This is an open label, multi-center, phase Ib/II trial of Pembrolizumab, Ibrutinib and
Rituximab in participants with recurrent Primary Central Nervous System Lymphoma.
- A Phase I clinical trial tests the safety of an investigational intervention and also
tries to define the appropriate dose(s) of the investigational intervention to use for
further studies.
- Phase II clinical trials test the safety and effectiveness of an investigational
intervention to learn whether the intervention works in treating a specific disease. The
dose of investigational intervention in Phase II will depend on the results from Phase
Ib
- "Investigational" means that the intervention is being studied.
- The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab,
ibrutinib or rituximab for recurrent primary central nervous system lymphoma
(PCNSL) but these have been approved for other uses including other types of
non-Hodgkin's lymphoma.
- Pembrolizumab (MK-3475) has been studied in lab experiments and in other types of
cancer, and information from these studies suggests that Pembrolizumab may be
beneficial in this type of cancer. Pembrolizumab is a humanized monoclonal
antibody. An antibody is a common type of protein made in the body in response to a
foreign substance. Antibodies attack foreign substances and protect against
infection. Antibodies can also be produced in the laboratory for use in treating
patients; an antibody that is made in the lab is also known as humanized monoclonal
antibody that is designed to block the action of the receptor, PD-1. PD-1 works to
help tumor cells continue to grow and multiply. There are now several approved
antibodies for the therapy of cancer and other diseases.
- Ibrutinib is a type of drug called a kinase inhibitor. It is believed to block a
type of protein called a kinase that helps lymphoma cells live and grow. By
blocking this, it is possible that the study drug will kill cancer cells or stop
them from growing.
- Rituximab is a type of drug called a monoclonal antibody. An antibody is a common
type of protein made in the body in response to a foreign substance. Antibodies
attack foreign substances and protect against infection. Rituximab works with the
immune system and has shown evidence for clinical activity when administered in
combinations to treat lymphoma.
- The research study procedures include: screening for eligibility and study treatment
including evaluations and follow up visits.
- The three drugs being used in the study are:
- Pembrolizumab (MK3475)
- Ibrutinib
- Rituximab
- Participants will receive study treatment for up to 2 years as long as they do not have
serious side effects and their disease does not get worse. Once off study, participants
will be followed every 3 months for the rest of their life.
- Phase I Enrollment: Approximately 9 to 12 participants
- Phase II Enrollment :Approximately 25 patients
Merck & Co., Inc, a pharmaceutical company, is supporting this research study by providing
funding for the research study and the study drug, Pembrolizumab (MK-3475)
Inclusion Criteria:
- Participant must be able to understand and willing to sign a written informed consent
document.
- Participant must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be obtained
before the performance of any protocol-related procedures that are not part of normal
subject care.
- Participant must be willing and able to comply with scheduled visits, treatment
schedule, laboratory tests, and other requirements of the study.
- Participant must be at least 18 years old on day of signing informed consent.
- Subjects with pathologically confirmed PCNSL who progressed after at least 1 line of
CNS-directed therapy (for Phase Ib patients, an unlimited amount of progressions is
allowed and can also include relapse; for Phase II, only first recurrence is allowed).
Recurrent subjects (for phase II only) that have previously responded to and completed
initial therapy at least 4 weeks prior to screening.
- PCNSL subjects should have evidence of measurable or evaluable enhancing disease on
MRI
- Able to submit at least 10 but up to 20 unstained formalin-fixed, paraffin-embedded
(FFPE) slides from the initial or most recent tissue diagnosis for correlative
studies. Histologically confirmed tissue will be required from the time of relapse or
at the time of initial surgery. If tissue is unavailable and/or diagnosis was made
from CSF or vitreal biopsy, approval from the overall PI is needed.
- Subjects must have a Eastern Cooperative Oncology Group (ECOG) performance status of
0-1 (Evaluation of ECOG is to be performed within 7 days prior to the date of
registration).
- Life expectancy of >3 months (in the opinion of the investigator)
- Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1
- Must be able to tolerate lumbar puncture and/or Ommaya taps
- Demonstrate adequate organ function as defined below, all screening labs should be
performed within 14 days of treatment initiation.
- Hematology
- White Blood Count (WBC) ≥ 2 K/μL
- Platelet count ≥ 100 K/μL
- Absolute Neutrophil Count ≥ 1.5 K/μL
- Hemoglobin > 9.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without
erythropoietin dependency and without packed red blood cell (pRBC)
transfusion within last 2 weeks)
- Biochemistry
- Serum creatinine ≤1.5 x institutional ULN OR Measured or calculated
creatinine clearance ≥30 mL/min for participant with creatinine levels >1.5
× institutional ULN (Creatinine clearance should be calculated per
institutional standard)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x
ULN(≤5 × ULN for participants with liver metastases)
- Total bilirubin (TBILI) ≤ 1.5 x institutional ULN (except subjects with
Gilbert Syndrome who must have a total bilirubin level of < 3.0 x
institutional ULN) OR Direct bilirubin ≤ULN for participants with total
bilirubin levels >1.5 × ULN)
- Coagulation studies
- INR OR PT and Activated aPTT ≤1.5 × institutional ULN unless participant is
receiving anticoagulant therapy as long as PT or aPTT is within therapeutic
range of intended use of anticoagulants
- Women of child-bearing potential (WOCBP), defined as all women physiologically capable
of becoming pregnant, must have a negative serum pregnancy within 72 hours prior to
registration.
- Women in the following categories are not considered WOCBP:
- Premenarchal
- Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
- Note: Documentation can come from the site personnel's review of the
participant's medical records, medical examination, or medical history
interview.
- Postmenopausal female:A postmenopausal state is defined as no menses for 12
months without an alternative medical cause.
- A high follicle stimulating hormone (FSH) level in the postmenopausal range
may be used to confirm a postmenopausal state in women not using hormonal
contraception or hormonal replacement therapy (HRT). However, in the absence
of 12 months of amenorrhea, confirmation with two FSH measurements in the
postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use
one of the non-hormonal highly effective contraception methods if they wish to
continue their HRT during the study. Otherwise, they must discontinue HRT to
allow confirmation of postmenopausal status before study enrollment.
- Women of child-bearing potential (WOCBP; see definition above), must agree to use a
highly effective method of contraception consistently and correctly as described below
during study treatment and for 120 days after study discontinuation.
- 1. Highly Effective Contraceptive Methods That Are User Dependent a (Failure rate
of < 1% per year when used consistently and correctly.)
- a. Combined (estrogen- and progestogen- containing) hormonal contraception
b, c
- i. Oral
- ii. Intravaginal
- iii. Transdermal
- iv. Injectable
- b. Progestogen-only hormonal contraception b, c
- i. Oral
- ii. Injectable
- 2. Highly Effective Methods That Have Low User Dependency (Failure rate of <1%
per year when used consistently and correctly)
- a. Progestogen- only contraceptive implant b, c
- b. Intrauterine hormone-releasing system (IUS) b
- c. Intrauterine device (IUD)
- d. Bilateral tubal occlusion
- e. Vasectomized partner: A vasectomized partner is a highly effective
contraception method provided that the partner is the sole male sexual
partner of the WOCBP and the absence of sperm has been confirmed. If not, an
additional highly effective method of contraception should be used.
- f. Sexual abstinence: Sexual abstinence is considered a highly effective
method only if defined as refraining from heterosexual intercourse during
the entire period of risk associated with the study treatment. The
reliability of sexual abstinence needs to be evaluated in relation to the
duration of the study and the preferred and usual lifestyle of the
participant.
- NOTES:Use should be consistent with local regulations regarding the use of
contraceptive methods for participants of clinical studies.
- Typical use failure rates are lower than perfect-use failure rates (i.e.
when used consistently and correctly).
- If hormonal contraception efficacy is potentially decreased due to
interaction with study treatment, condoms must be used in addition to the
hormonal contraception during the treatment period and for at least during
study treatment and for 120 days after study discontinuation after the last
dose of study treatment.
- If locally required, in accordance with Clinical Trial Facilitation Group
(CTFG) guidelines, acceptable contraceptive implants are limited to those
which inhibit ovulation.
- Male participants must agree to use at least one of the following methods of
contraception starting with the first dose of study therapy through 120 days after the
last dose of therapy:
- 1. Be abstinent from penile-vaginal intercourse as their usual and preferred
lifestyle (abstinent on a long term and persistent basis) and agree to remain
abstinent
- 2. Use a male condom plus partner use of a contraceptive method with a failure
rate of <1% per year as described in Eligibility criterion 3.1.13 when having
penile-vaginal intercourse with a woman of childbearing potential who is not
currently pregnant.
- a. Note: Men with a pregnant or breastfeeding partner must agree to remain
abstinent from penile-vaginal intercourse or use a male condom during each
episode of penile penetration.
Exclusion Criteria:
Participants who meet any of the following criteria will not be eligible for admission into
the study.
- Patients who cannot undergo MRI brain
- Patients with large brain stem lesions
- Intraocular PCNSL without evidence of brain or spinal cord disease.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
OX-40,CD137)
- Previous ibrutinib or other BTK inhibitor use
- Subjects that have progressed while on initial line therapy (refractory) are not
allowed for phase II part of the study
- Patients with > Grade 2 intracranial hemorrhage
- Subjects on anticoagulation are excluded, but the use of anticoagulants for the
treatment of thromboembolism is allowed, if PE/DVT is diagnosed while on study
- Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep
vein thrombosis or pulmonary embolism within 3 months before the start of study
treatment
- Active autoimmune disease requiring immunosuppressive agents or steroids (prednisone
>10mg or equivalent)
- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs).Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment
- Requires treatment for PCNSL with high dose systemic corticosteroids defined as
dexamethasone > 4 mg/day or bioequivalent for >3 consecutive days within 2 weeks of
registration
- Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks [could consider shorter interval for kinase inhibitors or other short
half-life drugs] prior to dosing. OR 5 half-lives, whichever is shorter --- Note:
Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or
baseline. Participants with≤Grade 2 neuropathy may be eligible.
- Patients who underwent major surgery ≤ 2 weeks before starting study treatment are
excluded. If participant underwent major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting study
treatment. Patients who plan to undergo surgery within 2 weeks of first dose of study
treatment are excluded.
- Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. Has received
prior radiotherapy to CNS disease within 2 weeks of start of study treatment.
- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella,varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment.
-- Note: Participants who have entered the follow-up phase of an investigational study
may participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.
- Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, transitional cell carcinoma of urothelial cancer,
or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have
undergone potentially curative therapy are not excluded.
- Has severe hypersensitivity (≥ Grade 3) to study agents and/or any of its excipients.
- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
- Patient is known to have an uncontrolled active systemic infection (>CTCAE grade 2)
and recent infection requiring intravenous anti-infective treatment that was completed
≤14 days before the first dose of study drug.
- Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure (New York Heart Association > Class 2), unstable
angina, or myocardial infarction within 6 months of screening, or any Class 3 or 4
cardiac disease as defined by the New York Heart Association Functional Classification
- Uncontrolled hypertension despite optimal medical management (per investigator's
assessment).
- Patient has poorly controlled diabetes mellitus with a glycosylated hemoglobin >8% or
poorly controlled steroid-induced diabetes mellitus with a glycosylated hemoglobin of
>8%.
- Non-healing wound, ulcer or bone fracture.
- Known bleeding diathesis (eg, von Willebrand's disease) or hemophilia.
- Unable to swallow capsules or disease significantly affecting gastrointestinal
function, such as malabsorption syndrome, resection of the stomach or small bowel, or
complete bowel obstruction.
- Concurrent administration of medications or foods that are moderate or strong
inhibitors or strong inducers of cytochrome P450 (CYP) 3A4/5 (need to be discontinued
2 weeks before starting study treatment)
- Enzyme-inducing antiepileptic drugs (EIAED) need to be discontinued and switched to a
non-EIAED 2 weeks prior to starting on trial drugs
- Has known history of HIV/AIDS
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
detected) infection.
- Has a known history of active TB (Bacillus Tuberculosis)
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent)
- Patients who have undergone prior allogeneic stem cell transplant
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment
