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Trial record 33 of 308 for:    IBRUTINIB

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

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ClinicalTrials.gov Identifier: NCT03703167
Recruitment Status : Recruiting
First Posted : October 11, 2018
Last Update Posted : April 25, 2019
Sponsor:
Collaborator:
Pharmacyclics LLC.
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Primary Central Nervous System Lymphoma (PCNSL) Secondary Central Nervous System Lymphoma (SCNSL) Drug: Ibrutinib Drug: Lenalidomide Drug: Rituximab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is an open-label, phase Ib trial with dose expansion of the BTK inhibitor ibrutinib in combination with rituximab and lenalidomide.
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : January 22, 2019
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2021


Arm Intervention/treatment
Experimental: ibrutinib in combination with rituximab and lenalidomide
Ibrutinib 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.
Drug: Ibrutinib
Oral ibrutinib will be given between days 1 and 28 of each 28-day cycle and will be continued daily after completion of rituximab and lenalidomide. The starting dose of ibrutinib is 560 mg/day (dose level 1) and (dose level 2 ibrutinib: 840 mg daily).

Drug: Lenalidomide
Oral lenalidomide will be given between days 1 and 21 of each 28-day cycle for a maximum of 12 cycles. The starting dose of lenalidomide is 10 mg/day (dose level 1 & 2) lenalidomide: 15 mg daily (dose level 3) and lenalidomide: 20 mg daily (dose level 4).

Drug: Rituximab
Intravenous rituximab (500mg/m2) will be given on day 1 of all cycles (+/- 3 days), for up to 6 cycles.




Primary Outcome Measures :
  1. maximum tolerated dose (MTD) of ibrutinib [ Time Frame: 1 year ]
    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 :
  1. progression free survival [ Time Frame: 2 years ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03703167


Contacts
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Contact: Christian Grommes, MD 212-639-4058 grommesc@mskcc.org
Contact: Ingo Mellinghoff, MD 646-888-2766

Locations
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United States, New Jersey
Memoral Sloan Kettering Basking Ridge Recruiting
Basking Ridge, New Jersey, United States, 07920
Contact: Christian Grommes, MD    212-639-4058      
Memorial Sloan Kettering Monmouth Recruiting
Middletown, New Jersey, United States, 07748
Contact: Christian Grommes, MD    212-639-4058      
Memorial Sloan Kettering Bergen Recruiting
Montvale, New Jersey, United States, 07645
Contact: Christian Grommes, MD    212-639-4058      
United States, New York
Memorial Sloan Kettering Commack Recruiting
Commack, New York, United States, 11725
Contact: Christian Grommes, MD    212-639-4058      
Memorial Sloan Kettering Westchester Recruiting
Harrison, New York, United States, 10604
Contact: Christian Grommes, MD    212-639-4058      
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Christian Grommes, MD    212-639-4058      
Contact: Ingo Mellinghoff, MD    646-888-2766      
Memorial Sloan Kettering Rockville Centre Recruiting
Rockville Centre, New York, United States, 11570
Contact: Christian Grommes, MD    212-639-4058      
Memorial Sloan Kettering Nassau Recruiting
Uniondale, New York, United States, 11553
Contact: Christian Grommes, MD    212-610-0344      
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Pharmacyclics LLC.
Investigators
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Principal Investigator: Christian Grommes, MD Memorial Sloan Kettering Cancer Center

Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03703167     History of Changes
Other Study ID Numbers: 18-432
First Posted: October 11, 2018    Key Record Dates
Last Update Posted: April 25, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Memorial Sloan Kettering Cancer Center:
Ibrutinib
Rituximab
Lenalidomide
relapsed/refractory PCNSL
relapsed/refractory SCNSL
18-432

Additional relevant MeSH terms:
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Lymphoma
Neoplasm Metastasis
Neurologic Manifestations
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplastic Processes
Pathologic Processes
Nervous System Diseases
Signs and Symptoms
Rituximab
Lenalidomide
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors