Ignite Creation Date:
2024-05-05 @ 5:25 PM
Last Modification Date:
2024-10-26 @ 9:31 AM
Study NCT ID:
NCT00455286
Status:
UNKNOWN
Last Update Posted:
2007-04-04
First Post:
2007-04-02
Brief Title:
a Phase II Study in Primary Central Nervous System Lymphoma
Sponsor:
National Health Research Institutes Taiwan
Organization:
National Health Research Institutes Taiwan
Study Overview
Official Title:
High-Dose Methotrexate Plus Steroid Followed by Concurrent Whole Brain Chemoradiation With Temozolomide for Immunocompetent Patients With Primary Central Nervous System Lymphoma - a Phase II Study
Status:
UNKNOWN
Status Verified Date:
2007-04
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
In this study we will test the hypothesis that concurrent chemoradiation CCRT with temozolomide after induction chemotherapy by conventional high-dose methotrexate HD-MTX plus dexamethasone may be an effective and well tolerated treatment for immunocompetent patients with PCSNL Corticosteroid can effectively reduce brain edema and corticosteroid alone has resulted in complete or partial remission in about 40 patients with PCNSL To enhance local disease control CCRT with temozolomide will be used in the study Temozolomide is a well-tolerated oral alkylating agent that is able to permeate the BBB Concurrent temozolomide with WBRT has shown superior effect to WBRT alone for the treatment of metastatic brain tumors and glioblastoma multiforme In addition temozolomide has single-agent activity for PCNSL 21 CR in relapsed or refractory PCNSL in a phase II trial
This is an open-label non-randomized multi-center phase II study The primary end point of is the complete response rate This study is a two-stage design for testing non-inferiority of the proposed treatment as compared to the approximately 80 response rate reported for conventional treatment Assuming a non-inferiority margin of 20 a sample size of 25 subjects which provides an 80 power for establishment of non-inferiority At the first stage 15 subjects are to be enrolled If equal to or more than 6 patients achieve complete response the study would accrue additional 10 subjects The treatment regimen is as follows
Induction chemotherapy MS regimen repeated every 14 days total 4 cycles
Methotrexate 35 gm2 iv infusion 4 hours on day1
Methylprednisolone 200 mgm2day iv infusion 30 minutes on day1-4 Concurrent chemoradiotherapy CCRT
Whole brain radiation therapy WBRT 2 Gy per fraction daily 5 days per week Temozolomide 75 mgm2day orally daily only on the days of WBRT
This is an open-label non-randomized multi-center phase II study The primary end point of is the complete response rate This study is a two-stage design for testing non-inferiority of the proposed treatment as compared to the approximately 80 response rate reported for conventional treatment Assuming a non-inferiority margin of 20 a sample size of 25 subjects which provides an 80 power for establishment of non-inferiority At the first stage 15 subjects are to be enrolled If equal to or more than 6 patients achieve complete response the study would accrue additional 10 subjects The treatment regimen is as follows
Induction chemotherapy MS regimen repeated every 14 days total 4 cycles
Methotrexate 35 gm2 iv infusion 4 hours on day1
Methylprednisolone 200 mgm2day iv infusion 30 minutes on day1-4 Concurrent chemoradiotherapy CCRT
Whole brain radiation therapy WBRT 2 Gy per fraction daily 5 days per week Temozolomide 75 mgm2day orally daily only on the days of WBRT
Detailed Description:
5 PATIENT SELECTION 51 Eligibility Criteria
Patients must fulfill all the following criteria to be eligible for admission for the study
1 Histologically proven central nervous system lymphoma of brain parenchyma with or without leptomeningeal involvement
2 No evidence of systemic lymphoma
3 Age between 18 years and 75 years
4 With at least one measurable lesion defined as at least one lesion that can be accurately measured in at least one dimension longest diameter to be recorded as 10 mm See Section 1021 for the evaluation of measurable disease
5 Laboratory requirements
Hematology Neutrophils 1500mm3 Hemoglobin 10 gdL and Platelet count 100000mm3
Hepatic function Total bilirubin level 15x upper normal limit UNL ALT SGPT and AST SGOT 25 x UNL
Renal function Creatinine 15 mgdL
6 No prior malignancy excluding in situ carcinoma of the cervix or non- melanomatous skin cancer unless disease free for at least 5 years
7 Signed informed consent
8 Patients must be accessible for treatment and follow-up 52 Ineligibility Criteria Patient meets any of the following will be excluded form the study
-- --
1 Patients who are seropositive for HIV AIDS use of immunosuppressant or who are post organ transplant are not eligible
2 Previously treated with chemotherapy radiotherapy or other investigational agents Patients with corticosteroid use are considered eligible
3 With ocular involvement or with any lesion beyond brain parenchyma except leptomeningeal
4 Pregnant or lactating patients patients of childbearing potential must implement adequate contractive measures during study participation
5 Other serious illness or medical conditions
Congestive heart failure or unstable angina pectoris High risk uncontrolled arrhythmias
Uncontrolled infection active serous infections that are not controlled by antibiotics
6 Concurrent treatment with any other experimental drugs
6 PLAN OF THE STUDY 61 Study Design This is an open-label multi-center phase II study designed to access the response rate including CR CRu and PR definition refers to 1022 in patients with primary central nervous system lymphoma receiving MS followed by CCRT with temozolomide The secondary objectives are to access time to progression and to the safety of the combination in this patient population
62 Sample Size The primary end point of this phase II study is the objective tumor response rate This study is a two-stage design for testing non-inferiority of the proposed treatment as compared to the approximately 80 response rate reported for conventional treatment Assuming a non-inferiority margin of 20 a sample size of 25 subjects which provides an 80 power for establishment of non-inferiority was selected based on the method described in Batchelor et al7 At the first stage 15 subjects are to be enrolled If fewer than six patients respond the one-sided 93 upper bound of the observed response rate is lower than 60 the study would be terminated Otherwise the study would accrue additional 10 subjects At the end of second stage if the one-sided lower 95 confidence limit of the point estimate of the response rate is greater than or equal to 60 the hypothesis that the study treatment is inferior to the conventional treatment would not be rejected
72 Treatments Schedules
Patient who meet the inclusion and exclusion criteria will receive induction chemotherapy MS regimen
If patient with leptomeningeal involvement or CSF at diagnosis intrathecal methotrexate will be given during the period of induction chemotherapy
Two to 4 weeks after completion of induction chemotherapy if the disease is confined within brain parenchyma or completely remitted concurrent temozolomide with whole brain radiation will be started Table 1 is and example of 2 weeks after induction chemotherapy
If the disease is beyond brain parenchyma or persistent leptomeningeal involvement during or after completion of induction chemotherapy the patient should be taken off the study
73 Induction Chemotherapy MS regimen
Methotrexate 35 gm2 iv infusion 4 hours on day1
Methylprednisolone 200 mgm2day iv infusion 30 minutes on day1-4
1 Cycles will be repeated every 2 weeks on week 1 3 5 and 7 if no evidence of disease progression
2 Sample orders are detailed in Appendix V
3 Hydration and urine alkalization It is mandatory that all patients receive adequate hydration and urine alkalization keep urine pH 7 post the methotrexate infusion
4 Antiemetics All patients could receive prophylactic antiemetic medication 30 minutes before each methotrexate infusion 5-HT3 antagonists are recommended
5 Leucovorin rescue Leucovorin 30 mg iv every 6 hours should be started since 24 hours after the start of methotrexate infusion until serum methotrexate level is less than 005 mcM and at least 8 doses
In patients with delayed early methotrexate elimination andor evidence of acute renal injury serum methotrexate level of 50 mcM or more at 24 hours or 5 mcM or more at 48 hours after administration or serum creatinine 20 mgdL at 24 hours give leucovorin 150 mg IV every 3 hours until methotrexate level is less than 1 mcM then 30 mg IV every 6 hours until methotrexate level is less than 005 mcM
In patients with delayed late methotrexate elimination serum methotrexate level remaining above 02 mcM at 72 hours or more than 005 mcM at 96 hours after administration continue leucovorin 30 mg iv every 6 hours until methotrexate level is less than 005 mcM
6 Others Allopurinol and antacid are recommended during the first 5 days of each cycle
74 Intrathecal Methotrexate Methotrexate 12 mg intrathecal injection on day 8 of induction chemotherapy
1 Only for leptomeningeal involvement or CSF cytology positive
2 Cycles repeat every 2 weeks on week 2 4 6 and 8 if no evidence of disease progression If the induction chemotherapy with MS is delayed intrathecal methotrexate schedule will be decided by treating physician
3 If CSF is newly found during treatment the patient must be off protocol
4 Leucovorin 15 mg po bid should be used 24 hours after intrathecal methotrexate for 3 days
75 Concurrent Whole Brain Radiation with Temozolomide 751 Whole Brain Radiation Therapy
Whole brain radiation therapy WBRT 2 Gy per fraction daily 5 days per week
1 For patients with CR or CRu after induction chemotherapy a total of 30 Gy will be given for patients with non-CR CRu after induction chemotherapy a total of 36 Gy will be given
2 WBRT should be initiated within 2-4 weeks after starting the last induction chemotherapy if no active infection or life threatening complication is noted
3 Continuation of WBRT as schedule is suggested unless the treating physicians judge the patients condition to be inappropriate to receive WBRT
4 Physical Factors Treatment will be delivered using megavoltage machines with photon beams ranging from 4 to 8 MV The minimum dose rate at the midplane in the brain on the central axis must be 050 Gyminute Electron particle or implant therapy is not permissible
5 Simulation Immobilization Localization The patient will be treated in the supine position Adequate immobilization and reproducibility of position are encouraged The target volume will cover the brain and the meninges to the foramen magnum
6 Treatment Planning Treatments must be delivered through parallel opposed or 5 degree RAO-LAO fields that cover the entire cranial contents There should be beam fall-off of at least 1 cm The eyes will be excluded from the beam either by field arrangement or shielding
7 Stereotactic radiosurgery and intensity modulated radiotherapy IMRT are not allowed
752 Temozolomide
Temozolomide 75 mgm2day orally daily only on the days of WBRT
1 Criteria for starting Temozolomide The initiation of temozolomide will be based upon complete blood counts CBC obtained within 48 hours prior to starting the treatment If ANC is 1000mm3 and platelet count is 75000mm3 the temozolomide may be started If study drug cannot be administered on the scheduled day of dosing the CBC will be repeated every 3 days
2 Since capsules of study drug are available in 20 and 100 mg capsules in Taiwan all doses will be rounded up to the nearest 20 mg to accommodate capsule strength
3 Subjects should be instructed to swallow capsules whole and in rapid succession and to not chew capsules If vomiting occurs during the course of treatment no re-dosing of the subject is allowed before the next scheduled dose
4 Temozolomide should be taken on an empty stomach It should be administered at approximately the same time every day within and during each cycle In general patient tolerability is best when the drug is given at bedtime with antiemetics one hour prior to temozolomide
5 Since this is an oral drug episodes of emesis will result in under dosing Prophylactic antiemetics oral metoclopramide is preferred either oral or intravenous administration 5-HT3 antagonist could also be used if intolerable or not response to metoclopramide must be administered to all subjects prior to temozolomide administration
76 Concomitant Treatments
Concomitant medications allowed and not allowed are described below
Allowed
Ancillary treatments will be given as medically indicated
Antiemetics or antiallergic medication are permitted Proton pump inhibitor or H2 block is permitted for prevention or treatment of steroid related peptic ulcer
G-CSF is recommended for patients who have absolute neutrophil count ANC 500 mm3 neutropenic fever or documented infection while neutropenic Prophylactic use of G-CSF could be decided by treating physicians
Preventive oral or iv antibiotics when neutropenia 500mm3 without fever are recommended but the decision to use antibiotics in this case will be left to the current policy within the different hospitals
Lamivudine 100 mg orally once a day is recommended for HBV carrier to prevent HBV reactivation during whole treatment period
Prophylactic anticonvulsant agents are not recommended For patients with seizure anticonvulsant agents could be used without dose adjustment of chemotherapy
Not Allowed
The patient will not receive other investigational drugs and anticancer treatment while on study
77 Recommended Treatment for Progression or Residual Disease If patients have progression disease during treatment or residual disease after concurrent whole brain chemoradiation further treatments will be decided by treated physician We recommended BOMES16 regimen with or without modification for patients with suitable general condition
9 OFF-STUDY CRITERIA A patient will be discontinued from the study under the following circumstances
Disease progression beyond brain parenchyma during protocol treatment
Residual disease or relapse after completion of WBRT
Treatment schedule delay longer than 35 days
Patients couldnt be done any dose reduction listed in section 81 and 82
Patients develop any condition of the exclusion criteria
Patients with poor compliance
Patient wishes to withdraw from this study at hisher own request
Patients must fulfill all the following criteria to be eligible for admission for the study
1 Histologically proven central nervous system lymphoma of brain parenchyma with or without leptomeningeal involvement
2 No evidence of systemic lymphoma
3 Age between 18 years and 75 years
4 With at least one measurable lesion defined as at least one lesion that can be accurately measured in at least one dimension longest diameter to be recorded as 10 mm See Section 1021 for the evaluation of measurable disease
5 Laboratory requirements
Hematology Neutrophils 1500mm3 Hemoglobin 10 gdL and Platelet count 100000mm3
Hepatic function Total bilirubin level 15x upper normal limit UNL ALT SGPT and AST SGOT 25 x UNL
Renal function Creatinine 15 mgdL
6 No prior malignancy excluding in situ carcinoma of the cervix or non- melanomatous skin cancer unless disease free for at least 5 years
7 Signed informed consent
8 Patients must be accessible for treatment and follow-up 52 Ineligibility Criteria Patient meets any of the following will be excluded form the study
-- --
1 Patients who are seropositive for HIV AIDS use of immunosuppressant or who are post organ transplant are not eligible
2 Previously treated with chemotherapy radiotherapy or other investigational agents Patients with corticosteroid use are considered eligible
3 With ocular involvement or with any lesion beyond brain parenchyma except leptomeningeal
4 Pregnant or lactating patients patients of childbearing potential must implement adequate contractive measures during study participation
5 Other serious illness or medical conditions
Congestive heart failure or unstable angina pectoris High risk uncontrolled arrhythmias
Uncontrolled infection active serous infections that are not controlled by antibiotics
6 Concurrent treatment with any other experimental drugs
6 PLAN OF THE STUDY 61 Study Design This is an open-label multi-center phase II study designed to access the response rate including CR CRu and PR definition refers to 1022 in patients with primary central nervous system lymphoma receiving MS followed by CCRT with temozolomide The secondary objectives are to access time to progression and to the safety of the combination in this patient population
62 Sample Size The primary end point of this phase II study is the objective tumor response rate This study is a two-stage design for testing non-inferiority of the proposed treatment as compared to the approximately 80 response rate reported for conventional treatment Assuming a non-inferiority margin of 20 a sample size of 25 subjects which provides an 80 power for establishment of non-inferiority was selected based on the method described in Batchelor et al7 At the first stage 15 subjects are to be enrolled If fewer than six patients respond the one-sided 93 upper bound of the observed response rate is lower than 60 the study would be terminated Otherwise the study would accrue additional 10 subjects At the end of second stage if the one-sided lower 95 confidence limit of the point estimate of the response rate is greater than or equal to 60 the hypothesis that the study treatment is inferior to the conventional treatment would not be rejected
72 Treatments Schedules
Patient who meet the inclusion and exclusion criteria will receive induction chemotherapy MS regimen
If patient with leptomeningeal involvement or CSF at diagnosis intrathecal methotrexate will be given during the period of induction chemotherapy
Two to 4 weeks after completion of induction chemotherapy if the disease is confined within brain parenchyma or completely remitted concurrent temozolomide with whole brain radiation will be started Table 1 is and example of 2 weeks after induction chemotherapy
If the disease is beyond brain parenchyma or persistent leptomeningeal involvement during or after completion of induction chemotherapy the patient should be taken off the study
73 Induction Chemotherapy MS regimen
Methotrexate 35 gm2 iv infusion 4 hours on day1
Methylprednisolone 200 mgm2day iv infusion 30 minutes on day1-4
1 Cycles will be repeated every 2 weeks on week 1 3 5 and 7 if no evidence of disease progression
2 Sample orders are detailed in Appendix V
3 Hydration and urine alkalization It is mandatory that all patients receive adequate hydration and urine alkalization keep urine pH 7 post the methotrexate infusion
4 Antiemetics All patients could receive prophylactic antiemetic medication 30 minutes before each methotrexate infusion 5-HT3 antagonists are recommended
5 Leucovorin rescue Leucovorin 30 mg iv every 6 hours should be started since 24 hours after the start of methotrexate infusion until serum methotrexate level is less than 005 mcM and at least 8 doses
In patients with delayed early methotrexate elimination andor evidence of acute renal injury serum methotrexate level of 50 mcM or more at 24 hours or 5 mcM or more at 48 hours after administration or serum creatinine 20 mgdL at 24 hours give leucovorin 150 mg IV every 3 hours until methotrexate level is less than 1 mcM then 30 mg IV every 6 hours until methotrexate level is less than 005 mcM
In patients with delayed late methotrexate elimination serum methotrexate level remaining above 02 mcM at 72 hours or more than 005 mcM at 96 hours after administration continue leucovorin 30 mg iv every 6 hours until methotrexate level is less than 005 mcM
6 Others Allopurinol and antacid are recommended during the first 5 days of each cycle
74 Intrathecal Methotrexate Methotrexate 12 mg intrathecal injection on day 8 of induction chemotherapy
1 Only for leptomeningeal involvement or CSF cytology positive
2 Cycles repeat every 2 weeks on week 2 4 6 and 8 if no evidence of disease progression If the induction chemotherapy with MS is delayed intrathecal methotrexate schedule will be decided by treating physician
3 If CSF is newly found during treatment the patient must be off protocol
4 Leucovorin 15 mg po bid should be used 24 hours after intrathecal methotrexate for 3 days
75 Concurrent Whole Brain Radiation with Temozolomide 751 Whole Brain Radiation Therapy
Whole brain radiation therapy WBRT 2 Gy per fraction daily 5 days per week
1 For patients with CR or CRu after induction chemotherapy a total of 30 Gy will be given for patients with non-CR CRu after induction chemotherapy a total of 36 Gy will be given
2 WBRT should be initiated within 2-4 weeks after starting the last induction chemotherapy if no active infection or life threatening complication is noted
3 Continuation of WBRT as schedule is suggested unless the treating physicians judge the patients condition to be inappropriate to receive WBRT
4 Physical Factors Treatment will be delivered using megavoltage machines with photon beams ranging from 4 to 8 MV The minimum dose rate at the midplane in the brain on the central axis must be 050 Gyminute Electron particle or implant therapy is not permissible
5 Simulation Immobilization Localization The patient will be treated in the supine position Adequate immobilization and reproducibility of position are encouraged The target volume will cover the brain and the meninges to the foramen magnum
6 Treatment Planning Treatments must be delivered through parallel opposed or 5 degree RAO-LAO fields that cover the entire cranial contents There should be beam fall-off of at least 1 cm The eyes will be excluded from the beam either by field arrangement or shielding
7 Stereotactic radiosurgery and intensity modulated radiotherapy IMRT are not allowed
752 Temozolomide
Temozolomide 75 mgm2day orally daily only on the days of WBRT
1 Criteria for starting Temozolomide The initiation of temozolomide will be based upon complete blood counts CBC obtained within 48 hours prior to starting the treatment If ANC is 1000mm3 and platelet count is 75000mm3 the temozolomide may be started If study drug cannot be administered on the scheduled day of dosing the CBC will be repeated every 3 days
2 Since capsules of study drug are available in 20 and 100 mg capsules in Taiwan all doses will be rounded up to the nearest 20 mg to accommodate capsule strength
3 Subjects should be instructed to swallow capsules whole and in rapid succession and to not chew capsules If vomiting occurs during the course of treatment no re-dosing of the subject is allowed before the next scheduled dose
4 Temozolomide should be taken on an empty stomach It should be administered at approximately the same time every day within and during each cycle In general patient tolerability is best when the drug is given at bedtime with antiemetics one hour prior to temozolomide
5 Since this is an oral drug episodes of emesis will result in under dosing Prophylactic antiemetics oral metoclopramide is preferred either oral or intravenous administration 5-HT3 antagonist could also be used if intolerable or not response to metoclopramide must be administered to all subjects prior to temozolomide administration
76 Concomitant Treatments
Concomitant medications allowed and not allowed are described below
Allowed
Ancillary treatments will be given as medically indicated
Antiemetics or antiallergic medication are permitted Proton pump inhibitor or H2 block is permitted for prevention or treatment of steroid related peptic ulcer
G-CSF is recommended for patients who have absolute neutrophil count ANC 500 mm3 neutropenic fever or documented infection while neutropenic Prophylactic use of G-CSF could be decided by treating physicians
Preventive oral or iv antibiotics when neutropenia 500mm3 without fever are recommended but the decision to use antibiotics in this case will be left to the current policy within the different hospitals
Lamivudine 100 mg orally once a day is recommended for HBV carrier to prevent HBV reactivation during whole treatment period
Prophylactic anticonvulsant agents are not recommended For patients with seizure anticonvulsant agents could be used without dose adjustment of chemotherapy
Not Allowed
The patient will not receive other investigational drugs and anticancer treatment while on study
77 Recommended Treatment for Progression or Residual Disease If patients have progression disease during treatment or residual disease after concurrent whole brain chemoradiation further treatments will be decided by treated physician We recommended BOMES16 regimen with or without modification for patients with suitable general condition
9 OFF-STUDY CRITERIA A patient will be discontinued from the study under the following circumstances
Disease progression beyond brain parenchyma during protocol treatment
Residual disease or relapse after completion of WBRT
Treatment schedule delay longer than 35 days
Patients couldnt be done any dose reduction listed in section 81 and 82
Patients develop any condition of the exclusion criteria
Patients with poor compliance
Patient wishes to withdraw from this study at hisher own request
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None