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Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Dose-Adjusted-Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (DA-TEDDI-R) in Primary CNS Lymphoma

This study has suspended participant recruitment.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT02203526
First received: July 29, 2014
Last updated: November 18, 2016
Last verified: October 2016
  Purpose

BACKGROUND:

  • Primary CNS lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma.
  • The outcome for patients with this diagnosis is significantly worse than for that of systemic DLBCL. Most treatment approaches in the past have included high dose methotrexate and radiation treatment.
  • Most PCNSLs appear to be of activated B-cell (ABC) origin.
  • Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and effective for systemic DLBCL of ABC origin.
  • We propose doing a study in which ibrutinib is combined with a novel chemotherapy platform called dose adjusted temozolomide, etoposide, doxil, dexamethasone, ibrutinib, rituximab (DA-TEDDI-R).

OBJECTIVE:

- Identify the maximum tolerated dose (MTD) of ibrutinib or the dose that achieves adequate CSF concentrations, whichever comes first, when ibrutinib is given with DA-TEDDI-R.

ELIGIBILITY:

  • Newly diagnosed or relapsed/refractory PCNSL.
  • Age greater than or equal to 18 years.
  • No pregnant or breast-feeding women.
  • Adequate organ function (defined in protocol).

STUDY DESIGN:

  • This is a phase 1 study of 40 patients.
  • The study will have two components.

    1. Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib achieves a concentration of less than or equal to 100 nM in the CSF, when given in combination with DA-TEDDI-R immuno-chemotherapy, whichever comes first.
    2. Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory or previously untreated PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with DA-TEDDI-R in 10 patients. Secondary objectives will be PFS and OS.


Condition Intervention Phase
Primary Central Nervious System Lymphoma
Drug: TEDDI
Biological: Rituximab
Drug: Cytarabine
Drug: TEDD
Drug: Ibrutinib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Dose-Adjusted-Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (DA-TEDDI-R) in Primary CNS Lymphoma

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • MTD of ibrutinib when given with TEDD-R [ Time Frame: After One Cycle ] [ Designated as safety issue: Yes ]

Enrollment: 17
Study Start Date: July 2014
Estimated Study Completion Date: June 2023
Estimated Primary Completion Date: June 2022 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 st Cohort
TEDD-R (TEDD plus Rituximab) without ibrutinib on 1st cycle; with ibrutinib on cycles 2-6;cytrarabine
Biological: Rituximab
Rituximab given with TEDD and TEDDI every 3 weeks for up to 6 cycles
Drug: Cytarabine
Cytarabine given via Ommaya reservoir (IT therapy) on Day 1 and day 5 of Cycles 2-6 for both cohorts.
Drug: TEDD
Temozolomide, etoposide, doxil, dexamthasone, (TEDD) given on first cycle for first cohort.
Drug: Ibrutinib
Ibrutinib given on Day -14 to Day -1 on Cycle 1 for both groups.
Experimental: Subsequent
TEDDI-R (TEDDI plus Rituximab) and IT therapy
Drug: TEDDI
Temozolomide, etoposide, doxil, dexamthasone, ibrutinib (TEDDI) given every 3 weeks for up to six cycles for second cohort and 5 cycles (cycles 2-6) for first cohort.
Biological: Rituximab
Rituximab given with TEDD and TEDDI every 3 weeks for up to 6 cycles
Drug: Cytarabine
Cytarabine given via Ommaya reservoir (IT therapy) on Day 1 and day 5 of Cycles 2-6 for both cohorts.

Detailed Description:

BACKGROUND:

  • Primary CNS lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma.
  • The outcome for patients with this diagnosis is significantly worse than for that of systemic DLBCL. Most treatment approaches in the past have included high dose methotrexate and radiation treatment.
  • Most PCNSLs appear to be of activated B-cell (ABC) origin.
  • Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and effective for systemic DLBCL of ABC origin.
  • We propose doing a study in which ibrutinib is combined with a novel chemotherapy platform called dose adjusted temozolomide, etoposide, doxil, dexamethasone, ibrutinib, rituximab (DA-TEDDI-R).

OBJECTIVE:

- Identify the maximum tolerated dose (MTD) of ibrutinib or the dose that achieves adequate CSF concentrations, whichever comes first, when ibrutinib is given with DA-TEDDI-R.

ELIGIBILITY:

  • Newly diagnosed or relapsed/refractory PCNSL.
  • Age greater than or equal to 18 years.
  • No pregnant or breast-feeding women.
  • Adequate organ function (defined in protocol).

STUDY DESIGN:

  • This is a phase 1 study of 40 patients.
  • The study will have two components.

    1. Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib achieves a concentration of less than or equal to 100 nM in the CSF, when given in combination with DA-TEDDI-R immuno-chemotherapy, whichever comes first.
    2. Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory or previously untreated PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with DA-TEDDI-R in 10 patients. Secondary objectives will be PFS and OS.
  Eligibility

Ages Eligible for Study:   18 Years to 100 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • ELIGIBILITY CRITERIA:
  • Patients must have histologically or cytologically confirmed primary central nervous system diffuse large B-cell lymphoma. Both newly diagnosed patients and patients with relapsed or refractory disease are eligible.
  • At least 2 weeks have passed since prior chemotherapy, biological therapy, radiation therapy, major surgery, other investigational or anti-cancer therapy that is considered disease-directed.
  • Ibrutinib must be discontinued 7 days before (when possible) until 7 days after major surgery, and 3 days before (when possible) until 3 days after minor surgery. Thus, patients to be enrolled on an ibrutinib trial must have completed major surgery > 7 days before initiating treatment, and/or must have completed minor surgery > 3 days before initiating treatment.
  • Recovered from prior toxicities to Grade 0-1 at least 2 weeks prior to investigational therapy.
  • Men and women age greater than or equal to 18 years.
  • ECOG performance status less than or equal to 2(Karnofsky greater than or equal to 60%) unless due to CNS Lymphoma.
  • Patients must have normal organ and marrow function as defined below, independent of growth factor or transfusion support. Patients should not receive growth factors or transfusions for at least 7 days prior to first dose of study drug with the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which require at least 14 days prior to screening and randomization..

    • absolute neutrophil count greater than or equal to750 cells/mcL (0.75 x 10(9)/L)
    • platelet count greater than or equal to 50,000 cells/mcL (50 X 10(9)/L)
    • hemoglobin greater than 8.0 g/dL
    • total bilirubin less than or equal to1.5 times ULN (unless Gilbert s syndrome or disease infiltration of the liver is present)
    • AST(SGOT)/ALT(SGPT) less than or equal to 3.0 times institutional ULN
    • Serum Creatinine less than or equal to 1.5 mg/dL or creatinine clearance > 40 ml/min/1.73m2 unless lymphoma related.
  • Prothrombin time/INR (PT) and activated partial thromboplastin time (aPTT) must be less than or equal to 1.5 times the upper limit of the normal range (ULN); except if, in the opinion of the Investigator, the aPTT is elevated because of a positive Lupus Anticoagulant.
  • Left ventricular ejection fraction (LVEF) > 40% as assessed by echocardiogram or MUGA
  • The effects of ibrutinib on the developing human fetus are unknown. For this reason and because tyrosine kinase inhibitors as well as other therapeutic agents used in this trial may be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry.

Female patients who are of non-reproductive potential (i.e., post-menopausal by history - no menses for (Bullet)1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female patients of childbearing potential must have a negative serum pregnancy test upon study entry.

Male and female patients who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete sexual abstinence, or sterilized partner) during the period of therapy and for 90 days after the last dose of study drug.

Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

-Patient or appointed surrogate decision-maker or legally authorized representative must have ability to understand the purpose and risks of the study and willingness to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).

EXCLUSION CRITERIA:

  • Chemotherapy less than or equal to 21 days prior to first administration of study treatment and/or monoclonal antibody 6 weeks prior to first administration of study treatment.
  • Prior exposure to a BTK inhibitor
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or other agents used in study.
  • Patients who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to the first dose of ibrutinib or patients who require continuous treatment with a strong CYP3A inhibitor.

Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as; medical reference texts such as the Physicians Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.

  • HIV positive patients will be excluded with the exception of patients without CD4 depletion (i.e. above the institutional lower limit of normal) and who have no other AIDS related complications and who have EBV negative tumors. The number of patients in this category is expected to be very low and the PI will decide their eligibility on a case by case basis.
  • Systemic cytotoxic therapy within 2 weeks of treatment.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or an infection requiring systemic antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Recent infections requiring systemic treatment need to have completed therapy greater than 14 days before the first dose of study drug.
  • Pregnant and breastfeeding women are excluded from this study. Pregnant women are excluded in this study because ibrutinib is a tyrosine kinase inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ibrutinib, breastfeeding should be discontinued if the mother is treated with ibrutinib.

Uncontrolled Autoimmune Hemolytic Anemia or ITP resulting in (or as evidenced by) declining platelet or Hgb levels within the 4 weeks prior to first dose of study drug.

  • Presence of transfusion-dependent thrombocytopenia.
  • Patients requiring daily corticosteroids at a prednisone equivalent of greater than or equal to 20 mg daily should not be enrolled. If corticosteroids can be discontinued (or reduced to less than 20 mg per day of prednisone or equivalent), the discontinuation or dose reduction should be done at least 7 days prior to first dose (see Section 5.3.1 for instructions regarding on-study use of corticosteroids).
  • History of prior malignancy, with the exception of the following:
  • Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to Screening and felt to be at low risk for recurrence by treating physician
  • Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
  • Adequately treated cervical carcinoma in situ without current evidence of disease.
  • Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction unstable angina, or acute coronary syndrome within 6 months prior to enrollment in the study.
  • Unable to swallow capsules, or disease significantly affecting gastrointestinal function or resection of the stomach or small bowel, or symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
  • Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  • Any life-threatening illness, medical condition, or organ system dysfunction that, in the Investigator s opinion, could compromise the patient s safety, or put the study at undue risk.
  • Concomitant use of warfarin or other vitamin K antagonists within the last 28 days.
  • Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g., cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug.
  • Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
  • Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade less than or equal to1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia.
  • Known bleeding disorders (e.g., von Willebrand s disease) or hemophilia.
  • Major surgery within 4 weeks of first dose of study drug.
  • Unwilling or unable to participate in all required study evaluations and procedures.
  • Currently active, clinically significant hepatic impairment ( (Bullet) moderate hepatic impairment according to the NCI/Child Pugh classification.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02203526

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: James L Gulley, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02203526     History of Changes
Other Study ID Numbers: 140157  14-C-0157 
Study First Received: July 29, 2014
Last Updated: November 18, 2016
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Tyrosine Kinase Inhibitor
ABC DLBCL
Lymphoma in Brain and CNS
Diffuse Large B-Cell Lymphomas in CNS

Additional relevant MeSH terms:
Neoplasms by Histologic Type
Neoplasms
Lymphoma
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Etoposide phosphate
Temozolomide
Liposomal doxorubicin
Rituximab
Etoposide
Dacarbazine
Cytarabine
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors

ClinicalTrials.gov processed this record on December 05, 2016