Pembrolizumab Ibrutinib and Rituximab in PCNSL

  • STATUS
    Recruiting
  • End date
    Mar 5, 2024
  • participants needed
    37
  • sponsor
    Dana-Farber Cancer Institute
Updated on 26 September 2021
platelet count
rituximab
hormonal contraception
anticoagulants
direct bilirubin
progestogen
oophorectomy
neutrophil count
follicle stimulating hormone
aptt
nervous
ibrutinib

Summary

This research study is evaluating a combination therapy of 3 drugs as possible treatments for recurrent primary central nervous system lymphoma (PCNSL).

The three drugs being used in the study are:

  • Pembrolizumab (MK3475)
  • Ibrutinib
  • Rituximab

Description

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)

Details
Condition Primary Central Nervous System Lymphoma, Central Nervous System Lymphoma, Primary CNS Lymphoma, Recurrent Carcinoma, Recurrent Cancer, cns lymphoma
Treatment Rituximab, Ibrutinib, Pembrolizumab
Clinical Study IdentifierNCT04421560
SponsorDana-Farber Cancer Institute
Last Modified on26 September 2021

Eligibility

Yes No Not Sure

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
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/L
Platelet count 100 K/L
Absolute Neutrophil Count 1.5 K/L
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 test 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
\. 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
\. 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
\. 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
\. 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 withGrade 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-Gurin (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
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