Pilot Study of MGd + High-dose MTX-Based Chemoimmunotherapy + RT for Newly Dx PCNSL

• Toxicity of motexafin gadolinium (MGd) and rituximab added to high-dose methotrexate, procarbazine hydrochloride, and vincristine (MPV) chemotherapy [ Time Frame: Day 1 (every 2 weeks), After 5th cycle, After 7th cycle, Pre Radiation Theray, Post Radiation Therapy, and Post ara-c. ] [ Designated as safety issue: Yes ]
  To evaluate toxicity of motexafin gadolinium (MGd) and rituximab to high-dose methotrexate, procarbazine hydrochloride, and vincristine (MPV) chemotherapy at Day 1 (every 2 weeks), After 5th cycle, After 7th cycle, Pre Radiation Theray, Post Radiation Therapy, and Post ara-c.
  
  
• Toxicity of MGd added to whole-brain radiotherapy (WBRT) [ Time Frame: Day 1 (every 2 weeks), After 5th cycle, After 7th cycle, Pre Radiation Theray, Post Radiation Therapy, and Post ara-c. ] [ Designated as safety issue: Yes ]
  To evaluate the toxicity of MGd added to whole-brain radiotherapy (WBRT).
  
  
• Tumor-selective uptake of MGd [ Time Frame: Day 1 (every 2 weeks), After 5th cycle, After 7th cycle, Pre Radiation Theray, Post Radiation Therapy, and Post ara-c. ] [ Designated as safety issue: No ]
  To evaluate Tumor-selective uptake of MGd
  
  

• Overall response rate (complete remission [CR] and partial remission [CR]) to pre-radiation chemo-immunotherapy (R-MPV with MGd) [ Time Frame: Every 3 months for the first year after completed treatment, every 4 months for the second year, every 6 months until the 5th year and then annually. ] [ Designated as safety issue: No ]
  MRI scan will be done with each neurologic evaluation. Neuropsychologic evaluation will be repeated approximately 6 months after the completion of therapy and at 6 months intervals thereafter for total of 2 years.
  
  
• Complete response rate to pre-radiation chemo-immunotherapy (R-MPV with MGd) [ Time Frame: Every 3 months after completion of treatment, exams every 3 months for the first year then every 4 - 6 months thereafter. ] [ Designated as safety issue: No ]
  Repeat CSF or ocular exam will be done 3 months after completion of treatment in those patients who had evidence of CSF or ocular involvement at diagnosis. CSF will be sampled at each visit. Ocular exams will occur every 3 months for the 1st year then every 4-6 months. Further exams will only be done as needed to rule out recurrent lymphoma.
  
  
• Overall survival at 1 year [ Time Frame: Every 3 months for the first year after completed treatment, every 4 months for the second year, every 6 months until the 5th year and then annually. ] [ Designated as safety issue: No ]
  To assess overall survival rate.
  
  
• Event-free survival at 1 year [ Time Frame: Every 3 months for the first year after completed treatment, every 4 months for the second year, every 6 months until the 5th year and then annually. ] [ Designated as safety issue: No ]
  To assess event-free survival rate.
  
  
• Progression-free survival at 1 year [ Time Frame: Every 3 months for the first year after completed treatment, every 4 months for the second year, every 6 months until the 5th year and then annually. ] [ Designated as safety issue: No ]
  To assess progression-free survival rate.
  
  
• Neurotoxicity of R-MVP + MGd based on pre- and post-treatment neuropsychologic testing [ Time Frame: At baseline ] [ Designated as safety issue: Yes ]
  MR perfusion and MR spectroscopy at baseline and serially when MRI imaging is done to assess response rates using these alternate forms of imaging.
  
  

Biological: Rituximab
Infusion will be given at week 2, week 4, week 6 and week 8. Infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.
Other Name: Rituxan
Drug: Cytarabine
Administered by IV over 3 hours at a dose of 3 g/m2/day for 2 days given at week 17 and week 21.
Other Names:
• Cytosar-U
• Ara-c
Drug: Methotrexate
Administered by IV at dose of 3.5 grams/m2 on day 1 of week 1, week 3, week 5, week 7 and week 9; if CSF was positive it will also be given intrathecally on day 8 of week 1, week 3, week 5, week 7 and week 9.
Other Names:
• MTX
• Rheumatrex
• Trexall
Drug: Motexafin gadolinium
• Administered to the first five patients enrolled on trial, MGd will be given at 5 mg/kg q day x2 doses (completed on 2 consecutive days 1 to 2 weeks prior to day of cycle 1) to be followed by a non-infused MRI (without contrast) 1-5 hours after 2nd MGd dose (to evaluate for MGd tumor selective uptake).
• For induction chemotherapy, MGd 10 mg/kg will be given intravenously on day 8 of each cycle. MGd will be given immediately after Rituxan.
• During radiation therapy, MGd will be administered at 5 mg/kg 2-5 hours prior to WBRT, daily for the first 10 days (fractions) and then every other day of radiation thereafter.
Other Name: MGd
Drug: Procarbazine hydrochloride
Taken orally, 100 mg/m2 days 1-7 of the 1st, 3rd, and 5th cycles of induction therapy.
Other Name: Matulane
Drug: Vincristine sulfate
Administered by IV at a dose of 1.4mg per meter squared on weeks 1, 3, 5, 7 and 9.
Other Name: Vincasar PFS
Radiation: Radiation therapy
Given at weeks 11 through 16.
Other Name: Whole Brain Radiation Therapy (WBRT)

OBJECTIVES:

Primary

• Determine the safety and efficacy of motexafin gadolinium (MGd) combined with high-dose methotrexate-based chemotherapy and radiotherapy in patients with newly diagnosed primary CNS lymphoma.
• Determine the toxicity of MGd and rituximab combined with high-dose methotrexate, procarbazine hydrochloride, and vincristine (MPV) in these patients.
• Determine the toxicity of MGd in combination with whole-brain radiotherapy (WBRT) in these patients.
• Determine the tumor-selective uptake of MGd.

Secondary

• Determine the overall response rate (complete remission [CR] and partial remission [PR]) in patients treated with pre-radiotherapy and chemo-immunotherapy (R-MPV with MGd).
• Determine the complete response rate in patients treated with this regimen.
• Determine the overall response rate (CR and PR) in patients who complete all MGd combined with high-dose methotrexate-based chemotherapy and WBRT.
• Determine the event-free and overall survival at 1 year of patients treated with this regimen.
• Determine the progression-free survival at 1 year of patients treated with this regimen.
• Evaluate the neurotoxicity of R-MVP with MGd based on pre- and post-treatment neuropsychologic testing.

OUTLINE:

• Tumor-selective imaging: Patients receive motexafin gadolinium (MGd) IV on days 1-2 beginning 1-2 weeks prior to induction therapy. They then undergo an MRI of the brain.
• Induction therapy: Patients receive methotrexate IV over 2-3 hours and vincristine IV on day 1 and rituximab IV over 5 hours and MGd IV over 30-60 minutes on day 8. Patients also receive oral procarbazine hydrochloride on days 1-7 of courses 1, 3, and 5. Treatment repeats every 14 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients with partial response receive an additional 2 courses of induction therapy.
• Chemoradiotherapy: Beginning 4 weeks after completion of induction therapy, patients undergo reduced-dose whole-brain radiotherapy for 6 weeks. Patients also receive MGd IV over 30-60 minutes, beginning 2-5 hours prior to radiotherapy, for 10 days and then every other day during radiotherapy.
• Consolidation therapy: After completion of chemoradiotherapy, patients receive cytarabine IV over 3 hours on days 1-2. Treatment repeats every 30 days for 2 courses.

After completion of study therapy, patients are followed every 3 months for the first year, every 3-4 months for the second year, every 4-6 months until the fifth year, and then annually thereafter.