Clinical Trials /

Pembrolizumab, Ibrutinib and Rituximab in PCNSL

NCT04421560

Description:

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

Related Conditions:
  • Primary Central Nervous System Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab, Ibrutinib and Rituximab in PCNSL
  • Official Title: A Phase Ib/II Study of Pembrolizumab, Ibrutinib and Rituximab in Recurrent Primary Central Nervous System Lymphoma (PCNSL)

Clinical Trial IDs

  • ORG STUDY ID: 20-144
  • NCT ID: NCT04421560

Conditions

  • Primary Central Nervous System Lymphoma
  • Recurrent Cancer

Interventions

DrugSynonymsArms
IbrutinibImbruvicaPembrolizumab + Ibrutinib + Rituximab
PembrolizumabKeytrudaPembrolizumab + Ibrutinib + Rituximab
RituximabRituxan, TruximaPembrolizumab + Ibrutinib + Rituximab

Purpose

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

Detailed 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)
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + Ibrutinib + RituximabExperimentalPhase 1b Dose escalation will occur using a standard 3+3 dose-escalation approach, beginning at dose level I (560 mg daily) and potentially escalating to dose level 2 (840mg) with rules for escalation and de-escalation. Ibrutinib: orally 2x daily Pembrolizumab: 200 mg intravenously every 3 weeks Rituximab: 375mg/m^2 intravenously once per week for 4 weeks (4 total doses). Phase 2 Participants will receive Pembrolizumab, Rituximab and Ibrutinib at the pre-determined dosage level established in Phase 1b. Ibrutinib: orally maximum tolerated dose from phase 1 daily (560 mg or 840mg) Pembrolizumab: 200 mg intravenously every 3 weeks Rituximab: 375 mg/m^2 intravenously once per week for 4 weeks (4 total doses).
  • Ibrutinib
  • Pembrolizumab
  • Rituximab

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival rate 6 months (PFS6)
Time Frame:6 months
Safety Issue:
Description:The primary endpoint of PFS6 will be estimated as a binomial response proportion. The efficacy analysis population will include all evaluable patients (subjects will be considered evaluable for efficacy as long as they have received at least 75% of the planned doses for the 1st 6 weeks of treatment). Patients missing 6 months progression evaluation (for any reason) will be counted as progressors. For the primary analysis, the proportion of progression free patients at 6 months will be evaluated and 95% exact binomial CI will be provided. The Kaplan-Meier method will be used as a secondary approach to evaluate the PFS6 based on the recorded times to progression for each patient, with patients without progression or lost to follow-up being censored at their last follow-up date.

Secondary Outcome Measures

Measure:Number of Participants With Treatment-Related Adverse Events CTCAE version 5.0.
Time Frame:24 Months
Safety Issue:
Description:All subjects receiving at least 1 dose of study treatment will be evaluated for toxicities. DLT rates will be summarized and 95% exact binomial CI will be reported.
Measure:Objective response rate (ORR)
Time Frame:24 months
Safety Issue:
Description:The objective response rate (ORR) is defined as the proportion of patients with a best response of CR or PR. Objective Response Rate will be reported with 95% exact binomial CI. OS, PFS and duration of response endpoints will be evaluated by the Kaplan-Meier method and medians will be provided with 95% pointwise CI based on the log-log transformation. For all time to event analysis, patients without event information will be censored at the time of last available data.
Measure:Duration of response rate
Time Frame:24 Months
Safety Issue:
Description:Duration of response will be defined as the time form initial, complete or partial response to the time of disease progression or death. If a patient does not experience disease progression or death before the end of study, duration of response will be censored at the day of the last tumor assessment. OS, PFS and duration of response endpoints will be evaluated by the Kaplan-Meier method and medians will be provided with 95% pointwise CI based on the log-log transformation. For all time to event analysis, patients without event information will be censored at the time of last available data.
Measure:Progression-free survival (PFS) Rate
Time Frame:24 Months
Safety Issue:
Description:Progression-free survival (PFS) is defined from start date of study treatment to the date of documented progression or death by any cause, whichever comes first. OS, PFS and duration of response endpoints will be evaluated by the Kaplan-Meier method and medians will be provided with 95% pointwise CI based on the log-log transformation. For all time to event analysis, patients without event information will be censored at the time of last available data.
Measure:Overall survival (OS) Rate
Time Frame:24 Months
Safety Issue:
Description:Overall survival (OS) is defined as the time from start date of study treatment to the date of death by any cause. Patients not known to have died will be censored at the time of last assessment or the analysis cut-off whichever comes first. OS, PFS and duration of response endpoints will be evaluated by the Kaplan-Meier method and medians will be provided with 95% pointwise CI based on the log-log transformation. For all time to event analysis, patients without event information will be censored at the time of last available data.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Primary Central Nervous System Lymphoma
  • Recurrent Cancer

Last Updated

June 9, 2020