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 involvement
- 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 58 evaluable participants with untreated and relapsed/refractory sCNSL
(accrual ceiling will be set at 65 to allow for a few possible inevaluable participants
and screen fails)
- Participants will first be treated with a 14-day "window" of ibrutinib monotherapy in
combination with isavuconazole to establish efficacy of ibrutinib. Participants who are
known refractory to BTK inhibitors will skip the 14-day and proceed on to chemotherapy.
- Following the 14-day ibrutinib window, participants 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. Participants 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.
- INCLUSION CRITERIA:
- Participants 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.
- Participants must have disease that is relapsed or refractory after initial systemic
treatment or participants without prior therapy for systemic DLBCL must have
concomitant involvement of the eyes, CSF or brain parenchyma.
- 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 participants
<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
- Participants 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 participants 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 participants of childbearing potential must have a negative pregnancy test upon
study entry. This is not required for female participants 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 participants 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 participants 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 participants 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
- Participants who are allergic to isavuconazole or any of its ingredients
- Participants 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
participants 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 participants 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 participants is considering a new over-the-counter medicine or herbal product.
- HIV positive participants 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. Participants 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. Those who are (PCR positivewill be excluded.) Those with a negative PCR
for hepatitis B will be treated with antivirals designed to prevent hepatitis B
reactivation (e.g., entecavir) and have monitoring for hepatitis B reactivation with
PCR.
- 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 participant s safety, or put the
study at undue risk. Participants 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
