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 is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Institutes of Health Clinical Center (CC)
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: August 7, 2014
Last verified: July 2014
  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
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 ]

Estimated Enrollment: 40
Study Start Date: July 2014
Estimated Study Completion Date: June 2023
Estimated Primary Completion Date: June 2023 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 st Cohort
TEDD-R without ibrutinib and withcytrarabine
Drug: TEDDI
Temozolomide, etoposide, doxil, dexamthasone, ibrutinib (TEDDI) given every 3 weeks for up to six cycles.
Biological: Rituximab
Rituximab given with 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 each cycle
Experimental: Subsequent
TEDDI-R and IT therapy
Drug: TEDDI
Temozolomide, etoposide, doxil, dexamthasone, ibrutinib (TEDDI) given every 3 weeks for up to six cycles.
Drug: Cytarabine
Cytarabine given via Ommaya reservoir (IT therapy) on Day 1 and day 5 of each cycle

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 and older
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.

Age greater than or equal to 18 years.

  • ECOG performance status less than or equal to 2.

    • Patients must have normal organ and marrow function as defined below, independent of growth factor or transfusion support. Subjects should not receive growth factors or transfusions for at least 7 days prior to first dose of study drug.
    • absolute neutrophil count greater than or equal to1000 cells/mcL (1 K/uL)
    • platelets greater than or equal to 75,000 cells/mcL (75 K/uL)
    • 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 2.5 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 (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.
  • Patients already receiving treatment with strong CYP3A4/5 inhibitors or inducers, prior to enrollment, may be eligible. Attempts should be made to change to an alternative agent with mild or no CYP3A4/5 inhibition or induction. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; 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.
  • 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 and for the duration of study treatment and 4 months after completion of ibrutinib administration. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ibrutinib administration.
  • Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

  • Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
  • Patients who are receiving any other investigational agents.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or other agents used in study.
  • 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.
  • 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.
  • Need for daily corticosteroids (prednisone equivalent of greater than or equal to 20 mg daily) is prohibited from 7 days prior to first dose and during treatment with ibrutinib.
  • Prior exposure to ibrutinib.
  • 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, any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months prior to first dose with study drug.
  • Unable to swallow capsules, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption, such as malabsorption syndrome, resection of the small bowel, or poorly controlled inflammatory bowel disease affecting the small intestine.
  • Patients with active Hepatitis B or C will be excluded. Patients who are PCR positive for

Hepatitis B or C will be excluded.

  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  • Received anticoagulation therapy with warfarin or equivalent vitamin K antagonists within the last 28 days.
  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

Contacts
Contact: Margaret Shovlin, R.N. (301) 594-6597 mshovlin@mail.nih.gov
Contact: Kieron M Dunleavy, M.D. (301) 435-1007 dunleavk@mail.nih.gov

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

Additional Information:
No publications provided

Responsible Party: National Institutes of Health Clinical Center (CC) ( 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: August 7, 2014
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:
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Rituximab
Temozolomide
Etoposide
Cytarabine
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors

ClinicalTrials.gov processed this record on September 16, 2014