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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02203526
Recruitment Status : Recruiting
First Posted : July 30, 2014
Last Update Posted : August 12, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE July 29, 2014
First Posted Date  ICMJE July 30, 2014
Last Update Posted Date August 12, 2020
Actual Study Start Date  ICMJE August 14, 2014
Estimated Primary Completion Date June 15, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 26, 2018)
MTD of ibrutinib when given with TEDD-R [ Time Frame: After one cycle ]
AEs will be tabulated and reported
Original Primary Outcome Measures  ICMJE
 (submitted: July 29, 2014)
MTD of ibrutinib when given with TEDD-R [ Time Frame: After one cycle ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2020)
  • Safety and Tolerability [ Time Frame: Initiation of ibrutinib until 30 days after treatment ]
    Incidence of adverse events (i.e., grade and frequency)
  • Progression-free survival [ Time Frame: every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly ]
    The response rate will be determined and reported along with a 95% confidence interval
  • Overall survival [ Time Frame: every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly ]
    The response rate will be determined and reported along with a 95% confidence interval
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Primary CNS Lymphoma
Official Title  ICMJE Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Primary CNS Lymphoma.
Brief Summary

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 (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 TEDDI-R.

ELIGIBILITY:

  • 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 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 TEDDI-R in 10 patients. Secondary objectives will be PFS and OS.
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 d temozolomide, etoposide, doxil, dexamethasone, ibrutinib, rituximab (TEDDI-R).

OBJECTIVE:

-To identify the dose of ibrutinib with anti-fungal prophylaxis that can be safely administered to achieve an ibrutinib median CSF CMAX of 1.98 nM (Range 0.69 to 11.1).

ELIGIBILITY:

  • 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 52 patients.
  • The study will have three components.

    • Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib achieves a concentration of greater than or equal to 100 nM in the CSF, when given in combination with TEDDI-R immuno-chemotherapy, whichever comes first.
    • Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with TEDDI-R in 10 patients. Secondary objectives will be PFS and OS.
    • Revised Study Design: Effective with Amendment G (version date: 7/31/2017), new ibrutinib dose levels are being added together with anti-fungal prophylaxis to determine the dose of ibrutinib that may be safely given with the chemotherapy platform.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Primary Central Nervous System Lymphoma
Intervention  ICMJE
  • Drug: Isavuconazole
    Isavuconazole to begin at least 3 days (and up to 7 days) prior to ibrutinib and continue throughout chemotherapy (cycles 1-6)
  • Drug: TEDDI
    Temozolomide, etoposide, doxil, dexamthasone, ibrutinib (TEDDI) given every 21 days for cycles 2-6 (Arm 1- A); given every 21 days for cycles 2-6 (Arm 1-A); given every 21 days for cycles 1-6 (Arms 1-B, 2 and 3)
  • Biological: Rituximab
    Rituximab (R) given with TEDD and TEDDI every 3 weeks for cycles 1-6 (all arms)
  • Drug: Cytarabine
    Cytarabine given via Ommaya reservoir (IT therapy) on days 1 and day 5 of cycles 2-6 (all arms)
  • Drug: TEDD
    Temozolomide, etoposide, doxil, dexamthasone, (TEDD) given on first cycle (Arm 1-A)
  • Drug: Ibrutinib (Arms 2 and 3)
    Ibrutinib given on day -3 to day -1 on cycle 1 (Arms 2 and 3)
  • Drug: Ibrutinib (Arm 1 - Closed with Amendment G)
    Ibrutinib given on day -14 to day -1 on cycle 1 (Arm 1)
Study Arms  ICMJE
  • Experimental: Arm 1-A (First Cohort; original study design)
    TEDD-R and IT therapy
    Interventions:
    • Drug: TEDDI
    • Biological: Rituximab
    • Drug: Cytarabine
    • Drug: TEDD
    • Drug: Ibrutinib (Arm 1 - Closed with Amendment G)
  • Experimental: Arm 1-B (Second Cohort; original study design)
    TEDDI-R and IT therapy
    Interventions:
    • Drug: TEDDI
    • Biological: Rituximab
    • Drug: Cytarabine
  • Experimental: Arm 2 (Dose Escalation; Amendment I)
    TEDDI-R and IT therapy with antifungals
    Interventions:
    • Drug: Isavuconazole
    • Drug: TEDDI
    • Biological: Rituximab
    • Drug: Cytarabine
    • Drug: Ibrutinib (Arms 2 and 3)
  • Experimental: Arm 3 (Dose Expansion; Amendment I)
    TEDDI-R and IT therapy with antifungals
    Interventions:
    • Drug: Isavuconazole
    • Drug: TEDDI
    • Biological: Rituximab
    • Drug: Cytarabine
    • Drug: Ibrutinib (Arms 2 and 3)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 26, 2018)
52
Original Estimated Enrollment  ICMJE
 (submitted: July 29, 2014)
40
Estimated Study Completion Date  ICMJE June 15, 2023
Estimated Primary Completion Date June 15, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • ELIGIBILITY CRITERIA:
  • Patients must have histologically or cytologically confirmed primary central nervous system diffuse large B-cell lymphoma. Only patients with relapsed or refractory disease are eligible. Patients with PCNSL that is only extracranial will not be eligible.
  • At least 2 weeks have passed since prior chemotherapy, biological therapy, radiation therapy,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 greater than or equal to 7 days before initiating treatment, and/or must have completed minor surgery greater than or equal to 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 neurologic deficits caused by CNS lymphoma with the following exceptions: patients with ECOG PS = 4 where neurologic deficits are unlikely to resolve with tumor resolution and may cause clinical management problems are excluded.
  • 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 to 750 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 greater than or equal to 40 ml/min/1.73m(2) 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 non-reproductive 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 greater than or equal to 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 must agree to use highly effective methods of birth control. A "highly effective method of birth control" is defined as a method that has a low failure rate (i.e., less than 1% per year) when used consistently and correctly and includes implants, injectables, birth control pills with two hormones, some intrauterine devices (IUDs). Male subject cannot use highly effective methods and are required to use barrier. The specific guidelines are as follows:

    • Women: If you can have children, you must use a highly effective method of birth control and a barrier method, or sexual abstinence (which is defined as refraining from all aspects of sexual activity), while taking study treatment, as well as for 12 months after the last dose of rituximab.
    • Men: You must use a barrier method while on treatment with ibrutinib and for 3 months after the last dose of treatment to prevent pregnancy of your partner. You should not donate sperm while you are taking the study drug and for 12 months after you stop taking the last dose of rituximab.
  • 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:

  • 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 are allergic to isavuconazole or any of its ingredients.
  • Patients who received a strong cytochrome P450 (CYP) 3A inhibitor or inducer within 7 days prior to the first dose of protocol anti-fungal prophylaxis, or patients who require continuous treatment with a strong CYP3A inhibitor/inducer (i.e., with the exception of any medication to be specifically studied in this protocol).
  • 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 because of their increased susceptibility to fungal infections which outweighs the potential benefit of participation.
  • 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.
  • 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 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. Patients with suspicious radiologic evidence of aspergillosis infection (i.e., Chest CT and/or Brain MRI) will not be eligible unless confirmatory laboratory testing of Beta-D glucan and aspergillus antigen are negative.
  • Concomitant use of warfarin or other vitamin K antagonists within the last 7 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 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 7 days of first dose of study drug.
  • Unwilling or unable to participate in all required study evaluations and procedures.
  • Currently active, clinically significant hepatic impairment (greater than or equal to moderate hepatic impairment according to the NCI/Child Pugh classification.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: A. Nicole Lucas (240) 760-6252 lucasan2@mail.nih.gov
Contact: Mark J Roschewski, M.D. (240) 760-6183 mark.roschewski@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02203526
Other Study ID Numbers  ICMJE 140157
14-C-0157
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mark J Roschewski, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date March 5, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP