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

A Pilot Study Incorporating Motexafin Gadolinium (MGd) Into High-dose Methotrexate (MTX)-Based Chemo-immunotherapy and Radiation for Patients With Newly Diagnosed Primary CNS Lymphoma

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Radiation therapy uses high-energy x-rays to kill cancer cells. Motexafin gadolinium may make cancer cells more sensitive to radiation therapy and combination chemotherapy. Giving motexafin gadolinium together with chemotherapy, rituximab, and radiation therapy may kill more cancer cells.

PURPOSE: This phase II trial is studying the side effects of giving motexafin gadolinium together with combination chemotherapy, rituximab, and whole-brain radiation therapy and to see how well it works in treating patients with newly diagnosed primary central nervous system lymphoma.

Study Overview

• Status: Withdrawn
• Conditions: Lymphoma; Brain and Central Nervous System Tumors; Neurotoxicity
• Intervention / Treatment: Biological: Rituximab; Drug: Cytarabine; Drug: Methotrexate; Drug: Motexafin gadolinium; Drug: Procarbazine hydrochloride; Drug: Vincristine sulfate; Radiation: Radiation therapy

Detailed Description

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.

• Study Type: Interventional
• Phase: Early Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed primary CNS lymphoma (PCNSL) diagnosed by brain biopsy, CSF cytology, or vitreal biopsy

  • Newly diagnosed disease

  • Patients who have an inconclusive biopsy or who are not candidates for biopsy may be eligible provided they have a typical cranial MRI or CT scan (defined as the presence of hypo-, iso- or hyperdense parenchymal contrast-enhancing, usually homogeneously) mass lesion(s) and meet at least one of the following criteria:

    • Positive cerebrospinal fluid cytology for lymphoma or a monoclonal lymphocyte population as defined by cell surface markers
    • Biopsy of the vitreous or uvea demonstrating non-Hodgkin lymphoma
• Measurable (defined as reproducibly measurable disease in two perpendicular dimensions on radiologic study) or evaluable disease

PATIENT CHARACTERISTICS:

• ECOG performance status 0-3
• Life expectancy ≥ 8 weeks
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Bilirubin ≤ 2.0 mg
• SGOT ≤ 2 times upper limit of normal
• Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance > 50 cc/min
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 6 months after completion of study therapy
• HIV negative
• No other active primary malignancy with the exception of basal cell carcinoma of the skin or cervical carcinoma in situ

PRIOR CONCURRENT THERAPY:

• No prior cranial irradiation
• No prior chemotherapy for CNS lymphoma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity of motexafin gadolinium (MGd) and rituximab added to high-dose methotrexate, procarbazine hydrochloride, and vincristine (MPV) chemotherapy	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.	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)	To evaluate the toxicity of MGd added to whole-brain radiotherapy (WBRT).	Day 1 (every 2 weeks), After 5th cycle, After 7th cycle, Pre Radiation Theray, Post Radiation Therapy, and Post ara-c.
Tumor-selective uptake of MGd	To evaluate Tumor-selective uptake of MGd	Day 1 (every 2 weeks), After 5th cycle, After 7th cycle, Pre Radiation Theray, Post Radiation Therapy, and Post ara-c.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (complete remission [CR] and partial remission [CR]) to pre-radiation chemo-immunotherapy (R-MPV with MGd)	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.	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.
Complete response rate to pre-radiation chemo-immunotherapy (R-MPV with MGd)	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.	Every 3 months after completion of treatment, exams every 3 months for the first year then every 4 - 6 months thereafter.
Overall survival at 1 year	To assess overall survival rate.	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.
Event-free survival at 1 year	To assess event-free survival rate.	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.
Progression-free survival at 1 year	To assess progression-free survival rate.	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.
Neurotoxicity of R-MVP + MGd based on pre- and post-treatment neuropsychologic testing	MR perfusion and MR spectroscopy at baseline and serially when MRI imaging is done to assess response rates using these alternate forms of imaging.	At baseline

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: Pharmacyclics LLC.
• Investigators: Principal Investigator: Andrew M. Evens, DO, MS, Robert H. Lurie Cancer Center

Study record dates

Study Major Dates

• Study Start: November 1, 2008

Study Registration Dates

• First Submitted: August 13, 2008
• First Submitted That Met QC Criteria: August 13, 2008
• First Posted (Estimate): August 14, 2008

Study Record Updates

• Last Update Posted (Estimate): May 18, 2012
• Last Update Submitted That Met QC Criteria: May 16, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: neurotoxicity; primary central nervous system non-Hodgkin lymphoma; primary central nervous system Hodgkin lymphoma
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Nervous System Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Poisoning; Lymphoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Neurotoxicity Syndromes; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Photosensitizing Agents; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Rituximab; Cytarabine; Methotrexate; Vincristine; Procarbazine; Motexafin gadolinium
• Other Study ID Numbers: NU 05H7; STU00002443 (Other Identifier: Northwestern University IRB)