Clinical Trials /

Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, and Rituximab (TEDDI-R) in Aggressive B-cell Lymphomas With Secondary Involvement of the Central Nervous System (CNS)

NCT03964090

Description:

Background: Secondary central nervous system lymphoma (sCNSL) is cancer that has spread to the central nervous system. Most drugs used to treat it do not cross the blood-brain barrier. This makes it hard to treat. Researchers hope that a new combination of drugs may be able to help. Objective: To find a better way to treat sCNSL. Eligibility: People ages 18 and older with sCNSL Design: Participants will be screened with: - Medical history - Physical exam - Blood, urine, and heart tests - Eye exam - Tissue or tumor biopsy - Collection of cerebrospinal fluid - CT, PET, and MRI scans: Participants will like in a machine that takes pictures of the body. - Bone marrow aspirations or biopsies: A needle will be inserted into the participant s hipbone. The needle will remove a small amount of marrow. Participants will take the study drugs in 21-day cycles. They will take some drugs by mouth. They will take others through a catheter: A small tube will be inserted into a vein in the arm, neck, or chest. They may have drugs given through a catheter placed through the brain or injected into the spinal canal. Participants will have regular visits during the study. These will include repeats of the screening test. They may also provide a saliva sample or have a cheek swab. Participants will have up to 4 treatment cycles. Participants will have a follow-up visit 30 days after their last treatment dose. Then they will have visits every 3-6 months for 3 years and then yearly. ...

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Central Nervous System Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, and Rituximab (TEDDI-R) in Aggressive B-cell Lymphomas With Secondary Involvement of the Central Nervous System (CNS)
  • Official Title: A Study of Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, and Rituximab (TEDDI-R) in Aggressive B-cell Lymphomas With Secondary Involvement of the Central Nervous System (CNS)

Clinical Trial IDs

  • ORG STUDY ID: 190103
  • SECONDARY ID: 19-C-0103
  • NCT ID: NCT03964090

Conditions

  • Central Nervous System Lymphoma
  • Secondary Central Nervous System Lymphoma

Interventions

DrugSynonymsArms
TEDD-R1
TEDDI-R1
Ibrutinib1
Cytarabine1
Isavuconazole1

Purpose

Background: Secondary central nervous system lymphoma (sCNSL) is cancer that has spread to the central nervous system. Most drugs used to treat it do not cross the blood-brain barrier. This makes it hard to treat. Researchers hope that a new combination of drugs may be able to help. Objective: To find a better way to treat sCNSL. Eligibility: People ages 18 and older with sCNSL Design: Participants will be screened with: - Medical history - Physical exam - Blood, urine, and heart tests - Eye exam - Tissue or tumor biopsy - Collection of cerebrospinal fluid - CT, PET, and MRI scans: Participants will like in a machine that takes pictures of the body. - Bone marrow aspirations or biopsies: A needle will be inserted into the participant s hipbone. The needle will remove a small amount of marrow. Participants will take the study drugs in 21-day cycles. They will take some drugs by mouth. They will take others through a catheter: A small tube will be inserted into a vein in the arm, neck, or chest. They may have drugs given through a catheter placed through the brain or injected into the spinal canal. Participants will have regular visits during the study. These will include repeats of the screening test. They may also provide a saliva sample or have a cheek swab. Participants will have up to 4 treatment cycles. Participants will have a follow-up visit 30 days after their last treatment dose. Then they will have visits every 3-6 months for 3 years and then yearly. ...

Detailed Description

      Background:

        -  Aggressive B-cell lymphomas with secondary involvement of the CNS (sCNSL) have a grave
           prognosis

        -  No standard of care exists for sCNSL; treatment approaches include combination
           chemotherapy regimens effective in primary CNS lymphoma (PCNSL)

        -  Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and has demonstrated a high
           response rate in PCNSL and sCNSL but with short response duration

        -  We developed a novel regimen that combines ibrutinib with a chemoimmunotherapy platform
           maximized for CNS penetrance that includes temozolomide, etoposide, Doxil,
           dexamethasone, and rituximab (TEDDI-R) for aggressive B-cell lymphomas in the CNS

        -  A phase 1 study of TEDDI-R demonstrated durable remissions in refractory PCNSL

        -  We propose a small phase 2 to study the safety and efficacy of TEDDI-R in sCNSL

      Objective:

      -To estimate the progression-free survival (PFS) after TEDDI-R or TEDD-R in secondary CNS
      lymphoma (sCNSL)

      Eligibility:

        -  Aggressive B-cell lymphomas with secondary involvement of the CNS (sCNSL)

        -  Relapsed/refractory from prior therapy or untreated with CNS parenchymal lesions

        -  Age greater than or equal to 18 years

        -  No pregnant or breast-feeding women.

        -  Adequate organ function (defined in protocol)

      Design:

        -  Phase II study of 29 evaluable patients with untreated and relapsed/refractory sCNSL
           (accrual ceiling will be set at 32 to allow for a few possible inevaluable patients)

        -  Patients will first be treated with a 14-day "window" of ibrutinib monotherapy in
           combination with isavuconazole to establish efficacy of ibrutinib. Patients who are
           known refractory to BTK inhibitors will skip the 14-day and proceed on to chemotherapy.

        -  Following the 14-day ibrutinib window, patients with at least a 20% reduction in
           bidimensional masses on imaging scans or those without measurable disease will receive
           ibrutinib with TEDD-R (TEDDI-R) chemotherapy for 4 cycles. Patients who are previously
           known to be refractory to BTK inhibitors and those who have less than a 20% reduction
           during the ibrutinib window will receive TEDD-R (without ibrutinib) for 4 cycles.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalTemozolomide, etoposide, doxil, dexamethasone, andrituximab without ibrutinib (TEDD-R) or TEDD-R with ibrutinib (TEDDI-R), concurrent with cytarabine and isavuconazole, based upon response to 14-day ibrutinib window
  • TEDD-R
  • TEDDI-R
  • Ibrutinib
  • Cytarabine
  • Isavuconazole

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed secondary involvement of
             an aggressive B-cell lymphoma in the CNS (eye, CSF, and/or brain parenchyma).

        NOTE: B-cell lymphomas that were previously indolent but now involve the CNS (i.e.
        transformed from previous follicular lymphoma or chronic lymphocytic leukemia and mantle
        cell lymphoma) are eligible.

          -  Patients must have disease that is relapsed or refractory after initial systemic
             treatment or patients without prior therapy for systemic DLBCL must have concomitant
             involvement of the eyes or brain parenchyma; untreated patients with CSF only
             involvement are not eligible

          -  Men and women age greater than or equal to18 years. NOTE: Because no dosing or adverse
             event data are currently available on the use of ibrutinib and TEDDI-R in patients <18
             years of age, children are excluded from this study, but may be eligible for future
             pediatric trials.

          -  ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to
             60%) unless due to disease

          -  Patients must have adequate organ function as defined below, independent of growth
             factor or platelet transfusion support:

               -  Absolute neutrophil count (ANC): greater than or equal to 750 cells/mcL (0.75
                  (SqrRoot) 10^9/L)

               -  Platelets: greater than or equal to 50,000 cells/mcL (50 (SqrRoot) 10^9/L)

               -  Hemoglobin: greater than or equal to 8 g/dL (transfusions permitted)

               -  Serum total bilirubin: less than or equal to 1.5 X ULN unless Gilbert s syndrome
                  or disease infiltration of the liver is present)

               -  AST (SGOT) and ALT (SGPT): less than or equal to 3.0 (SqrRoot) institutional ULN
                  (less than or equal to 5 x ULN for patients with liver involvement by lymphoma)

               -  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 <
             1.5 x the upper limit of the normal range (ULN); except if, in the opinion of the
             Investigator, the aPTT is prolonged because of a positive Lupus Anticoagulant.

          -  Female patients of childbearing potential must have a negative pregnancy test upon
             study entry. This is not required for female patients who are of non-reproductive
             potential (i.e., post-menopausal by history - defined as: 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).

          -  The effects of ibrutinib and TEDDI-R on the developing human fetus are unknown. For
             this reason, 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: Women of childbearing potential (WOCBP) 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 the study
                  treatment, as well as for 12 months after the last dose of rituximab.

               -  Men: Men must use a barrier method to prevent pregnancy of their partner and
                  should also not donate sperm while taking the study treatment and for 12 months
                  after the last dose of rituximab.

          -  Ability of patient or Legally Authorized Representative (LAR) to understand and the
             willingness to sign a written informed consent document

        EXCLUSION CRITERIA:

          -  Systemic chemotherapy less than or equal to 14 days prior to ibrutinib window study

          -  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).

        NOTE: In addition, because the lists of these agents are constantly changing, it is
        important to regularly consult a frequently-updated list; 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 >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.

          -  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 2 years prior to screening and felt to be at low risk for
                  recurrence by treating physician

               -  Adequately treated non-melanomatous skin cancer or lentigo malignant 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 3 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.

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:every 3-6 months
Safety Issue:
Description:time from study enrollment until disease progression or death from any cause

Secondary Outcome Measures

Measure:Safety and tolerability of TEDDI-R and TEDD-R in sCNSL
Time Frame:ongoing
Safety Issue:
Description:the proportion of patients with adverse events leading to discontinuation of therapy
Measure:Best overall response after 14 days of ibrutinib monotherapy in sCNSL; after up to 4 cycles of TEDDI-R; and, after up to 4 cycles of TEDD-R (no ibrutinib)
Time Frame:after 14 days and 4 cycles
Safety Issue:
Description:proportion of patients who achieve at least a partial response (PR) to therapy
Measure:Duration of response (DOR)
Time Frame:every 2 cycles during treatment; every 3-6 months in follow-up
Safety Issue:
Description:time from first documentation of tumor response to disease progression
Measure:Assessment of pharmacokinetics (PK) and safety of TEDDI-R with concomitant anti-fungal prophylaxis
Time Frame:at least each cycle, up to cycle 4
Safety Issue:
Description:time from study enrollment until disease progression or death from any cause
Measure:Overall survival (OS) to TEDDI-R and TEDD-R in sCNSL
Time Frame:every 3-6 months
Safety Issue:
Description:time from study enrollment until death from any cause

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Tyrosine Kinase Inhibitor
  • Lymphoma in Brain and CNS
  • ABC DLBCL
  • Diffuse Large B-Cell Lymphomas in CNS

Last Updated

February 12, 2020