Rituximab, Methotrexate, Procarbazine and Vincristine Followed by High-dose Chemotherapy With Autologous Stem-cell Rescue in Newly-diagnosed Primary CNS Lymphoma (PCNSL)
Phase: PHASE2
Conditions: CNS Lymphoma, CNS Brain Cancer, Non-Hodgkin's Lymphoma
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Page 1 of 26 
 
 
Approval date: 04-Nov-2020 
Rituximab, methotrexate, procarbazine  and vincristine followed by high-dose 
chemotherapy with autologous stem-cell rescue in newly 
lymphoma  (PCNSL) 
THERAPEUTIC/DIAGNOSTIC  PROT
Principal  Investigator: 
Christian Grommes, MD 
-diagnosed primary  CNS 
OCOL 
Neurology 
Co-Principal  Investigator(s): Craig Sauter, MD 
Medicine 
Investigator(s): 
Denise Correa, PhD 
Craig Nolan, MD 
Virginia  Klimek, MD 
Igor Gavrilovic,  MD 
Ingo Mellinghoff,  MD 
Xi Chen, MD 
Thomas Kaley, MD 
Edward Avila, DO 
Lisa DeAngelis,  MD 
Elena Pentsova, MD 
Antonio Omuro, MD 
Neurology 
Neurology - Commack 
Medicine 
Neurology – Basking Ridge 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Consenting Professional(s): 
Lisa DeAngelis,  MD 
Igor Gavrilovic,  MD 
Neurology 
Neurology–  Basking Ridge 
Craig Nolan, MD 
Ingo Mellinghoff,  MD 
Xi Chen, MD 
Thomas Kaley, MD 
Edward Avila, MD 
Christian Grommes, MD 
Elena Pentsova, MD 
Neurology-  Commack 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 
Neurology 

Page 2 of 26 
Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
 
 
 
 
Table Of Contents 
 
1.0       PROTOCOL SUMMARYAND/ORSCHEMA…………………………………...4 
2.0       OBJECTIVES AND SCIENTIFIC AIMS………………………………………...5 
3.0       BACKGROUND AND RATIONALE …………………………………………...5 
4.0       OVERVIEW OF STUDY DESIGN/INTERVENTION………………………...10 
5.0       THERAPEUTIC/DIAGNOSTIC  AGENTS……………………………………..10 
6.1 
CRITERIA FOR PATIENT/SUBJECT  ELIGIBILITY…………………………13 
6.2 
Patient/subject  Inclusion Criteria…….13 
6.3 
Patient/subject  Exclusion Criteria……14 
7.0       RECRUITMENT  PLAN…………………………………………………………14 
8.0       PRETREATMENT  EVALUATION…………………………………………….14 
9.0       TREATMENT/INTERVENTION  PLAN……………………………………….15 
10.0 EVALUATION DURING TREATMENT/INTERVENTION………………….19 
11.0     TOXICITIES/SIDE  EFFECTS…………………………………………………..21 
12.0     CRITERIA FOR THERAPEUTIC  RESPONSE/OUT COME ASSESSMENT..22 
13.0 CRITERIA FOR REMOVAL FROM STUDY…………………………………23 
14.0     BIOSTATISTICS………………………………………………………………..23 
15.1 
SUBJECT REGISTRATION  AND RANDOMIZATION PROCEDURES……24 
15.2 
Patient/Subject  Registration………24 
15.3 
Randomization……………………25 
16.1 
DATA MANAGEMENT ISSUES………………………………………………25 
16.2 
Quality Assurance………………...26 
17.0     PROTECTION OF HUMAN SUBJECTS………………………………………26 
18.0 INFORMED CONSENT PROCEDURES………………………………………28 
19.0 
REFERENCE(S)…………………………………………………………………28 
20.0     APPENDICE(S)………………………………………………………………….30 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 3 of 26 
 
 
 
 
 
 
 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stem Cell Reinfusion 
Off-study 
Response assessment 
(MRI) 
PD or SD 
CR 
Response assessment 
(MRI) 
PD 
PR or 
SD 
Off-study 
R-MPV (5 cycles) 
& Stem Cell Harvesting 
Newly diagnosed PCNSL 
Registration,  neuropsychological  evaluation 
HD-chemotherapy 
2 Additional cycles of R-MPV 
Stem Cell Reinfusion 
CR or PR 
HD-chemotherapy 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 4 of 26 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1- Primary objective: to evaluate  the safety and efficacy of the use of R-MPV followed  by high-dose 
chemotherapy using thiotepa,  cyclophosphamide  and busulfan with stem cell rescue in patients with 
newly diagnosed PCSNL. Primary endpoint will be 1-year event-free survival  and acute treatment-related 
toxicity. 
 
2.2- Secondary objectives: 
1- to evaluate  response rates with the combination of rituximab  and  MPV as induction 
chemotherapy 
2- to determine  overall survival and progression-free  survival with this regimen 
3-  To evaluate the incidence  of treatment  related neurotoxicity with this regimen. 
 
3.0 
BACKGROUND AND RATIONALE 
3.1- Treatment  for PCNSL 
PCNSL is a non-Hodgkin’s  lymphoma  (NHL) that arises within the brain, eyes, leptomeninges  or 
spinal cord, in the absence of systemic  disease. Despite being a relatively rare tumor, its incidence  has 
been increasing  in the immunocompetent  patient population  over the past several decades.1, 2 
Numerous reports have shown that the addition of pre-irradiation methotrexate  (MTX) in doses of 
1 g/m2  or higher significantly  improves patient survival.  Currently,  multiple  treatment regimens  using 
high dose MTX alone or in combination with other chemotherapeutic  agents have been reported. 
Although response rates may reach 90% in some series, the incidence  of relapses is high and progression 
free-survival  ranges from 12 to 20 months. Relapse yields a reserved prognosis and is associated with 
decreased quality  of life and survival.  The median overall survival  remains  30-60 months 3-6. Moreover, 
patients successfully  treated with chemoradiation  are at risk for developing  late delayed neurotoxicity3,  7, 8. 
The usual form of presentation of neurotoxicity is of a devastating subcortical dementia,  with executive 
dysfunction,  memory abnormalities,  gait ataxia and incontinence.  Neurotoxicity is associated  with a fatal 
course in a majority of patients. The incidence  of neurotoxicity increases with longer survival and it has 
been reported in up to 40% of patients treated with chemotherapy and radiation therapy. Elderly are at 
increased risk and the incidence  in patients over 60 can be as high as 90%. Some studies reporting on the 
use of intensive  chemotherapy regimens  without  RT in an attempt of decreasing the risk of neurotoxicity 
have demonstrated  increased  acute toxicity  and/or less effective  disease control.5, 6, 9-11 Therefore, the 
optimal treatment for PCNSL remains  controversial. 
 
3.2- Methotrexate,  procarbazine and vincristine  for PCNSL 
The rationale  underlying the choice of drugs in PCNSL is based on two premises: demonstrated 
activity in non-Hodgkin’s  lymphoma  and penetration of the blood-brain barrier (BBB). Successful 
regimens  for non-Hodgkin’s  lymphoma  such as CHOP have been unsuccessful in the treatment  of 
PCNSL because of inability of these drugs to cross an intact blood-brain barrier. Although some areas of 
the tumor may have a disrupted BBB, several reports have demonstrated  the presence of tumor cells 
beyond those areas, where the BBB is intact.12 
Methotrexate is the single most important drug in PCNSL. Its activity has been demonstrated in 
several trials as a single agent 6 or in combination  with other drugs3-5, 9. It has the ability of crossing an 
intact BBB when used in doses higher  than 1g/m2. Procarbazine  and vincristine  are drugs that are active 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
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in NHL and have a good penetration of the BBB. They have been incorporated in a variety of regimens 
for PCNSL, although  the single  contribution  of these drugs is difficult  to ascertain.13 
The activity of the combination of methotrexate,  procarbazine and vincristine  was demonstrated in 
a prospective study conducted by the RTOG. That study enrolled 98 patients with newly-diagnosed 
PCNSL. The regimen consisted of IV MTX 2.5g/m2, IO MTX 12mg, vincristine  1.4g/m2 and 
procarbazine  100mg/m2, followed  by WBRT.  A complete response to chemotherapy was observed in 
58% of patients and a partial response in 36%. Median progression- free  survival  was 24 months and 
overall survival was 36.9 months.4  Another prospective study was conducted at Memorial Sloan- 
Kettering using a similar  regimen,  but with MTX in a dose of 3.5g/m2. The median overall survival  was 
60 months.3  However, in both studies, the incidence  of neurotoxicity by the time of reporting was high  
(15 and 25%, respectively).  Nevertheless,  MPV has been considered the standard of care by many 
institutions  and in the proposed study, it will be used for achieving maximum  response rates as induction 
chemotherapy. 
 
 
3.3- The use of high-dose chemotherapy with autologous  stem cell rescue in PCNSL 
High-dose chemotherapy with or without  radiotherapy with autologous  stem transplantation has 
been proven to be an effective  salvage treatment  modality for refractory or relapsed NHL. In patients with 
chemosensitive  disease, the long-term disease free survival may approach 40 to 50%. Some studies have 
suggested an improved  outcome when high dose chemotherapy with bone marrow transplantation is used 
as part of the initial treatment  of patients with poor prognosis/stage  IV NHL.14 
A study using high-dose chemotherapy and stem cell rescue for refractory or recurrent PCNSL 
was reported by Soussain et al. Induction chemotherapy with high-dose cytarabine  and etoposide was 
given prior to stem cell harvesting to 22 patients. Two patients died after induction chemotherapy;  eight 
patients achieved a CR; four a PR and one had SD; seven patients had refractory disease. High-dose 
chemotherapy consisted of thiotepa (250mg/mg),  busulfan (10mg/kg)  and cyclophosphamide  (60mg/kg), 
followed  by stem cell rescue and it was given to 20 patients. A CR was achieved in 16 patients, PR in 
two, SD in one; disease progressed in one patient. At least one death was direct consequence of treatment, 
from severe thrombocytopenia.  Acute neurotoxicity developed in two patients (one of them is the one 
patient who died from bleeding).  The other patient recovered. Chronic neurotoxicity developed in 5 
patients, two of them died from it. Among those 5 patients, 3 had received prior RT, the other two were 
older than 60. That study demonstrated  that the regimen utilized  was feasible and effective,  although 
cumulative  toxicity inherent  to patients with recurrent disease precluded better results.9 
Encouraging results with high-dose chemotherapy and stem cell rescue in PCNSL were also 
reported by Cheng et al. Seven patients with unfavorable  prognostic  factors (KPS <50, age>60 or relapsed 
disease) were treated with an induction chemotherapy consisting of MTX 3.5g/m2, procarbazine 
100mg/m2  and cytarabine  3 g/m2. A CR was obtained in one patient, a PR in 5 patients and PD in one. 
The high-dose regimen consisted of thiotepa 300mg/m2 and oral busulfan 4mg/kg, which achieved a CR 
in all patients. One early treatment-related  death occurred in a patient with multiple  comorbid medical 
conditions.  Five patients were alive at 5, 8, 24, 36 and 42 months of follow-up.  No neurotoxicity had been 
observed but no patient had been treated with RT. This study suggested that the use of drugs that cross the 
BBB for the high-dose chemotherapy part of the regimen may achieve better results than non-crossing 
agents.15 
A study conducted in our institution treated 28 patients with newly-diagnosed  PCNSL with MTX 
3.5g/m2 and cytarabine  (3g/m2) followed  by BEAM chemotherapy and stem-cell rescue. Of the 25 
patients evaluable  for response, only 16 patients had a PR or better after MTX and proceeded to 
cytarabine.  After cytarabine,  8 patients had a CR and 6 had a PR; those patients proceeded with HD 

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IRB Number: 04-129 A(18) 
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chemotherapy.  The other two patients did not proceed with HD chemotherapy because of disease 
progression in one and systemic  complications  in another patient. Among the 14 patients who were 
treated with HD chemotherapy,  a CR was achieved in 8 and PR in 2; disease progressed in three patients; 
one patient died from transplantation-related  complications.  The median event-free survival  was 9.3 
months. No neurotoxicity developed. The conclusions  of this study were that a better induction regimen 
was necessary for improving response rates as to allow more patients to receive the high-dose 
chemotherapy and that BEAM may not be the optimal choice for high-dose chemotherapy because these 
drugs do not have a good CNS penetration.10Therefore,  in the present study, MPV will  be utilized  for 
improving initial response rates; the regimen described by Soussain using thiotepa, busulfan and 
cyclophosphamide  will replace BEAM in an attempt to decrease relapse rates, since these drugs have a 
better BBB penetration. 
 
 
3.4- The role of Rituximab  in PCNSL and NHL 
Rituximab  is a chimeric  anti-CD20 monoclonal  antibody designed to target the CD20 antigen 
which is a transmembrane  phosphoprotein expressed on greater than 90% of all B-celll      NHL’s lymphoma. 
Data from patients with systemic  lymphoma  indicates  that rituximab  may increase the susceptibility of 
tumor cells to chemotherapy. 
 
Ruhstaller  et al evaluated the anti-tumor  activity and CNS penetration of intravenously  
administered  Rituximab  in a 38-year old male with follicular  lymphoma  relapsing in the CNS. Rituximab 
800 mg was administered  intravenously once weekly for four weeks.  Following therapy, marked 
neurologic  improvement  occurred and MRI showed reduction of leptomeningeal  enhancement.  Intrathecal 
cytarabine  and hydrocortisone  were then administered  weekly alternating with intravenous  Rituximab  for 
two months and then alternating every two weeks for 3 months (total 12 Rituximab  infusions  and 5 
intrathecal  chemotherapies).   Eight  months after initiating this regimen,  neurological  evaluation was 
normal and repeat MRI showed near complete disappearance of CNS lesions.   Rituximab  peripheral blood 
and cerebral spinal fluid  (CSF) levels  were measured 4 days after the sixth infusion and immediately after 
the seventh infusion.   The CSF concentration was 1.76% (10 uG/ml)  and 1.04% (8.5 ML/ml)  of the 
corresponding serum levels after the sixth and seventh infusions,  respectively.  Despite being a heavy 
molecular  weight,  rituximab  may penetrate the BBB via leakage across areas of BBB breakdown and/or 
macromolecular  vesicular  transport of the antibody across an intact BBB.16 
 
At MSKCC we have treated 9 PCNSL patients  using rituximab  including 3 patients with 
refractory CD20 positive  PCNSL treated with systemic  Rituximab  as single  agent therapy. The first 
2 
patient was a 61-year-old man who received Rituximab  375mg/m administered  IV once weekly for four 
doses.  The patient achieved a radiographic  partial response with clinical improvement.   The second 
subject was a 39-year old woman with a left periatrial lesion who had a radiographic  partial response and 
2 
clinical stabilization following Rituximab  administered  as a 500 mg/m dose for four weeks.  The third 
patient was a 71-year old man with leptomeningeal  disease who had no radiographic  response after 
2 
receiving 500 mg/m 
2 
of antibody for four doses.  The other 6 patients received doses ranging between 
500mg/m and 750mg/m2.17 
 
Wong et al. reported their experience using the combination of rituximab  (375mg/m2)  and 
temozolomide  for PCNSL in 7 patients. That regimen was well tolerated and 5 patients had an objective 
response.18  At MSKCC, 15 patients with relapsed or refractory PCNSL with a combination of 
temozolomide  and Rituxan (750 mg/m2). A CR was observed in 6 patients and a PR in 2. grade 3 anemia, 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 7 of 26 
 
 
 
 
thrombocytopenia  and leukopenia  was seen in 4 patients.19 
 
In an ongoing clinical trial at MSKCC using the combination of rituximab  500mg/m2  and MPV, 
15 patients have completed therapy and were deemed evaluable  for response. After 5 cycles of R-MPV, 
13 patients responded, but only 5/14 had a CR. However, after 7 cycles, 14 of the 15 patients achieved a 
CR, suggesting that the combination of Rituxan and MPV is effective  in PCNSL. In that study, patients 
presenting with a CR will be treated with reduced dose RT (2340 cGy), while  the remaining patients will 
be treated with 4500 cGy. Hematologic  toxicity was the main adverse event, with 1 grade 3 
thrombocytopenia,  one grade 3, one grade 4 and one grade 5 neutropenia  among 18 patients assessable for 
toxicity.  Among non-hematologic  toxicity,  grade 3 nausea and vomiting occurred in one patient; elevated 
ALT developed in a grade 3 in one and grade 4 in another patient.20 
Based on these encouraging results, Rituxan will be added to MPV in an attempt to improve 
response rates to induction chemotherapy,  selecting more patients for the high-dose chemotherapy part of 
the treatment and maybe improving disease-free survival. 
 
3.5- Rationale  for this study 
This study is an effort to build on the results of two prior MSKCC studies: 98-86 and 01-146. 
The strategy of treating newly diagnosed PCNSL patients with high-dose chemotherapy and stem 
cell rescue was pioneered at MSKCC with the protocol 98-86. That study clearly demonstrated that this 
strategy is feasible  and likely cured a proportion of patients. However, the two major concerns in 
analyzing the results of 98-86 were that too few patients had an adequate response to induction regimen 
and a substantial  proportion of patients recurred early after stem cell rescue. 
To improve response rates to induction chemotherapy,  we will use an identical regimen as used in 
01-146, consisting of 5-7 cycles of R-MPV. This strategy gives the potential additive  benefit  of 
combining immunotherapy and chemotherapy and the proven benefit of enhanced CR rates with 2 
additional cycles of chemotherapy in select patients. Furthermore,  assays of CD-34 counts in patients on 
01-146 suggest that we should be able to collect adequate number of stem cells during induction 
chemotherapy.  This is critical since many of these patients require urgent treatment and could not 
reasonably delay definitive  therapy for 1-2 weeks to allow stem cell collection. 
To improve the efficacy of the high-dose chemotherapy regimen,  the present protocol will 
incorporate different  drugs in comparison to protocol 98-96. That study used BEAM chemotherapy,  a 
well tolerated regimen that is particularly safe in the elderly (over 60) population,  which constitutes  half 
of the patients with PCNSL. However, in that study, nearly 50% of patients relapsed  within a few months 
after high-dose chemotherapy.  A possible explanation for this lack of efficacy is that the drugs in BEAM 
may not achieve ideal levels in the CNS due to incomplete  penetration of the BBB. A study by Soussain 
et al using high-dose thiotepa and busulfan with stem-cell support in PCNSL resulted in lower relapse 
rates, with acceptable toxicity9. A small study by Cheng et al using that same combination for PCNSL in 
patients with poor prognosis (elderly,  poor functional  status or recurrent disease), demonstrated that the 
regimen was effective  and well tolerated in that population.15   Those studies suggest that thiotepa and 
busulfan may be more effective  than BEAM in preventing relapse in PCNSL and, therefore, we will 
utilize  the regimen described by Soussain for the high-dose chemotherapy portion of our study. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
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4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1- Design 
In this single  arm, multi- institution,  phase II trial, patients with newly-diagnosed  PCNSL will undergo 
base-line clinical  and radiographic  evaluation,  including neuropsychologic  evaluation and will be initially 
treated with induction chemotherapy,  which will consist of R-MPV (one cycle=14 days). After 5 initial 
cycles of R-MPV, all patients will be evaluated for response with an MRI. 
 
4.1.1-  Patients with CR after the initial  5 cycles will proceed with the HD-chemotherapy portion of the 
study. 
 
4.1.2-  Patients with SD or PR after the initial  5 cycles will receive 2 additional cycles of R-MPV and  
will then be reassessed with an another MRI.  After 7 cycles, those with a CR, PR, or continued  
PR as compared with the baseline (pretreatment)  MRI, will proceed to HD chemotherapy.   After 7 
cycles, patients with SD will be taken off study. 
 
4.1.3-  Patients with PD at any time or with PD after 7 cycles of R-MPV cycles will be taken off study. 
 
 
4.1.4-  Patients will be off study at the time of death. All patients will be followed  for survival every 6 
months throughout  their lifetime. Survival status may be obtained by phone call, clinical visit  or 
medical records (e.g. physician notes/laboratory results of clinic  or hospital visit. 
 
The response documented  in the MRI after the 5th or 7th cycles of R-MPV will be considered 
response rate to induction chemotherapy.  Patients selected for the HD-chemotherapy portion of the study 
will receive thiotepa, busulfan and cyclophosphamide  followed  by stem cell reinfusion.   Response rates to 
high-dose chemotherapy will be assessed 3 months after stem cell infusion.  Patients will have 
neuropsychologic  evaluation 6 months  after high-dose chemotherapy and every 6 months  thereafter. All 
patients will be followed  for survival. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC  AGENTS 
5.1- Rituximab: 
Mechanism of action: rituximab  is a genetically engineered  chimeric  (murine  and human)  monoclonal 
antibody directed against the CD20 antigen found on the surface of normal cells and in high copy number 
on malignant  B lymphocytes.   The Fab domain of rituximab  binds to the CD20 antigen on B-lymphocytes 
and B-cell non-Hodgkin's  lymphomas,  and the Fc domain recruits immune  effector functions  to mediate 
B-cell lysis. Rituximab  is supplied as 100mg and 500mg of sterile, preservative- free,  single- use 
vials. DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS 
Preparation: Use appropriate aseptic technique.   Withdraw the necessary amount  of Rituximab  and dilute 
to a final concentration of 1 to 4 mg/ml into an infusion bag containing either 0.9% Sodium Chloride, 
USP, or 5% Dextrose in Water, USP.  Gently invert  the bat to mix the solution.  Discard any unused 
portion left in the vial. 
 
5.2- Methotrexate: 

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Mechanism of action: Inhibition of dihydrofolate  reductase leads to partial depletion of reduced folates, 
which leads to inhibition of purine and thymidylate  biosynthesis. 
Formulation:  Methotrexate sodium for injection is supplied  as a sterile lyophilized 
powder, which comes in 20 mg, 50 mg and 1 g, vials. 
Preparation: Immediately before use the contents of each vial should be reconstituted 
with preservative  free medium (5% dextrose solution USP or sodium chloride  injection 
USP).  The 20 and 50 mg vials should be reconstituted  to a concentration no greater than 
25mg/ml;  the 1 g vial should be reconstituted  with 19.4 ml to a concentration of 50 
mg/ml.   The drug is then further  diluted with D5W for intravenous  administration. 
Storage: Vials should be stored at room temperature  and protected from light. 
 
5.3-Vincristine: 
Mechanism of action:  The mechanism of action of vincristine  has been related to the 
inhibition of microtubule  formation in the mitotic  spindle,  resulting in an arrest of 
dividing cells at the metaphase stage. 
Formulation:  Preparation of vincristine  is for IV use, available  in 1mg, 2mg and 5mg 
vials. 
Preparation: Do not add extra fluid  to the vial prior to removal of the dose. Withdraw the 
solution of vincristine  into an accurate dry syringe,  measuring the dose carefully. 
 
5.4- Procarbazine: 
Mechanism of action: Procarbazine may act by inhibition of protein, RNA and DNA 
synthesis.   Studies have suggested that procarbazine  may inhibit  transmethylation of 
methyl groups of methionine  into t-RNA. The absence of functional  t-RNA could cause 
the cessation of protein synthesis  and consequently  DNA and RNA synthesis. 
Formulation:  Procarbazine is available  as capsules containing the equivalent  of 50 mg 
procarbazine  as the hydrochloride. 
Preparation: Each capsule also contains cornstarch, mannitol and talc.  Gelatin capsule 
shells contain parabens (methyl and propyl), potassium sorbate, titanium dioxide, FD&C 
yellow  No. 6 and D&C Yellow  No.10. 
Storage: The drug is stored in room temperature. 
 
5.5- Busulfan (Busulfex): 
Mechanism of action: polyfunctional-alkylating agent that interacts with nucleic  acids 
causing inter-strand  cross-linking and DNA protein cross-linking.   Busulfan is 
extensively metabolized  to inactive  compounds that are renally excreted. 
Formulation:  60 mg vials for intravenous  use 
Preparation: Sterile solution in 10 ml single  use clear glass ampoules each containing 60 
mg of busulfan at concentration of 6 mg/ml for IV use 
Storage: Refrigerated  conditions  between 2-8°C 
 
5.6- Thiotepa (Thioplex): 
Mechanism of action: cell cycle non-specific  chemotherapeutic  agent capable of killing 
cells in any phase of the cell cycle.  Thiotepa forms covalent  cross-links with DNA or 
DNA protein complexes, resulting in cytotoxic,  mutagenic  and carcinogenic  effects. 
Formulation:   15mg vials. 
Preparation: vials containing 15mg of non-pyrogenic,  sterile lyophilized  powder 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
 
 
 
Storage: Refrigerated  conditions  between 2-8°C. Protect from light  at all times. 
 
 
 
 
 
5.7- Cyclophosphamide  (Cytoxan): 
Mechanism of action: alkylating agent that is metabolized to cytotoxic metabolites that 
form cross-links with DNA resulting in inhibition of DNA synthesis and function. It is 
active in all phases of the cell cycle. 
Formulation:  Available  in 100, 200, 500 1,000 and 2,000 mg vials for intravenous  use 
Preparation: Standard IV fluid  – D5W; maximum  concentration = 20 mg/ml;  IVPB 
volume: for doses < 1500 mg, infuse  in 25 ml D5W; for doses > 1500 mg, infuse  as 
straight  drug. 
Storage: Store vials at room temperature. Reconstituted  vials are stable for 2 days at room 
temperature and 28 days under refrigeration.  Refrigerated- infusions  prepared in D5W are 
stable for 24 hours. Room temperature-infusions  prepared in D5W are stable for 24 hours. 
 
5.8- Filgrastim (G-CSF): 
Mechanism of action: human protein involved in the promotion of the growth and 
maturation of neutrophil/granulocyte progenitors and the stimulation of functional 
activity. 
Formulation:  Prepared from recombinant  DNA, G-CSF is supplied  containing clear 
colorless sterile protein solution. 
Storage: It can be stored at 2-6 C and is stable for at least 30 months. 
 
5.9- Leucovorin: Mechanism of action: Leucovorin is an active chemical derivative  of 
folic acid.  It is useful as an antidote to drugs, which act as folic acid antagonists 
(methotrexate). 
 
Formulation:  50 mg, 100 mg, and 350 mg vials to be reconstituted  for intravenous  use; 
5mg and 25 mg tablets for oral use. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pag

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Preparation: Vials for intravenous  use must be reconstituted  with sterile diluent.   If bacteriostatic  water is 
used the product is stable for 7 days.  If reconstituted  with sterile water for injection it must be used 
immediately. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
6.1.1- All patients must have non-Hodgkin's  lymphoma  involving the brain, as demonstrated by CT or 
MRI and histologic  confirmation by one of the following: 
• i) A positive  CSF cytology for lymphoma  or a monoclonal  lymphocyte  population as 
defined by cell surface markers. 
 
• ii) A biopsy of the vitreous  or uvea demonstrating non-Hodgkin's  lymphoma 
 
• iii)  Brain biopsy 
 
6.1.2- Patients must be HIV-1 negative. 
 
6.1.3- Patient must have left ventricular  ejection fraction ≥ 50% 
 
6.1.4- Patients must have no evidence of systemic  lymphoma.  This must be demonstrated  by a CT scan 
of the chest, abdomen and pelvis  prior to registration. 
 
6.1.5- Patients must have adequate bone marrow function (defined as peripheral leucocyte count >3000 
cells/mm3 and platelet count > 100,000 cells/mm3), liver function (bilirubin < 2.0 mg%), and adequate 
renal function (serum creatinine  < 1.5 mg/dl or creatinine  clearance > 50cc/min/1.73M2). 
 
6.1.6- Men and women of reproductive  potential must agree to use an acceptable method of birth control 
during treatment and for six months after completion of treatment. 
 
6.1.7- Patients must be between 18 and 72 years-old. 
 
6.1.8- Patients must sign an informed  consent 
 
6.3 
Subject Exclusion Criteria 
 
The following would exclude a patient from the study: 
 
• Prior cranial irradiation 
 
• Other active primary malignancy with the exception of basal cell carcinoma 
of the skin and cervical carcinoma  in situ 
 
• Pre-existing immunodeficiency such as renal transplant  recipient 
 
• Prior treatment with chemotherapy for CNS lymphoma. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 12 of 26 
 
 
 
 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited from the Neurology and Neurosurgery services. All patients will be seen by 
a Neuro-Oncology attending physician.  Every effort will be made to include  encourage eligible 
women and minorities  to participate. All patients will be required to sign a written informed  consent 
prior to being registered on this protocol. Every effort will be made to answer questions raised by 
patient and their family or advocate regarding the protocol and alternative  therapies prior to asking a 
patient to sign the consent form. 
 
Estimated  accrual: based on previous clinical trials conducted at MSKCC, the estimated  accrual is 3-4 
patients/month.  Estimated  study duration: 2-3 years. 
 
 
8.0 
PRETREATMENT EVALUATION 
 
8.1- Bloods: CBC with white cell differential,  PT/PTT, screening profile  including  creatinine, 
electrolytes,  and liver enzymes  and EBV, CMV, HSV, hepatitis  B and C serology. 
 
8.2- HIV testing within 3 months  prior to enrollment  in the protocol.  (Separate counseling and consent if 
done at MSKCC) 
 
8.3- Urine: 24 creatinine  clearance and routine urinalysis. 
 
8.4- Radiographic  studies: Chest X-ray (PA and lateral),  CT scan of chest, abdomen and pelvis,  MR scan 
of brain with gadolinium  (CT scan may be substituted  if patient has a medical contraindication to MR 
scanning)  within 14 days of starting chemotherapy.   MR spectroscopy will be done if available  (not 
required for protocol). 
 
8.5- Complete ophthalmologic  exam including slit lamp. 
 
8.6- A complete physical and neurological exam including KPS and MMSE. 
 
8.7- Baseline  neuropsychologic  evaluation (appendix). If neuropsychological evaluation is not possible 
patients may still participate  in the study. 
 
8.8- Bone marrow biopsy and aspirate. Results of bone marrow biopsy and aspirate are not required for 
study enrollment,  but if evidence of bone marrow lymphomatous  infiltration is documented, then  the 
patient should be taken  off protocol since the patient no longer meets the definition of primary CNS 
lymphoma  and  therefore no longer meets eligibility criteria. Such patients will be treated at the discretion 
of treating physician and may continue  with induction  treatment  off-protocol if deemed appropriate. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 13 of 26 
 
 
 
 
 
 
 
9.0 
TREATMENT/INTERVENTION  PLAN 
9.1- Induction  chemotherapy: 
After registration and initial evaluation,  patients will receive 5 cycles of the combination of Rituximab, 
methotrexate  (MTX), procarbazine and vincristine  (R-MPV).  Rituximab  will typically be administered 
on an outpatient  basis.  Patients will then be admitted to receive methotrexate,  procarbazine, and 
vincristine  as inpatients.   One cycle was defined as 14 days and will consist of the following: 
 
 
2 
9.1.1- Rituximab  500 mg/m will be given intravenously on day 1 of each cycle typically as an outpatient. 
Prior to Rituximab  infusion,  patients will be pre-medicated with lorazepam 0.5 mg - 1 mg IV, Benadryl 
25-50mg IV/po, Tylenol 650 mg po.  Demerol 25-50 mg will be given to the patient prn rigors. 
Rituximab  will be infused  over approximately 5 hours or per institutional guidelines. 
 
 
2 
9.1.2- Methotrexate,  3.5 gm/m , diluted  in 500cc D5W containing  50meq NaHCO3 will be infused 
intravenously over approximately 2 hours on day 2 of each cycle.  Standard pretreatment  hydration and 
alkalinization of urine will be done per institutional guidelines  (MSKCC: Infuse 1 liter D5W + 100mEq 
sodium bicarbonate over 4 hours and urine output should be > 150 ml/hour  and urine pH > 7.5 prior to the 
start of the high-dose  Methotrexate).   Prior to MTX administration,  1meq/kg of NaHCO3 in 50cc D5W 
will be given.  Oral NaHCO3 (2 tabs po q 6h) will be given for the 3 days following  MTX infusion to 
maintain urine pH > 7.0. If a patient is unable to take NaHCO3 by mouth, or if adequate alkalinization of 
the urine is not accomplished,  IV NaHCO3 will be started.  15 meq NaHCO3 in 50 cc D5W are 
administered  IV over 15 minutes  q 6h; the frequency can be increased to every 4 hr if the urine pH 
remains  < 7.0. 
Leucovorin,  25 mg po q 6h for 12 doses, (if a patient is unable to take oral leucovorin,  it will be 
administered  IV at 20 mg q 6 hr) will begin approximately 24 hours after MTX infusion and continue  for 
-8 
72 hours or until the MTX level is < 1 X 10 . 
MTX levels, CBC and electrolytes  (including BUN/Cr) will be obtained daily for 3 days following MTX 
administration.   If MTX levels are toxic at 48 hrs (>1 x 10-6 M), leucovorin will be increased to 40 mg 
2 
-8 
po/IV q 4h and total fluid  intake will increase to 3000 cc/m . MTX levels > 1 X 10 
2 
at 72 hr will dictate 
continued  leucovorin (40 mg po/IV q 6h), hydration at 3000 cc/m /day and NaHCO3 (or per institutional 
-8 
guidelines)  until MTX level is 1 X 10 or less. 
 
All patients will be instructed  to maintain vigorous  oral hydration throughout  the MTX infusion and for 
72 hours thereafter.  For the first 24 hours after the MTX administration,  total fluid  intake should be at 
2 
least 1500-1800 cc/m 
2 
and increased to 2000 cc/m for the following 48 hours.  Patients will be instructed 
to refrain from eating citrus fruit, drinking citrus fruit  juices or taking vitamin C supplements  during MTX 
administration and for the following 72 hrs. 
 
 
2 
9.1.3- Vincristine  1.4mg/m IV will be given concomitantly with each dose of systemic  MTX. 
2 
Vincristine  is capped at 2mg/m (or 2.8mg maximum dose). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 14 of 26 
 
 
 
 
 
 
 
2 
9.1.4- Procarbazine,  beginning on day 2, 100mg/m /day PO for 7 days will be given with the first, third, 
fifth,  and seventh (if patient receives this) cycle of R-MPV.  Patients will be maintained  on a tyramine- 
free diet during procarbazine administration. 
9.1.5- G-CSF support should be used with each cycle of induction chemotherapy.   Patients will be 
treated with 5ug/kg/day subcutaneously daily for 3-5 days starting 24 hours after their last dose of 
procarbazine  (cycles 1,3,5,7) or starting 96 hours after MTX dose or when MTX level is < 1 X 10 -8 
(cycles 2,4,6).  If for any reason a patient cannot receive GCSF then a CBC should be done at least twice 
a week between cycles of induction chemotherapy and between cycle 7 and the start of high-dose 
chemotherapy. 
 
9.1.6- All patients will undergo a repeat brain MRI (or CT) after 5 cycles. The response achieved will 
determine  the total number of cycles as follows: 
 
-CR: Patients with CR after the initial  5 cycles will proceed with the HD-  chemotherapy 
portion of the study. 
 
-SD or PR:  Patients with SD or PR after the initial  5 cycles will receive 2 additional cycles 
of R-MPV and will be reassessed with an MRI.  After 7 cycles, those with a CR, PR, or 
continued  PR as compared with the baseline  (pretreatment)  MRI, will proceed to HD 
chemotherapy.   After 7 cycles, patients with SD will be taken off study. 
 
-PD: Patients with PD after 5 cycles of R-MPV or after 7 cycles of R-MPV or with PD at 
any time during the study will taken off study. 
 
 
9.2- Peripheral Blood Stem Cell Cytapheresis 
 
The peripheral blood stem cell (PBSC) harvest procedure will be performed at the discretion of the 
hematology  attending  (usually  after the 1st or 2nd cycle of R-MPV).  Cytapheresis  will start after bone 
6 
marrow recovery and repeated daily up to day 7 until a target yield of > 5 X 10 
6 
CD34+ cells have been 
6 
collected; the minimum acceptable total yield is 2 X 10 CD 34+ cells/kg. If fewer than 2 X 10 CD34+ 
cells are collected then bone marrow harvest is required.  The minimum  acceptable yield for patients 
8 
undergoing bone marrow harvest is 1.5 X 10 mononuclear  cells/kg. 
 
Some patients will have inadequate  peripheral venous access and require placement  of a catheter suitable 
for hemodialysis.  All patients will have a 13.5 Fr Davol double-lumen catheter (or similar  catheter) placed 
prior to PBSC leukophoresis.  If this catheter requires replacement  subsequently,  a standard 10 Fr catheter 
may be used. 

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IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 15 of 26 
 
 
 
 
9.3- HD chemotherapy with autologous stem cell support 
 
9.3.1- The high-dose chemotherapy program will include  thiotepa, busulfan and cyclophosphamide 
administered  as follows: 
 
 
Agent 
Total Dose 
Route 
Days 
Thiotepa 
250 mg/m2/day 
intravenous 
-9, -8, -7 
Busulfan 
3.2 mg/kg/day 
intravenous 
-6, -5, -4 
Cyclophosphamide 
60mg/kg/day 
intravenous 
-3, -2 
 
9.3.2- Stem cell reinfusion occurs on day 0 and will follow  institutional standard procedures. 
(Please see appendix for general recommendations) 
 
 
[NOTE: When patient weight exceeds the maximum  large frame value from the Metropolitan Life table, 
doses of chemotherapy will be based on ideal body weight,  not actual weight  (ie. the maximum large 
frame weight  from said table).] 
 
 
9.3.2- Support therapy 
Support therapy during high-dose  chemotherapy and post-transplant  care will follow  institutional 
guidelines  and usually will include  the following: 
 
- 
Seizure prophylaxis: all patients should be on prophylactic  anticonvulsants  prior to the 
administration of busulfan.   The general recommendation in patients not already on an 
anticonvulsant  is to use a benzodiazepine  (clonazepam 2mg/day or diazepam 10mg/day) 
starting the first day of busulfan administration and continuing until the day after the last 
dose of busulfan. 
 
- 
Hydration: To ensure a urine output >100 ml/hr  patients will receive normal saline at 200 
2 
ml/m /hr  x 6 hours prior to commencing high-dose chemotherapy.  Normal saline  plus 20 
(milliequivalents)  of KCL/l will be infused  intravenously between doses of busulfan and 
thiotepa and during the rest phase prior to stem cell reinfusion.   Subsequently,  intravenous 
fluid  requirements  will be dictated by oral intake and other factors. Fluid intake and output 
will be continuously measured.  If there is a lag in urine output greater than 800 ml/12 
hours, furosemide  or an equivalent  diuretic  should be administered  intravenously (± low 
dose dopamine).  Prior to cyclophosphamide  infusion hydration  will consist of D51/2 NS + 
8 mEq magnesium sulfate/Liter  + 20 mEq potassium chloride/liter  and D51/2 NS + 20mEq 
potassium chloride/Liter  + 50 mEq sodium bicarbonate/Liter  to infuse  simultaneously or 
alternate bottle sequence (prefer simultaneous  infusion).  Start IV hydration with each liter 
at 75 ml/hour  to total 150 ml/hour  at 7 PM the night  before, then increase IV rate to 300 
ml/hour  (each liter at 150 ml/hour)  at 7AM the next day. After the infusion,  hydration will 
consist of D51/2 NS + 8 mEq magnesium  sulfate/Liter  + 20 mEq potassium chloride/Liter 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 16 of 26 
 
 
 
 
and D51/2 NS + 20 mEq potassium chloride/Liter  + 50 mEq sodium bicarbonate/Liter  to 
infuse  simultaneously or alternate bottle sequence (prefer simultaneous  infusion)  @ 300 
ml/hour  (each liter at 150 ml/hour)  for 24 hours after last dose of cyclophosphamide.  Lasix 
will be given as needed. Urinalysis  will be sent stat every 4 hours for 24 hours post 
treatment and monitored for hematuria. 
 
- 
Anti-emesis:  All antiemetic  prophylaxis  will be done according to standard institutional 
procedures. (Please see appendix for general recommendations). 
 
- 
Patients will be given vitamin K 10 mg po or sq one to three times per week unless added 
to TPN. 
 
- 
Patients will start G-CSF 5 ug/kg sq bid beginning day +1. It will be continued  until ANC 
> 1000/mm3 X 3 days. 
 
- 
Blood transfusion:  All blood products will be irradiated to 3000 cGy to prevent 
transfusion associated GVHD. Platelets will be given prophylactically to maintain a 
platelet count > 20,000/mm3 for the first 10 days post PBPCT in all patients and beyond 
that period in patients with active bleeding,  fever or coagulopathy.  After day 10 
prophylactic  platelet transfusions  will be given to maintain a platelet count > 10,000/mm3 
in the low risk, non-bleeding patient. Patients will be transfused  to maintain a hemoglobin 
> 7 g/dl. If clinically indicated,  additional transfusions  can be given. Patients who are 
CMV seronegative  will receive white blood cell depleted products using a third generation 
white cell filter,  or CMV negative  blood products. 
 
- 
Nutritional status will be carefully monitored by the physician and the dietician.  TPN will 
be administered  to patients if caloric intake is < 25% of his/her estimated  calorie needs for 
3 days. 
 
- 
Antibiotics:  On admission,  patients will receive: 
 
 Ciprofloxacin 500 mg po bid which will be continued  until the patient requires 
broad spectrum antibiotics  for neutropenic  fever. 
 
 Fluconazole  100 mg po or IV bid which will continue  until the ANC is > 
1000/mm3 X 3 days or until amphotericin B therapy is initiated  (except for patients 
concurrently enrolled on MSKCC protocol 97-112, who will not receive 
fluconazole  prophylaxis). 
 
 Bactrim ds po bid until day -2 for PCP prophylaxis. 
 
 Nystatin powder will be applied to the groin and axilla  bid. 
 
 Patients seropositive  for HSV will be given acyclovir  400 mg po bid or 250 mg 
IVPB q 8h until the ANC > 1000/mm3 X 3 days. Acyclovir  will be restarted upon 
discharge at 400 mg po bid for 90 days post PBPCT. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 17 of 26 
 
 
 
 
 On day 60 post PBPCT patients will receive aerosolized  pentamidine.  On day 90 if 
the platelet count is > 50,000/ul Bactrim will  be restarted at 1 po bid for 2 
consecutive  days/weeks for 180 days post PBPCT. If on day 90 the platelet count is 
< 50,000/ul aerosolized  pentamidine  will continue  monthly until day 180 post 
PBPCT. 
 
 
10.0 
EVALUATION  DURING TREATMENT/INTERVENTION 
10.1- During induction  chemotherapy: 
Electrolytes  including BUN/Cr and MTX level will be drawn daily prior to and for at least 72 hours after 
each cycle of MTX. (1 st MTX level 24 hr after infusion). 
Urine pH will be checked several times daily for at least 72 hours after each cycle of MTX until MTX 
levels are not toxic. CBC will be checked twice weekly until WBC and platelets have recovered. 
 
Evaluation of response will take place after 5 or 7 cycles of R-MPV and 90 days after chemotherapy.  At 
each step, the following tests will be performed: 
 
-Complete neurologic  examination including KPS and MMSE. 
 
-MRI of the brain with gadolinium  to evaluate  response to treatment.  MR spectroscopy will 
be done if available  (not required). CT scan will be performed in case of contra-indications  to 
MRI. 
-If CSF cytology  was positive  at initial diagnosis,  repeat CSF will be sent for cytologic  examination, 
and routine chemistries  and cell count. 
-Patients with ocular involvement  at diagnosis  will have a complete eye exam including slit lamp 
examination. 
 
 
10.2 Evaluation prior to HD-chemotherapy/PBPCT  : 
 
- Pulmonary function tests, including DLCO 
 
- Dental evaluation prior to hospitalization  for PBPCT. 
 
- Echocardiogram or MUGA scan. 
 
- CBC, electrolytes,  liver function. 
 
- Neuropsychological evaluation will be performed upon completion of R-MPV (induction 
chemotherapy)  and prior to transplant. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 18 of 26 
 
 
 
 
 
 
10.3 Post treatment evaluation: 
 
Patients will be examined  at least weekly until they become transfusion independent. 
Follow-up neurologic  status will be assessed monthly for the first 3 months post PBPCT and 
approximately every 3 months thereafter for the first two years.  Follow up will then be done every 4 
months for third year and fourth years and then every 6 months throughout  their lifetime.  Survival  status 
may be obtained by phone call, clinical visit  or medical records (e.g. physician notes/laboratory results of 
clinic  or hospital visit). 
 
. All neurologic  evaluations  will include  a MMSE and KPS.  An MRI scan will be done at the time of 
each neurologic  evaluation beginning at 3 months post PBPCT. 
 
Repeat CSF and/or ocular exam will be done 3 months post PBPCT in those patients who had evidence of 
involvement  at diagnosis.  Further exams will only be done for recurrent symptoms. 
 
Neuropsychologic  evaluation will be repeated approximately 6 months after the completion of therapy 
and at 6 months intervals  thereafter. 
 
 
11.0 
TOXICITIES/SIDE  EFFECTS 
 
Toxicity will be graded using the NCI Common Toxicity  Criteria, version 3.0. 
 
11.1- Rituximab  may cause infusion-related  symptoms,  consisting of fever and chills  that occurs in most 
patients during the first infusion.   Other hypersensitivity symptoms,  including nausea, urticaria,  fatigue, 
headache, pruritus,  bronchospasm,  dyspnea, sensation of tongue or throat swelling,  rhinitis,  vomiting, 
hypotension,  flushing,  and pain at disease sites, may also be seen. They occurred primarily during 
Rituximab  infusion and resumption at a slower rate. 
Other adverse events caused by Rituximab  include  neutropenia,  thrombocytopenia  and asthenia.  Patients 
with preexisting cardiac conditions,  including arrhythmia  and angina,  have had recurrences of these 
cardiac events during Rituximab  infusions. 
Although rare, tumor lysis syndrome has been reported in post-marketing studies and is characterized  in 
patients with a high number of circulating malignant  cells (>25,000 ul) by rapid reduction in tumor 
volume,  renal insufficiency,  hyperkalemia,  hypocalcemia,  hyperuricemia,  and hyperphosphatemia. 
In rare cases, severe and fatal cardiopulmonary events, including hypoxia,  pulmonary infiltrates,  acute 
respiratory distress syndrome,  myocardial infarction,  and cardiogenic  shock, have occurred (4-7/10,000 
patients or 0.04-0.07%) Nearly all fatal infusion-related  events occurred in association with the first 
infusion. 
The following immune  serious adverse events have been reported to occur rarely (<0.1%) in patients 
following completion of Rituximab  infusions: arthritis,  disorders of blood vessels (vasculitis,  serum 
sickness and lupus-like  syndrome),  lung disorders including pleuritis  and scarring of the lung 
(bronchiolitis  obliterans),  eye disorders (uveitis  and optic neuritis),  and severe bullous  skin reactions 
(including toxic epidermal necrolysis  and pemphigus)  that may result in fatal outcomes.  Patients may 
have these symptoms  alone or in combination with rash and polyarthritis. 
 
11.2- MTX can produce myelosuppression,  GI toxicity,  particularly mucositis,  liver  dysfunction,  renal 

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IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 19 of 26 
 
 
 
 
failure  and rarely interstitial pneumonitis  and gastrointestinal epithelial  denudation. 
 
 
 
11.3- Procarbazine  can produce myelosuppression,  nausea and vomiting.   Hypertension can occur when 
foods containing tyramine  are ingested due to inhibition of monoamine  oxidase, and Antabuse-like 
reactions may occur when alcohol is taken with PCB. Cutaneous and pulmonary hypersensitivity 
reactions are rare complications. 
11.4- Vincristine  can cause a peripheral neuropathy including autonomic  dysfunction such as 
constipation.  It also causes alopecia and can result in local necrosis after extravasation. 
11.5- Busulfan can cause moderate nausea and vomiting,  diarrhea, dose limiting mucositis,  and severe 
myelosuppression with high dose therapy. Severe or irreversible  effects include  veno-occlusive  disease 
(VOD) of the liver,  seizures, confusion,  hyperpigmentation of the skin, interstitial  pulmonary fibrosis 
(“busulfan lung”),  increased incidence  of secondary malignancies  after prolonged administration.  Because 
of the risk of seizures,  prophylactic  anti-convulsants  are recommended. 
 
11.5- Thiotepa can cause bone marrow depression, which is dose limiting and requires stem cell support 
2 
at doses >60 mg/m . Neutropenia and thrombocytopenia  occur within 7 to 10 days. Other common side 
effects include  nausea and vomiting (usually mild),  mucositis,  esophagitis  and enterocolitis. 
Dermatological  toxicity consisting of an acute erythrodermia  with desquamation and peeling of skin of 
soles and palms is uniformly seen. General darkening of the skin may occur (resembling a mild  suntan) 
which can persist for several months. Central nervous system toxicity characterized  by inappropriate 
2 
behavior, forgetfulness,  confusion and somnolence  occurs in ~5% patients given 900 mg/m . 
 
11.6- Cyclophosphamide  can cause dose dependent myelosuppression.  Bladder toxicity in the form of 
hemorrhagic  cystitis,  dysuria, and increased urinary frequency occurs in 5-10% of patients. It is usually 
reversible  upon discontinuation of the drug. Uroprotection with mesna and hydration must be used with 
high-dose therapy. Nausea and vomiting usually occur within 2-4 hours after infusion.  Alopecia is severe 
and skin and nails may become hyperpigmented.  Amenorrhea  with ovarian failure  may occur and sterility 
may be permanent. Cardiac toxicity may be observed. Secondary malignancies  may develop, including 
acute leukemia  and bladder cancer. Immunosuppression,  SIADH and hypersensitivity reactions may 
occur. 
 
11.6- Filgrastin can cause bone pain, exacerbation of pre-existing autoimmune  disorders, transient  and 
reversible  changes in alkaline  phosphatase, uric acid and LDH. 
 
11.7- Leucovorin can cause allergic  reactions. 
 
12.0  CRITERIA FOR THE THERAPEUTIC  RESPONSE/OUTCOME  ASSESSMENT 
 
Radiographic  response: 
As assessed by MRI/CT. Tumor measurements  must be recorded in centimeters  and must be measured at 
the longest diameter and its perpendicular  at the widest portion of the tumor. For tumors that are difficult 
to measure (ie. irregular  shape), a visual interpretation of the magnitude  of response is acceptable. 

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Approval date: 04-Nov-2020 
Page 20 of 26 
 
 
 
 
• 
Complete response (CR) - disappearance of all enhancing tumor. Patients must be off steroid 
therapy and neurologically stable or improved.  If CSF cytology was previously positive,  it must be 
reassessed and negative.  If ophthalmologic  examination was previously positive, it must be reassessed 
and negative  for cells. 
 
• 
Partial response (PR) - > 50 % decrease in tumor size in comparison with baseline scan. Patients 
must be neurologically improved or stable on a stable or decreasing dose of corticosteroids. 
• 
Progressive  disease (PD) - > 25% increase in enhancing tumor or the appearance of new lesions. 
The patient may be neurologically stable or worse and on stable or increasing doses of steroids. 
• 
Stable disease (SD) - all other situations. 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients may be removed from the study if any one or more of the events listed below occurs. The reason 
for removal and the date are to be recorded. An end of study treatment  evaluation should be performed 
whenever possible. 
- 
Ineligibility of the patient as defined in the inclusion/exclusion criteria 
- 
Significant  protocol violation 
- 
Non-compliance  of the patient 
- 
Unacceptable toxicity 
- 
Refusal of the patient to continue  treatment and/or observations 
- 
Unrelated medical illness  or complication 
- 
Disease progression or a requirement  for an alternative  therapy 
- 
Decision by the investigator  that termination is in the patient's best medical interest or as 
an administrative  decision 
- 
Loss to follow-up 
- 
Death of the patient. 
 
14.0 
BIOSTATISTICS 
 
14.1- The primary end-point will be one-year event-free survival,  defined as time from diagnosis  to tumor 
relapse, progression or death. An exact binomial test with a nominal  0.050 one-sided significance  level 
will have 90% power to detect the difference  between the null hypothesis  proportion,  π0 of 0.5 (estimated 
1-year event-free survival with chemotherapy only regimens)  and the alternative  proportion  πA, of 0.750 
when the sample size is 33 patients. 
 
14.2- Early stopping rule: If more than two toxic deaths occur among the first 15 patients, the study will 
be stopped. The study will also be stopped if four toxic deaths occur at anytime.  If the true risk of toxic 
death is 16% or higher,  then the probability of seeing 4 toxic deaths (and stopping the trial) will be at least 
80%. 
 
14.3- Secondary end-point will include  response rate to induction chemotherapy,  response rate to high- 
dose chemotherapy,  progression-free  and overall survival,  and incidence  of neurotoxicity.  Survival curves 
will be constructed using Kaplan-Meier method. Overall and induction response rates will be reported 
with a confidence  interval.  With a total of 33 patients, response rates will be estimated with a 95% 
confidence  interval to +/- 13%. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 04-129 A(18) 
Approval date: 04-Nov-2020 
Page 21 of 26 
 
 
 
 
14.4- All patients will be included  in the analysis  in an intent-to-treat  fashion. 
 
 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
All patients will be registered into the Clinical  Research Database at Memorial Sloan Kettering 
Cancer Center. Registration should be complete prior to initiation of therapy. There is no 
planned randomization. 
 
15.2 
RESEARCH PARTICIPANT REGISTRATION 
 
Confirm eligibility as defined in the section entitled  Criteria for Patient/Subject  Eligibility. 
Obtain informed  consent, by following procedures defined in section entitled  Informed  Consent 
Procedures. 
During the registration process registering individuals  will be required to complete a protocol 
specific  Eligibility  Checklist. 
All participants  must be registered through the Protocol Participant  Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available  Monday through Friday from 8:30am 
– 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735-0008 and (646) 735-0003. 
Registrations  can be phoned in or faxed. The completed signature  page of the written 
consent/verbal script and a completed Eligibility Checklist must be faxed to PPR. 
 
15.3 Randomization 
 
N/A 
 
16.1 
DATA  MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned  to the study. The responsibilities  of the RSA 
include  project compliance,  data collection,  abstraction and entry, data reporting,  regulatory 
monitoring,  problem resolution and prioritization,  and coordinate the activities  of the protocol 
study team. 
 
The data collected for this study will be entered into a secure database.  Source 
documentation will be available  to support the computerized  patient record. 
Data will be collected centrally at Memorial Sloan Kettering Cancer Center.  For each patient, 
the following forms will be completed and submitted: 
 
Form 
To be completed 
Eligibility I/On-Study 
Prior to registration 
Consent 
Prior to registration 
Induction Chemotherapy 
At time of registration on study 

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IRB Number: 04-129 A(18) 
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Page 22 of 26 
 
 
 
 
 
Central Pathology Review 
Prior to registration 
Eligibility II 
Prior to busulfan + thiotepa + cyclophosphamide 
H-D Chemotherapy 
After busulfan + thiotepa + cyclophosphamide 
Follow-up 
q3monthly x 2 yrs, then q6monthly x 3 yrs, then 
yearly 
Final Report 
At progression or death 
Adverse Events 
Within 10 days 
 
 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor  patient accruals and completeness  of 
registration data.  Routine data quality reports will be generated to assess missing data and 
inconsistencies.   Accrual rates and extent and accuracy of evaluations  and follow-up  will be 
monitored  periodically throughout  the study period and potential problems will be brought to the 
attention of the study team for discussion and action. 
 
Random-sample  data quality and protocol compliance  audits will be conducted by the study team, 
at a minimum  of two times per year, more frequently if indicated. 
 
17.1 
PROTECTION  OF HUMAN SUBJECTS 
 
17.2 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure  of 
protected health information will be limited  to the individuals  described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator  and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2- Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient  hospitalization or prolongation of existing 
hospitalization 
• A persistent or significant  incapacity or substantial disruption of the ability to conduct normal 
life functions 
• A congenital anomaly/birth defect 

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• Important Medical Events (IME) that may not result in death, be life threatening,  or require 
hospitalization may be considered serious when, based upon medical judgment,  they may 
jeopardize the patient or participant  and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition 
• List any additional events that require SAE reporting (pregnancy, AEs of special interest 
(AESI), secondary malignancies, etc) 
 
Note: Hospital admission for a planned procedure/disease  treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant  starts investigational  treatment/intervention. 
SAE reporting is required for 30-days after the participant’s  last investigational 
treatment/intervention.  Any event that occur after the 30-day period that is unexpected and at least 
possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational  treatment/intervention and is 
related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted  in PIMS. If an SAE requires submission to the HRPP office per IRB 
SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted  within 5 
calendar days of the event.  All other SAEs must be submitted  within 30 calendar days of the 
event. 
The report should contain the following information: 
• The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship  of the adverse event to the treatment(s) 
• If the AE was expected 
• Detailed text that includes  the following 
o An explanation of how the AE was handled 
o A description of the participant’s  condition 
o Indication if the participant  remains on the study 
• If an amendment  will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated  Problem 
 
17.3- Risks to human subjects 
Potential risks to human subjects include  drug related toxicity,  pain and discomfort  associated with 
phlebotomy,  and possible psychologic  discomfort  while obtaining MRI scans. 
The side effects and potential toxicities of all chemotherapeutic  agents are listed in  section 11. Death 
may occur as a result of treatment. All efforts will be made to avoid any complication by completely 
reviewing patients’ symptoms  and monitoring blood tests. 
 
Periodic phlebotomy is necessary to monitor for the potential treatment related toxicities; trained 
phlebotomy technicians  or nurses will perform all phlebotomy. 

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MRI scans are the accepted and best method for assessing central nervous system tumors and patients 
with substantial  anxiety can be treated with an anxiolytic  prior to the study. In those patients where an 
MRI is not possible for medical reasons (eg. pacemaker, ferromagnetic  intracranial  aneurysm clips) a CT 
scan will be obtained instead. 
 
17.4- Potential benefit  to society will be the establishment  of an effective  medical therapy, which may 
offer prolonged survival  or improved quality of survival  to other patients with this disease. Potential 
benefit to society will be the enhanced productivity and decreased cost of any individual  spared 
progressive  neurologic  impairment. 
 
17.5- If an adverse medical event occurs, the patient will first contact the principal investigator  or 
treating physician.  At nights  and on weekends, there is a neuro-oncology physician on call at all times. 
Patients may either call or come directly to the urgent care center at Memorial Hospital (or their 
collaborating institution)  to be seen. 
 
17.6- Costs to the patient will include  the cost of the chemotherapy,  MRI scans, office  visits,  blood tests 
and any hospital admission including those admissions  as a consequence of treatment-related 
complications. 
 
 
 
 
17.7- All serious adverse events incurred while  a patient is on study will be reported to the IRB at 
Memorial Hospital. All serious adverse experiences  and relevant laboratory findings  must be reported to 
Dr. Christian  Grommes immediately.  An adverse experience  is considered serious if death occurs, the 
condition is life threatening,  hospitalization is required, prolonged hospitalization results, or there is 
permanent  disability or incapacity.  All information regarding serious adverse experiences must be 
recorded on the form provided. Patients suffering serious adverse reactions must be carefully followed 
and all follow-up  information also recorded. In addition, all life  threatening and lethal (grade 4 or grade 
5) known, unknown,  or suspected reactions (toxicities)  must be reported to Dr. Christian Grommes by 
telephone  (212) 639-4058, or fax (212) 718-3296. A written report must be sent within ten days to Dr. 
Christian Grommes, Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York 
Avenue, New York, NY 10021. Any death, regardless of cause, must be reported to Dr. Christian 
Grommes by telephone or fax and in writing.  It is the treating physician's  responsibility to investigate 
and report the date and cause of death of any patient entered on this trial. All unusual reactions (grade 2 
or 3 toxicities)  must be reported in writing within 10 days to Dr. Christian Grommes. To protect patient 
confidentiality,  names or other identifying characteristics  will not be used in any reports or publications 
resulting from this study.  Patient records relating to this study will be stored in the department of 
Neurology;  access to these records will be restricted to study investigators,  appropriate instit utional and 
federal review agencies. Samples of peripheral blood, bone marrow, CSF or tumor will be anonymized 
before storage. 
 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified  procedures are carried out, consenting professionals  will explain full 
details of the protocol and study procedures as well as the risks involved  to participants  prior to 
their inclusion in the study. Participants  will also be informed  that they are free to withdraw  from 

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Page 25 of 26 
 
 
 
 
the study at any time. All participants  must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements  of the Code of Federal 
Regulations  and the Institutional  Review Board/Privacy Board of this Center. The consent form 
will include  the following: 
1. The nature and objectives, potential risks and benefits  of the intended study. 
2. The length of study and the likely follow-up  required. 
3. Alternatives  to the proposed study. (This will include  available  standard and 
investigational therapies. In addition,  patients will be offered an option of supportive  care 
for therapeutic  studies.) 
4. The name of the investigator(s)  responsible  for the protocol. 
5. The right of the participant  to accept or refuse study interventions/interactions  and to 
withdraw from participation at any time. 
Before any protocol-specific  procedures can be carried out, the consenting professional  will fully 
explain the aspects of patient privacy concerning research specific  information.   In addition to 
signing the IRB Informed  Consent, all patients must agree to the Research Authorization 
component of the informed  consent form. 
Each participant  and consenting professional will sign the consent form. The participant  must 
receive a copy of the signed informed  consent form. 
 
 
19.0 
REFERENCES 
 
1. 
Eby NL, Grufferman S, Flannelly CM et al. Increasing incidence  of primary brain lymphoma  in 
the US. Cancer. 1988;62:2461-2465 
2. 
Olson JE, Janney CA, Rao RD et al. The continuing increase in the incidence of primary central 
nervous system non-Hodgkin lymphoma: a surveillance, epidemiology, and end results analysis. 
Cancer. 2002;95:1504-1510 
3. 
Abrey LE, Yahalom J, DeAngelis  LM. Treatment  for primary CNS lymphoma: the next step. J 
Clin Oncol. 2000;18:3144-3150 
4. 
DeAngelis LM, Seiferheld W, Schold SC et al. Combination chemotherapy and radiotherapy for 
primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J 
Clin Oncol. 2002;20:4643-4648 
5. 
Pels H, Schmidt-Wolf IGH, Glasmacher  A et al. Primary Central Nervous System Lymphoma: 
Results of a Pilot and Phase II Study of Systemic and Intraventricular  Chemotherapy With 
Deferred Radiotherapy.  J Clin Oncol. 2003;21:4489-4495 
6. 
Batchelor T, Carson K, O'Neill A et al. Treatment  of primary CNS lymphoma  with methotrexate 
and deferred radiotherapy:  a report of NABTT 96-07. J Clin Oncol. 2003;21:1044-1049 
7. 
Abrey LE, DeAngelis  LM, Yahalom J. Long-term survival in primary CNS lymphoma.  J Clin 
Oncol. 1998;16:859-863 
8. 
Omuro AMP, DeAngelis  LM, Panageas KS et al. Neurotoxicity as a result of treatment for 
primary CNS lymphoma.  NEUROLOGY. 2004;62:A478 
9. 
Soussain C, Suzan F, Hoang-Xuan K et al. Results of intensive  chemotherapy followed  by 
hematopoietic  stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma 
or intraocular  lymphoma.  J Clin Oncol. 2001;19:742-749 

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Approval date: 04-Nov-2020 
Page 26 of 26 
 
 
 
 
10. 
Abrey LE, Moskowitz CH, Mason WP et al. Intensive Methotrexate and Cytarabine Followed by 
High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Patients With Newly Diagnosed 
Primary CNS Lymphoma: An Intent-to-Treat Analysis.  J Clin Oncol. 2003;21:4151-4156 
11. 
Hoang-Xuan K, Taillandier  L, Chinot O et al. Chemotherapy Alone as Initial Treatment  for 
Primary CNS Lymphoma  in Patients Older Than 60 Years: A Multicenter  Phase II Study (26952) 
of the European Organization for Research and Treatment  of Cancer Brain Tumor Group. J Clin 
Oncol. 2003;21:2726-2731 
12. 
Lai R, Rosenblum MK, DeAngelis  LM. Primary CNS lymphoma:  a whole-brain disease? 
Neurology. 2002;59:1557-1562 
13. 
Omuro AMP, Abrey LE, Yahalom J, DeAngelis  LM. Combined methotrexate,  procarbazine  and 
thiotepa followed by radiation therapy for primary central nervous system lymphoma: a clinical 
trial. Neuro-oncol. 2003;5:TA-24 
14. 
Lin TSTS, Copelan EAEA. Autologous  stem cell transplantation for non-Hodgkin's  lymphoma. 
15. 
Cheng T, Forsyth P, Chaudhry A et al. High-dose thiotepa, busulfan,  cyclophosphamide  and 
ASCT without  whole-brain radiotherapy for poor prognosis primary CNS lymphoma.  Bone 
Marrow Transplant.  2003;31:679-685 
16. 
Ruhstaller  TTW, Amsler  UU, Cerny TT. Rituximab: active treatment of central nervous system 
involvement  by non-Hodgkin's  lymphoma? 
17. 
Raizer J, DeAngelis  LM, Zelenetz AD, Abrey LE. Activity of rituximab  in primary central 
nervous system lymphoma.  ASCO Annual Meeting Proceedings. 2000:abstract 166A 
18. 
Wong ETET, Tishler  RR, Barron LL, Wu JKJK. Immunochemotherapy with rituximab  and 
temozolomide  for central nervous system lymphomas. 
 
 
19. 
Enting RH, Demopoulos  A, DeAngelis  LM, Abrey LE. Salvage therapy for primary CNS 
lymphoma  with combiantion of rituximab  and temozolomide.  NEUROLOGY. 2004;62:A478 
20. 
El-Kamar FG, DeAngelis  LM, Yahalom J et al. Combined immunotherapy with reduced dose 
whole brain radiotherapy for newly diagnosed patients with primary CNS lymphoma.  ASCO 
Annual Meeting Proceedings.  2004:111 
 
 
 
20.0 
APPENDICES