Conditions: Mantle Cell Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
This study is designed to evaluate the efficacy and safety of acalabrutinib plus bendamustine and rituximab followed by acalabrutinib plus cytarabine and rituximab in subjects with treatment naïve mantle cell lymphoma (MCL), as a preparation for a larger cooperative group trial with the goal of achieving a standard induction regimen for MCL in transplant eligible patients. The investigators hypothesize that the addition of acalabrutinib to BR/CR regimen will prove safe and increase the complete response (CR) rate as well as minimal residual disease (MRD) negativity pre-transplant, thus improving clinical outcomes.

Detailed description:

Arms:
arm 1: * Patients will receive (6) 28 day cycles
* Cycles 1-3 will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28.
* Cycles 4-6 will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard
* After Cycle 6, patients will undergo leukapheresis

Interventions: intervention 1: Bendamustine intervention 2: Rituximab intervention 3: Acalabrutinib intervention 4: Cytarabine intervention 5: Leukapheresis intervention 6: Peripheral blood intervention 7: Oral rinse intervention 8: Bone marrow collection
Intervention descriptions: intervention 1: Bendamustine will be administered at a dose of 90 mg/m\^2 IV over 30 minutes on Days 1 and 2 of Cycles 1-3 intervention 2: In Cycle 1, rituximab will be administered at a dose of 375 mg/m\^2 IV on Day 1 or 2 at the investigator's discretion in order to reduce the risk of a first infusion reaction. Rituximab will be given on Day 1 of Cycles 1 through 6. intervention 3: The capsules should be swallowed intact with water and with or without food. intervention 4: On Days 1 and 2 of Cycles 4-6, following rituximab dosing, cytarabine will be administered IV every 12 hours for a total of 4 doses. intervention 5: Until collection of ≥ 2 x 106 CD34+ stem cells / kg intervention 6: -Baseline, end of Cycle 3, 4-6 weeks after Cycle 6 Day 1, and if the patient discontinues protocol therapy prior to completion of Cycle 6 intervention 7: -Baseline intervention 8: -Bone marrow will be collected at baseline if the patient requires a marrow for staging purposes and at end of treatment if the patient requires a marrow for restaging.

Protocol document:
Prot_SAP_000.pdf: 
      
 
 
Protocol Clarification Letter 
October 18, 2019 
Protocol 201809111 
“A pilot study of acalabrutinib with alternating cycles of bendamustine / rituximab and cytarabine / 
rituximab for untreated mantle cell lymphoma” 
The purpose of this letter is clarify the intent of the protocol. 
10.0 Study Calendar  
 
The protocol currently reads: 
 
Tests and observations 
Baseline 
examination1 
Treatment phase2 
EOT17 
Follow-up3 
Informed consent 
X 
 
 
 
Physical exam 
X 
X 
 
 
Medical history 
X 
 
 
 
Medication Review18 
X 
X 
 
 
Performance status 
X 
 
 
 
Toxicity assessment4 
X 
X 
X15 
 
Pill diary 
 
X 
 
 
Review of medical record for 
progression and survival 
 
 
 
X 
Laboratory Studies 
 
 
 
 
CBC with differential5 
X 
X 
 
 
CMP6 
X 
X 
 
 
Uric acid 
X 
X 
 
 
LDH 
X 
X 
 
 
Serum pregnancy test 7 
X 
 
 
 
HIV-1/2 antibody 
X 
 
 
 
Hepatitis B surface antigen, 
surface antibody, and core 
antibody8 
X 
 
 
 
Hepatitis C antibody9 
X 
 
 
 
MIPI score10 
X 
 
 
 
PET11 
X 
X 
X 
 
Bone marrow aspiration and 
biopsy12 
X 
X 
X 
 
EKG 
X 
 
 
 
Correlative Studies 
Ki-67 (WU pathology review)13 
X 
 
 
 


      
 
Blood for immune biomarkers14 
X 
X 
X 
 
Lymphoma tissue for genomic 
alterations and MRD assessment 
X 
 
 
 
Oral rinse 
X 
 
 
 
Blood for MRD assessment14 
X 
X 
X 
 
Bone marrow aspiration for 
research16 
X 
X12 
 
 
Notes:  
1. All baseline examinations are to be performed within 28 days of the start of therapy 
2. Treatment phase begins with first dose of acalabrutinib (Day 1). Tests, observations, and laboratory studies will 
be performed on Day 1 of each cycle. 
3. The frequency of follow-up after completion of protocol treatment is per investigator’s discretion. Review of the 
medical record will occur on an every 6-month basis for 5 years from study entry to collect data on relapse and 
survival.  
4. Only toxicities which worsen from baseline need be collected, and only the worst grade per cycle need be 
recorded.  Toxicity will be assessed from time of treatment initiation until the end-of-study restaging visit, 
approximately one month after the last dose of chemotherapy. 
5. CBC with differential will be performed on Day 1 each cycle. On cycles 1, 3, and 5 the CBC will be repeated between 
day 10 and day 14. On cycles 2, 4, and 6 the CBC will be repeated at least twice between days 8-14 and twice between 
days 15-21.  
6. CMP will be performed during screening and on Day 1 of each cycle 
7. For women of child bearing potential.  Perform within 14 days of study entry. 
8. Subjects who are hepatitis B core antibody positive but surface antigen negative will need negative polymerase 
chain reaction (PCR) prior to enrollment. Hepatitis B surface antigen positive or PCR positive patients are ineligible. 
9. Subjects who are hepatitis C antibody positive will need negative PCR prior to enrollment. Patients with PCR 
positive hepatitis C are ineligible. 
10. The mantle cell IPI (MIPI) calculator can be accessed at http://www.european-mcl.net/en/clinical_mipi.php 
11. PET scans are required for every restaging scan while on protocol. PET scans will be performed at baseline, after 
Cycle 3, and after Cycle 6.  Patients who come off treatment early for reasons other than progression who are 
suspected to be responders should have an EOT assessment with PET imaging. 
12. Bone marrow aspirate will be collected at baseline if the patient has not already had a bone marrow biopsy 
performed prior to enrolling to the study. If marrow is involved at baseline, repeat bone marrow aspiration and 
biopsy is required after 6 cycles of chemotherapy.  Patients who come off treatment early for reasons other than 
progression who are suspected to be responders should have an EOT bone marrow aspiration and biopsy if they had 
a baseline assessment.  
13. Pathology review of the patient’s baseline diagnostic tissue, including lymph node, bone marrow biopsy, or 
blood, will include an immunohistochemical assessment of Ki-67. If the Ki-67 is already available in the WU pathology 
report at time of screening, the test does not need to be repeated. The result is not required at the time of patient 
enrollment.  
14. Peripheral blood will be collected at baseline, end of Cycle 3, 4-6 weeks after Cycle 6 Day 1, and at discontinuation 
of treatment (if prior to Cycle 6). See Section 9.0.  
15. Adverse events will be tracked for 30 days after the last dose of study treatment.  Refer to Section 7.6 for details.  
If the investigator becomes aware of any SAEs or deaths that are causally attributed to acalabrutinib after the 30-
day time period, they must be reported to AstraZeneca. 
16. Only if required clinically. 
17. End of treatment visit will take place 4-6 weeks after Cycle 6 Day 1. 
18. Medication review at baseline and at Day 1 of each cycle to verify that patients is not taking PPIs or CYP3A4 
inhibitor/inducers.  
 
We wanted to clarify how the protocol criteria is implemented: 


      
 
 
Tests and observations 
Baseline 
examination1 
Treatment phase2 
EOT18 
Follow-up3 
Informed consent 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
 
Medical history 
X 
 
 
 
Medication Review19 
X 
X 
 
 
Performance status 
X 
 
 
 
Toxicity assessment4 
X 
X 
X16 
 
Pill diary 
 
X 
 
 
Review of medical record for 
progression and survival 
 
 
 
X 
Laboratory Studies 
 
 
 
 
CBC with differential5 
X 
X 
 
 
CMP6 
X 
X 
 
 
Uric acid 
X 
X 
 
 
LDH 
X 
X 
 
 
Serum pregnancy test 7 
X 
 
 
 
HIV-1/2 antibody 
X 
 
 
 
Hepatitis B surface antigen, 
surface antibody, and core 
antibody8 
X 
 
 
 
Hepatitis C antibody9 
X 
 
 
 
MIPI score10 
X 
 
 
 
PET11 
X 
X 
X 
 
Bone marrow aspiration and 
biopsy12 
X 
X 
X 
 
EKG 
X 
 
 
 
Treatment Administration 
 
C 1 – 3 
C 4 - 6 
 
 
Acalabrutinib  
 
X 
X 
 
 
Rituximab  
 
X 
X 
 
 
Bendamustine  
 
X 
 
 
 
Cytarabine  
 
 
X 
 
 
Growth Factor13  
 
 
X 
 
 
Correlative Studies 
Ki-67 (WU pathology review)14 
X 
 
 
 
Blood for immune biomarkers15 
X 
X 
X 
 
Lymphoma tissue for genomic 
alterations and MRD assessment 
X 
 
 
 
Oral rinse 
X 
 
 
 
Blood for MRD assessment14 
X 
X 
X 
 
Bone marrow aspiration for 
research17 
X 
X12 
 
 
Notes:  


      
 
1. All baseline examinations are to be performed within 28 days of the start of therapy 
2. Treatment phase begins with first dose of acalabrutinib (Day 1). Tests, observations, and laboratory studies will 
be performed on Day 1 of each cycle. 
3. The frequency of follow-up after completion of protocol treatment is per investigator’s discretion. Review of the 
medical record will occur on an every 6-month basis for 5 years from study entry to collect data on relapse and 
survival.  
4. Only toxicities which worsen from baseline need be collected, and only the worst grade per cycle need be 
recorded.  Toxicity will be assessed from time of treatment initiation until the end-of-study restaging visit, 
approximately one month after the last dose of chemotherapy. 
5. CBC with differential will be performed on Day 1 each cycle. On cycles 1 - 3 the CBC will be repeated between day 
10 and day 14. On cycles 4 - 6 the CBC will be repeated at least twice between days 8-14 and twice between days 
15-21.  
6. CMP will be performed during screening and on Day 1 of each cycle 
7. For women of child bearing potential.  Perform within 14 days of study entry. 
8. Subjects who are hepatitis B core antibody positive but surface antigen negative will need negative polymerase 
chain reaction (PCR) prior to enrollment. Hepatitis B surface antigen positive or PCR positive patients are ineligible. 
9. Subjects who are hepatitis C antibody positive will need negative PCR prior to enrollment. Patients with PCR 
positive hepatitis C are ineligible. 
10. The mantle cell IPI (MIPI) calculator can be accessed at http://www.european-mcl.net/en/clinical_mipi.php 
11. PET scans are required for every restaging scan while on protocol. PET scans will be performed at baseline, after 
Cycle 3, and after Cycle 6.  Patients who come off treatment early for reasons other than progression who are 
suspected to be responders should have an EOT assessment with PET imaging. 
12. Bone marrow aspirate will be collected at baseline if the patient has not already had a bone marrow biopsy 
performed prior to enrolling to the study. If marrow is involved at baseline, repeat bone marrow aspiration and 
biopsy is required after 6 cycles of chemotherapy.  Patients who come off treatment early for reasons other than 
progression who are suspected to be responders should have an EOT bone marrow aspiration and biopsy if they had 
a baseline assessment.  
13 Growth factors may be initiated during cycles 1-3 at the discretion of the treating physician per institutional 
guidelines.  Mandatory growth factors will be administered as per institutional guidelines within 72 hours of 
completion of cycles 4-6 of chemotherapy.  On-body injector may be used at the discretion of the treating physician.   
14. Pathology review of the patient’s baseline diagnostic tissue, including lymph node, bone marrow biopsy, or 
blood, will include an immunohistochemical assessment of Ki-67. If the Ki-67 is already available in the WU pathology 
report at time of screening, the test does not need to be repeated. The result is not required at the time of patient 
enrollment.  
15. Peripheral blood will be collected at baseline, end of Cycle 3, 4-6 weeks after Cycle 6 Day 1, and at discontinuation 
of treatment (if prior to Cycle 6). See Section 9.0.  
16. Adverse events will be tracked for 30 days after the last dose of study treatment.  Refer to Section 7.6 for details.  
If the investigator becomes aware of any SAEs or deaths that are causally attributed to acalabrutinib after the 30-
day time period, they must be reported to AstraZeneca. 
17. Only if required clinically. 
18. End of treatment visit will take place 4-6 weeks after Cycle 6 Day 1. 
19. Medication review at baseline and at Day 1 of each cycle to verify that patients is not taking PPIs or CYP3A4 
inhibitor/inducers.  
 
This language clarification will be updated in the next protocol amendment.  
If you have any questions, please contact me or the regulatory coordinator (Danielle Rancilio, 
dmrancilio@wustl.edu, 314-286-1198).  
 


      
 
Regards, 
 
Brad Kahl, MD 
Medical Oncology 
Washington University in Saint Louis School of Medicine 
660 South Euclid, Box 8056 
St. Louis, MO 63110 
Tel: (314) 747-7222 
E-mail: bkahl@wustl.edu  


Protocol Version: 07/31/19 
 
Page 1 of 49 
 
 
 
A pilot study of acalabrutinib with bendamustine / rituximab followed by cytarabine / 
rituximab for untreated mantle cell lymphoma 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201809111 
Version Date: 07/31/19 
 
 
Principal Investigator: 
Brad S. Kahl, M.D. 
Phone: 314-273-3591 
E-mail: bkahl@wustl.edu  
 
Sub-Investigators 
 
 
 
 
Modality 
Nancy Bartlett, M.D.  
 
 
 
Medical Oncology 
Amanda F. Cashen, M.D.  
 
 
 
Medical Oncology 
Todd Fehniger, M.D., Ph.D.   
 
 
Medical Oncology 
Armin Ghobadi, M.D.  
 
 
 
Medical Oncology 
Daniel Guy, M.D.  
 
 
 
 
Medical Oncology 
Neha Mehta-Shah, M.D.  
 
 
 
Medical Oncology 
Fei Wan, Ph.D.  
 
 
 
 
Biostatistics 
 
Study Drug(s): 
 
Acalabrutinib 
Bendamustine 
Cytarabine 
Rituximab 
 
IND #: 
140805 
ClinicalTrials.gov #: 
NCT03623373 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 


Protocol Version: 07/31/19 
 
Page 2 of 49 
A pilot study of acalabrutinib with bendamustine / rituximab followed by cytarabine / 
rituximab for untreated mantle cell lymphoma 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
09/17/2018 
Amendment #1 Version 
 
 
 
 
 
 
11/05/2018 
Amendment #2 Version 
 
 
 
 
 
 
07/31/2019 
 
 


Protocol Version: 07/31/19 
 
Page 3 of 49 
A pilot study of acalabrutinib with bendamustine / rituximab followed by cytarabine / 
rituximab for untreated mantle cell lymphoma 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Restaging PET Scan 
Treatment Plan- 28 day cycle length 
Cycles 4-6: 
• 
Rituximab 375mg/m2 IV on Day 1 
• 
Cytarabine 2 g/m2 IV q12 hours on Days 1-2 (1.5 g/m2 if over the age of 60) 
• 
Acalabrutinib 100 mg BID on Days 1-7 and 22-28 
• 
Growth factor per protocol 
Leukapheresis 
• 
Growth factor per institutional standards 
• 
Leukapheresis until collection of ≥ 2 x 106 CD34+ stem cells / kg 
Eligible Patients 
Patients 18-70 years old with histologically confirmed, untreated MCL who are eligible for ASCT 
*Rituximab may be administered on Cycle 1 Day 1 or Day 2 at investigator’s discretion in order to limit the risk of first infusion reactions 
Treatment Plan- 28-day cycle length 
Cycles 1-3: 
• 
Bendamustine 90mg/m2 IV on Days 1 and 2 
• 
Rituximab 375mg/m2 IV on Day 1* 
• 
Acalabrutinib 100 mg BID on Days 1-28 
 
Restaging PET Scan +/- Bone Marrow Biopsy/Aspiration 


Protocol Version: 07/31/19 
 
Page 4 of 49 
Table of Contents 
SCHEMA ........................................................................................................................................ 3 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 6 
1.1 
Mantle Cell Lymphoma ................................................................................................... 6 
1.2 
Frontline Therapeutic Options for MCL .......................................................................... 6 
1.3 
Bruton Tyrosine Kinase Inhibition in MCL ..................................................................... 6 
1.4 
Rationale for Combining Acalabrutinib with Alternating Cycles of Bendamustine and 
Rituximab .................................................................................................................................... 7 
2.0 
OBJECTIVES ...................................................................................................................... 8 
2.1 
Primary Objective ............................................................................................................ 8 
2.2 
Secondary Objectives ....................................................................................................... 8 
2.3 
Exploratory Objective ...................................................................................................... 8 
3.0 
PATIENT SELECTION ...................................................................................................... 8 
3.1 
Inclusion Criteria .............................................................................................................. 8 
3.2 
Exclusion Criteria ............................................................................................................. 9 
3.3 
Inclusion of Women and Minorities............................................................................... 11 
4.0 
REGISTRATION PROCEDURES ................................................................................... 11 
4.1 
Confirmation of Patient Eligibility ................................................................................. 11 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 11 
4.3 
Assignment of UPN ....................................................................................................... 12 
5.0 
TREATMENT PLAN ........................................................................................................ 12 
5.1 
WU Pathology Review of Ki-67 .................................................................................... 12 
5.2 
Premedication Administration........................................................................................ 12 
5.3 
Agent Administration ..................................................................................................... 13 
5.4 
Definitions of Evaluability ............................................................................................. 14 
5.5 
General Concomitant Medication and Supportive Care Guidelines .............................. 14 
5.6 
Women of Childbearing Potential .................................................................................. 15 
5.7 
Duration of Therapy ....................................................................................................... 16 
5.8 
Duration of Follow-up .................................................................................................... 16 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 17 
6.1 
Criteria for Initiating a New Cycle ................................................................................. 17 
6.2 
Guidelines for Dose Modification and Discontinuation for Acalabrutinib .................... 17 
6.3 
Guidelines for Dose Modifications and Discontinuation for Bendamustine / Rituximab
 
18 
6.4 
Guidelines for Dose Modifications and Discontinuation for Cytarabine / Rituximab ... 21 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 23 
7.1 
Definitions ...................................................................................................................... 23 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
25 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 26 
7.4 
Reporting to Acerta ........................................................................................................ 26 
7.5 
Reporting to the FDA ..................................................................................................... 26 
7.6 
Timeframe for Reporting Required Events .................................................................... 27 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 27 
8.1 
Acalabrutinib .................................................................................................................. 27 


Protocol Version: 07/31/19 
 
Page 5 of 49 
8.2 
Cytosine Arabinoside ..................................................................................................... 30 
8.3 
Rituximab ....................................................................................................................... 31 
8.4 
Bendamustine ................................................................................................................. 32 
9.0 
CORRELATIVE STUDIES .............................................................................................. 33 
9.1 
Lymphoma Tissue Collection ........................................................................................ 33 
9.2 
Non-Malignant Oral Rinse Collection ........................................................................... 34 
9.3 
Peripheral Blood Collection ........................................................................................... 34 
9.4 
Bone Marrow Collection ................................................................................................ 34 
9.5 
Sample Storage ............................................................................................................... 35 
10.0 STUDY CALENDAR ....................................................................................................... 36 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 38 
12.0 MEASUREMENT OF EFFECT........................................................................................ 38 
12.1 Antitumor Effect ............................................................................................................ 38 
12.2 Methods for Evaluation of Measurable Disease ............................................................ 39 
12.3 Criteria for extranodal involvement(18) ........................................................................ 39 
12.4 Response Assessment ..................................................................................................... 39 
13.0 DATA AND SAFETY MONITORING ............................................................................ 41 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 41 
15.0 REFERENCES .................................................................................................................. 43 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 46 
APPENDIX B: PATIENT’S MEDICATION DIARY – ODD CYCLES .................................... 47 
APPENDIX C: PATIENT’S MEDICATION DIARY – EVEN CYCLES .................................. 48 
APPENDIX D: Known Strong in Vivo Inhibitors or Inducers of CYP3A .................................. 49 
 
 


Protocol Version: 07/31/19 
 
Page 6 of 49 
1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Mantle Cell Lymphoma 
 
Mantle cell lymphoma (MCL) is an incurable aggressive subtype of non-Hodgkin 
lymphoma (NHL) comprising approximately 7% of all adult NHL. Translocation t(11;14) 
and overexpression of cyclin D1 are the defining genetic characteristics in MCL, 
facilitating malignant transformation by dysregulation of the cell cycle (Rimokh 1994). 
Cyclin D1 is not expressed in normal B lymphocytes.  
 
The incidence of MCL is approximately 4-8 cases per million persons per year, and 
increases with age. The median age at diagnosis is 65 years and patients typically present 
with advanced stage disease with associated bone marrow and blood involvement (Argatoff 
1997, Bosch 1998). While combination chemotherapy and stem-cell transplant provide 
high response rates in the frontline setting, most of these patients eventually relapse and 
die from their disease (Romaguera 2010). Median OS from initial diagnosis varies from 18 
to 61 months depending on prognostic risk category at baseline (Hoster 2008). Median PFS 
for relapsed MCL varies from 4 to 14 months (Wang 2013, Goy 2013). Thus, more 
effective frontline regimens for MCL are needed.  
 
1.2 
Frontline Therapeutic Options for MCL 
 
To date there is no standard induction regimen for MCL and it remains an incurable disease 
with conventional therapy. The use of autologous stem cell transplantation in first 
remission is associated with an improvement in progression-free survival and thus 
conventional chemoimmunotherapy (e.g rituximab / cyclophosphamide / doxorubicin / 
vincristine / prednisone [R-CHOP], rituximab / cyclophosphamide / vincristine / 
prednisone [R-CVP], benadmustine / rituximab [BR]) followed by autologous transplant 
is generally the preferred therapeutic approach. 
 
Several trials have shown an important role for cytarabine-based regimens prior to 
autologous transplant. To date the treatments associated with the longest PFS are the 
cytarabine and ASCT containing regimens from the Nordic MCL2 (Geisler 2012, Eskelund 
2016) and the European Mantle Cell Lymphoma Network (Hermine et al, 2016), with 
median PFS of 8.5 years. Both of these regimens use R-CHOP as a component of therapy. 
However, it now has been shown in two randomized Phase 3 studies (the StIL trial and the 
BRIGHT trial) that bendamustine-rituximab (BR) was superior to R-CHOP in terms of CR 
rates and longer PFS with no increase in toxicity (Rummel 2013, Flinn 2014). In fact, a 
recently published phase II study of BR for 3 cycles followed by rituximab/high dose 
cytarabine for 3 cycles has shown impressive CR and MRD negativity (90%) rates in a 
small cohort of transplant-eligible patients (Armand 2016).   
 
1.3 
Bruton Tyrosine Kinase Inhibition in MCL 
 
Bruton tyrosine kinase (Btk) is a non-receptor enzyme in the Tec kinase family that is 
expressed among cells of hematopoietic origin, including B-cells, myeloid cells, mast cells, 


Protocol Version: 07/31/19 
 
Page 7 of 49 
and platelets, where it regulates multiple cellular processes including proliferation, 
differentiation, apoptosis, and cell migration (Khan 2001, Mohamed 2009, Bradshaw 
2010).  In addition, Btk-dependent activation of mast cells, myeloid cells, and other 
immunocytes in peritumoral inflammatory stroma has been shown to sustain the complex 
microenvironment needed for lymphoid and solid tumor maintenance (Soucek 2011, 
Ponader 2012, de Rooij 2012).  Taken together, these findings suggest inhibition of Btk 
may offer an attractive strategy for treating B-cell neoplasms, other hematologic 
malignancies, and solid tumors. 
 
Several studies have shown that targeting the B-cell receptor (BCR) signaling pathway by 
inhibiting Bruton tyrosine kinase (BTK) produces significant clinical benefit in patients 
with NHL, including MCL. Ibrutinib, has demonstrated substantial efficacy in patients with 
relapsed MCL based on data from a single-arm Phase 2 study of 111 patients (Wang 2013). 
Recent data from a Phase 1/1b study of ibrutinib plus BR, which included 17 patients with 
previously untreated or relapsed or refractory (R/R MCL), recently reported a CR rate of 
76% (Maddocks 2015). A randomized Phase 3 study of frontline ibrutinib plus BR in 
patients with MCL is currently ongoing (clinicaltrials.gov; NCT01776840). 
 
1.4 
Rationale for Combining Acalabrutinib with Cycles of Bendamustine and 
Rituximab followed by acalabrutinib with cycles of cytarabine and rituximab 
 
As previously mentioned, a recently published phase II study of BR for 3 cycles followed 
by rituximab/high dose cytarabine for 3 cycles has shown impressive CR and MRD 
negativity (90%) rates in a small cohort of transplant-eligible patients (Armand 2016).  
To maintain excellent results and improve tolerability, Washington University (Kahl – PI) 
has piloted a regimen of BR with alternating cycles of high dose cytarabine –rituximab 
(CR). Results were as expected, with all patients successfully completing stem cell 
collections (NCT02728531). We have pooled our results with the Dana-Farber Cancer 
Institute (DFCI) trial and this combined experience has been submitted for publication. The 
pooled experience suggests similar tolerability between the DFCI approach and the Wash 
U approach. However, the DFCI approach is simpler with regards to management of 
toxicities and dose modificaitons. Therefore, we plan to adopt the DFCI version of the 
regimen for combination with novel agents. The most promising novel agent in MCL is 
acalabrutinib.  
 
Acalabrutinib was specifically designed to be a more potent and selective inhibitor of BTK, 
and unlike ibrutinib, does not inhibit ITK and TXK, 2 members of the Tec kinase family 
(Covey 2015). Preclinical data indicates that this lack of inhibition against ITK and TXK 
may preserve natural killer (NK) cell function, and therefore may offer the potential for 
better synergy with rituximab (Rajasekaran 2014).   
 
Recently a phase 2 study of acalabrutinib as monotherapy in relapsed/refractory MCL 
(ACE-LY-004 study) has shown high ORR (81%) as well as CR (40%) with durable and 
clinically meaningful responses (at 15.2 months median PFS and OS not yet reached). This 
combined with a favorable safety profile, with a low frequency and severity of adverse 
events and few discontinuations due to AE. (Wang 2017).  Other trials involving 


Protocol Version: 07/31/19 
 
Page 8 of 49 
acalabrutinib in combination with BR (NCT02717624) and with rituximab 
(NCT02180711) are ongoing providing safety data for the combination of acalabrutinib 
with these regimens.  
 
Our pilot study is designed to evaluate the efficacy and safety of acalabrutinib plus BR 
followed by acalabrutinib plus CR in subjects with treatment naïve MCL, as a preparation 
for a larger cooperative group trial with the goal of achieving a standard induction regimen 
for MCL in transplant eligible patients. We hypothesize that the addition of acalabrutinib 
to BR/CR regimen will prove safe and increase the CR rate as well as MRD negativity pre-
transplant, thus improving clinical outcomes. 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the stem cell mobilization success rate in subjects with MCL treated with 
acalabrutinib combined with the regimen of bendamustine and rituximab and cytarabine 
and rituximab. Stem cell mobilization success is defined as a yield of >2x106 CD34+ stem 
cells/kg with a maximum of 5 courses of apheresis. 
 
2.2 
Secondary Objectives 
 
1. To determine the safety and tolerability of acalabrutinib plus BR/CR in subjects with 
MCL. 
2. To estimate the overall response rate (ORR = CR + PR) of subjects with MCL treated 
with acalabrutinib plus BR/CR. 
3. To estimate the pre-transplant complete response rate of subjects with MCL treated 
with acalabrutinib plus BR/CR. 
4. To estimate the progression-free survival (PFS) of subjects with MCL treated with 
acalabrutinib plus BR/CR. 
5. To estimate the overall survival (OS) of subjects with MCL treated with acalabrutinib 
plus BR/CR. 
 
2.3 
Exploratory Objective 
 
To assess MRD negativity throughout and after completion of induction therapy. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically confirmed mantle cell lymphoma with documented expression of Cyclin 
D1 by immune-histochemical stains and/or t(11;14) by cytogenetics or FISH. 
 


Protocol Version: 07/31/19 
 
Page 9 of 49 
2. Presence of evaluable disease by PET imaging per the Lugano classification. 
 
3. Eligible for autologous stem cell transplantation. 
 
4. Between 18 and 70 years of age, inclusive. 
 
5. ECOG performance status ≤ 2 (see Appendix A) 
 
6. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,000/mcL unless, in the opinion of the treating 
physician, neutropenia is due to splenomegaly or bone marrow involvement 
b. Platelets ≥ 100,000/mcL unless, in the opinion of the treating physician, 
thrombocytopenia is due to splenomegaly or bone marrow involvement 
c. Total bilirubin ≤ 2.0 x IULN and AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN except 
when, in the opinion of the treating physician, elevation is due to direct involvement 
of lymphoma (e.g. hepatic infiltration or biliary obstruction due to lymphoma) or 
Gilbert’s disease 
d. Creatinine ≤ IULN OR creatinine clearance ≥ 40 mL/min for patients with 
creatinine levels above institutional normal 
 
7. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she must inform her treating physician 
immediately. 
 
8. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Any previous chemotherapy or radiation for mantle cell lymphoma.  Short course of 
steroids for symptom relief prior to presentation is permissible. 
 
2. Symptomatic meningeal or parenchymal brain lymphoma. 
 
3. Prior exposure to a BTK inhibitor. 
 
4. Currently receiving any other investigational agents. 
 
5. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to acalabrutinib, rituximab, cytarabine, bendamustine, or other agents 
used in the study. 
 
6. Received a live virus vaccination within 28 days of first dose of study drug. 
 


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7. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as 
exhibiting ongoing signs/symptoms related to the infection and without improvement, 
despite appropriate antibiotics or other treatment), or intravenous anti-infective 
treatment within 2 weeks before first dose of study drug. 
 
8. Clinically 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) > 480 msec at 
screening.  Exception: subjects with controlled, asymptomatic atrial fibrillation during 
screening are allowed to enroll on study. 
 
9. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach or small bowel that is likely to affect absorption, symptomatic 
inflammatory bowel disease, partial or complete bowel obstruction, or gastric 
restrictions and bariatric surgery, such as gastric bypass. 
 
10. Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand 
disease). 
 
11. Uncontrolled 
AIHA 
(autoimmune 
hemolytic 
anemia) 
or 
ITP 
(idiopathic 
thrombocytopenic purpura). 
 
12. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before 
screening. 
 
13. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 
 
14. Requires or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug. 
 
15. Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) >2x ULN. 
Exception: Subjects receiving warfarin are excluded; however, those receiving other 
anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this 
study after discussion with the PI.  
 
16. Requires treatment with proton pump inhibitors (e.g., 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. 
 
17. History of significant cerebrovascular disease/event, including stroke or intracranial 
hemorrhage, within 6 months before the first dose of study drug. 
 
18. 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 


Protocol Version: 07/31/19 
 
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complications from the intervention before the first dose of study drug. 
 
19. Subjects with serologic status reflecting active viral hepatitis B or C infection.  Subjects 
who are hepatitis B core antibody positive but surface antigen negative will need 
negative polymerase chain reaction (PCR) prior to enrollment.  Hepatitis B surface 
antigen positive or PCR positive patients will be excluded.  Subjects who are hepatitis 
C antibody positive will need negative PCR prior to enrollment.  Subjects with positive 
hepatitis C PCR will be excluded. 
 
20. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
serum pregnancy test within 14 days of study entry. 
 
21. Known HIV-positivity on combination antiretroviral therapy because of the potential 
for pharmacokinetic interactions with acalabrutinib.  In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 


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4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
Consenting and eligible patients (people aged 18 to 70 with histologically confirmed, untreated 
MCL who are eligible for ASCT) will receive six 28-day cycles of treatment.  Cycles 1-3 will 
consist of bendamustine 90 mg/m2 on Days 1 and 2, rituximab 375 mg/m2 on Day 1, and 
acalabrutinib 100 mg BID on Days 1 through 28.  Cycles 4-6 will consist of rituximab 375 mg/m2 
on Day 1, cytarabine 2 g/m2 (1.5 g/m2 if over the age of 60) q12 hours on Days 1 and 2, 
acalabrutinib 100 mg BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, 
one week on), and growth factors as per institutional standard.  After Cycles 3 and 6, patients will 
be restaged.  After Cycle 6, patients will undergo leukapheresis for the collection of at least 2 x 
106 CD34+ stem cells/kg.  The purpose of this study is to determine the stem cell mobilization 
success rate in these patients. 
 
5.1 
WU Pathology Review of Ki-67 
 
As per institutional practice, WU pathologists will review all in-house and outside 
diagnostic specimens available for each patient prior to treatment. In addition to 
histological confirmation of mantle cell lymphoma, Ki-67 will be assessed by 
immunohistochemistry at baseline. The Ki-67 proliferative index is a biologic marker with 
prognostic significance in advanced-stage MCL. If Ki-67 staining was performed at an 
outside facility, it will not need to be repeated at Washington University. 
 
5.2 
Premedication Administration 
 
For acalabrutinib: No specific premedications or supporting medications are required in 
conjunction with acalabrutinib administration.  
 
For rituximab: Pre-medicate before each infusion with acetaminophen and an antihistamine 
in accordance with prescribing information or institutional standards. 
 
For bendamustine: Institutional standards for antiemetic prophylaxis should be followed. 
Consider antipyretic and antihistamine prophylaxis for subjects with a previous Grade 1 or 
2 infusion reaction to bendamustine. 
 
For cytarabine: No specific premedications are required in conjunction with cytarabine. 
See below discussion for supportive care discussion. 
 


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5.3 
Agent Administration 
 
5.3.1 Acalabrutinib 
 
Acalabrutinib is an oral drug taken twice per day at a dose of 100 mg approximately 
every 12 hours on every day of each 28-day cycle during Cycles 1-3 and on Days 
1 through 7 and 22 through 28 during Cycles 4-6. The capsules should be 
swallowed intact with water and with or without food.  Subjects should not attempt 
to open capsules or dissolve them in water.  Compliance will be assessed through 
use of a medication diary (Appendices B and C). 
 
If a dose is missed, it can be taken up to 3 hours after the scheduled time with a 
return to the normal schedule with the next dose.  If it has been > 3 hours, the dose 
should not be taken and the subject should take the next dose at the scheduled time.  
The missed dose will not be made up and must be returned to the site at the next 
scheduled visit. 
 
Guidance on co-administration of acalabrutinib with agents that affect gastric pH 
is provided below. 
 
On days when other drugs are administered, they may be given before or after the 
first acalabrutinib dose of the day. 
 
5.3.2 Bendamustine 
 
Bendamustine will be administered at a dose of 90 mg/m2 IV over 30 minutes on 
Days 1 and 2 of Cycles 1-3.  (Rate of administration may vary according to 
institutional standards.) 
 
5.3.3 Rituximab 
 
In Cycle 1, rituximab will be administered at a dose of 375 mg/m2 IV on Day 1 or 
2 at the investigator’s discretion in order to reduce the risk of a first infusion 
reaction.  Rituximab will be given on Day 1 of Cycles 2 through 6.  The rituximab 
infusion may be completed on Day 2 if logistical considerations result in a delay. 
 
5.3.4 Cytarabine 
 
On Days 1 and 2 of Cycles 4-6, for patients up to age 59 cytarabine will be 
administered at a dose of 2 g/m2 IV every 12 hours for a total of 4 doses. Patients 
between ages 60-70 will receive 1.5 g/m2 IV every 12 hours for a total of 4 doses.  
 
 
5.3.5 Growth Factors 
 


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Mandatory growth factors will be administered as per institutional guidelines 
within 72 hours of completion of cycles 4-6 of chemotherapy.  On-body injector 
may be used at the discretion of the treating physician.   
 
Growth factors may be initiated during cycles 1-3 at the discretion of the treating 
physician per institutional guidelines. 
 
5.4 
Definitions of Evaluability 
 
Patients who do not undergo attempted stem cell mobilization will not be evaluable for the 
primary objective and will be replaced. 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion 
of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment prior to 
completion of Cycle 2 and have not had any disease assessment. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Supportive care for prevention of tumor lysis syndrome (hydration, monitoring, etc.) must 
be performed per local institutional guidelines. Additional supportive care (e.g. 
transfusions, prophylactic antibiotics, antifungals and/or antivirals) is also allowed per 
institutional guidelines.  
 
Use of growth factor is required for cycles 4-6.  Growth factors may be initiated during 
cycles 1-3 at the discretion of the treating physician per institutional guidelines. 
 
Prophylactic antiviral medications are obligatory during each cycle.  Prophylactic 
antifungals are optional and may be administered at the discretion of the treating physician.  
PJP prophylaxis is optional and may be administered at the discretion of the treating 
physician. Autologous stem cell transplantation and post-transplant supportive care are not 
part of this study and will be undertaken per institutional standard and at the investigator’s 
discretion. 
 
Co-administration of corticosteroids and corticosteroid-containing eye drops (or 
equivalent) is recommended for patients receiving cytarabine-containing regimens. Eye 
drops should continue for at least 2 days following the last dose of cytarabine.  
 
Antiemetic prophylaxis given per institutional guidelines is recommended. 
 
Allopurinol should be used with caution along with bendamustine in view of potentially 
dangerous drug interactions. 
 


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Management of infusion reactions to rituximab and/or bendamustine will be undertaken as 
per institutional guidelines/standard of care. 
 
5.5.1 Prohibited or Restricted Concomitant Therapy 
 
In addition to the exclusion criteria:  
The concomitant use of strong inhibitors/inducers of CYP3A4 (see Appendix D) 
should be avoided when possible.  If a subject requires a strong CYP3A inhibitor 
while on study, monitor the subject closely for potential toxicities. 
 
Acalabrutinib is not a strong direct inhibitor or inducer or CYP isoforms; thus, 
acalabrutinib, at the currently used clinical doses, is unlikely to be a perpetrator of 
a drug drug interaction at the level of inhibition or induction of CYP isoforms.  
Acalabrutinib is partially metabolized by CYP3A; its exposure is affected when co-
administered with strong CYP3A4 inducers or inhibitors.  Consequently, the 
concomitant use of strong inhibitors/inducers of CYP3A4 (see Appendix D) should 
be avoided when possible.   
 
If medically justified, subjects may be enrolled if such inhibitors or inducers can be 
discontinued or alternative drugs that do not affect these enzymes can be substituted 
within 7 days before first dose of study drug.  If a subject requires a strong CYP3A4 
while on study, monitor the subject closely for potential drug-related toxicities.    
 
The effect of agents that reduce gastric acidity (antacids or proton pump inhibitors) 
on acalabrutinib absorption was evaluated in a healthy volunteer study.  Results 
from this study indicate that subjects should avoid the use of calcium carbonate 
containing drugs or supplements for a period of at least 2 hours before and 2 hours 
after taking acalabrutinib.  Use of omeprazole, esomeprazole, lansoprazole or any 
other proton pump inhibitors while taking acalabrutinib is not recommended due to 
a potential decrease in study drug exposure.  Although the effect of H2-receptor 
antagonists (such as famotidine or ranitidine) on acalabrutinib absorption has not 
been evaluated, if treatment with an H2-receptor antagonist is required, the H2-
receptor antagonist should be taken approximately 2 hours after an acalabrutinib 
dose. 
 
5.6 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative serum pregnancy test within 14 days prior to the first dose of study 
treatment.   
 
Female and male patients (along with their female partners) are required to use highly 
effective contraception (defined as methods with failure rate < 1% per year) during 
participation in the study and for 12 months after last dose of any study drug.  


Protocol Version: 07/31/19 
 
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If a patient is suspected to be pregnant, the study drugs should be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within one month after the last dose of study treatment, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.7 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for 6 
cycles or until one of the following criteria applies: 
 
• Documented and confirmed disease progression based on PET imaging 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.8 
Duration of Follow-up 
 
Refer to Section 7.6 for adverse assessment timeframe. 
 
Patients who have had a response to treatment will be followed clinically as part of routine 
care for 5 years or until death, whichever occurs first. Clinical follow-up frequency will be 
dictated per investigator’s discretion, as per institutional standards. Data pertaining to PFS 
and OS will be collected from the medical record every 6 months for 5 years from study 
entry.  Patients will initially be followed for disease status and development of any new 
malignancies.  If a patient has progressive disease during the 5-year period, s/he will 
thereafter be followed only for survival. 


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Patients stopping protocol therapy early for any reason will be followed for disease status 
by review of the patient’s medical record every 6 months for 5 years from study entry until 
progressive disease or initiation of alternative therapy, whichever occurs first, at which 
point the patient will be followed for survival. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Subjects should be followed closely for AEs or laboratory abnormalities that might indicate 
treatment-related toxicity.  If a subject experiences a treatment-related toxicity or other intolerable 
AE during the course of therapy, the treatment will be held or modified as described in the next 
paragraphs.  
 
6.1 
Criteria for Initiating a New Cycle 
 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if  
• ANC > 1000 (unless neutropenia is due to splenomegaly or marrow involvement 
by MCL). 
• Platelets>100,000 (unless thrombocytopenia is due to splenomegaly or marrow 
involvement by MCL). 
• Any non-hematologic grade 3 or 4 AE that is considered at least possibly related to 
chemotherapy has resolved to Grade 1 or lower. 
 
6.2 
Guidelines for Dose Modification and Discontinuation for Acalabrutinib 
 
Agent 
Starting Dose 
Dose Level -1 
Dose Level -2 
Acalabrutinib 
100mg BID 
100mg QD 
Discontinue 
 
The actions in the table below should be followed for the following drug-related toxicities:  
• Grade 3 or 4 thrombocytopenia in presence of significant bleeding regardless of 
marrow involvement. 
• Grade 4 neutropenia lasting longer than 7 days 
• Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal antiemetic 
and/or anti-diarrheal therapy. 
• Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
 
6.2.1 Drug Modification Actions for Acalabrutinib during BR and CR 
cycles 
 
Occurrence Action 
1st 
Hold acalabrutinib until recovery to Grade ≤1 or baseline; may 
restart at original dose level.  
2nd 
Hold acalabrutinib until recovery to Grade≤1 or baseline; restart 
at one dose level lower (100mg QD).  
3rd 
For non-hematologic AEs, discontinue acalabrutinib. 


Protocol Version: 07/31/19 
 
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For thrombocytopenia with significant bleeding, discontinue 
acalabrutinib.  
For other hematologic AEs, hold acalabrutinib until recovery to 
Grade ≤1 or baseline; restart at one dose level lower (100 mg 
QD). 
4th 
For hematologic AEs, discontinue acalabrutinib.  
 
Acalabrutinib may be held for a maximum of 28 consecutive days from expected 
dose due to toxicity. During this period, appropriate laboratory monitoring should 
be performed per institutional guidelines.  
 
Acalabrutinib should be discontinued in the event of a grade 3 or 4 toxicity 
considered at least possibly related lasting > 28 days.  
 
If acalabrutinib is reduced for apparent treatment-related toxicity, the dose need not 
be re-escalated, even if there is minimal or no toxicity with the reduced dose. 
However, if the subject tolerates a reduced dose of acalabrutinib for ≥ 4 weeks then 
the dose may be increased to the next higher dose level, at the discretion of the 
investigator. Such re-escalation may be particularly warranted if further evaluation 
reveals that the AE that led to the dose reduction was not treatment-related. Any 
changes to the dosing regimen must be recorded in the case report forms.  
 
Acalabrutinib will be held if infusions of rituximab/bendamustine or 
rituximab/cytarabine are being held due to not meeting treatment parameters. 
Acalabrutinib will be restarted once these infusions are restarted in order to begin 
treatment cycles on the same day.  
 
6.3 
Guidelines for Dose Modifications and Discontinuation for Bendamustine / 
Rituximab (Cycles 1-3). 
 
The following dose modifications should be made for grade 4 febrile neutropenia or 
cytopenias discovered on Day 1 of each cycle. Once reduced, dose levels may not be 
escalated.  Of note, rituximab does not require dose reduction for cytopenias or life 
threatening febrile neutropenia. 
 
For AE following bendamustine/rituximab cycles: dose decrease for the next bendamustine 
containing cycles (Cycles 2-3). A patient who requires a dose decrease of bendamustine 
will automatically require a dose decrease for the cytarabine containing cycles (cycles 4-
6) as detailed below under 6.4. 
 
Agent 
Starting Dose 
Dose Level -1 
Dose Level -2 
Bendamustine 
90 mg/m2 
70 mg/m2 
50 mg/m2 
 
6.3.1 Neutropenia 
 


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• For ANC < 1000/mcl on the scheduled Day 1 of each cycle, delay 
bendamustine/rituximab treatment (unless neutropenia is due to marrow 
involvement by MCL) and follow CBC weekly until ANC ≥ 1000/mcl.  
• For patients not receiving G-CSF with the previous bendamustine/rixutimab 
cycle, initiate filgrastim or pegfilgrastim for all subsequent cycles.  No dose 
reduction for subsequent cycles is required if no growth factor was utilized in 
previous cycle. 
• For patients receiving G-CSF with the previous bendamustine/rituximab cycle, 
if ANC recovers to ≥ 1000/mcl within 3 weeks of the scheduled Day 1, resume 
treatment. One dose level reduction will be used for the next 
bendamustine/rituximab cycle. All subsequent cycles will proceed at the 
reduced dose, which may not be re-escalated. Patients who require a dose 
decrease of bendamustine will also require a dose decrease for 
cytarabine/rituximab cycles (Cycles 4-6).  
• There are no dose reductions below dose level -2. If dose reduction below dose 
level -2 is required for neutropenia, discontinue all protocol therapy. 
• If any patient requires treatment delay > 21 days for persistent neutropenia 
despite optimal G-CSF usage, the patient will be removed from the study. 
 
6.3.2 Thrombocytopenia 
 
• For platelets <100,000/mcl on the scheduled Day 1 of each cycle, delay 
bendamustine/rituximab treatment (unless thrombocytopenia is due to marrow 
involvement by MCL) and follow CBC weekly until platelets ≥ 100,000/mcl.  
• If 
platelets 
recover 
to 
≥ 
100,000/mcl 
within 
21 
days, 
resume 
bendamustine/rituximab treatment. One dose level reduction will be used for 
the next bendamustine/rituximab cycle. All subsequent cycles will proceed at 
the reduced dose, which may not be re-escalated. Patients who require a dose 
decrease of bendamustine will also require a dose decrease for 
cytarabine/rituximab cycles (Cycles 4-6).  
• If any patient requires treatment delay > 21 days, the patient will be removed 
from the study. 
• There are no dose reductions below dose level -2. If dose reduction below dose 
level -2 is required for thrombocytopenia, discontinue all protocol therapy. 
 
6.3.3 CTCAE Grade 4 febrile neutropenia 
 
• For CTCAE Grade 4 febrile neutropenia which has resolved in time for next 
cycle, resume bendamustine/rituximab treatment. One dose level reduction will 
be used for the next bendamustine/rituximab cycle. All subsequent cycles will 
proceed at the reduced dose, which may not be re-escalated. Patients who 
require a dose decrease of bendamustine will also require a dose decrease for 
cytarabine/rituximab cycles (Cycles 4-6).  
• For CTCAE Grade 4 febrile neutropenia that has not resolved, hold 
bendamustine/rituximab until fever resolves and ANC is >1000, and then 
resume treatment. One dose level reduction will be used for the next 


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bendamustine/rituximab cycle. All subsequent cycles will proceed at the 
reduced dose, which may not be re-escalated. Patients who require a dose 
decrease of bendamustine will also require a dose decrease for 
cytarabine/rituximab cycles (Cycles 4-6).  
• If patient experiences CTCAE Grade 4 febrile neutropenia at dose level -2, 
protocol therapy should be discontinued.  
• Grade 3 febrile neutropenia does not require dose reductions in chemotherapy. 
 
6.3.4 Non-Infectious Non-hematologic toxicity 
 
• For grade 3-4 non-hematologic toxicity not related to an infection that is 
considered at least possibly, probably, or definitely related to chemotherapy, 
hold bendamustine/rituximab therapy, and follow weekly until toxicity 
improves to grade 1 or less. Delay cycle up to 21 days for resolution of the 
adverse event. Contact the study chair for delays exceeding 21 days.  
• Once 
the 
toxicity 
has 
resolved 
to 
grade 
1 
or 
less, 
resume 
bendamustine/rituximab treatment. One dose level reduction will be used for 
the next bendamustine/rituximab cycle. All subsequent cycles will proceed at 
the reduced dose, which may not be re-escalated. Patients who require a dose 
decrease of bendamustine will also require a dose decrease for 
cytarabine/rituximab cycles (Cycles 4-6).  
• For infusion reactions attributable to rituximab, supportive care should be 
provided per institutional protocols. Rituximab can be continued without dose 
reduction.  
• For Grade 3 or 4 skin reactions or infusion reaction/anaphylaxis at least 
possibly, probably or definitely attributable to bendamustine, bendamustine 
should be permanently discontinued and rituximab may be discontinued as well 
at the discretion of the treating physician. 
 
6.3.5 Infectious non-hematologic Toxicity 
 
• For CTCAE Grade 4 infection, that is considered at least possibly, probably, or 
definitely related to chemotherapy, which has resolved in time for next cycle, 
resume bendamustine/rituximab treatment. One dose level reduction will be 
used for the next bendamustine/rituximab cycle. All subsequent cycles will 
proceed at the reduced dose, which may not be re-escalated. Patients who 
require a dose decrease of bendamustine will also require a dose decrease for 
cytarabine/rituximab cycles (Cycles 4-6).  
• For 
CTCAE 
Grade 
4 
infection 
that 
has 
not 
resolved, 
hold 
bendamustine/rituximab therapy until event resolves and ANC is >1000, and 
then resume treatment. One dose level reduction will be used for the next 
bendamustine/rituximab cycle. All subsequent cycles will proceed at the 
reduced dose, which may not be re-escalated. Patients who require a dose 
decrease of bendamustine will also require a dose decrease for 
cytarabine/rituximab cycles (Cycles 4-6).  
• If patient experiences CTCAE Grade 4 infection at dose level -2, all protocol 


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Page 21 of 49 
therapy (including acalabrutinib) should be discontinued.  
• Infections which are grade 1, 2 or 3 do not require holding or dose reducing 
chemotherapy.  
• Rituximab should be discontinued in the following circumstances: progressive 
multifocal leukoencephalopathy (PML), significant vesicular or bullous 
dermatitis, or Stevens-Johnsons syndrome.  
 
6.4 
Guidelines for Dose Modifications and Discontinuation for Cytarabine / 
Rituximab (Cycles 4-6) 
 
The following dose modifications should be made for grade 4 febrile neutropenia or 
cytopenias discovered on Day 1 of each cycle. Once reduced, dose levels may not be 
escalated.  Of note, rituximab does not require dose reduction for cytopenias or life 
threatening febrile neutropenia. 
 
For AE following cytarabine/rituximab cycles: dose decrease for the next Cytarabine 
containing cycles (Cycles 4-6).  
Patients who required a dose decrease in bendamusine/rituximab cycles will automatically 
require a dose decrease for their cytarabine/rituximab cycles (begin at dose level -1).  
 
Agent 
Starting Dose 
Dose Level -1 
Dose Level -2 
Cytarabine 
2g/m2 
(1.5 g/m2 for patients 60-70) 
1.5 g/m2 
(1.0 g/m2 for patients 60-70) 
1 g/m2 
(0.5 g/m2 for patients 60-70) 
 
6.4.1 Neutropenia 
 
• For ANC < 1000/mcl on the scheduled Day 1 of each cycle, delay 
cytarabine/rituximab treatment (unless neutropenia is due to marrow 
involvement by MCL) and follow CBC weekly until ANC ≥ 1000/mcl.  
• For patients not receiving G-CSF with the previous cytarabine/rituximab cycle, 
initiate filgrastim or pegfilgrastim for all subsequent cycles.  No dose reduction 
for subsequent cycles is required if no growth factor was utilized in previous 
cycle. 
• For patients receiving G-CSF with the previous cytarabine/rituximab cycle, if 
ANC recovers to ≥ 1000/mcl within 3 weeks of the scheduled Day 1, resume 
cytarabine/rituximab treatment. One dose level reduction will be used for the 
next cytarabine/rituximab cycle. All subsequent cycles will proceed at the 
reduced dose, which may not be re-escalated.  
• There are no dose reductions below dose level -2. If dose reduction below dose 
level -2 is required for neutropenia, discontinue all protocol therapy (including 
acalabrutinib). 
• If any patient requires treatment delay > 21 days for persistent neutropenia 
despite optimal G-CSF usage, the patient will be removed from the study. 
 
6.4.2 Thrombocytopenia 
 


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• For platelets <100,000/mcl on the scheduled Day 1 of each cycle, delay 
cytarabine/rituximab treatment (unless thrombocytopenia is due to marrow 
involvement by MCL) and follow CBC weekly until platelets ≥ 100,000/mcl.  
• If 
platelets 
recover 
to 
≥ 
100,000/mcl 
within 
21 
days, 
resume 
cytarabine/rituximab treatment. One dose level reduction will be used for the 
next cytarabine/rituximab cycle. All subsequent cycles will proceed at the 
reduced dose, which may not be re-escalated.  
• If any patient requires treatment delay > 21 days, the patient will be removed 
from the study. 
• There are no dose reductions below dose level -2. If dose reduction below dose 
level -2 is required for thrombocytopenia, discontinue all protocol therapy 
(including acalabrutinib). 
 
6.4.3 CTCAE Grade 4 febrile neutropenia 
 
• For CTCAE Grade 4 febrile neutropenia which has resolved in time for next 
cycle, resume cytarabine/rituximab treatment. One dose level reduction will be 
used for the next cytarabine/rituximab cycle. All subsequent cycles will proceed 
at the reduced dose, which may not be re-escalated.  
• For CTCAE Grade 4 febrile neutropenia that has not resolved, hold 
cytarabine/rituximab therapy until fever resolves and ANC is >1000, and then 
resume cytarabine/rituximab treatment. One dose level reduction will be used 
for the next cytarabine/rituximab cycle. All subsequent cycles will proceed at 
the reduced dose, which may not be re-escalated. If patient experiences CTCAE 
Grade 4 febrile neutropenia at dose level -2, all protocol therapy (including 
acalabrutinib) should be discontinued.  
• Grade 3 febrile neutropenia does not require dose reductions in chemotherapy. 
 
6.4.4 Non-Infectious Non-hematologic toxicity 
 
• For grade 3-4 non-hematologic toxicity not related to an infection that is 
considered at least possibly, probably, or definitely related to chemotherapy, 
hold cytarabine/rituximab therapy, and follow weekly until toxicity improves 
to grade 1 or less. Delay cycle up to 21 days for resolution of the adverse event. 
Contact the study chair for delays exceeding 21 days.  
• Once the toxicity has resolved to grade 1 or less, resume cytarabine/rituximab 
treatment. One dose level reduction will be used for the next 
cytarabine/rituximab cycle. All subsequent cycles will proceed at the reduced 
dose, which may not be re-escalated.  
• For infusion reactions attributable to rituximab, supportive care should be 
provided per institutional protocols. Rituximab can be continued without dose 
reduction.  
 
6.4.5 Infectious non-hematologic Toxicity 
 


Protocol Version: 07/31/19 
 
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• For CTCAE Grade 4 infection, that is considered at least possibly, probably, or 
definitely related to chemotherapy, which has resolved in time for next cycle, 
resume cytarabine/rituximab treatment. One dose level reduction will be used 
for the next cytarabine/rituximab cycle. All subsequent cycles will proceed at 
the reduced dose, which may not be re-escalated.  
• For CTCAE Grade 4 infection that has not resolved, hold cytarabine/rituximab 
therapy until event resolves and ANC is >1000, and then resume 
cytarabine/rituximab treatment. One dose level reduction will be used for the 
next cytarabine/rituximab cycle. All subsequent cycles will proceed at the 
reduced dose, which may not be re-escalated.  
• If patient experiences CTCAE Grade 4 infection at dose level -2, all protocol 
therapy should be discontinued (including acalabrutinib).  
• Infections which are grade 1, 2 or 3 do not require holding or dose reducing 
chemotherapy. 
• Rituximab should be discontinued in the following circumstances: progressive 
multifocal leukoencephalopathy (PML), significant vesicular or bullous 
dermatitis, or Stevens-Johnsons syndrome.  
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 7.2. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in Section 
7.5.  In addition, any fatal or life-threatening adverse experiences where there is a reasonable 
possibility of relationship to study intervention must be reported. 
 
Acerta requires that all events be reported as outlined in Section 7.4. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP website. 
 


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Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
 
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 


Protocol Version: 07/31/19 
 
Page 25 of 49 
the characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 


Protocol Version: 07/31/19 
 
Page 26 of 49 
event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
7.4 
Reporting to AstraZeneca 
 
All SAEs must be reported to AstraZeneca within 7 days of discovery for fatal and life-
threatening reports (15 days for other SAE and special situation reports) and to the IRB. 
AstraZeneca Pharma may request follow-up and other additional information from the 
investigator. 
 
Whenever possible, SAEs should be reported by diagnosis term; not as a constellation of 
symptoms.  All deaths should be reported with the primary cause of death as the AE term, 
as death is typically the outcome of the event, not the event itself.  The primary cause of 
death on the autopsy report should be the term reported.   
 
If study drug is discontinued because of an SAE, this information must be included in the 
SAE report. 
 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the SAE 
is attributable to the investigational product and is not listed in the current Investigator 
Brochure (ie, an unexpected event).   
 
Drug Safety Contact Information 
AZ Patient Safety - TCS 
Fax: 1-302-886-4114 
Email: AEMailboxClinicalTrialTCS@astrazeneca.com  
 
7.5 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the investigator to report any unanticipated problem to the FDA as 
follows: 
 
• Report any unexpected fatal or life-threatening adverse experiences (Section 7.1.4) 


Protocol Version: 07/31/19 
 
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associated with use of the drug (i.e., there is a reasonable possibility that the 
experience may have been caused by the drug) by telephone or fax no later than 7 
calendar days after initial receipt of the information.   
• Report any serious, unexpected adverse experiences (Section 7.1.2), as well as 
results from animal studies that suggest significant clinical risk within 15 calendar 
days after initial receipt of this information.  
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
7.6 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked from start of treatment until 30 days after the last dose of 
study treatment regardless of the start of subsequent treatment for MCL.  AE assessment 
may be done by phone call or in-person visit.  Beyond this timeframe, if the investigator 
becomes aware of any SAEs or deaths that are assessed as related to acalabrutinib, they 
must be reported to Acerta as described in Section 7.4. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Acalabrutinib 
 
8.1.1 Acalabrutinib Description  
 
Chemical 
Name: 
4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-
yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide 
Molecular formula: C26H23N7O2 
Molecular weight: 465.517 g/mol 
Pharmacologic class: Small molecule.   
 
8.1.2 Clinical Pharmacology 
 
Acalabrutinib is a small-molecule inhibitor of BTK. Acalabrutinib and its active 
metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK 
active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling 
molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. In 
B cells, BTK signaling results in activation of pathways necessary for B-cell 
proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, 


Protocol Version: 07/31/19 
 
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acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins 
CD86 and CD69 and inhibited malignant B-cell proliferation and survival.  
 
In patients with B-cell malignancies dosed with 100 mg twice daily, median steady 
state BTK occupancy of ≥ 95% in peripheral blood was maintained over 12 hours, 
resulting in inactivation of BTK throughout the recommended dosing interval. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
The pharmacokinetics (PK) of acalabrutinib was studied in healthy subjects and 
patients with B-cell malignancies. Acalabrutinib exhibits almost linear PK across a 
dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single 
dose) and exhibits dose-proportionality. The daily area under the plasma drug 
concentration over time curve (AUC) was 1111 ng•h/mL and maximum plasma 
concentration (Cmax) of acalabrutinib was 323 ng/mL. 
 
Absorption 
The geometric mean absolute bioavailability of acalabrutinib was 25%. Median 
time to peak acalabrutinib plasma concentrations (Tmax) was 0.75 hours. 
 
Effect of Food 
In healthy subjects, administration of a single 75 mg dose of acalabrutinib (0.75 
times the approved recommended single dose) with a high-fat, high-calorie meal 
(approximately 918 calories, 59 grams carbohydrate, 59 grams fat, and 39 grams 
protein) did not affect the mean AUC as compared to dosing under fasted 
conditions. Resulting Cmax decreased by 73% and Tmax was delayed 1-2 hours. 
 
Distribution 
Reversible binding of acalabrutinib to human plasma protein was 97.5%. The in 
vitro mean blood-to plasma ratio was 0.7. The mean steady-state volume of 
distribution (Vss) was approximately 34 L. 
 
Elimination 
Following a single oral dose of 100 mg acalabrutinib, the median terminal 
elimination half-life (t1/2) of acalabrutinib was 0.9 (range: 0.6 to 2.8) hours. The 
t1/2 of the active metabolite, ACP-5862, was 6.9 hours. Acalabrutinib mean 
apparent oral clearance (CL/F) was 159 L/hr with similar PK between patients and 
healthy subjects, based on population PK analysis. 
 
Metabolism 
Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor 
extent, by glutathione conjugation and amide hydrolysis, based on in vitro studies. 
ACP-5862 was identified as the major active metabolite in plasma with a geometric 
mean exposure (AUC) that was approximately 2- to 3-fold higher than the exposure 
of acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib 
with regard to BTK inhibition. 


Protocol Version: 07/31/19 
 
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Excretion 
Following administration of a single 100 mg radiolabeled acalabrutinib dose in 
healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose 
was recovered in the urine, with less than 1% of the dose excreted as unchanged 
acalabrutinib. 
 
Specific Populations 
Age, Race, and Body Weight 
Age (42 to 90 years), sex, race (Caucasian, African American), and body weight 
did not have clinically meaningful effects on the PK of acalabrutinib, based on 
population PK analysis. 
 
Renal Impairment 
Acalabrutinib undergoes minimal renal elimination. Based on population PK 
analysis, no clinically relevant PK difference was observed in 368 patients with 
mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2, as estimated by 
MDRD (modification of diet in renal disease equation)). Acalabrutinib PK has not 
been evaluated in patients with severe renal impairment (eGFR < 29 
mL/min/1.73m2, MDRD) or renal impairment requiring dialysis. 
 
Hepatic Impairment 
Acalabrutinib is metabolized in the liver. In a hepatic impairment study, compared 
to subjects with normal liver function (n=6), acalabrutinib exposure (AUC) was 
increased by less than two-fold in subjects with mild (n=6) (Child-Pugh A) and 
moderate (n=6) (Child-Pugh B) hepatic impairment, respectively. Based on a 
population PK analysis, no clinically relevant PK difference was observed in 
subjects with mild (n=41) or moderate (n=3) hepatic impairment (total bilirubin 
between 1.5 to 3 times the upper limit of normal [ULN] and any AST) relative to 
subjects with normal (n=527) hepatic function (total bilirubin and AST within 
ULN). Acalabrutinib PK has not been evaluated in patients with severe hepatic 
impairment (Child-Pugh C or total bilirubin between 3 and 10 times ULN and any 
AST). 
 
8.1.4 Supplier(s) 
 
Acalabrutinib capsules for this trial will be supplied by AstraZeneca.    
 
8.1.5 Dosage Form and Preparation 
 
Acalabrutinib capsules for oral administration are supplied as yellow and blue, 
opaque hard gelatin capsules, with 100 mg of acalabrutinib as the active ingredient.  
Each capsule also contains compendial inactive ingredients: silicified 
microcrystalline cellulose, which is composed of microcrystalline cellulose and 
colloidal silicon dioxide, partially pregelatinized starch, sodium starch glycolate, 
and magnesium stearate.  The capsule shell contains gelatin, titanium dioxide, 


Protocol Version: 07/31/19 
 
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yellow iron oxide and indigotine (FD&C Blue 2). 
 
Acalabrutinib will be provided in white, high-density polyethylene bottles.   
 
8.1.6 Storage and Stability 
 
Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F).  
 
8.1.7 Administration 
 
Acalabrutinib 100mg BID administered orally Days 1-28 of Cycles 1, 3, and 5 and 
Days 1-7 and 22-28 of Cycles 2, 4, and 6.   
 
8.2 
Cytosine Arabinoside 
 
8.2.1 Cytosine Arabinoside Description  
 
Chemical Name: 4-amino-1-S-D-arabino-furanosyl-2(1H)-primidinone 
Molecular formula: C9H13N3O5 
Molecular weight: 243.217g/mol 
Pharmacologic class: Antimetabolite  
 
8.2.2 Clinical Pharmacology 
 
Cytarabine is metabolized to its active form, cytarabine triphosphate (AraCTP) by 
deoxycytidine kinase and related kinases. AraCTP serves as an inhibitor of DNA 
polymerase. AraC also is incorporated into cellular RNA and DNA. It exhibits cell 
phase specificity, and is active against cells in the S-phase and may also block cells 
from progressing to S phase from G1.  
 
8.2.3 Pharmacokinetics and Drug Metabolism 
 
After intravenous administration, the disappearance of Cytarabine from plasma is 
biphasic. There is an initial distributive phase with a half-life of approximately 10 
minutes, followed by a second elimination phase with a half-life of approximately 
1 to 3 hours. Within 24 hours about 80 percent of the administered drug can be 
recovered in the urine as the inactive metabolite, AraI. After a single IV 
administration of Cytarabine, levels in CSF are low. There is little conversion to 
AraU because of low CSF levels of diaminase. 
 
8.2.4 Supplier(s) 
 
Cytarabine is commercially available and will be supplied by the treating 
institution.  
 


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8.2.5 Dosage Form and Preparation 
 
Cytarabine is supplied as a sterile powder in 100 mg, 500 mg, 1 gram, and 2 gram 
vials for injection. Cytarabine should be reconstituted with sterile water for 
injection. Please refer to the package insert for further instructions. 
 
8.2.6 Storage and Stability 
 
Sterile powder should be stored at room temperature 15° -30°C (59°- 86°F). 
Solutions reconstituted with sterile water without preservative should be used 
immediately; solutions reconstituted with Bacteriostatic of Water are stable up to 
48 hours at room temperature 15° -30°C (59°- 86°F). Solutions with a slight haze 
should be discarded.  
 
8.2.7 Administration 
 
Cytarabine 2 g/m2 every 12 hours for 4 doses by intravenous infusion over 2 hours. 
Patients 60-70 years will receive 1.5 g/m2.  
 
8.3 
Rituximab 
 
8.3.1 Rituximab Description 
 
Other Names: IDEC-C2B8, Chimeric anti-CD20 monoclonal antibody, Rituxan, 
NSC# 687451  
Classification: Monoclonal Antibody  
 
8.3.2 Clinical Pharmacology 
 
Rituximab is a chimeric murine/human gamma 1 kappa monoclonal antibody 
(Chinese hamster ovary [CHO] transfectoma). It recognizes the CD20 antigen 
expressed on normal B cells and most malignant B-cell lymphomas. It binds with 
high affinity to CD20-positive cells, performs human effector functions in vitro, 
and depletes B-cells in vivo. The Fab domain of Rituximab binds to the CD20 
antigen on B-lymphocytes and the Fc domain recruits immune effector functions to 
mediate B-cell lysis in vitro. The biological effect is manifested by B-cell depletion 
in peripheral blood, lymph nodes, and bone marrow.  
 
8.3.3 Pharmacokinetics and Drug Metabolism 
 
Rituximab may be detectable in serum up to 3-6 months after infusion. B cell 
recovery commences approximately 6 months after completion of treatment with 
median recovery time of 12 months. Intravenous administration results in rapid and 
sustained tissue and circulating B cell depletion. Its elimination is uncertain but 
thought to be through catabolism in the reticuloendothelial system with a t1/2 of 22 
days (range 6-52 days) 


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8.3.4 Supplier(s) 
 
Rituximab is commercially available will be supplied by the treating institution.  
 
8.3.5 Dosage Form and Preparation 
 
Rituximab will be diluted with 0.9% Sodium Chloride or 5% Dextrose Injection to 
prepare a standard product with concentration of 2 mg/ml. Caution should be taken 
during the preparation of the drug, as shaking can cause aggregation and 
precipitation of the antibody 
 
8.3.6 Storage and Stability 
 
Vials should be protected from direct sunlight. Diluted drug product at a 
concentration of 1 to 4 mg/ml in polyvinylchloride or polyolefin IV bags containing 
normal saline or dextrose 5% can be stored for up to 24 hours at 2 to 8˚C, and at 
room temperature for an additional 24 hours. 
 
8.3.7 Administration 
 
Rituximab will be administered as an intravenous infusion at 375 mg/m2 on Day 1 
of each cycle (or on Day 2 of Cycle 1).  The first dose of rituximab should be 
infused at 50 mg/hour and the rate of infusion increased by 50 mg/hour gradually 
to a rate of 400 mg/hour.  Subsequent doses may be administered at 100 mg/hour 
over 30 minutes.  The remainder of the dose may be administered over 60 minutes.  
During rituximab infusion, a patient's vital signs (blood pressure, pulse, respiration, 
temperature) should be monitored according to the standard of care. 
 
8.4 
Bendamustine 
 
8.4.1 Bendamustine Description 
 
Classification: Alkylating agent 
 
8.4.2 Clinical pharmacology 
 
Bendamustine is a nitrogen mustard derivative with a benzimidazole ring (purine 
analog) which demonstrates only partial cross-resistance (in vitro) with other 
alkylating agents. It leads to cell death via single and double strand DNA cross-
linking. Bendamustine is active against quiescent and dividing cells. The primary 
cytotoxic activity is due to bendamustine (as compared to metabolites). 
 
8.4.3 Pharmacokinetics and Drug Metabolism 
 
Bendamustine is highly protein bound (94-96%) It is extensively hepatically 


Protocol Version: 07/31/19 
 
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metabolized 
via 
CYP1A2 
to 
active 
(minor) 
metabolites 
gamma-
hydroxybendamustine (M3) and N-desmethyl-bendamustine (M4); also via 
hydrolysis to low cytotoxic metabolites, monohydroxybendamustine (HP1) and 
dihydroxybendamustine (HP2). The elimination t1/2 of bendamustine (the cardinal 
active agent) is ~40 minutes. The elimination t1/2of M3 is ~3 hours and M4 is about 
30 minutes. Bendamustine is excreted through urine (50%, 3% as active drug) and 
feces (25%) 
 
8.4.4 Supplier(s) 
 
Bendamustine is commercially available and will be supplied by the treating 
institution 
 
8.4.5 Dosage Form and Preparation  
 
Bendamustine is supplied in a multi-dose vial at a concentration of 100 mg/4mL 
vial (25 mg/mL).  Aseptically withdraw the volume needed for the required dose 
and immediately transfer into a 50 mL infusion bag containing 0.9% NS or 5% 
dextrose or 2.5% dextrose/0.45% sodium chloride. 
 
8.4.6 Storage and Stability 
 
Intact vials should be stored at room temperature and protected from light. Once 
reconstituted or further diluted for infusion, bendamustine is stable for 24 hours 
when stored refrigerated (2-8°C or 36-47°C) or for 6hours when stored at room 
temperature (15-30°C or 59-86°F) and room light.  
 
8.4.7 Administration 
 
Bendamustine is infused at a dose of 90 mg/m2 over 30 minutes and is an irritant 
with vesicant like properties. Bendamustine solution contains N, N-
dimethylacetamide, which is incompatible with closed-system transfer devices 
(CSTDs), adapters, and syringes containing polycarbonate or acrylonitrile-
butadiene-styrene (ABS). After dilution of bendamustine solution into the infusion 
bag, devices containing polycarbonate or ABS (including infusion sets) may be 
used. 
 
 
9.0 
CORRELATIVE STUDIES 
 
Correlative studies will include evaluating the genomic alterations, immune cell composition, and 
minimal residual disease (MRD) prior to, during, and at the end of treatment.  
 
9.1 
Lymphoma Tissue Collection 
 
Lymphoma tissue will be collected for defining baseline genomic alterations for correlation 


Protocol Version: 07/31/19 
 
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with clinical outcomes and to provide a baseline for the lymphoma clones that will be 
monitored in follow-up samples (MRD tests). 
 
This assay will be performed by the Fehniger Lab at WUSM. A fresh/frozen or formalin-
fixed paraffin embedded (FFPE) tissue block that includes the patient’s iNHL, other MCL 
involved tissue, or bone marrow aspirate. 
 
Genomic DNA will be isolated and analyzed for recurrent mutations via next-generation 
sequencing. While fresh/frozen tissue is not required, it is greatly preferred over FFPE 
tissue blocks. A biopsy specimen obtained immediately prior to the start of study treatment 
is preferred, as this reflects the tumor genomic content at time of entering the study. If the 
FFPE tissue block is not available, 10 unstained slides or ribbons sufficient to isolate 10 
mcg of gDNA may be substituted. 
 
9.2 
Non-Malignant Oral Rinse Collection 
 
An oral rinse will be performed to obtain an additional non-tumor cellular sample (Oragene 
–discover DNA genotek) in order to define baseline genomic alterations for correlation 
with clinical outcomes and to provide a baseline for the lymphoma clones that will be 
monitored in follow-up samples (MRD tests). 
 
Genomic DNA will be isolated and analyzed for recurrent mutations via next-generation 
sequencing. 
 
9.3 
Peripheral Blood Collection 
 
Peripheral blood will be collected for the MRD test and immune monitoring at the 
following time points: 
• Baseline 
• End of Cycle 3 
• 4-6 weeks after Cycle 6 Day 1 
• If the patient discontinues protocol therapy prior to completion of Cycle 6 
 
Peripheral blood will be collected in two 10-mL pink top EDTA tubes and two 10-mL 
green top heparin tubes (total of 4 tubes).  Pink top tubes will be used to generate plasma 
for cfDNA MRD testing.  Green top tubes will be used to isolate immune cells for 
immunomonitoring. 
 
9.4 
Bone Marrow Collection 
 
Bone marrow will be collected at baseline if the patient requires a marrow for staging 
purposes and has not already had a bone marrow biopsy performed. Bone marrow will also 
be collected at end of treatment if the patient requires a marrow for restaging.  At each time 
point, 2-5 mL of bone marrow aspirate should be collected in a 10-mL pink top EDTA 
tube. 
 


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9.5 
Sample Storage 
 
All samples should be submitted to the Fehniger Lab Monday through Friday 8 am until 
5 pm:  
Attention: Fehniger Lab / Michelle Hapak 
Fehniger Lab 7 
Southwest Tower Building 
Room 724 
4940 Parkview Place 
St Louis MO 63110 
Phone: 314-273-0156 or 314-747-1547  
Email: mbecker-hapak@wustl.edu; tfehnige@wustl.edu 
 
 
 


Protocol Version: 07/31/19 
 
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10.0 
STUDY CALENDAR 
 
Screening/baseline evaluations are to be conducted within 28 days prior to start of protocol 
therapy.  There is a +/- 3 day window for tests, observations, labs, and/or treatment. 
 
Tests and observations 
Baseline 
examination1 
Treatment 
phase2 
EOT17 
Follow-up3 
Informed consent 
X 
 
 
 
Physical exam 
X 
X 
 
 
Medical history 
X 
 
 
 
Medication Review18 
X 
X 
 
 
Performance status 
X 
 
 
 
Toxicity assessment4 
X 
X 
X15 
 
Pill diary 
 
X 
 
 
Review of medical record for 
progression and survival 
 
 
 
X 
Laboratory Studies 
 
 
 
 
CBC with differential5 
X 
X 
 
 
CMP6 
X 
X 
 
 
Uric acid 
X 
X 
 
 
LDH 
X 
X 
 
 
Serum pregnancy test 7 
X 
 
 
 
HIV-1/2 antibody 
X 
 
 
 
Hepatitis B surface antigen, 
surface antibody, and core 
antibody8 
X 
 
 
 
Hepatitis C antibody9 
X 
 
 
 
MIPI score10 
X 
 
 
 
PET11 
X 
X 
X 
 
Bone marrow aspiration and 
biopsy12 
X 
X 
X 
 
EKG 
X 
 
 
 
Correlative Studies 
Ki-67 (WU pathology 
review)13 
X 
 
 
 
Blood for immune 
biomarkers14 
X 
X 
X 
 
Lymphoma tissue for genomic 
alterations and MRD 
assessment 
X 
 
 
 
Oral rinse 
X 
 
 
 
Blood for MRD assessment14 
X 
X 
X 
 
Bone marrow aspiration for 
research16 
X 
X12 
 
 
Notes:  


Protocol Version: 07/31/19 
 
Page 37 of 49 
1. All baseline examinations are to be performed within 28 days of the start of therapy 
2. Treatment phase begins with first dose of acalabrutinib (Day 1). Tests, observations, and laboratory studies will be 
performed on Day 1 of each cycle. 
3. The frequency of follow-up after completion of protocol treatment is per investigator’s discretion. Review of the 
medical record will occur on an every 6-month basis for 5 years from study entry to collect data on relapse and 
survival.  
4. Only toxicities which worsen from baseline need be collected, and only the worst grade per cycle need be recorded.  
Toxicity will be assessed from time of treatment initiation until the end-of-study restaging visit, approximately one 
month after the last dose of chemotherapy. 
5. CBC with differential will be performed on Day 1 each cycle. On cycles 1, 3, and 5 the CBC will be repeated 
between day 10 and day 14. On cycles 2, 4, and 6 the CBC will be repeated at least twice between days 8-14 and twice 
between days 15-21.  
6. CMP will be performed during screening and on Day 1 of each cycle 
7. For women of child bearing potential.  Perform within 14 days of study entry. 
8. Subjects who are hepatitis B core antibody positive but surface antigen negative will need negative polymerase 
chain reaction (PCR) prior to enrollment. Hepatitis B surface antigen positive or PCR positive patients are ineligible. 
9. Subjects who are hepatitis C antibody positive will need negative PCR prior to enrollment. Patients with PCR 
positive hepatitis C are ineligible. 
10. The mantle cell IPI (MIPI) calculator can be accessed at http://www.european-mcl.net/en/clinical_mipi.php 
11. PET scans are required for every restaging scan while on protocol. PET scans will be performed at baseline, after 
Cycle 3, and after Cycle 6.  Patients who come off treatment early for reasons other than progression who are suspected 
to be responders should have an EOT assessment with PET imaging. 
12. Bone marrow aspirate will be collected at baseline if the patient has not already had a bone marrow biopsy 
performed prior to enrolling to the study. If marrow is involved at baseline, repeat bone marrow aspiration and biopsy 
is required after 6 cycles of chemotherapy.  Patients who come off treatment early for reasons other than progression 
who are suspected to be responders should have an EOT bone marrow aspiration and biopsy if they had a baseline 
assessment.  
13. Pathology review of the patient’s baseline diagnostic tissue, including lymph node, bone marrow biopsy, or blood, 
will include an immunohistochemical assessment of Ki-67. If the Ki-67 is already available in the WU pathology 
report at time of screening, the test does not need to be repeated. The result is not required at the time of patient 
enrollment.  
14. Peripheral blood will be collected at baseline, end of Cycle 3, 4-6 weeks after Cycle 6 Day 1, and at discontinuation 
of treatment (if prior to Cycle 6). See Section 9.0.  
15. Adverse events will be tracked for 30 days after the last dose of study treatment.  Refer to Section 7.6 for details.  
If the investigator becomes aware of any SAEs or deaths that are causally attributed to acalabrutinib after the 30-day 
time period, they must be reported to AstraZeneca. 
16. Only if required clinically. 
17. End of treatment visit will take place 4-6 weeks after Cycle 6 Day 1. 
18. Medication review at baseline and at Day 1 of each cycle to verify that patients is not taking PPIs or CYP3A4 
inhibitor/inducers.  
 
 
 
 


Protocol Version: 07/31/19 
 
Page 38 of 49 
 
11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Lymph Node Tumor Biopsy Form 
Bone Marrow Biopsy Form (if 
applicable) 
MRD Testing Form 
Research Blood Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Disease Assessment Form 
Baseline, and after Cycles 3 and 6 at restaging 
Research Blood Form 
MRD Testing Form 
End of Cycle 3 
4-6 weeks after Cycle 6 Day 1 
Treatment Summary Form 
Leukapheresis and Transplant Form 
Bone Marrow Biopsy Form (if 
applicable) 
MRD Testing Form (if applicable) 
Research Blood Form (if applicable) 
Completion of treatment 
Disease Status Follow-Up Form 
Every 6 months for 5 years after study entry 
until the patient’s first relapse.  After a patient 
has disease progression within the 5-year period, 
switch to the Survival Follow-Up Form. 
Survival Follow-Up Form 
Beginning from patient’s first relapse, every 6 
months for 5 years after study entry 
Adverse Event Form 
Baseline, and at the time of any toxicity from 
starting treatment to one month after completing 
treatment 
MedWatch Form 
See Section 7.0 for reporting requirements 
Death Form 
Time of death 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect 
 
For the purposes of this study, patients should be re-evaluated for response after 3 and 6 
cycles of therapy while on treatment with PET imaging.  
 


Protocol Version: 07/31/19 
 
Page 39 of 49 
12.2 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. PET based evaluation 
is required over evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
12.3 
Criteria for extranodal involvement(18) 
 
Measurable extranodal disease should be assessed in a manner similar to that for nodal 
disease. For these recommendations, the spleen is considered nodal disease. Focal uptake 
in extranodal sites that is in keeping with lymphoma, according to the distribution and/or 
CT characteristics, is considered involvement with lymphoma, including spleen, liver, 
bone, thyroid, skin, lung, and bone marrow. A measurable extranodal lesion should have a 
longest diameter greater than 1.0 cm. All other lesions (including nodal, extranodal, and 
assessable disease) should be followed as nonmeasured disease (e.g. cutaneous, GI, bone, 
spleen, liver, kidneys, pleural or pericardial effusions, ascites). 
 
12.4 
Response Assessment 
Response to treatment is guided based upon the Recommendations for Initial Evaluation, 
Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano 
Classification.(18)PET restaging scans will be performed after Cycle 3 and Cycle 6, then as 
clinically indicated. 
 
Tissue site 
Clinical 
Test 
Positive finding 
Lymph node 
Palpable 
PET/CT 
Increased FDG avidity 
Spleen 
Palpable 
PET/CT 
Diffuse uptake, solitary mass, miliary 
lesions, nodules 
Liver 
Palpable 
PET/CT 
Diffuse uptake, mass 
CNS 
Signs, symptoms 
CSF (if clinically 
indicated) 
Cytology, flow cytometry 
 
Other (e.g. skin, lung, GU 
tract, bone, marrow) 
Site dependent 
PET/CT 
Biopsy, if clinically indicated 
 
12.4.1 Complete Response (CR) 
 
• Complete disappearance of all detectable clinical evidence of disease and 
disease-related symptoms if present before therapy. 
• London Deauville score of 1 and 2 in lymph nodes and extra lymphatic sites is 


Protocol Version: 07/31/19 
 
Page 40 of 49 
considered to represent complete metabolic response. A London Deauville 
score 3 in the post treatment PET scan may be considered to represent complete 
metabolic response especially if it is not higher than the surrounding normal 
physiologic uptake. 
• No evidence of FDG avid disease in the bone marrow 
• No new lesions 
• If the bone marrow was involved by lymphoma before treatment, the infiltrate 
must have cleared on repeat bone marrow biopsy. The biopsy sample on which 
this determination is made must be adequate (with a goal of > 20 mm unilateral 
core). If the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry. A sample that is negative by immunohistochemistry 
but that demonstrates a small population of clonal lymphocytes by flow 
cytometry will be considered a CR until data become available demonstrating 
a clear difference in patient outcome.  
 
12.4.2 Partial Response (PR) 
 
• London Deauville score of 4 or 5 in lymph nodes and extra lymphatic sites with 
reduced uptake compared with the baseline and residual mass(es) of any size 
on interim scan 
• Residual bone marrow uptake higher than the uptake in the normal marrow but 
reduced when compared with baseline If there are persistent focal changes in 
the marrow in the context of a nodal response consideration should be given to 
further evaluation with MRI or biopsy or an interval scan 
• No new lesions 
 
12.4.3 No Metabolic Response (SD) 
 
• London Deauville score of 4 or 5 in target nodes/masses/extranodal lesions with 
no significant change in FDG uptake from baseline at interim or end of 
treatment 
• No change in bone marrow from baseline 
• No new lesions 
 
12.4.4 Progressive Disease (PD)  
 
• London Deauville score of 4 or 5 in individual target nodes/masses with an 
increase in intensity of uptake from the baseline and/or new FDG avid foci 
consistent with lymphoma at interim or end of treatment assessment 
• New FDG avid foci of extranodal disease consistent with lymphoma. If there is 
concern regarding the etiology of the new lesions, biopsy or interval scan may 
be considered.  
• New or recurrent FDG avid foci in the bone marrow 
 


Protocol Version: 07/31/19 
 
Page 41 of 49 
12.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least monthly and provide a semi-annual 
report to the Quality Assurance and Safety Monitoring Committee (QASMC).  This report will 
include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date  
• Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
• Early study suspension rules with supporting data and list the number of participants who 
have met the early stopping rules 
• Summary of toxicities  
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
All patients who receive study treatment and undergo at least a single pheresis procedure with the 
aim of harvesting stem cells are evaluable for the primary objective. Patients who do not undergo 


Protocol Version: 07/31/19 
 
Page 42 of 49 
attempted stem cell collection due to disease progression, toxicity, patient preference, or discretion 
of the treating physician will be replaced. 
 
Mobilization failure is expected to be 5% or less. Such a small amount is difficult to monitor 
statistically in a sample of 15 evaluable patients. Instead, the study will allow no more than 2 cases 
among 15 evaluable patients. The study will be suspended for review if the third case is observed. 
95% confidence intervals for 0, 1 and 2 cases in 15 evaluable patients are (0.0, 0.22), (.0017, .32) 
and (.017, .40), respectively. 
 
The study also will be suspended for review following the death of a patient during protocol 
defined treatment or within 30 days after the last dose of protocol treatment or until initiation of a 
new anti-cancer therapy (whichever is first).  The study will not be suspended for review if a death 
was determined to be related to disease progression. 
 
Treatment related non-hematologic toxicity of grade 3 or higher will be monitored using a 
continuous toxicity monitoring rule. 
 
The expected rate is 30% and the maximum allowable rate is 60%. The toxicity monitoring rule 
has type 1 and 2 error rates of 0.05 and 0.20, respectively. The probability of incorrect study 
suspension is 0.059 if the true toxicity rate is 30%. The probability of correct study suspension is 
0.70 if the true toxicity rate is as high as 60%.    
 
Suspend the study for review if 
the number of patients with 
treatment related grade 3+ non 
hematologic toxicities 
EXCEEDS: 
In the following number of 
enrolled patients: 
2 
3 
3 
4 
4 
6 
5 
9 
6 
11 
7 
13 
8 
15 
 
Analysis Plan: Stem cell mobilization rate, ORR and CRR will be documented as proportions with 
exact binomial 95% confidence intervals. Kaplan-Meier method will be used to describe OS and 
PFS, as well as to estimate median times to these events with 95% confidence intervals if the 
median is reached. Adverse and serious adverse events will be tabulated by cycle, patient, type 
and grade. 
 
 


Protocol Version: 07/31/19 
 
Page 43 of 49 
15.0 
REFERENCES 
 
Argatoff LH, Connors JM, Klasa RJ, et al. Mantle cell lymphoma: a clinicopathologic study of 80 
cases. Blood. 1997;89(6):2067-78. 
 
Armand P, Redd R, Bsat J et al. A phase 2 study of Rituximab-Bendamustine and Rituximab-
Cytarabine for transplant-eligible patients with mantle cell lymphoma. Br J Haematol. 
2016;173(1)89-95.  
 
Bosch F, López-Guillermo A, Campo E, et al. Mantle cell lymphoma: presenting features, 
response to therapy, and prognostic factors. Cancer. 1998;82(3):567-75. 
 
Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular switches. Cell 
Signal 2010;22:1175-84. 
 
Covey T, Barf T, Gulrajani M, et al. ACP-196: a novel covalent Bruton’s tyrosine kinase (Btk) 
inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia 
(CLL) patients. In: Proceedings of the 106th Annual Meeting of the American Association for 
Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; 2015. Abstract 
#2596. 
 
de Rooij MF, Kuil A, Geest CR, et al. The clinically active Btk inhibitor PCI-32765 targets B-cell 
receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. 
Blood 2012;119:2590-4.   
 
Eskelund CW, Kolstad A, Jerkeman M et al. 15-year follow-up of the Second Nordic Mantle Cell 
Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 
2016;175(3):410-418.  
 
Food and Drug Administration. Guidance for Industry and Investigators:  Safety Reporting 
Requirements 
for 
INDs 
and 
BA/BE 
Studies 
(December 
2012). 
Available 
at: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM227351.pdf, accessed on:  24June2015. 
 
Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-
CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 
2014;123(19):2944-2952 
 
Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: six-year follow-up after 
intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC 
+ autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 
2012;158(3):355-62. 
 
Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell 
lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 
(EMERGE) study. J Clin Oncol 2013;31(29):3688-3695. 
 


Protocol Version: 07/31/19 
 
Page 44 of 49 
Hermine O, Hoster E, Walewski J et al. Addition of high-dose cytarabine to immunochemotherapy 
before autologous stem-cell transplantation in patients aged 65 or younger with mantle cell 
lymphoma (MCL Younger): a randomized, open label, phase 3 trial of the European Mantle Cell 
Lymphoma Network. Lancet. 2016;388(10044):565-75. 
 
Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with 
advanced-stage mantle cell lymphoma. Blood 2008;111(2):558-565. 
 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. 2014 Dec.  Available 
from: http://www.ICMJE.org.  Accessed February 04, 2015. 
 
Khan WN. Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase. 
Immunol Res 2001;23:147-156. 
 
Maddocks K, Christian B, Jaglowski S et al. A phase 1/1b study of rituximab, bendamustine and 
ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma. Blood. 
2015;125(2):242-8.  
 
Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton's tyrosine kinase (Btk): function, regulation, and 
transformation with special emphasis on the PH domain. Immunol Rev 2009;228:58-73. 
 
Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts 
chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 
2012;119:1182-1189.   
 
Rajasekaran N, Sadaram M, Hebb J, et al. Three BTK-specific inhibitors, in contrast to ibrutinib, 
do not antagonize rituximab-dependent NK-cell mediated cytotoxicity. Blood 2014 ASH Annual 
Meeting Abstract #3118. 
 
Rimokh R, Berger F, Delsol G, et al. Detection of the chromosomal translocation t(11;14) by 
polymerase chain reaction in mantle cell lymphomas. Blood 1994;83:1871-1875. 
 
Romaguera JE, Fayad LE, Feng L, et al. Ten-year follow-up after intense chemoimmunotherapy 
with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-
MA) and without stem cell transplantation in patients with untreated aggressive mantle cell 
lymphoma. Br J Haematol 2010 Jul;150(2):200-8  
 
Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, et al. 
Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with 
indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-
inferiority trial. Lancet. 2013;381(9873):1203-10. 
 
Soucek L, Buggy JJ, Kortlever R, et al. Modeling pharmacological inhibition of mast cell 
degranulation as a therapy for insulinoma. Neoplasia 2011;13:1093-1100. 
 


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Visco C, Finotto S, Zambello R, Paolini R, Menin A, Zanotti R, et al. Combination of rituximab, 
bendamustine, and cytarabine for patients with mantle-cell non-Hodgkin lymphoma ineligible for 
intensive regimens or autologous transplantation. J Clin Oncol. 2013;31(11):1442-9. 
 
 
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle 
cell lymphoma. NEJM 2013;369(6):507-516. 
 
Wang M, Rule S, Zinzani PL et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma 
(ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2017; S0140-6736(17)33108-2 
 
 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development services. The Siteman Cancer Center is supported in 
part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 
 


Protocol Version: 07/31/19 
 
Page 46 of 49 
APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


Protocol Version: 07/31/19 
 
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APPENDIX B: PATIENT’S MEDICATION DIARY –CYCLES 1-3 
 
Today’s Date:    
 
     Study ID#:    
     Agent:  Acalabrutinib      Cycle:   
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take 100 mg of acalabrutinib twice daily (approximately 12 
hours apart) with or without food.  Take it with a glass of water and drink the glass of water in as 
little time as possible.  Swallow the capsules whole and do not chew the capsules. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forgot to take your acalabrutinib dose and it’s been more than 3 hours since the regular 
dosing time, then do not take that dose.  Restart taking it with the next scheduled dose. 
4. If you have any questions or notice any side effects, please record them in the comments section.  
Record the time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next 
appointment.  Please bring your unused study medications and/or empty bottles with you to each 
clinic visit so that a pill count can be done. 
Day 
Date 
What time was dose taken? 
# of capsules taken 
Comments 
AM dose 
PM dose 
AM dose 
PM dose 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 


Protocol Version: 07/31/19 
 
Page 48 of 49 
APPENDIX C: PATIENT’S MEDICATION DIARY –CYCLES 4-6 
 
Today’s Date:    
 
     Study ID#:    
     Agent:  Acalabrutinib      Cycle:   
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take 100 mg of acalabrutinib twice daily (approximately 12 
hours apart) with or without food.  Take it with a glass of water and drink the glass of water in as 
little time as possible.  Swallow the capsules whole and do not chew the capsules. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forgot to take your acalabrutinib dose and it’s been more than 3 hours since the regular 
dosing time, then do not take that dose.  Restart taking it with the next scheduled dose. 
4. If you have any questions or notice any side effects, please record them in the comments section.  
Record the time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next 
appointment.  Please bring your unused study medications and/or empty bottles with you to each 
clinic visit so that a pill count can be done. 
Day 
Date 
What time was dose taken? 
# of capsules taken 
Comments 
AM dose 
PM dose 
AM dose 
PM dose 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 


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APPENDIX D: Known Strong in Vivo Inhibitors or Inducers of CYP3A 
 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ae 
boceprevir 
carbamazepinef 
clarithromycinb 
phenytoinf 
conivaptinb 
rifampinf 
grapefruit juicec 
St John's wortf  
indinavir 
 
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
mibefradild 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
  
a. 
A strong inhibitor for CYP3A is defined as an inhibitor that increases the AUC of a substrate for CYP3A by ≥ 5-fold. 
b. 
In vivo inhibitor of P-glycoprotein. 
c. 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies 
have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (eg, high dose, 
double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (eg, low dose, single strength). 
d. 
Withdrawn from the United States market because of safety reasons. 
e. 
A strong inducer for CYP3A is defined as an inducer that results in ≥ 80% decrease in the AUC of a substrate for CYP3A. 
f. 
In vivo inducer of P-glycoprotein.   
 
Note: The list of drugs in these tables is not exhaustive.  Any questions about drugs not on this list should be addressed to 
the Medical Monitor of the protocol. 
Source: 
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers . Web link Accessed 11 June 
2015: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.ht
m#inVivo