Rituximab, Methotrexate, Vincristine Sulfate, Procarbazine Hydrochloride, and Cytarabine With or Without Radiation Therapy in Treating Patients With Primary Central Nervous System Lymphoma

OBJECTIVES:

Primary

* To determine median progression-free survival (PFS) in both arms on an intent-to-treat basis.

Secondary

* To determine overall survival (OS) defined as the interval from randomization to death due to any cause.
* To determine treatment-related neurotoxicity rates and disease-related cognitive deterioration in each arm, through the following methods: prospective formal neuropsychological evaluation, utilizing competing-risk methodology to account for death as a competing risk to neurotoxicity or cognitive deterioration from relapsed tumor burden/salvage treatment and incidence of clinically defined neurotoxicity as per investigator's assessment.
* To determine if there exists differences between the two treatment arms in terms of health-related quality-of-life and symptoms over time.
* To determine response (partial response (PR) and complete response (CR)) rate after methotrexate-based chemotherapy and after consolidation whole-brain radiotherapy (WBRT).
* To determine chemotherapy-related toxicity, measured by Common Toxicity Criteria for Adverse Effects (CTCAE), v.4.0.

OUTLINE: This is a multicenter study. Patients are stratified according to Memorial Sloan-Kettering Cancer Center recursive-partitioning analysis (RPA) classification for primary central nervous system lymphoma on age and Karnofsky performance status (KPS) (Class 1: age ≤ 50 years vs Class 2: age > 50 years and KPS ≥ 70% vs Class 3: age > 50 years and KPS < 70%). Patients are randomized to 1 of 2 treatment arms.

• Rituximab (Biological): One 28-day cycle = 500 mg/m\^2 intravenously on day 1 and day 5.
• Cytarabine (Drug): One 28-day cycle = 3 g/m\^2 intravenously on day 1 and day 2.
• Methotrexate (Drug), also known as MTX: One 28-day cycle = 3.5 g/m\^2 intravenously (standard hydration/leucovorin support) on day 2.
• Procarbazine (Drug): One 28-day cycle = 100 mg/m\^2 orally on days 2-8.
• Vincristine (Drug): One 28-day cycle = 1.4 mg/m\^2 intravenously, dose capped at 2.4mg, on day 2 and day 16.
• low-dose whole-brain radiation therapy (Radiation), also known as WBRT: Total dose of 2340 cGy administered as 13 daily fractions of 180 cGy over 3 weeks. Participants with progressive disease on magnetic resonance imaging (MRI) do not receive WBRT.

Primary outcomes

• Progression-free Survival [From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.]: Progression is defined as any of the following: more than 25% increase in the contrast-enhancing lesion seen on magnetic resonance imaging (MRI) compared with baseline or best response; new site of disease (central nervous system or systemic); recurrent or new ocular disease; recurrent or positive cerebrospinal fluid (CSF) cytology. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method.

Secondary outcomes

• Overall Survival [From randomization to last follow-up. Maximum follow-up at time of analysis was 7.3 years.]: Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.
• Percentage of Participants Experiencing Partial Response or Complete Response [After 4th cycle of chemotherapy, approximately 4 months after randomization.]: Response was evaluated using the international criteria proposed by the International Primary Central Nervous System Lymphoma (PCNSL) Study Group criteria. Complete Response was defined as no contrast brain enhancement on magnetic resonance imaging (MRI), no corticosteroid use for at least 2 weeks, a normal eye exam, and negative CSF cytology. Partial response was defined as at least 50% decrease in enhancing tumor on MRI compared with baseline imaging, no or minor retinal pigment epithelium (RPE) abnormality, and negative CSF cytology.
• Global Heath Status (GHS) Score of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [EORTC QLQ-C30 was administered at baseline, after cycle 4 of treatment (4 months), then every six months after end of treatment (7 months) for five years.]: Global Health Status is calculated from two questions on the EORTC QLQ-C30. The question responses range from 1 "very poor" to 7 "excellent" such that a higher response indicates better quality of life (QOL). The mean of these responses is linearly transformed to a range of 0 (worst) to 100 (best). Data through five years after end of protocol treatment is included in the analysis, while summary data is provided only through three years due to very few participants after that timepoint.
• Percentage of Participants With Neurocognitive Failure [Neurocognitive function tests were administered at baseline, after cycle 4 of treatment (4 months), then every six months after end of treatment (7 months) for five years. Two-year rates are provided here.]: Neurocognitive failure is defined as cognitive failure on two or more of the following tests: Hopkins Verbal Learning Test - Revised (HVLT-R) Free Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Trail Making Test Part A, Trail Making Test Part B, and Controlled Oral Word Association. Cognitive failure for each test is defined as a change from baseline in raw score (post baseline score - baseline score) at or exceeding the minimally important difference reported in the literature \[determined by the reliable change index (RCI) method\] of -5, -3, -2,12, 26, and -12, respectively, indicating a worsening of neurocognitive function. Time to neurocognitive failure is defined as time from randomization to date of first failure, last known follow-up (censored), or death without failure (competing risk). Failure rates are estimated using the cumulative incidence method and the distributions of failure times are compared between the arms. Two-year estimates are provided here.
• Distribution of Participants by Highest Grade Adverse Event Related to Protocol Treatment [At the end of each chemotherapy 28-day cycle, then every 2 months for two years starting 4 weeks after treatment, then every 6 months for 3 years, then yearly. Maximum follow-up at time of analysis was 7.3 years.]: Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. Adverse events reported as definitely, probably, or possibly related to protocol treatment are considered to be related to treatment.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. B-cell non-Hodgkin's lymphoma(NHL) involving the brain, as demonstrated by contrast-enhanced Magnetic resonance imaging (MRI) and histologic confirmation by one of the following within 6 weeks prior to registration:

   * A positive cerebral spinal fluid (CSF) cytology for lymphoma or a monoclonal lymphocyte population as defined by cell surface markers
   * A biopsy of the vitreous or uvea demonstrating non-Hodgkin's lymphoma
   * Brain biopsy

   Note: Patients in whom the type of lymphoma could not be determined or is unknown (eg, not enough tissue for further analysis) are assumed to have a B cell lymphoma and are eligible.
2. The patient must agree to submit tissue (i.e., the original H/E stained slides and immunohistochemistry studies) for central pathology review post-registration.
3. No evidence of systemic non-Hodgkin lymphoma as demonstrated by a computed tomography (CT) scan of the chest, abdomen and pelvis within 6 weeks prior to registration (Note: Bone marrow biopsy is not required for registration but must be obtained prior to start of treatment.)
4. Age ≥ 18
5. History and physical examination within 6 weeks of registration
6. Karnofsky performance status (KPS) equal to 50 or higher, with the following exception

   • Patients with KPS 30 to 50 are eligible if the reason for the poor performance status is neurologic deficit from primary central nervous system (CNS) lymphoma. (Patients with KPS 30 to 50 due to reasons other than primary CNS lymphoma are ineligible. Patients with KPS under 30 for any reason are ineligible)
7. Patient must have documentation of negative HIV-1 testing within 6 weeks prior to study registration (Separate counseling and consent as per institutional guidelines)
8. Complete blood count (CBC)/differential obtained within 2 weeks prior to study registration, with adequate bone marrow function defined as follows:

   * Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;
   * Platelets ≥ 100,000 cells/mm3;
   * Hemoglobin (Hgb) ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.);
9. Adequate liver function within 2 weeks prior to study registration, defined as follows:

   * Bilirubin < 2.0 mg/dl
   * Aspartate aminotransferase (AST) <2.5 times upper limit of normal
10. Adequate renal function within 2 weeks prior to study registration, defined as follows

    * Serum creatinine < 1.5 mg/dl
    * Calculated creatinine clearance (CrCl) > 50cc/min/1.73m2, using the Cockcroft-Gault equation, as follows:

    Male: CrCl (ml/min) = (140-age) X (Actual weight in kg) / 72 x serum Creatinine (mg/dl).

    Female: CrCl (ml/min) = (140-age) X (Actual weight in kg) X 0.85 / 72 x serum Creatinine (mg/dl).

    Note: A measured CrCl from a 24 hour urine collection may also be used.
11. Women of childbearing potential and male participants must agree to practice adequate contraception during therapy
12. Patient must provide study-specific informed consent prior to study registration
13. Patient must be able to swallow pills.

Exclusion Criteria:

1. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
2. Prior treatment with chemotherapy or radiotherapy for lymphoma or chronic lymphocytic leukemia; note that prior chemotherapy for a different cancer is allowable; see section 1
3. Prior cranial irradiation
4. Severe, active co-morbidity, defined as follows:

   * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months;
   * Transmural myocardial infarction within the last 6 months;
   * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
   * Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration
   * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol.
   * Known pre-existing immunodeficiency as seen in organ transplant recipient.
5. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
6. Prior allergic reaction to any of the study drugs involved in this protocol.

Participant flow

Outcome results

• Progression-free Survival (Primary), Median, years: Chemotherapy 2.1 (1.0 to NA); Chemotherapy + Low-Dose WBRT NA (3.3 to NA) (p 0.015)
• Overall Survival (Secondary), Median, years: Chemotherapy NA (2.6 to NA); Chemotherapy + Low-Dose WBRT NA (4.5 to NA) (p 0.48)
• Percentage of Participants Experiencing Partial Response or Complete Response (Secondary), Number, percentage of participants: Chemotherapy 83.3 (65.3 to 94.4); Chemotherapy + Low-Dose WBRT 80.6 (62.5 to 92.5)
• Global Heath Status (GHS) Score of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (Secondary), Mean, score on a scale: Chemotherapy 62.78 +/- 23.54; Chemotherapy + Low-Dose WBRT 54.90 +/- 26.91 (p 0.005)
• Percentage of Participants With Neurocognitive Failure (Secondary), Number, percentage of participants: Chemotherapy 31.6 (14.3 to 50.5); Chemotherapy + Low-Dose WBRT 17.9 (6.3 to 34.1) (p 0.18)
• Distribution of Participants by Highest Grade Adverse Event Related to Protocol Treatment (Secondary), Count of participants, Participants: Chemotherapy 2; Chemotherapy + Low-Dose WBRT 3

Adverse events

Time frame: At the end of each chemotherapy 28-day cycle, then every 2 months for two years starting 4 weeks after treatment, then every 6 months for 3 years. Maximum follow-up at time of analysis was 7.3 years.

Serious adverse events by term

11 more terms not shown.

Other adverse events by term

45 more terms not shown.

Limitations and caveats: A planned interim efficacy analysis was performed after 42 events (death or progression). The final analysis was planned to occur after 67 events. The Data Monitoring Committee (DMC) recommended releasing the interim results for early reporting and these results are considered the final study results.

• Study Protocol and Statistical Analysis Plan (PDF, 2019-09-19)
• Informed Consent Form (PDF, 2019-09-19)

• Antonio Omuro, MD, Principal investigator, Yale University