics - Gemtuzumab is given in two doses 14 days apart. The mean half-life of calicheamicin after the second dose is about 60 hours. Concentrations of calicheamicin increase after the second dose compared to the first, possibly due to reduced tumor burden and decreased clearance by CD33-positive leukemia cells.Most patients in the clinical trials received two doses. Forty-two (30%) of 142 AML patients in first relapse treated with gemtuzumab had a complete remission or a complete remission without platelet recovery. Remission rates were similar in patients less than 60 years old and those more than 60 years old. These rates are similar to remission rates with conventional chemotherapy. No studies have been published on use of gemtuzumab for first-line treatment of AML.
Adverse Effects - Infusion-related effects of gemtuzumab, which usually occur within four hours of administration, include fever, nausea, chills, hypotension and shortness of breath. Prophylaxis with acetaminophen and antihistamines is recommended, but its effectiveness is unclear. As with conventional chemotherapy, more than 90% of patients develop severe neutropenia and thrombocytopenia. Several patients treated with gemtuzumab had hyperbilirubinemia or increased aminotransferase activity, and one patient died of hepatic failure after three doses of the drug. Two patients developed anti-gemtuzumab antibodies. Four patients who had a second course of therapy did not develop antibodies to the drug.
Dosage and Cost - The recommended dosage of gemtuzumab is 9 mg/m2 given by intravenous infusion over two hours with a second dose two weeks later. The manufacturer recommends oral premedication with antihistamines and Acamol 500 to 1000 mg one hour before treatment. Gemtuzumab will be given on an outpatient basis. The drug is available in single-dose 20-ml vials containing 5 mg each.
Gemtuzumab is the first in a new class of drugs that use monoclonal antibodies to target leukemia cells for chemotherapy. As a single agent, it produces remissions in some patients with a first relapse of AML, and may be better tolerated than conventional chemotherapy.
2A.ii. STI571 (Glivec) - This trial is no longer open for recruitment of new patients. The drug can now be obtained through your local healthcare branch (HMO) since it is no longer on a trial basis. The Novartis agent STI571 is a new drug that represents a new class of antiproliferative agents called signal transduction inhibitors, which interfere with the pathways that signal the growth of tumor cells. STI571 is targeted to the specific biochemical abnormality found predominantly in a form of leukemia called chronic myeloid leukemia (CML). Chronic myeloid leukemia is a specific type of hematological stem cell disorder caused by an abnormality in the DNA of the stem cells in the bone marrow. This results in a gene that produces an abnormal protein. This abnormal protein disrupts the bone marrow's normally well-controlled production of white blood cells, which leads to an uncontrolled increase in their numbers in the blood.
Currently, studies focus on patients in the chronic phase of chronic myeloid leukemia (CML) who are no longer responsive to interferon; patients in the chronic phase of CML who are unable to tolerate interferon; patients with accelerated phase CML; and patients with CML in myeloid blast crisis. Exploratory trials also are underway in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia and acute myeloid leukemia.
STI571 is still at a relatively early phase of clinical testing, and its safety and efficacy profile is not yet completely known, so that patients need to be monitored closely at centers that are experienced in both treating patients with CML and administering this agent. At Hadassah, we were fortunate enough to be selected to be one of the first centers around the world with access to this highly effective drug. The drug is currently approved by the FDA, and it is recognized by the State of Israel's Ministry of Health. For additional information the company's website can be accessed at:www.pharma.novartis.com.
The results so far on the effectiveness of STI571 are very encouraging. The preliminary data presented at the American Society of Hematology meeting in December 1999 indicated the following:
Chronic Phase CML
1) At daily dose levels from 300 mg to 600 mg: 31 of 31 patients (100%) have achieved a complete hematological response
2) At daily dose levels from 300 mg to 600 mg: cytogenetic responses have been observed in 11 out of 31 patients (33%) at 2 months.
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In CML in blast crisis, at daily dose levels from 300 mg to 600 mg, a 61% response rate (11 out of 18 patients) [marrow response] was observed. However, these responses were not sustained in a majority of the patients.
2.B. Drugs for Lymphoma, Myeloma or CLL
2.B.i. GEMCITABINE AND ETOPOSIDE
This trial uses a combination of chemotherapeutic drugs, which have been previously found to be useful for other malignancies, to treat relapsed or refractory Hodgkin's and non-Hodgkin's lymphomas. Etoposide has been successfully used in lymphomas for many years, but Gemcitabine (Gemzar) is a new agent that has only recently been used for lymphoma treatment.
Gemcitabine has been given in the US and in Europe in varying doses as a failure regimen for resistance or relapsed lymphomas. The response rate was for 22% to 69% with some patients achieving a complete remission. The drug was found to have a modest toxicity profile, making it ideal for patients who were heavily pretreated.
Eligible patients are those who have relapsed or failed prior treatment with at least 2 prior chemotherapy protocols. The drug is administered on days 1, 8 and 15 of each month. Treatment is administered in most cases in the Day Care, and the patients must bring the Gemcitabine from their local health care branch (HMO). The patient will be screened for eligibility (blood counts, general fitness) by the referring doctor who will submit a "29-gimmel" form to their health care branch in order to obtain the drug.
Trial is closed for new patients - 2005.
2.B.ii. MABTHERA (antiCD20 antibodies, also called Rituximab) with or without BBR 2778:
BBR 2778 is a new drug which resembles mitoxantrone (a powerful anthracycline anticancer drug) which has been proven effective against lymphoma in early clinical trials. The main advantage of this new drug is that although it is powerful, like mitoxantrone, it is less toxic to the heart (which is one of the potential side effects of mitoxantrone).
This randomized clinical trial is open to patients with relapsed low grade non-Hodgkin's lymphoma. It is aimed at a particularly challenging group of patients: those who've had multiple relapses. The trial will compare the success of treatment with Mabthera alone with treatment using Mabthera in combination with the novel chemotherapeutic agent. Mabthera, also known as antiCD20, or Rituximab, is itself a relatively new drug. It has already been proven to be effective when used as a single agent for relapsed low grade non Hodgkin's lymphoma. This drug targets B-cell lymphoma cells which have the CD20 marker on their surface. Prior treatment with Mabthera does not exclude the patient from the trial, as long as the patient has responded for a period of at least six months.
Trial is closed for new patients - 2005.
2.B.iii. TROXICITABINE is a novel chemotherapeutic drug which is similar to gemcitabine, a drug known to be effective for lymphoproliferative disease. This drug is a nucleoside analogue with a completely unique structure possessed by no other chemotherapeutic agent. Troxicitabine is incorporated into DNA during replication and repair, but because of its novel structure, it inhibits drug resistance mechanisms which would otherwise counteract the beneficial effects of the drug. Troxicitabine is well-tolerated and has few side effects aside from reversibly lowering blood counts and causing dermatological manifestations (rashes, hair loss, dry skin). The aims of the study are to determine the efficacy of the drug and also its toxicity profile.
In this study, the drug will be offered to patients with a very wide spectrum of refractory lymphoproliferative diseases. Eligible candidates are those who have relapsed with any of the following diseases: Hodgkin's disease, non-Hodgkin's lymphoma, chronic lymphocytic leukemia or multiple myeloma. Each disease has its criteria for response to therapy, and is evaluated by these criteria. The drug is given intravenously and can be given as an outpatient (5 consecutive days a week).
Trial is closed for new patients - 2005.
2.B.iv. VALCADE (bortezomib, PS-341) is a very new agent, which is just beginning to be used for the treatment of refractory multiple myeloma. This drug is a small molecule which functions as a proteosome inhibitor. This drug represents an entirely new class of drugs, and it has only recently entered clinical trials. Valcade's mechanism is multifactorial: inhibition of NF-kappaB, direct antiapoptotic effect, and attenuation of IL-6-mediated cell growth. The goal of the study is to determine both the efficacy and the toxicity profile of this drug in the treatment of the heavily treated myeloma patient. The drug is given intravenously twice weekly on an ambulatory basis, for several consecutive weeks. The drug will be available to patients who have been heavily treated with conventional agents, and who have failed to respond.
Trial is closed for new patients - 2005.
2.C. Miscellaneous Therapeutic Agents
2.C.i. PRODUCT R
Product R is a novel and unique nontoxic peptide with unique amino acid sequences. It has been found to be resistant to many enzymes which usually break down proteins. This peptide has been found to have immunomodulatory function. It can turn on the immune system when necessary, by activating the body's immune response during viral infections. It can also turn off an excessive immune response, such as in rheumatoid arthritis. Therefore, Product R has been termed a "switch-type" immunomodulator.
Product R has been found to have a wide range of antiviral activity. It has been used in clinical trials in patients infected with viruses, such as HIV. However, the effect we are interested in are those which can be useful in treating patients with malignancies. There are 2 types of effects which can be beneficial: 1- The agent seems to mitigate the toxicity of "nucleic" acid synthesis inhibitors, such as chemotherapeutic drugs, and 2-Product R also stimulates the immune system to attack tumor cells. Although clinical studies using Product R in cancer patients have been limited, there have been some encouraging reports of success in refractory patients.
Trial is closed for new patients - 2005.
3. New Therapies for Nonmalignant Diseases.
At present, there are no trials related to other diseases besides coagulation disorders or malignancies. However, in the past, we have participated in trials of drugs for the treatment of thalassemia, such as L1, a new iron chelator, and erythropoietin and hemin, for the treatment of the anemia of thalassemia. We have also been involved in using new antimicrobial agents: antibiotics and antifungal drugs in hematological patients with opportunistic infections after chemotherapy.
New trials will be added to this site in the future, as they are initiated.
4. Clinical Science Studies
Applying the CPA method (Cone Plate(let) Analyzer) we studied platelet function among patients with a variety of clinical conditions. The CPA was found useful in the diagnosis of primary hemostasis abnormalities, including von Willebrand's disease, Glanzmann's thrombasthenia and others. It is a useful method for monitoring vWF replacement therapy and was found to predict the risk of bleeding among thrombocytopenic patients. In addition, this method is sensitive to increased platelet reactivity in a variety of conditions associated with an increased risk of thrombosis. Thus patients with diabetes mellitus, hyperlipidemia, unstable angina and APLA syndrome (antiphospholipid antibody syndrome), were found to have an increased platelet performance in the CPA test, suggesting the CPA as a potential method for predicting thrombosis.
Currently we are evaluating the potential application of the CPA method in monitoring patients including surgical and trauma patients and patients under anti platelet drugs (such as the GPIIb-IIIa inhibitors).
Professor Varon is the head researcher in coagulation studies and is also involved in a number of clinical trials.