NABTT 9911, Phase I/II Trial of the Safety of EMD 121974 for Treatment of Patients with Recurrent Malignant Gliomas
The objective of the Phase I component of this investigation is to (1) determine the maximum tolerated dose of EMD 121974 when administered on a once a day, twice weekly regimen to adults with recurrent anaplastic glioma, and in the Phase II component of this investigation to (2) determine the six month progression free survival, (3) determine the duration of disease free survival and survival associated with this therapy, (4) describe the toxicity associated with this regimen in adult patients with recurrent glioma, and (5) determine the effects of this therapy on tumor perfusion, endothelial assays of cell migration and markers for angiogenesis.
Approximately 17,500 new cases of primary central nervous system malignancy are diagnosed each year. These same types of tumors account for approximately 12, 000 deaths a year. Although many advances have been made in tumor biology in the past decade, overall survival in patients with glioblastoma is still less than a year and in anaplastic astrocytoma it is less than two years.
Surgery and radiation remain the primary components of the therapy of these lesions. Systemic chemotherapy can be of benefit, with the most reliable agents being nitrosoureas. BCN, an agent of this case, is known to prolong survival, but its use is associated with systemic toxicity (at amounts not much different than those necessary for therapeutic effect) and eventual development of resistance. Newer agents such as temozolomide have been shown to be useful in the setting of recurrent disease, but is by no means curative.
Malignant gliomas have a significant vascular component and it is believed that induction of new vessel growth, angiogenesis, contributes to their invasive and aggressive behavior. This fact may also provide an opportunity for therapy. They are known to secrete growth factors that induce vessel growth such as vascular endothelial growth factor. As a result of this endothelial proliferation several integrin receptors, known to be necessary for continued proliferation and invasion, are expressed. Two are particularly related to angiogenesis, and therefore the avb5 and avb5 present logical targets for anti-angiogenesis. These two receptors allow endothelial cells to attach to the RGD sequences found in the extracellular matrix. Cyclized RGD-containing peptides can inhibit the angiogenic process. EMD 12197 (cyclic-[Arg-dPhe-NmeVal] binds avb3 with nanomolar affinity, 2000 times more specific than the a11b3 integrin. This agent clearly inhibits angiogenesis in the rabbit cornmeal implant model.
Activity has been demonstrated in mouse models of melanoma and pancreatic carcinoma. Nude mice with human melanoma xenografts have also studied and shown activity. Cynomolgus monkeys receiving 90 mg/kg daily by an IV route showed a slight decrease in RBC number, Hb, and PCV. No overt hemorrhage of change in activity was noted. In a Phase I study of twelve humans with various end stage cancers using doses of up to 600 mg/m2 showed mild to moderate toxicity. This included nausea and fatigue as the main systemic symptoms and liver function value elevation as the main lab change. All these were in the NCI CTC grade 2-3 range and all were reversible. Thus use of this agent represents a novel method of therapy of cancer in general, with the primary focus of this proposal being malignant gliomas.
Eligibility: Primary enrollment criteria include (1) age ³ 18 years, (2) prior histologically proven diagnosis of anaplastic astrocytoma or oligodendroglioma, or glioblastoma, and be ³ 1 week out from the most recent surgery, (3) evidence of tumor growth, (4) prior completion of radiation therapy, and recovery from chemotherapy. No more than two chemotherapy regimens can have been used previously, (5) hematologic, hepatic, and renal function within standard acceptable ranges as defined in the protocol, (6) a Karnofsky Performance Status (KPS) ³ 60, and (7) not being pregnant or breast feeding. They cannot have serious concurrent infection, be receiving concurrent investigational agents, or have a history of prior malignancies or healing disorders.
Phase I: The treatment plan for EMD 121974 will include initial placement of a central venous access catheter. The initial dose of EMD 121974 will be administered as a one hour infusion, once a day, twice a week on a Monday/Thursday, or Tuesday/Friday schedule. Four consecutive weeks will continue one cycle. No break in treatment will occur between cycles. Depending on toxicity observed, up to 6 patients will be enrolled initially at a given dose level. If two instances of dose limiting toxicity occur, as defined in the protocol, an additional 6 patients will be enrolled. As long as a third case of dose limiting toxicity is not observed in these next six cases, movement to the next dose level will occur. Dose reductions of 50% will be used for dose limiting toxicities from which recovery occurs. No G-CSF is to be used. Once four weeks have elapsed since the initiation of the dosing of the last patient treated, and providing no dose limiting toxicity has been reached, accrual to the next dose level will be carried out.
Phase II: Once an MTD has been defined, another group of patients will be enrolled at the MTD using the same dosage and cycle regimen. Toxicity will be tabulated and managed as above.
In the Phase I and II components, response will be measured with volumetric MRI just prior to every odd cycle using standard NABTT criteria. Additionally, because EMD 121974 is supposed to function in part by inhibition of angiogenesis, perfusion MRI will be carried out at the time of progression. Surrogate markers remain of interest in measurement of response. In both the Phase I and II components, blood and urine will be collected for vascular endothelial growth factor, integrin assay at baseline and one hour post infusion of each odd cycle, again with intent of analyzing the antiangiogenic and anti-invasive qualities of the treatment. Progression free survival will be calculated at 6 months.
Statistical Considerations: It is planned that patients will be enrolled in six patient cohorts in the Phase I component of this protocol the initial estimate is that up to 30 cases will be enrolled for this portion of the study. The Phase II component will be carried out in a two portion design with a minimum of 23 cases in the first portion and if responses are identified, accrual will be extended to 35 patients. This investigation will be done in as many as nine centers and is estimated to accrue at 3 cases per month with completion of accrual in 14 months or more depending on the length of time needed to reach an MTD in the Phase I component of the study.
In the Phase I component of the study tabular and descriptive statistics will be used to reflect toxicity and adverse event findings as well as any pertinent response, time to progression and surrogate marker information from this study. It is estimated that 4 patients will be accrued from Emory over the first year. In the Phase II work, if £ 3 patients demonstrate a 6 month progression free survival, then the study will be stopped. Otherwise accrual will continue to 38 cases. Provided accrual proceeds as predicted, completion of the study will occur approximately two years.
Resource Utilization: It is anticipated that patients will be selected from the patient population at the Emory Clinic and Emory University Hospital.
