comprising a four-stage process of testing how safe a clinical intervention is and how it is to be used. The stages of clinical trials test different aspects of usability and safety of a drug for patients. The first stage is called a phase I trial, which is used to evaluate the safety of a new clinical method or drug; typically this is conducted in a small group of people. This may include healthy, unhealthy, or a combination of both, used to evaluate any side effects and determine the right dosage. The next stage is a phase II trial, which is aimed at testing the clinical procedure or drug that has passed through stage I on a larger group of people; often ill people are used in this stage of the trial to evaluate how effective the new procedure or drug works in people with the target condition and how well it works in a controlled, short period of time. The middle stage is a phase III trial, designed only for the drugs that are deemed successful in phase I and II trials. Again the procedure or drug is tested on a large number of ill individuals, and the outcome is compared to existing intervention for the target condition or placebo drug in the case of a drug trial. This trial allows researchers to determine whether the new drug or approach works better than the existing ones for the target condition, while evaluating any clinically significant side effects. Finally, in some cases, a last stage is conducted. Phase IV trials are conducted on drugs and procedures that are successful in the first three trial stages and a marketing license is given for the drug. With a marketing license, the drug can be given to patients. This phase allows the further understanding of the safety, side effects, and effectiveness of the drug while it is used in normal clinical practice.
Current Therapies for Hematological Cancer in Clinical Trials
The use of CD4 lymphocyte infusion to improve outcome after stem cell transplantation in treatment of hematological cancer
An ongoing phase II clinical trial aims to evaluate the efficacy of CD4 infusion in improving the ability of transplanted stem cells to replenish blood cells during treatment of leukemia, lymphoma, and myeloma and myelodysplastic syndrome. The use of very low doses of melphalan and fludarabine prior to stem cell transplant in cancer patients helps in stopping cancer growth. In addition, the chances of immune rejection by the host is also reduced by using this low dose of chemotherapy. Ultimately, these stem cells when transplanted have the capability to replace the host immune cells and enhance destruction of cancers cells that are not affected by the chemotherapy regime.
Researchers suggest lymphocyte infusion combined with stem cell transplant may have possible beneficial effects in the stem cell–induced killing of cancer cells and enhanced immune stem. However, it is still unclear whether lymphocyte transplant in this case may elicit immune response against the host cells, since the new immune cells produced by the transplanted stem cells may adjust to the donor cells. Because of this possible risk, the investigators believe that treatment with some cancer drugs like alemtuzumab or cyclosporine before and after transplant may help in stopping any likely immune response induced by the lymphocytes against the normal cells.
To assess the usability of this approach, the trial will investigate the progression of survival following transplant of the stem cells and estimate the ability of patients to achieve a significant or full donor chimerism in the circulating peripheral blood. In addition, the study will check for any occurrence of infections that may require clinical intervention and determine the relative proportion of re-formation and re-constitution T-cell-specific viral-specific immunity. Because of the likelihood of mortality arising from complications, the study will investigate cumulative occurrence of nonrelapse death rates, as well as monitor overall survival, incidence, and pattern of graft-versus-host disease following the combined lymphocytes and stem cell transplantation.
The use of unrelated donor umbilical cord blood in treatment of patients with hematological cancer
There is currently a phase II clinical trial investigating how transplantation of unrelated donor umbilical cord blood combined with reduced intensity of chemotherapy will affect the overall survival of patients with an advanced hematological cancer. The reduced-intensity chemotherapy in this trial will involve a preparative nonmyeloblative regime, which may improve the efficiency of the transplanted stem cells. All forms of transplantation, including cells and stem cells, are often faced with the challenge of host immune response, making the use of preparative regimens very important in suppressing host immune system and subsequent integration of the stem cells. Although the use of myeloblative regimes are typical for less severe cases of hematological cancer, the benefits to more serious cases are largely unknown.
The current study will determine the rate of survival and progression following two years of transplantation. The study will look at the proportion of patients who achieve full donor chimerism after two years. The occurrence of possible clinically significant infections and engraftment of neutrophil and platelets after two years of transplant will be monitored by the study as well. Monitoring the rate of mortality and survival rate six months following nonmyeloablative conditioning is important in this study since the regime is normally not utilized in serious cases of hematological cancers. The incidence of acute or extensive chronic graft-versus-host disease will also be monitored after two years to help establish the effectiveness of the procedure.
Several clinical studies have found that infusion of unrelated donor stem cells that do not match exactly with those of the hematological cancer patient may help their bone marrow in producing stem cells and other types of blood cells. But the effectiveness and safety of such an approach is not fully characterized to allow routine usage in the clinics. With donor-matched stem cells, several risks will be averted, but the availability of these matched donors currently do not meet the demand. Transplanting stem cells that do not match patients has a higher likelihood of increasing the rejection and failure of these cell grafts; therefore, it is important to understand fully how the use of unrelated stem cells will react and work in patients if this method is allowed in the clinics.
Currently a phase II trial is investigating how unrelated umbilical cord blood transplanted to patients with hematological cancers works. To achieve this feat, unrelated donor stem cells will be transplanted to the patients and many indicators of effectiveness will be monitored. This will include overall survival, rate of progression-free survival, and occurrence of clinically relevant infections after two years.
In addition to monitoring neutrophil and platelet engraftment, the incidence of nonrelapse mortality will be monitored for six months, as will the incidence of chronic graft-versus-host disease and several stages of acute graft-versus-host disease. The progression of the cancer and graft rejection or failure will be examined following the transplant.
Preparative administration of rabbit antithymocyte globulin following transplantation of matched peripheral blood stem cells to optimize donor T-cell engraftment
Like the above, the use of stem cells in treating hematological cancer has been challenged by a high rate of rejection, infection, and graft failure. The use of pharmacological molecules in combination with stem cell transplantation has the potential to thwart these challenges and increase efficiency of the stem cell at the same time. For instance, preparative administration of rabbit antithymocyte globulin followed by cyclophosphamide, busulfan, and fludarabine before the stem cell transplant may help reduce the complications. There is a phase II trial currently investigating how well giving rabbit antithymocyte globulin together with a low intensity of cyclophosphamide, busulfan, or fludarabine before the transplantation of allogeneic peripheral blood stem cells will enhance engraftment of T-cells in patients with hematological cancer.
In most cases less than 50% of T-cell chimerism is achieved after stem cell transplant, hence the study will assess the percentage of patients in the study group that achieved up to 90% T-cell chimerism after one month of treatment with the above procedure. The overall safety, including transplant toxicity and tolerability of the drugs, and efficacy of the procedure will be assessed to determine the ability of the regimen to induce durable remissions
