Thema: Studie: Oxaliplatin as Neoadjuvant Treatment in Adults with GBM
Studie: Oxaliplatin as Neoadjuvant Treatment in Adults with GBM
Jörg[a]
07.10.2003 23:15:55
Clinical Trial -
Clinical Trial - TT 9902
Phase I/II Trial of Oxaliplatin as Neoadjuvant Treatment in Adults with Newly Diagnosed Glioblastoma Multiforme
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.
When used in newly diagnosed malignant glioma, carboplatin and cisplatin have yielded objective response rates of 39-45%. Full potential of these platinum compounds has been limited by toxicity. Oxaliplatinum is a novel platinum complex that has shown efficacy in colorectal cancer.
Traditional platinum compounds form DNA adducts that block DNA replication and transcription leading to cell death. Oxaliplatin contains a dach ring that is more effective in forming these adducts and blocking DNA replication than traditional compounds. Interestingly, Oxaliplatin is effective against cell lines and tumor types that are intrinsically resistant to cisplatin possibly due to less dependence on the mismatch repair enzyme complex (MMR) for cell killing.
Toxicity in a series of 682 patients with cancer at other organ sites has been reported. Oxaliplatin toxicity has included neuropathy as in traditional platinum compounds. However, the paresthesias and dysesthesias are somewhat predictable based on cumulative dose and, unlike cisplatin, reversible in most cases. Other toxicities encountered have included mild hematologic toxicity, nausea and vomiting, diarrhea, nephrotoxicity in those with pre-existing renal impairment, fever, erythema and clinical ototoxicity (in < 1%).
Neoadjuvant administration allows the drug to be assessed without the confounding influences of other concurrent or prior treatments. Other platinum compounds have been given in this setting with low toxicity. Experience in NABTT with 9-AC and taxol, revealed no efficacy, but this did not adversely impact the survival of the participants as they went on to radiation therapy.
Clinical experience with Oxaliplatin is limited in malignant gliomas. Two phase I reports are available in which partial response was seen in 2/6 cases in one and complete response in 1/11 in the other. Pretreatment status, doses and follow-up were incompletely defined. Based on the improved response rates seen in colon cancer at doses of 130 mg/m2 every 2 weeks this study will carry out a dose escalation plan with that as the target dose. The toxicities at that level were considered acceptable in the colon cancer patients, but this cannot be concluded in brain tumor patients. Therefore initiation at 85 mg/m2 is chosen here and correlative pharmacokinetic studies will be conducted.
ELIGIBLE PATIENTS: Primary enrollment criteria include [1] age > 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] demonstration of adequate recovery from surgery and on stable corticosteroid doses for 5 days, [6] hematologic, hepatic, and renal function within standard acceptable ranges as defined in the protocol, and [7] a Karnofsky Performance Status (KPS) > 60, [8] not being pregnant or breast feeding, and [9] being able to provide informed consent. Patients with prior malignancy except cured carcinoma-in-situ and basal cell carcinoma are excluded, as are those with pre-existing sensory neuropathy and allergy to platinum compounds or anti-emetics.
OBJECTIVES: The objective of this investigation in Phase I is to (1) determine the maximum tolerated dose (MTD) to a maximum of 130 mg/m2 of Oxaliplatin when administered as a single 2 hour infusion, every two weeks, for 6 treatments prior to irradiation to adults with glioblastoma multiforme (GBM), receiving (Group A) or not receiving (Group B) anticonvulsants known to be metabolized by the P450 hepatic enzyme complex, (2) determine the dose-limiting toxicity (DLT) and safety profile of Oxaliplatin when administered as above, (3) define the pharmacokinetics of Oxaliplatin on this schedule and determine the effects of hepatic enzyme inducing anticonvulsants on the pharmacokinetics of Oxaliplatin, and in Phase II to (4) determine the radiographic response rate of newly diagnosed GBM treated with Oxaliplatin at the MTD, and (5) determine the time to radiographic progression, survival and drug toxicity of a larger series of patients treated at MTD.
This study will be carried out as Phase I followed by a Phase II trial. 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.
TREATMENT PLAN: The patients in Phase I will be stratified into Group A (those on anticonvulsants known to induce cytochrome P450: dilantin, 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 Oxaliplatin regimen will be administered and completed prior to radiation therapy. A treatment cycle will consist of 14 days with Oxaliplatin being administered on day one starting with a dose of 85 mg/m2 and escalating to 130 mg/m2, delivered as a 2-hour intravenous infusion. Each patient will be treated at a single dose level over the entire treatment course. Six cycles of Oxaliplatin will be administered prior to initiation of radiation therapy. If tumor progression occurs prior to this goal, the patient will discontinue the course of Oxaliplatin 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 patient groups provided there is no dose limiting toxicity (DLT) as defined in the protocol. The next higher dose level will not start enrollment until six weeks have passed since the last patient at the last dose level started treatment. If one of the three patients at a dose level develops a DLT, up to three additional patients will be enrolled at that level. The dose escalation will continue if only one of the six enrolled develop DLT. If DLT occurs in two patients, the current dose will be call the MTD. If three patients develop DLT, then the prior dose will be called the DLT. If 3/6 cases develop DLT at the initial dose, accrual will be suspended and the PI and NABTT will determine if lower doses are indicated. Ongoing laboratory and clinical evaluation will be carried out as outlined in the protocol. Individuals who encounter DLT will continue therapy after reduction as outlined in the protocol. After completion of the Oxaliplatin therapy or 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. Progression will be defined as a > 25% increase in tumor volume or development of new lesions in stable or increasing doses of corticosteroids. To determine if a surrogate marker of toxicity, response or time to progression can be developed, pharmacokinetic studies will carried out in each patient. This will be done at cycle one only in Phase I and Phase II cases with blood samples being taken immediately before infusion, immediately after infusion, and 2 and 22 hours after the end of the infusion.
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 as well as any pertinent response or time to progression information. 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 4 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
Clinical Trial - TT 9902
Phase I/II Trial of Oxaliplatin as Neoadjuvant Treatment in Adults with Newly Diagnosed Glioblastoma Multiforme
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.
When used in newly diagnosed malignant glioma, carboplatin and cisplatin have yielded objective response rates of 39-45%. Full potential of these platinum compounds has been limited by toxicity. Oxaliplatinum is a novel platinum complex that has shown efficacy in colorectal cancer.
Traditional platinum compounds form DNA adducts that block DNA replication and transcription leading to cell death. Oxaliplatin contains a dach ring that is more effective in forming these adducts and blocking DNA replication than traditional compounds. Interestingly, Oxaliplatin is effective against cell lines and tumor types that are intrinsically resistant to cisplatin possibly due to less dependence on the mismatch repair enzyme complex (MMR) for cell killing.
Toxicity in a series of 682 patients with cancer at other organ sites has been reported. Oxaliplatin toxicity has included neuropathy as in traditional platinum compounds. However, the paresthesias and dysesthesias are somewhat predictable based on cumulative dose and, unlike cisplatin, reversible in most cases. Other toxicities encountered have included mild hematologic toxicity, nausea and vomiting, diarrhea, nephrotoxicity in those with pre-existing renal impairment, fever, erythema and clinical ototoxicity (in < 1%).
Neoadjuvant administration allows the drug to be assessed without the confounding influences of other concurrent or prior treatments. Other platinum compounds have been given in this setting with low toxicity. Experience in NABTT with 9-AC and taxol, revealed no efficacy, but this did not adversely impact the survival of the participants as they went on to radiation therapy.
Clinical experience with Oxaliplatin is limited in malignant gliomas. Two phase I reports are available in which partial response was seen in 2/6 cases in one and complete response in 1/11 in the other. Pretreatment status, doses and follow-up were incompletely defined. Based on the improved response rates seen in colon cancer at doses of 130 mg/m2 every 2 weeks this study will carry out a dose escalation plan with that as the target dose. The toxicities at that level were considered acceptable in the colon cancer patients, but this cannot be concluded in brain tumor patients. Therefore initiation at 85 mg/m2 is chosen here and correlative pharmacokinetic studies will be conducted.
ELIGIBLE PATIENTS: Primary enrollment criteria include [1] age > 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] demonstration of adequate recovery from surgery and on stable corticosteroid doses for 5 days, [6] hematologic, hepatic, and renal function within standard acceptable ranges as defined in the protocol, and [7] a Karnofsky Performance Status (KPS) > 60, [8] not being pregnant or breast feeding, and [9] being able to provide informed consent. Patients with prior malignancy except cured carcinoma-in-situ and basal cell carcinoma are excluded, as are those with pre-existing sensory neuropathy and allergy to platinum compounds or anti-emetics.
OBJECTIVES: The objective of this investigation in Phase I is to (1) determine the maximum tolerated dose (MTD) to a maximum of 130 mg/m2 of Oxaliplatin when administered as a single 2 hour infusion, every two weeks, for 6 treatments prior to irradiation to adults with glioblastoma multiforme (GBM), receiving (Group A) or not receiving (Group B) anticonvulsants known to be metabolized by the P450 hepatic enzyme complex, (2) determine the dose-limiting toxicity (DLT) and safety profile of Oxaliplatin when administered as above, (3) define the pharmacokinetics of Oxaliplatin on this schedule and determine the effects of hepatic enzyme inducing anticonvulsants on the pharmacokinetics of Oxaliplatin, and in Phase II to (4) determine the radiographic response rate of newly diagnosed GBM treated with Oxaliplatin at the MTD, and (5) determine the time to radiographic progression, survival and drug toxicity of a larger series of patients treated at MTD.
This study will be carried out as Phase I followed by a Phase II trial. 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.
TREATMENT PLAN: The patients in Phase I will be stratified into Group A (those on anticonvulsants known to induce cytochrome P450: dilantin, 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 Oxaliplatin regimen will be administered and completed prior to radiation therapy. A treatment cycle will consist of 14 days with Oxaliplatin being administered on day one starting with a dose of 85 mg/m2 and escalating to 130 mg/m2, delivered as a 2-hour intravenous infusion. Each patient will be treated at a single dose level over the entire treatment course. Six cycles of Oxaliplatin will be administered prior to initiation of radiation therapy. If tumor progression occurs prior to this goal, the patient will discontinue the course of Oxaliplatin 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 patient groups provided there is no dose limiting toxicity (DLT) as defined in the protocol. The next higher dose level will not start enrollment until six weeks have passed since the last patient at the last dose level started treatment. If one of the three patients at a dose level develops a DLT, up to three additional patients will be enrolled at that level. The dose escalation will continue if only one of the six enrolled develop DLT. If DLT occurs in two patients, the current dose will be call the MTD. If three patients develop DLT, then the prior dose will be called the DLT. If 3/6 cases develop DLT at the initial dose, accrual will be suspended and the PI and NABTT will determine if lower doses are indicated. Ongoing laboratory and clinical evaluation will be carried out as outlined in the protocol. Individuals who encounter DLT will continue therapy after reduction as outlined in the protocol. After completion of the Oxaliplatin therapy or 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. Progression will be defined as a > 25% increase in tumor volume or development of new lesions in stable or increasing doses of corticosteroids. To determine if a surrogate marker of toxicity, response or time to progression can be developed, pharmacokinetic studies will carried out in each patient. This will be done at cycle one only in Phase I and Phase II cases with blood samples being taken immediately before infusion, immediately after infusion, and 2 and 22 hours after the end of the infusion.
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 as well as any pertinent response or time to progression information. 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 4 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
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