Inclusion Criteria:
- - Documented informed consent of the participant and/or legally authorized
representative.
- - Assent, when appropriate, will be obtained per institutional guidelines.
- - Agreement to allow the use of archival tissue from diagnostic tumor biopsies.
- - If unavailable, exceptions may be granted with study principal investigator
(PI) approval.
- - Karnofsky performance status (KPS) ≥ 30.
- - Histologically confirmed primary or secondary CNS lymphoma.
Tumor must be positive
for CD20 by immunohistochemistry or flow cytometry on the most recent biopsy.
Neuroimaging alone is acceptable in secondary CNS lymphoma cases where all of the
following criteria are met: 1) brain MRI findings are consistent with CNS lymphoma,
2) the disease has been histologically documented in other sites, 3) the CNS lesions
are concomitant with systemic progression, and 4) a brain biopsy would be unadvised
per the treating provider.
- - Cohort 1: Primary CNS lymphoma.
- - Cohort 2: Secondary CNS lymphoma.
- - Patients must not require urgent treatment initiation due to bulky or rapidly
progressing CNS lymphoma that poses risk for impending critical brain failure.
This
includes > 5 mm of midline shift, radiographic evidence of impending brain
herniation, or clinical evidence of significantly increased intracranial pressure
such as papilledema.
- - Have failed methotrexate-based therapy or are ineligible/refuse high-dose
methotrexate treatment (e.g. creatinine clearance [CrCl] < 50 mL/min, effusions,
ascites etc)
- Measurable CNS lymphoma based on gadolinium enhancement of brain or spine MRI and/or
positive CSF or intravitreal fluid cytology.
- - Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior
anti-cancer therapy.
- - Alert and able to participate in a full neurological exam.
- - Without bone marrow involvement: Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
- - NOTE: Growth factor is not permitted within 14 days of ANC assessment unless
cytopenia is secondary to disease involvement.
- - With bone marrow involvement: ANC ≥ 500/mm^3.
- - NOTE: Growth factor is not permitted within 14 days of ANC assessment unless
cytopenia is secondary to disease involvement.
- - Without bone marrow involvement: Platelets ≥ 75,000/mm^3.
- - NOTE: Platelet transfusions are not permitted within 14 days of platelet
assessment unless cytopenia is secondary to disease involvement.
- - With bone marrow involvement: Platelets ≥ 50,000/mm^3.
- - NOTE: Platelet transfusions are not permitted within 14 days of platelet
assessment unless cytopenia is secondary to disease involvement.
- - Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease,
then ≤ 3.0 x ULN is allowed)
- Aspartate aminotransferase (AST) ≤ 2.5 x ULN.
- - Alanine aminotransferase (ALT) ≤ 2.5 x ULN.
- - Creatinine clearance of ≥ 30 mL/min per 24 hour urine test or the Cockcroft-Gault
formula.
- - If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin
(PT) ≤ 1.5 x ULN.
- - If on anticoagulant therapy: PT must be within therapeutic range of intended use of
anticoagulants.
- - If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.5
x ULN.
- - If on anticoagulant therapy: aPTT must be within therapeutic range of intended use
of anticoagulants.
- - Seronegative for HIV antigen/antibody (Ag/Ab) combo.
- - Individuals with a positive HIV test at screening are eligible provided, prior
to enrollment, they are stable on antiretroviral therapy, have a CD4 count ≥
200/uL, and have an undetectable viral load.
- - Seronegative for active hepatitis B virus (HBV) (surface antigen negative)
- Participants with occult or prior hepatitis B infection (defined as positive
total hepatitis B core antibody and negative hepatitis B virus surface antigen
[HBsAg]) may be included if hepatitis B virus (HBV) deoxyribonucleic acid (DNA)
is undetectable at the time of screening.
Such participants must be willing to
undergo HBV DNA testing on day 1 of every cycle and every 3 months for at least
12 months after the final cycle of study treatment and appropriate antiviral
therapy as indicated.
- - Participants positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
- Women of childbearing potential (WOCBP): Negative serum pregnancy test.
- - Agreement by females and males of childbearing potential to use an effective method
of birth control or abstain from heterosexual activity for the course of the study
and after completion of study treatment as described below separately for males and
females.
- - Female participants must remain abstinent or use contraceptive methods with a
failure rate of < 1% per year during the treatment period and for at least 18
months after pretreatment with obinutuzumab, 2 months after the final dose of
glofitamab and 3 months after the final dose of tocilizumab (as applicable),
whichever is longer.
Women must refrain from donating eggs during this same
period.
- - Examples of contraceptive methods with a failure rate of < 1% per year
include bilateral tubal ligation, male sterilization, hormonal
contraceptives that inhibit ovulation, hormone-releasing intrauterine
devices, and copper intrauterine devices.
- - Hormonal contraceptive methods must be supplemented by a barrier method.
- - For male participants: agreement to remain abstinent (refrain from heterosexual
intercourse) or use contraceptive methods, and agree to refrain from donating
sperm, as defined below:
- With a female partner of childbearing potential or pregnant female
partners, male participants must remain abstinent or use a condom plus an
additional contraceptive method that together result in a failure rate of
< 1% per year during the treatment period and for at least 3 months after
pretreatment with obinutuzumab, 2 months after the final dose of
glofitamab or 2 months after the last dose of tocilizumab (as applicable),
whichever is longer.
Male participants must refrain from donating sperm
during this same period.
- - The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
individual.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not adequate methods of
contraception.
- - Childbearing potential defined as not being permanently surgically sterilized
(men and women) or have not been free from menses for > 1 year (women only).
Per this definition, a female participant with tubal ligation is considered to
be of childbearing potential.
Exclusion Criteria:
- - Contraindication to any of the individual components of glofitamab or history of
severe allergic or anaphylactic reactions to humanized or murine monoclonal
antibodies or known sensitivity or allergy to murine products.
- - Prior solid organ transplantation.
- - Prior treatment with systemic immunotherapeutic agents, including but not limited
to, radio-immuno-conjugates, antibody-drug conjugates, immune/cytokines and
monoclonal antibodies (mAbs) (e.g., anti cytotoxic T lymphocyte associated protein
4, anti PD-1, and anti PD-L1) within 2 weeks or five half-lives of the drug,
whichever is shorter, prior to day 1 of protocol therapy.
- - Prior treatment with glofitamab or other CD20 x CD3 bispecific antibodies.
- - Prior use of systemic chemotherapy within 2 weeks of the start of cycle 1.
- - Prior treatment with intrathecal chemotherapy within 1 week of the start of cycle 1.
Note, in patients with lymphoma restricted to the CSF and no other measurable sites
of CNS disease, positive CSF cytology must be documented following the most recent
administration of intrathecal chemotherapy.
- - Prior treatment with radiotherapy within 2 weeks prior to day 1 of protocol therapy.
- - If patients have received radiotherapy within 4 weeks prior to day 1 of
protocol therapy, patients must have at least one measurable lesion outside of
the radiation field.
Patients who have only one measurable lesion that was
previously irradiated but subsequently progressed are eligible.
- - Prior treatment with chimeric antigen receptor T cell (CAR-T) therapy within 30 days
prior to day 1 of protocol therapy.
- - Any investigational therapy for the purposes of treating cancer within 21 days prior
to the start of cycle 1.
- - Corticosteroid use for purposes other than lymphoma symptom control.
- - The use of inhaled corticosteroids is permitted.
- - The use of mineralocorticoids for management of orthostatic hypotension is
permitted.
- - The use of physiologic doses of corticosteroids for management of adrenal
insufficiency is permitted.
- - Participants who require lymphoma symptom control during screening may receive
steroids in the following manner:
- Up to 50 mg/day of prednisone or equivalent may be used for lymphoma
symptom control during screening.
- - History of other malignancy that could affect compliance with the protocol or
interpretation of results:
- Participants with a history of curatively treated basal or squamous cell
carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any
time prior to the study are eligible.
- - Participants with any malignancy appropriately treated with curative intent and
the malignancy has been in remission without treatment for > 2 years prior to
enrollment are eligible.
- - Participants with low-grade, early-stage prostate cancer (Gleason score 6 or
below, stage 1 or 2) with no requirement for therapy at any time prior to study
are eligible.
- - If the malignancy is expected to not require any treatment for at least 2 years
(this exception should be discussed with the study PI)
- Unstable cardiac disease as defined by one of the following:
- Cardiac events such as myocardial infarction (MI) within the past 3 months.
- - NYHA (New York Heart Association) heart failure class III-IV.
- - Unstable arrhythmias, or unstable angina.
- - Recent major surgery within 4 weeks prior to the start of cycle 1, other than for
diagnosis.
- - Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis or
neurodegenerative disease with the exception of CNS lymphoma.
Exceptions can be
granted after discussion with the PI of the study.
- - Participants with a history of stroke who have not experienced a stroke or
transient ischemic attack in the past 2 years and have no residual neurological
deficits, as judged by the investigator, are allowed.
- - Known or suspected history of hemophagocytic lymphohistiocytosis (HLH)
- History or presence of an abnormal electrocardiogram (ECG) that is clinically
significant in the investigator's opinion.
- - Known or suspected active infection, or reactivation of a latent infection, whether
bacterial, viral, fungal, mycobacterial, or other pathogens (excluding fungal
infections of nail beds) or any major episode of infection requiring hospitalization
or treatment with IV antibiotics (for IV antibiotics this pertains to completion of
last course of antibiotic treatment) within 4 weeks of dosing.
- - Active autoimmune disease requiring treatment with immune suppressive medications
other than physiologic doses of steroids.
- - Participants with a history of autoimmune-related hypothyroidism on a stable
dose of thyroid-replacement hormone may be eligible.
- - Participants with controlled type 1 diabetes mellitus who are on an insulin
regimen are eligible for the study.
- - Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only are eligible (e.g., participants with
psoriatic arthritis are excluded) if all the following conditions are met:
- Rash covers < 10% of body surface area.
- - Disease is well controlled for the last 12 months and requires only low
potency topical corticosteroids.
- - Clinically significant liver disease, including active viral or other hepatitis or
cirrhosis.
- - Live, attenuated vaccine within 4 weeks before study treatment infusion on day 1 of
cycle 1 or anticipation that such a live, attenuated vaccine will be required during
the study.
Live vaccines during the study and until participants B cells recover,
are prohibited.
- - Influenza vaccination should be given during influenza season only.
Participants must not receive live, attenuated influenza vaccine at any time
during the study treatment period.
- - Suspected active or latent tuberculosis (as confirmed by a positive interferon gamma
release assay)
- Participants with a history of progressive multifocal leukoencephalopathy.
- - Females only: Pregnant or breastfeeding or intention of becoming pregnant during the
study or within 18 months after pretreatment with obinutuzumab or 2 months after the
final dose of glofitamab, whichever is longer.
- - Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns with clinical
study procedures.
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)
