This is a 2-stage phase 1B study of nivolumab consolidation following completion of HD-MTX
containing induction chemotherapy in older (≥ 65 years old) patients with previously
untreated primary CNS lymphoma. Stage 1 is designed to evaluate the safety of nivolumab
consolidation. We plan to use 3+3 design and start at the FDA approved single agent dose of
nivolumab 480 mg intravenously every 4 weeks. Stage 2 is designed to evaluate the safety as
well as efficacy of nivolumab consolidation after HD-MTX containing induction chemotherapy in
an expansion cohort.
Subjects must meet all of the following criteria to participate in this study:
1. Written informed consent and HIPAA authorization for release of personal health
information of subject or subject's legally authorized representative.
2. Age ≥ 65 years at the time of consent
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 3 within 14 days
prior to day 1 of treatment
4. Histological or cytological confirmation of PCNSL, CD20 positive by
5. Received at least 2 cycles of high-dose methotrexate (HD-MTX) containing induction
chemotherapy per institutional standard (R-MPV preferred; see Appendix VI ) without
evidence of progressive disease. No less than 4 weeks and no more than 8 weeks may
have elapsed between last dose of HD-MTX containing induction chemotherapy and day 1
of study treatment
6. Recovered from all reversible acute toxic effects of prior therapy (other than
alopecia) to ≤ Grade 1 or baseline)
7. Measurable disease at the time of diagnosis (i.e. prior to pre-study HD-MTX containing
induction chemotherapy) including lesions that can be accurately measured in 2
dimensions by CT or MRI of brain and with a greatest transverse diameter of ≥ 1 cm.
The following disease assessments must have been obtained prior to initiation of
pre-study HD-MTX containing induction chemotherapy: MRI of the brain (and spine if
8. Deemed poor candidate for whole brain irradiation (WBI) or autologous stem cell
transplant (ASCT) due to advanced age, ECOG performance status of 2, or in the opinion
of the treating physician, subject would not tolerate the administration of WBI or
ASCT for other reasons
9. Life expectancy of at least 3 months
10. Demonstrate adequate organ function as defined below (all screening labs to be
obtained within 14 days prior to day 1 of treatment):
1. Absolute Neutrophil Count (ANC) ≥ 1000K/mm3
2. Platelet Count ≥ 75 K/mm3
3. Hemoglobin (Hgb) ≥ 8 g/dL
4. Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 cc/minute as measured
by a 24-hour urine collection or estimated by the Cockcroft and Gault formula
5. Bilirubin ≤ 1.5 x upper limit of normal (ULN) (except subjects with Gilbert
Syndrome who must have a total bilirubin level of < 3.0 x ULN)
6. Aspartate aminotransferase (AST) ≤ 3 x ULN
7. Alanine aminotransferase (ALT) ≤ 3 x ULN
11. Females of childbearing potential (FCBP) must have a negative serum pregnancy test
within 3 days prior to day 1 of treatment. NOTE: Females are considered of child
bearing potential unless they are surgically sterile (have undergone a hysterectomy,
bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least
12 consecutive months with no menses without an alternative medical cause).
12. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a
failure rate of <1% per year when used consistently and correctly) from the time of
informed consent until 5 months after treatment discontinuation. Contraceptive methods
with low user dependency are preferable but not required.
13. Male subjects must be willing to use condoms from the time of treatment initiation
until 7 months after last dose of nivolumab. For a non-pregnant FCBP partner,
contraception recommendations should also be considered.
14. As determined by the enrolling physician, ability of the subject to understand and
comply with study procedures for the entire length of the study.
Subjects must not meet any of the following criteria:
1. Documented or suspected ophthalmologic involvement at the time of enrollment as
determined by the investigator. Subjects with ophthalmologic involvement prior to or
during pre-study induction are allowed if there is no evidence of ophthalmologic
involvement prior to enrollment as determined by the investigator.
2. Any concurrent systemic involvement by lymphoma outside CNS or intraocular lymphoma
without evidence of brain disease
3. Any previous chemotherapy or radiation therapy for PCNSL except for treatment with a
HD-MTX containing induction chemotherapy. Subjects treated with corticosteroids for
PCNSL are allowed.
4. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study)
5. Has a known additional malignancy within the past 5 years that is active and/or
progressive requiring treatment; exceptions include basal cell or squamous cell skin
cancer, in situ cervical or bladder cancer, or carcinoma of the prostrate with a
current PSA value of <0.5 ng/mL or other cancer for which subject has completed
treatment, been disease-free for at least five years, and is considered by
Sponsor-Investigator to be at <30% risk of relapse, or on hormonal therapy for a
history of either prostate cancer or breast cancer, provided that there has been no
evidence of disease progression during the previous three years.
6. Treatment with any investigational drug (including drugs not FDA-approved for the
indication for which they are given) within 28 days prior to day 1 of treatment
7. Subjects with active, uncontrolled infections (subjects must be afebrile for >48 hours
off systemic antibiotics).
8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements as determined by the investigator.
9. Major surgery and/or radiotherapy within 14 days prior to initiation of study
10. Known history of positive test for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at
sites where mandated locally.
11. Active infectious hepatitis, type B or C. Subjects with a past or resolved HBV
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence
of HBsAg) may be included if HBV DNA is undetectable.
12. Subjects with active interstitial pneumonitis.
13. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted