Phase 1 Study of Escalating Doses of Ibrutinib and Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, Rituximab (TEDDI-R) with Isavuconazole for Relapsed and Refractory Primary CNS Lymphoma

Author:

Mark Roschewski, MD,1
Christopher Melani, MD,2
Rahul Lakhotia, MD,3
Stefania Pittaluga, MD
PhD,4
James D. Phelan, PhD,*,3
Cody Peer, PhD,*,5 Michail S. Lionakis, MD ScD,*,6 Lydia
L. Chou, CRNP,*,3 Matthias Holdhoff, MD PhD,*,7 Michael Glantz, MD PhD,*,8 Jan Drappatz, MD,*,9
Catherine Lai, MD MPH,10 John A. Butman, MD PhD,*,11 Andrea Nicole Lucas, RN,*,12 Seth
M. Steinberg, PhD,*,13 William D. Figg, PhD,*,14 Elaine S. Jaffe, MD,4
S. Percy Ivy, MD,*,15
Richard F. Little, MDMPH,16 Louis M. Staudt, MD PhD,3
Wyndham H. Wilson, MD PhD3

Author address:

1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
2
Lymphoid Malignancies Branch, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Baltimore, MD
3
Lymphoid Malignancies Branch, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Bethesda, MD
4
Laboratory of Pathology, Center for Cancer Research, National
Cancer Institute, National Institutes of Health, Bethesda, MD
5Clinical Pharmacology Program, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Bethesda, MD
6
Laboratory of Clinical Infectious Diseases, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, MD
7Department of Neuro-Oncology, Johns Hopkins Cancer Center, Baltimore, MD
8Department of Neurosurgery, Penn State College of Medicine, Hershey, PA
9University of Pittsburgh, Pittsburgh, PA
10Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC
11Radiology and Imaging Sciences, Clinical Center, National
Cancer Institute, National Institutes of Health, Bethesda, MD
12Lymphoid Malignancies Branch, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Bethesda, MD
13Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD
14Molecular Pharmacology Section, Genitourinary Malignancies Section, National Cancer Institute, Bethesda, MD
15National Cancer Institute Cancer Therapy Evaluation Program, Rockville, MD
16Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD

Full conference title:

62nd American Society of Hematology Annual Meeting and Exposition

Date: 5 December 2020

Abstract:

Background: Primary DLBCL of the CNS (PCNSL) relies on chronic active B-cell receptor (BCR)
signaling. Ibrutinib targets BCR signaling through BTK inhibition (BTKi), which may also impair
innate immunity. We showed that ibrutinib and temozolomide, etoposide, liposomal doxorubicin,
dexamethasone, rituximab (TEDDI-R) induces durable remissions in relapsed/refractory PCNSL but
7 (39%) pts developed Aspergillus infections without fungal prophylaxis. Newer triazoles are effective
against Aspergillus but inhibit ibrutinib clearance through CYP3A4. Isavuconazole has less effect on
CYP3A4 and less hepatotoxicity than voriconazole. We hypothesized that ibrutinib and isavuconazole
could be safely co-administered in TEDDI-R and ameliorate the risk of Aspergillus while maintaining
efficacy. We studied escalating doses of ibrutinib in TEDDI-R with isavuconazole to determine the safety
profile, ibrutinib PK, and clinical activity in relapsed/refractory PCNSL.
Methods: Pts with relapsed/refractory PCNSL, age ≥18, ECOG PS ≤2, and adequate organ function
were enrolled. Previous BTKi, HIV, EBV+
, and pregnancy were excluded. Pts had baseline MRI brain,
FDG-PET brain and body, Ommaya placed, CSF with flow cytometry, and eye exam. Isavuconazole
200mg BID x 3d started prior to ibrutinib then 200mg daily. Three dose levels of ibrutinib (280mg, 420mg,
560mg) were given continuously through each cycle. Pts received up to 6 cycles of TEDDI-R with IT
cytarabine. No one received maintenance or consolidation. If a DLT occurred in the first 3 pts at a given
ibrutinib dose level, 3 more pts were treated before escalating. Full safety and PK data was reviewed
after two dose levels prior to escalating. An expansion of 10 pts was planned at the highest ibrutinib dose
level to confirm safety and clinical activity. Surveillance for fungal infections included chest CT mid-cycle
1 and after each cycle along with Beta-D glucan and aspergillus galactomannan in blood and CSF. Brain
MRI was performed after cycles 1, 2, 4, and 6 to determine response and screen for CNS Aspergillus. All
remissions by MRI were confirmed with FDG-PET and CSF analysis. Surveillance brain MRI were q3m
for 1y, q4m x 1y, q6m x 1y, then annually. Primary objective was to identify the highest dose of ibrutinib
safely co-administered with isavuconazole in TEDDI-R that achieves adequate PK concentrations.
Results: 13 relapsed/refractory PCNSL pts enrolled between 11/2018 and 06/2020. 10 (77%) pts were
male and the median age was 65 (range 46-77), including 3 pts ≥age 70. 13 (100%) pts had prior highdose MTX, and 2 (15%) pts had prior autologous stem cell transplant (ASCT). Three evaluable pts
received ibrutinib 280mg, 3 pts received ibrutinib 420mg, and 6 pts received ibrutinib 560mg. One pt in
the 280mg cohort was not evaluable. Toxicity was evaluated in 13 pts across 49 cycles and the toxicity
was mainly hematologic. G3 and G4 neutropenia occurred in 45% and 37% of cycles, respectively, while
febrile neutropenia occurred in 8% of cycles. The median (range) duration of neutropenia was 4.5 (1-12)
days. One pt with prior ASCT stopped after 4 cycles due to myelosuppression. Four (8%) cycles were
complicated by ≥G3 infection, but no opportunistic infections (including Aspergillus) were observed. G3
and G4 thrombocytopenia occurred in 22% and 8% of cycles, respectively, and 1 pt developed melena
with no overt GI bleeding. ≥G3 mucositis occurred in 6% of cycles and 1 patient stopped therapy after 5
cycles due to recurrent mucositis. Palmar-plantar-erythrodysesthesia led to dose reductions of liposomal
doxorubicin in 9 (69%) pts, but only 1 G3 event occurred. Twelve pts were evaluable for response, and
11 (92%) pts have responded and all after receiving only 1 cycle (Figure 1). All 8 (100%) pts who have
completed at least 4 cycles have achieved CR and the other 4 remain on therapy. Six (75%) pts who
achieved CR remain in remission while 2 (25%) pts relapsed within 3 months of stopping therapy. After a
median potential f/u of 5.2 months, the 1-year PFS is estimated at 60.0% (95% CI, 12.6-88.2) and the OS
is 100%.
Conclusions: Ibrutinib 560mg was safely co-administered with isavuconazole in TEDDI-R for relapsed/
refractory PCNSL. No DLTs were observed, no cases of Aspergillus occurred, and no new safety signals.
The first 8 (100%) patients who have completed therapy achieved complete response. Updated clinical
results from this ongoing study (NCT02203526) will be presented at the meeting.