Thema: Studie: PZA in Adults with Newly Diagnosed GBM
Studie: PZA in Adults with Newly Diagnosed GBM
Jörg[a]
07.10.2003 23:18:10
Clinical Trial - NABTT 9804
Phase I/II Study of Pyrazoloacridine (PZA) in Adults with Newly Diagnosed Glioblastoma Multiforme
The objective of this investigation in Phase I is to determine the maximum tolerated dose (MTD) for PZA in adult patients with newly diagnosed glioblastoma multiforme (GBM) receiving (Group A) or not receiving (Group B) anticonvulsants known to be metabolized by the P450 hepatic enzyme complex. In the Phase II portion of the study, the objectives are to (1) determine the response rate of adult patients with newly diagnosed to PZA administered at the MTD as a 3 hour infusion every 21 days for 4 courses (12 weeks), (2) determine the duration of disease free survival associated with this therapy in adult patients with newly diagnosed GBM, (3) describe the toxicity of this regimen in adult patients with newly diagnosed GBM, and (4) determine the pharmacokinetic behavior of PZA in adult patients with newly diagnosed GBM when given as a 3 hour infusion.
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. BCNU, an agent of this class, 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.
New chemotherapeutic agents for malignant gliomas are typically assessed in patients who have failed conventional therapy and recurred with massive disease. Thus, these new therapies are assessed in the post-radiotherapy, post-chemotherapy setting where a deterioration in the patients performance status secondary to disease progression and the emergence of acquired drug resistance may compromise the evaluation of efficacy. A regimen of pre-irradiation chemotherapy given in the immediate post0operative period has several potential advantages for the management of malignant gliomas. The ability of successful up-front chemotherapy to reduce tumor cell burden beyond the extent possible with surgical resection may enhance the effect of subsequent radiotherapy and may also avert the synergistic toxicity encountered with concurrent chemotherapy and radiotherapy.
In this trial the use of a new agent, PZA, will be evaluated by using it in newly diagnosed glioblastoma in the immediate post-operative period. As an acridine compound, its mechanism of cytotoxicity revolves around RNA inhibition at lower concentrations and both DNA and RNA functional inhibition at higher concentrations. Though it´s precise mechanism remains to be worked out completely, preclinical data suggests it is selective for hypoxic cells (seen frequently in GBMs), has activity against noncycling cells (seen frequently in GBMs), has activity against multidrug resistant tumor cells, and has broad activity in in vivo models.
Preclinical toxicity profiles have emphasized myelosuppression and emesis in canines and neutotoxicity (ataxia, lethargy, tachypnea, and convulsions) in rodents. The neurotoxicity is overcome by changing administration from a bolus to a slow infusion.
Phase I experience with one hour infusions every 21 days in 28npatients with cancer has demonstrated dose limiting toxicity (DLT) at 720 mg/m2 including grade 3 and 4 myelosuppression, and grade 3 neurotoxicity (restlessness, dizziness, agitation, personality changes, nightmares and myoclonus). The nadir for neutropenia was a mean of 15 days. At Johns Hopkins, prolonging the infusion to 3 hours, even with greater total doses and frequency resulted in a lower incidence of neurotoxicity. Additionally, premedication with lorazepam resulted in a significant reduction in the incidence of neurotoxicity. Significant interindividual variability has been observed in drug peaks and troughs. No significant experience with malignant brain tumors has been gained. In these Phase I trials responses were seen in ovarian, cervical and colorectal carcinomas. In a Phase II trial in metastatic colon carcinoma a dose of 750 mg/m2 as a three-hour infusion was utilized. No responses were seen in this study and pharmacokinetic data showed a slow elimination phase with multiple drug peaks after administration suggesting enterophepatic recirculation. Myelosuppression was the major toxicity observed.
This study will be carried out as Phase I followed by a Phase II trial. Based on prior experience with Continuous Reassessment Method (CRM) based studies, it is estimated that 24 patients will be enrolled in the Phase I portion of the protocol (Group A and B combined) and 35 or fewer patients will be enrolled in the Phase II portion. This will be done in as many as nine centers and is estimated to accrue at £ 3 cases per month in the Phase I portion of the trial and £ 4 patients per month in the Phase II component. Allowing for 2 months between the Phase I and Phase II components completion of accrual would occur no sooner than 19 months after study initiation. Primary enrollment criteria include [1] age ³ 18 years, [2] prior histologically proven diagnosis of glioblastoma, [3] residual contrast enhancing disease on the postoperative MRI/CT, [4] no prior radiation therapy, chemotherapy, biologic therapy, hormonal therapy or immunotherapy, [5] no serious concurrent infection or medical illness, or malignancy, [6] hematologic, hepatic, and renal function within standard acceptance ranges as defined in the protocol, and [7] a Karnofsky Performance Status (KPS) ³ 60, [8] not being pregnant or breast feeding, and [9] being able to provide informed consent. Patients on concurrent investigational agents with no measurable disease on MRI/CT or with needs for ongoing therapy for psychoses with antipsychotic medication are ineligible.
Treatment Plan
The patients in Phase I will be stratified into Group A (those on anticonvulsants known to induce cytochrome P450: dilatin, tegretol, Phenobarbital, mysoline and felbatol) and Group B (those that are not on the prior list of drugs). This is done because of prior NABTT experience with significantly different responses between these two groups when evaluating other new agents. The PZA regimen will be administered and completed prior to radiation therapy. A treatment cycle will consist of 21 days with PZA being administered on day one starting with a dose of 750 mg/m2 delivered as a 3-hour intravenous infusion. Each patient will be treated at a single dose lever over the entire treatment course. Four cycles of PZA will be administered prior to initiation of radiation therapy. No GM-CSF or G-CSF will be used prophylactically. If tumor progression occurs prior to this goal, the patient will discontinue the course of PZA and proceed directly to radiation. Three patients in each Group (A and B) will be treated at the starting dose with subsequent dose escalation in three patients groups provided there is no dose limiting toxicity (DLT, Grade ¾ Modified CTC) as defined in the protocol. After completion of the first cycle in all three patients the toxicity data obtained will be modeled with the logistic dose response function from the CRM and the next dose chosen. Three patients will be treated at this dose and the logistic dose response function utilized again. Escalation (or de-escalation) will occur until the method recommends the same dose twice in a row and the MTD will be declared at that point. Dose reduction is provided for in the first dose level and subsequent escalations and will impact subsequent CRM calculations. Ongoing laboratory and clinical evaluation will be carried out as outlined in the protocol. Pharmacokinetic studies will be done in each patient during the first cycle only and will finish 72 hours after completion of the infusion. Individuals who encounter DLT will continue therapy after reduction as outlined in the protocol. In the Phase II portion of the protocol the MTD will be utilized. 25% dose reductions will be used for major toxicities as defined in the protocol. After (1) completion of the PZA therapy, (2) development of toxicity that precludes further therapy, or (30 detection of progression, patients will receive conventional fractionated cranial radiation to a dose of 60 Gy using the parameters in the protocol. Response will be measured by MRI/CT obtained at baseline (after surgery), just prior to every odd cycle of therapy, and just prior to initiation of radiation and then every 2 months until progression. Progression will be defined as a ³ 25% increase in tumor volume or development of new lesions in the presence of stable or increasing doses of corticosteroids. As mentioned above, to determine is a surrogate marker of (1) toxicity, (2) response or (3) time to progression can be developed, pharmacokinetic studies will carried out in each patient.
Statistical Considerations
This will be a Phase I/II study. Therefore, in the Phase I portion of the work tabular and descriptive statistics will be used to reflect toxicity and adverse event findings, pertinent response or time to progression information, and pharmacokinetic data. In the Phase II component of the study 18 patients will be accrued and assessed for response. If 3 or more demonstrate partial or complete response an additional 17 cases will be enrolled. It is estimated that 3 patients will accrued from Emory over the first year with a total of 6 being entered over the entire period of the study.
Resource Utilization
It is anticipated that patients will be selected from the patient population at the Emory Clinic, Emory University Hospital, and Crawford long Hospital.
Winship Cancer Institute of Emory University
1365 Clifton Road, N.E. Building C
Atlanta, GA 30322 - (404) 778-5180, (404) 778-5016 - Fax
Phase I/II Study of Pyrazoloacridine (PZA) in Adults with Newly Diagnosed Glioblastoma Multiforme
The objective of this investigation in Phase I is to determine the maximum tolerated dose (MTD) for PZA in adult patients with newly diagnosed glioblastoma multiforme (GBM) receiving (Group A) or not receiving (Group B) anticonvulsants known to be metabolized by the P450 hepatic enzyme complex. In the Phase II portion of the study, the objectives are to (1) determine the response rate of adult patients with newly diagnosed to PZA administered at the MTD as a 3 hour infusion every 21 days for 4 courses (12 weeks), (2) determine the duration of disease free survival associated with this therapy in adult patients with newly diagnosed GBM, (3) describe the toxicity of this regimen in adult patients with newly diagnosed GBM, and (4) determine the pharmacokinetic behavior of PZA in adult patients with newly diagnosed GBM when given as a 3 hour infusion.
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. BCNU, an agent of this class, 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.
New chemotherapeutic agents for malignant gliomas are typically assessed in patients who have failed conventional therapy and recurred with massive disease. Thus, these new therapies are assessed in the post-radiotherapy, post-chemotherapy setting where a deterioration in the patients performance status secondary to disease progression and the emergence of acquired drug resistance may compromise the evaluation of efficacy. A regimen of pre-irradiation chemotherapy given in the immediate post0operative period has several potential advantages for the management of malignant gliomas. The ability of successful up-front chemotherapy to reduce tumor cell burden beyond the extent possible with surgical resection may enhance the effect of subsequent radiotherapy and may also avert the synergistic toxicity encountered with concurrent chemotherapy and radiotherapy.
In this trial the use of a new agent, PZA, will be evaluated by using it in newly diagnosed glioblastoma in the immediate post-operative period. As an acridine compound, its mechanism of cytotoxicity revolves around RNA inhibition at lower concentrations and both DNA and RNA functional inhibition at higher concentrations. Though it´s precise mechanism remains to be worked out completely, preclinical data suggests it is selective for hypoxic cells (seen frequently in GBMs), has activity against noncycling cells (seen frequently in GBMs), has activity against multidrug resistant tumor cells, and has broad activity in in vivo models.
Preclinical toxicity profiles have emphasized myelosuppression and emesis in canines and neutotoxicity (ataxia, lethargy, tachypnea, and convulsions) in rodents. The neurotoxicity is overcome by changing administration from a bolus to a slow infusion.
Phase I experience with one hour infusions every 21 days in 28npatients with cancer has demonstrated dose limiting toxicity (DLT) at 720 mg/m2 including grade 3 and 4 myelosuppression, and grade 3 neurotoxicity (restlessness, dizziness, agitation, personality changes, nightmares and myoclonus). The nadir for neutropenia was a mean of 15 days. At Johns Hopkins, prolonging the infusion to 3 hours, even with greater total doses and frequency resulted in a lower incidence of neurotoxicity. Additionally, premedication with lorazepam resulted in a significant reduction in the incidence of neurotoxicity. Significant interindividual variability has been observed in drug peaks and troughs. No significant experience with malignant brain tumors has been gained. In these Phase I trials responses were seen in ovarian, cervical and colorectal carcinomas. In a Phase II trial in metastatic colon carcinoma a dose of 750 mg/m2 as a three-hour infusion was utilized. No responses were seen in this study and pharmacokinetic data showed a slow elimination phase with multiple drug peaks after administration suggesting enterophepatic recirculation. Myelosuppression was the major toxicity observed.
This study will be carried out as Phase I followed by a Phase II trial. Based on prior experience with Continuous Reassessment Method (CRM) based studies, it is estimated that 24 patients will be enrolled in the Phase I portion of the protocol (Group A and B combined) and 35 or fewer patients will be enrolled in the Phase II portion. This will be done in as many as nine centers and is estimated to accrue at £ 3 cases per month in the Phase I portion of the trial and £ 4 patients per month in the Phase II component. Allowing for 2 months between the Phase I and Phase II components completion of accrual would occur no sooner than 19 months after study initiation. Primary enrollment criteria include [1] age ³ 18 years, [2] prior histologically proven diagnosis of glioblastoma, [3] residual contrast enhancing disease on the postoperative MRI/CT, [4] no prior radiation therapy, chemotherapy, biologic therapy, hormonal therapy or immunotherapy, [5] no serious concurrent infection or medical illness, or malignancy, [6] hematologic, hepatic, and renal function within standard acceptance ranges as defined in the protocol, and [7] a Karnofsky Performance Status (KPS) ³ 60, [8] not being pregnant or breast feeding, and [9] being able to provide informed consent. Patients on concurrent investigational agents with no measurable disease on MRI/CT or with needs for ongoing therapy for psychoses with antipsychotic medication are ineligible.
Treatment Plan
The patients in Phase I will be stratified into Group A (those on anticonvulsants known to induce cytochrome P450: dilatin, tegretol, Phenobarbital, mysoline and felbatol) and Group B (those that are not on the prior list of drugs). This is done because of prior NABTT experience with significantly different responses between these two groups when evaluating other new agents. The PZA regimen will be administered and completed prior to radiation therapy. A treatment cycle will consist of 21 days with PZA being administered on day one starting with a dose of 750 mg/m2 delivered as a 3-hour intravenous infusion. Each patient will be treated at a single dose lever over the entire treatment course. Four cycles of PZA will be administered prior to initiation of radiation therapy. No GM-CSF or G-CSF will be used prophylactically. If tumor progression occurs prior to this goal, the patient will discontinue the course of PZA and proceed directly to radiation. Three patients in each Group (A and B) will be treated at the starting dose with subsequent dose escalation in three patients groups provided there is no dose limiting toxicity (DLT, Grade ¾ Modified CTC) as defined in the protocol. After completion of the first cycle in all three patients the toxicity data obtained will be modeled with the logistic dose response function from the CRM and the next dose chosen. Three patients will be treated at this dose and the logistic dose response function utilized again. Escalation (or de-escalation) will occur until the method recommends the same dose twice in a row and the MTD will be declared at that point. Dose reduction is provided for in the first dose level and subsequent escalations and will impact subsequent CRM calculations. Ongoing laboratory and clinical evaluation will be carried out as outlined in the protocol. Pharmacokinetic studies will be done in each patient during the first cycle only and will finish 72 hours after completion of the infusion. Individuals who encounter DLT will continue therapy after reduction as outlined in the protocol. In the Phase II portion of the protocol the MTD will be utilized. 25% dose reductions will be used for major toxicities as defined in the protocol. After (1) completion of the PZA therapy, (2) development of toxicity that precludes further therapy, or (30 detection of progression, patients will receive conventional fractionated cranial radiation to a dose of 60 Gy using the parameters in the protocol. Response will be measured by MRI/CT obtained at baseline (after surgery), just prior to every odd cycle of therapy, and just prior to initiation of radiation and then every 2 months until progression. Progression will be defined as a ³ 25% increase in tumor volume or development of new lesions in the presence of stable or increasing doses of corticosteroids. As mentioned above, to determine is a surrogate marker of (1) toxicity, (2) response or (3) time to progression can be developed, pharmacokinetic studies will carried out in each patient.
Statistical Considerations
This will be a Phase I/II study. Therefore, in the Phase I portion of the work tabular and descriptive statistics will be used to reflect toxicity and adverse event findings, pertinent response or time to progression information, and pharmacokinetic data. In the Phase II component of the study 18 patients will be accrued and assessed for response. If 3 or more demonstrate partial or complete response an additional 17 cases will be enrolled. It is estimated that 3 patients will accrued from Emory over the first year with a total of 6 being entered over the entire period of the study.
Resource Utilization
It is anticipated that patients will be selected from the patient population at the Emory Clinic, Emory University Hospital, and Crawford long Hospital.
Winship Cancer Institute of Emory University
1365 Clifton Road, N.E. Building C
Atlanta, GA 30322 - (404) 778-5180, (404) 778-5016 - Fax
Jörg[a]
