Acalabrutinib Plus RICE for Relapsed/Refractory DLBCL

This is a phase II study with a safety run-in. There will be two planned cohorts, Cohort A
and Cohort B. Cohort A will be open to R/R DLBCL patients who are medically eligible for
autologous HSCT (autoHSCT). Cohort B will be open to R/R DLBCL patients who are medically
ineligible for autologous transplant. Historical outcomes from completed, published
prospective clinical trials using RICE salvage chemotherapy will serve as a comparator
population.

Safety run-in: To assess for safety of the combination of acalabrutinib and RICE
chemotherapy, we will pause enrollment in both cohorts to assess for any safety concerns once
a total 10 patients have been enrolled to either cohort. After the first ten patients have
all completed at least one cycle of therapy without unacceptable or unexpected concerns,
enrollment will resume. If there are concerns about adverse events or the ability of patients
to proceed as expected to HSCT, then the study team will convene to determine whether the
protocol should be modified. Data obtained for the first ten patients will be included in the
data sample for final analysis.

Cohort A: After confirmation of medical eligibility for autologous HSCT, patients enrolled in
Cohort A will receive 2 cycles of standard dose RICE salvage chemotherapy in combination with
acalabrutinib 100mg twice daily (BID) day 1-21 of a 21 day cycle. After 2 cycles of therapy,
patients will undergo autologous cell collection per standard institutional procedures.
Acalabrutinib will be held 3 days before planned placement of an apheresis collection
catheter and resumed 3 days after completion of stem cell collection and catheter removal.
Patients will then receive a 3rd cycle of RICE chemotherapy in combination with acalabrutinib
100mg BID. For patients with bone marrow disease at enrollment, a repeat bone marrow will be
performed after 2 cycles of salvage therapy, prior to autologous stem cell collection. For
patients with continued bone marrow disease after 2 cycles of salvage therapy, a 3rd cycle
may be given prior to autologous cell collection. PET-CT (PET3) will be performed 14-21 days
after day 1 of cycle 3 to assess response. Those patients with complete response (CR) or
partial response (PR) after PET3 will move onto autologous transplant with Carmustine,
Etoposide, Cytarabine, and Melphalan (BEAM) conditioning within 28-42 days of PET3. After
adequate hematopoietic recovery (expected around 30 days after autologous HSCT), patients
will restart acalabrutinib 100mg BID as maintenance therapy for a period of 12 months.
Patients with a minor response (MR) or stable disease (SD) after PET3 will delay HSCT and
will continue acalabrutinib 100mg BID with repeat PET every 6 weeks. If patient converts to
CR at subsequent PET-CT, they may proceed with BEAM autologous HSCT within 28-42 days of
achieving this response followed by 12 months of post-transplant acalabrutinib maintenance.
Patients with continued PR/MR/SD may continue on study, if felt to be clinically benefitting
without limiting toxicity, but will not receive a transplant. Patients demonstrating
progressive disease (PD) at any stage will be withdrawn from study treatment but their
outcomes will be tracked and included in final data analysis.

Cohort B: Patients medically ineligible for autologous HSCT but fit for salvage chemotherapy
will receive 3 cycles or RICE salvage chemotherapy in combination with acalabrutinib 100mg
BID day 1-21 of a 21 day cycle followed by PET-CT (PET3) 14-21 days after start of Cycle 3.
Patients with CR/PR/MR/SD would continue with acalabrutinib maintenance with repeat PET-CT
every 3 months until disease progression or toxicity. Patients demonstrating progressive
disease (PD) will be withdrawn from study treatment but their outcomes will be tracked and
included in final data analysis.

Establishing the feasibility of combining acalabrutinib with RICE chemotherapy in transplant
eligible and transplant ineligible patients with R/R DLBCL will provide the foundation for a
larger study of efficacy and long-term outcomes of the combination therapy for patients with
R/R DLBCL. Such a study, if demonstrative of improvements in the complete response rate to
salvage therapy at PET3, could provide evidence to support a new standard of care of for
patients with R/R DLBCL.

Inclusion Criteria:

1. Histologically confirmed R/R DLBCL (per 2008 WHO classification)

1. GCB or ABC cell of origin (by IHC using Hans algorithim)

2. Transformation from prior indolent NHL is permitted

2. Relapsed or refractory to 1 prior line of anthracycline containing chemoimmunotherapy
considered a standard 1st line therapy for DLBCL. Acceptable 1st line regimens are
R-CHOP, R-EPOCH, or R-HyperCVAD chemotherapy regimens. Treatment with prior
radiotherapy is allowed.

3. ECOG Performance status 0-2

4. Expected life expectancy of at least 3 months

5. Age 18 years or older

6. Disease measurable by FDG-PET that meets iWNHL size criteria (>1.5cm in longest
diameter for lymph node or nodal mass, or >1.0cm in longest diameter for extranodal
disease)

7. For Cohort A, patients must meet institutional eligibility guidelines for autologous
HCT and all of the following

1. Ejection fraction >40% by ECHO or MUGA

2. Pulmonary function testing with corrected DLCO >50% of predicted

3. Charlson Comorbidity Index <6

8. For Cohort B, patients must be considered medically ineligible for autologous HCT by
fulfilling one or more of following.

1. Do not meet inclusion criteria 7a, 7b, or 7c

2. Age >75

3. Any chronic medical condition, treated or untreated, for which the anticipated
risks of autologous HCT are deemed by the investigator to outweigh potential
benefit of autologous HCT.

9. Women of childbearing potential (WOCBP): Must use highly effective method of birth
control during acalabrutinib treatment as well as for 2 days after the last dose of
acalabrutinib Highly effective forms of contraception are defined in Section F13.

10. Willing and able to participate in all required evaluations and procedures in this
study protocol including swallowing capsules without difficulty.

11. Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use protected health information (in accordance
with national and local subject privacy regulations).

Exclusion Criteria:

1. Inadequate organ function, including the following

1. Hematologic: ANC <1000/uL, PLT <50,000/uL, and hemoglobin <7.0g/dL. If the
patient is known to have bone marrow involvement with cytopenias directly
attributed to disease, eligibility may be permitted per investigator's
discretion.

2. Hepatic: Total bilirubin ≥ 2.0 x ULN unless bilirubin elevation is due to
Gilbert's syndrome or of non-hepatic origin. Alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) ≥ 3 x upper limit of normal (ULN)

3. Renal: Estimated creatinine clearance of < 29 mL/min, calculated using the
formula of Cockcroft and Gault [(140-Age) • Mass (kg)/(72 • creatinine mg/dL);
multiply by 0.85 if female].

4. GI: Malabsorption syndrome or gastrointestinal disease that limits oral
absorption of medication

2. Prior history of autologous or allogeneic HCT

3. Any known contraindication to ifosfamide, etoposide, carboplatin, or rituximab

4. Active chronic hepatitis B infection, defined by positive Hep B DNA PCR.

5. Active chronic hepatitis C infection, defined by positive Hep C RNA PCR

6. Requires treatment with a strong CYP3A inhibitor/inducer

7. Any history of known significant bleeding diathesis

8. History of stroke or intracranial hemorrhage within 6 months before the first dose of
study drug.

9. Pregnant or breastfeeding

10. Any uncontrolled active fungal, bacterial, or viral systemic infection that is
untreated or not responsive to antimicrobial therapy.

11. Any life-threatening illness, medical condition, or organ system dysfunction which, in
the investigator's opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.

12. Uncontrolled HIV/AIDS. Patients who are HIV positive, but clinically stable and
compliant with HAART >3months and with CD4 >200 may be considered for eligibility at
the investigators discretion unless taking excluded strong CYP3A inhibitor/inducer

13. Prior exposure to a BTK inhibitor

14. Prior malignancy (other than DLBCL or indolent NHL), except for adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from
which the subject has been disease free for ≥ 2 years or which will not limit survival
to < 2 years. Note: these cases must be discussed with the principal investigator

15. Known central nervous system metastases and/or carcinomatous meningitis. Brain
metastases, but not carcinomatous meningitis, are allowed if they had been previously
treated (either surgically resected or by radiation therapy) and had remained stable
by repeat imaging ≥ 4 weeks after treatment before enrolling on this protocol.

16. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
congestive heart failure, or myocardial infarction within 6 months of screening, or
any Class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification, or corrected QT interval (QTc) > 500 msec at screening (By
Fridericia's formula). Atrial fibrillation that is controlled or considered stable by
the investigator is permitted.

17. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
screening.

18. Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.

19. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving
proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible
for enrollment to this study.

20. Major surgical procedure within 28 days of first dose of study drug. Note: If a
subject had major surgery, they must have recovered adequately from any toxicity
and/or complications from the intervention before the first dose of study drug.

21. Subject has received anti-cancer therapy within a period of 14 days or 5 half-lives
(whichever is shorter) or radiotherapy within 28 days of first dose of study drug.

22. Concurrent participation in another therapeutic clinical trial.