Clinical Trials /

Ibrutinib With Rituximab and Lenalidomide for Patients With Recurrent/Refractory Primary or Secondary Central Nervous System Lymphoma (PCNSL/SCNSL)

NCT03703167

Description:

The investigator's want to find out if treatment with ibrutinib, rituximab, and lenalidomide are safe and better than the usual approach in patients with recurrent or refractory central nervous system lymphoma.

Related Conditions:
  • Central Nervous System Lymphoma
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib With Rituximab and Lenalidomide for Patients With Recurrent/Refractory Primary or Secondary Central Nervous System Lymphoma (PCNSL/SCNSL)
  • Official Title: Phase Ib Trial With Dose Expansion of the Bruton‟s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination With Rituximab and Lenalidomide in Patients With Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL) and Refractory/Recurrent Secondary Central Nervous System Lymphoma (SCNSL)

Clinical Trial IDs

  • ORG STUDY ID: 18-432
  • NCT ID: NCT03703167

Conditions

  • Primary Central Nervous System Lymphoma (PCNSL)
  • Secondary Central Nervous System Lymphoma (SCNSL)

Interventions

DrugSynonymsArms
Ibrutinibibrutinib in combination with rituximab and lenalidomide
Lenalidomideibrutinib in combination with rituximab and lenalidomide
Rituximabibrutinib in combination with rituximab and lenalidomide

Purpose

The investigator's want to find out if treatment with ibrutinib, rituximab, and lenalidomide are safe and better than the usual approach in patients with recurrent or refractory central nervous system lymphoma.

Trial Arms

NameTypeDescriptionInterventions
ibrutinib in combination with rituximab and lenalidomideExperimentalIbrutinib will be given day 1-28; Lenalidomide will be given day 1-21; Rituximab will be given on day 1. Rituximab is given for 6 cycles; Lenalidomide is given for 12 cycles; Ibrutinib is continued until disease progression, intolerable toxicity or death.
  • Ibrutinib
  • Lenalidomide
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must be able to understand and be willing to sign a written informed
             consent document.

          -  Men and woman who are at least 18 years of age on the day of consenting to the study.

          -  Histologically documented PCNSL or histologically documented systemic diffuse large
             B-cell lymphoma (DLBCL).

          -  Patients must have relapsed/refractory PCNSL or relapsed/refractory SCNSL

          -  All patients need to have received at least one prior CNS directed therapy. There is
             no restriction on the number of recurrences.

          -  Patients with parenchymal lesions must have unequivocal evidence of disease
             progression on imaging (MRI of the brain or head CT) 21 days prior to study
             registration. For patients with leptomeningeal disease only, CSF cytology must
             document lymphoma cells and/or imaging findings consistent with CSF disease 21 days
             prior to study registration (at the discretion of the investigator).

          -  Participants must have an ECOG performance status of 0, 1, or 2.

          -  Participants must have adequate bone marrow and organ function shown by:

               -  Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L

               -  Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 21 days prior
                  to study registration

               -  Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past
                  21 days prior to study registration

               -  International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper
                  limit of normal

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the
                  upper limit of normal

               -  Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3
                  times the upper limit of normal with direct bilirubin within the normal range in
                  patients with well documented Gilbert Syndrome.

               -  Serum creatinine ≤ 2 times the upper limit of normal

               -  Escalation: calculated creatinine clearance(CrCl) ≥ 60ml/min using the
                  Cockcroft-Gault equation (Men: CrCl (min/ml) = (140-age) X (actual weight in kg)
                  / 72 X serum creatinine (mg/dL); Women: CrCl (ml/min) = (140-age) X (actual
                  weight in kg) X 0.85 / 72 X serum creatinine (mg/dL))

               -  Extension: calculated creatinine clearance(CrCl) ≥30ml/min using the
                  Cockcroft-Gault equation (Men: CrCl (min/ml) = (140-age) X (actual weight in kg)
                  / 72 X serum creatinine (mg/dL); Women: CrCl (ml/min) = (140-age) X (actual
                  weight in kg) X 0.85 / 72 X serum creatinine (mg/dL))

          -  Woman of reproductive potential must agree to use highly effective methods of birth
             control during the period of therapy and for 30 days after the last dose of the study
             drug. Men who are sexually active must agree to use highly effective contraception
             during the period of therapy and for 3 months after the last dose.

          -  Female subjects of childbearing potential must have a negative plasma pregnancy test
             upon study entry. See section on Pregnancy and Reproduction.

          -  Patients must be able to tolerate MRI/CT scans.

          -  Patients must be able to tolerate lumbar puncture and/or Ommaya taps.

          -  Participants must have recovered to grade 1 toxicity from prior therapy.

          -  Participants should be able to submit up to 20 unstained formalin-fixed,
             paraffinembedded (FFPE) slides from the initial tissue diagnosis prior to study
             registration for confirmation of diagnosis and correlative studies

          -  All study participants must be registered into the mandatory Revlimid REMS® program,
             and be willing and able to comply with the requirements of the REMS® program.

          -  Females of reproductive potential must adhere to the scheduled pregnancy testing as
             required in the Revlimid REMS® program.

        NOTE: Prior autologous stem cell transplant as well as prior radiation to the CNS does NOT
        prevent patients from enrollment into the trial.

        Exclusion Criteria:

          -  Patients with SCNSL actively receiving treatment for extra-CNS disease are excluded.

          -  Patient is concurrently using other approved or investigational antineoplastic agents.

          -  Patient has received chemotherapy, monoclonal antibodies or targeted anticancer
             therapy ≤ 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for nitrosourea or
             mitomycin-C prior to starting the study drug, or the patient has not recovered from
             the side effects of such therapy.

          -  Patient has received external beam radiation therapy to the CNS within 21 days of the
             first dose of the study drug.

          -  Patient requires more than 8 mg of dexamethasone daily or the equivalent

          -  Patient has an active concurrent malignancy requiring active therapy

          -  The patient has been treated with radio- or toxin-immunoconjugates within 70 days of
             the first dose of the study drug.

          -  Patient is allergic to components of the study drug.

          -  Patient is using warfarin or any other Coumadin-derivative anticoagulant or vitamin K
             antagonists. Patients must be off warfarin-derivative anticoagulants for at least
             seven days prior to starting the study drug. Low molecular weight heparin is allowed.
             Patients with congenital bleeding diathesis are excluded.

          -  Patient is taking a drug known to be a moderate and strong inhibitor or inducers of
             the P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducers
             for at least two weeks prior to starting the study drug.

          -  Patient is using systemic immunosuppressant therapy, including cyclosporine A,
             tacrolimus, sirolimus, and other such medications, or chronic administration of > 5
             mg/day or prednisone or the equivalent. Participants must be off immunosuppressant
             therapy for at least 28 days prior to the first dose of the study drug.

          -  Patient has significant abnormalities on screening electrocardiogram (EKG) and active
             and significant cardiovascular disease such as uncontrolled or symptomatic
             arrhythmias, congestive heart failure, hypertension, valvular disease, pericarditis,
             or myocardial infarction within 6 months of screening,

          -  Patient has a known bleeding diathesis (e.g. von Willebrand‟s disease) or hemophilia.

          -  Patient is known to have human immunodeficiency virus (HIV) infection.

          -  Patient is known to have a history of active or chronic infection with hepatitis C
             virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests.

          -  Patient is known to have an uncontrolled active systemic infection.

          -  Patient underwent major systemic surgery ≤ 4 weeks prior to starting the trial
             treatment or who has not recovered from the side effects of such surgery, or who plan
             to have surgery within 2 weeks of the first dose of the study drug.

          -  Patient is unable to swallow capsules or has a disease or condition significantly
             affecting gastrointestinal function, such as malabsorption syndrome, resection of the
             stomach or small bowel, or complete bowel obstruction.

          -  Patient has poorly controlled diabetes mellitus with a glycosylated hemoglobin >8% or
             poorly controlled steroid-induced diabetes mellitus with a glycosylated hemoglobin of
             >8%.

          -  Patient has a life-threatening illness, medical condition, or organ system dysfunction
             that, in the opinion of the investigator, could compromise the subject‟s safety or put
             the study outcomes at undue risk.

          -  Women who are pregnant or nursing (lactating), where pregnancy is defined as a state
             of a female after conception until the termination of gestation, confirmed by a
             positive serum hCG laboratory test of > 5 mIU/mL (See section on Pregnancy and
             Reproduction)

          -  Patient has undergone prior allogenic stem cell transplant (autologous stem cell
             transplant is NOT an exclusion)

          -  The patient is unwell or unable to participate in all required study evaluations and
             procedures

          -  Known hypersensitivity to ibrutinib, thalidomide or lenalidomide

          -  Females who are pregnant.

        Women:

          -  Women are considered post-menopausal and not of child bearing potential if they have
             had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
             (i.e. age appropriate, history of vasomotor symptoms) or six months of spontaneous
             amenorrhea with serum FSH levels >40 mIU/mL and estradiol < 20 pg/mL or have had
             surgical bilateral oophorectomy with or without hysterectomy at least six weeks prior
             to enrollment in the study. In the case of oophorectomy alone, only when the
             reproductive status of the woman has been confirmed by follow up of hormone level
             assessment is she considered not of child bearing potential.

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, must use highly effective contraception during study treatment and
             for 4 weeks after study discontinuation. Highly effective contraception is defined as
             either

               -  True abstinence: When this is the line with the preferred and usual lifestyle of
                  the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception

               -  Sterilization: Surgical bilateral oophorectomy, with or without hysterectomy, or
                  tubal ligation at least six weeks prior to study enrollment.

               -  Male partner sterilization (with appropriate post-vasectomy documentation of the
                  absence of sperm in the ejaculate). For female patients participating in the
                  study, the vasectomized male partner should be the sole partner for that patient.

               -  Use of a combination of any two of the following:

               -  Placement of an intrauterine device (IUD) or intrauterine system (IUS)

               -  Barrier methods of contraception: Condom or occlusive cap (diaphragm or cervical
                  vault caps) with spermicidal form/gel/film/cream/vaginal suppository

          -  Women of child-bearing potential must have two negative serum pregnancy tests at
             screening

          -  In addition to having a negative pregnancy test confirmed at screening, all female
             participants of child bearing potential must have a negative pregnancy test confirmed
             within 48 hours prior to dosing with the study drug.

          -  Blood Donation: Patients must not donate blood during treatment with lenalidomide and
             for 4 weeks following discontinuation of the drug because the blood might be given to
             a pregnant female patient whose fetus must not be exposed to lenalidomide.

        Men:

          -  Fertile males, defined as all male subjects physiologically capable of conceiving
             offspring, must use a condom during study treatment and for 12 weeks after study
             discontinuation and should not father a child in this period.

          -  Female partner of a male study subject should use a highly effective method of
             contraception while the male partner is receiving the study agent and for 12 weeks
             after the final dose of the study therapy

          -  Male patients taking lenalidomide must not donate sperm

          -  Blood Donation: Patients must not donate blood during treatment with lenalidomide and
             for 4 weeks following discontinuation of the drug because the blood might be given to
             a pregnant female patient whose fetus must not be exposed to lenalidomide.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:maximum tolerated dose (MTD) of ibrutinib
Time Frame:1 year
Safety Issue:
Description:A standard 3+3 design will be employed. Four dose levels will be investigated. Patients will be treated in cohorts of size three to six and the dosage will be escalated if the clinical toxicity is acceptable. A dose limiting toxicity (DLT) is defined as in any of the following during cycle 1: any grade 4 hematologic toxicity, grade 3 febrile neutropenia and grade 3 thrombocytopenia associated with bleeding or any grade ≥3 non-hematologic toxicity that does not respond to supportive therapy and at least possibly related to treatment with ibrutinib. A minimum of 4 up to a maximum of 30 patients will be enrolled.

Secondary Outcome Measures

Measure:progression free survival
Time Frame:2 years
Safety Issue:
Description:Progression-free survival (PFS) is defined as the time from the date of treatment start to the date of the first documented PD or death due to any cause. If a patient is not known to have progressed or died at the date of the analysis cut-off or when he/she receives any further anti-cancer therapy, PFS is censored at the time of the last tumor assessment before the cutoff date and before the anti-cancer therapy date. PFS will be based on the investigator‟s assessment of MRI, CSF studies and clinical presentation.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Ibrutinib
  • Rituximab
  • Lenalidomide
  • relapsed/refractory PCNSL
  • relapsed/refractory SCNSL
  • 18-432

Last Updated

December 5, 2019