a Phase II Study in Primary Central Nervous System Lymphoma
a Phase II Study in Primary Central Nervous System Lymphoma
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 3.5 g/m2 i.v. infusion 4 hours on day1

 -  Methylprednisolone 200 mg/m2/day i.v. 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 mg/m2/day orally daily, only on the days of WBRT
5 PATIENT SELECTION 5.1 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 10.2.1 for the evaluation of measurable disease.

 5. Laboratory requirements :

 -  Hematology: Neutrophils≧ 1500/mm3, Hemoglobin≧ 10 g/dL, and Platelet count≧
 100000/mm3.

 -  Hepatic function: Total bilirubin level≦ 1.5x upper normal limit (UNL), ALT (SGPT)
 and AST (SGOT)≦ 2.5 x UNL.

 -  Renal function: Creatinine≦ 1.5 mg/dL.

 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. 5.2 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 6.1 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 10.2.2)
 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.

 6.2 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 al.7 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.

 7.2 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.

 7.3 Induction Chemotherapy (MS regimen)

 -  Methotrexate 3.5 g/m2 i.v. infusion 4 hours on day1

 -  Methylprednisolone 200 mg/m2/day i.v. 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 i.v. every 6 hours should be started since 24
 hours after the start of methotrexate infusion until serum methotrexate level is
 less than 0.05 mcM and at least 8 doses.

 -  In patients with delayed early methotrexate elimination and/or 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≧ 2.0 mg/dL
 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 0.05 mcM.

 -  In patients with delayed late methotrexate elimination (serum methotrexate
 level remaining above 0.2 mcM at 72 hours or more than 0.05 mcM at 96 hours
 after administration), continue leucovorin 30 mg i.v. every 6 hours until
 methotrexate level is less than 0.05 mcM;

 6. Others: Allopurinol and antacid are recommended during the first 5 days of each
 cycle.

 7.4 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 p.o. bid should be used 24 hours after intrathecal methotrexate for 3
 days.

 7.5 Concurrent Whole Brain Radiation with Temozolomide 7.5.1 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 patient's 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 0.50 Gy/minute. 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.

 7.5.2 Temozolomide

 -  Temozolomide 75 mg/m2/day 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 ≥ 1,000/mm3 and platelet count is ≥ 75,000/mm3, 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.

 7.6 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 i.v. antibiotics when neutropenia < 500/mm3 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.

 7.7 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 couldn't be done any dose reduction listed in section 8.1 and 8.2.

 • Patients develop any condition of the exclusion criteria

 -  Patients with poor compliance

 -  Patient wishes to withdraw from this study at his/her own request
Inclusion 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 10.2.1 for the evaluation of measurable disease.

 5. Laboratory requirements :

 -  Hematology: Neutrophils≧ 1500/mm3, Hemoglobin≧ 10 g/dL, and Platelet count≧
 100000/mm3.

 -  Hepatic function: Total bilirubin level≦ 1.5x upper normal limit (UNL), ALT
 (SGPT) and AST (SGOT)≦ 2.5 x UNL.

 -  Renal function: Creatinine≦ 1.5 mg/dL.

 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.

 Exclusion 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.

 -