Conditions: Follicular Lymphoma (FL/Indolent NHL) Aggressive NHL (a NHL) Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL) T-cell Lymphoma (PTCL and CTCL) B-cell Non Hodgkin Lymphoma (NHL)
Keywords: Leukemia Lymphocytic Chronic B Cell
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 260
Healthy volunteers: no

Brief summary:
This study will identify the highest dose, and assess the safety, of cerdulatinib (PRT062070) that may be given in participants with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma or non-hodgkin lymphoma.

Detailed description:
This is an open-label, Phase 1/2a, multi-dose, multi-center trial of orally administered cerdulatinib assessing safety, tolerability, and pharmacokinetic (PK) parameters conducted in 2 phases:

* Phase 1: Dose-escalation portion, during which participants will be enrolled to receive a single-agent cerdulatinib at their assigned dose level starting at 15 milligrams (mg) once daily (QD), administered in increasing doses until the maximum tolerated dose (MTD)/maximum administered dose (MAD) is identified.
* Phase 2a: Consisting of planned cohorts based on cancer type. The participants will receive single agent cerdulatinib at a starting dose of 35, 30, or 20 mg twice daily (BID) for 28-day cycles except for one of the cohorts, the participants will receive cerdulatinib plus intravenous (IV) rituximab at 375 mg/square meter (m\^2) for 28-day cycles.

Arms:
arm 1: During Phase 1, participants will receive oral cerdulatinib on Day 1 and then starting on Day 4 at doses of 15 mg up to 100 mg QD or oral cerdulatinib at doses of 15 mg up to 45 mg BID in 28-day cycles (except Cohort 1 will have a 21-day cycle starting on Day 1) for up to 10 cycles. arm 2: During Phase 2a, participants in cohorts based on cancer type will receive oral cerdulatinib at starting doses of 35, 30, or 20 mg BID on Day 1 in 28-day cycles for up to 10 cycles. Doses of cerdulatinib can be reduced to a minimum dose of 15 mg BID or increased to a maximum dose of 30 mg BID at the discretion of the Investigator based upon clinical judgment and with Sponsor Medical Monitor approval. arm 3: During Phase 2a, participants in this cohort will receive oral cerdulatinib at their applicable dose and an IV injection of rituximab 375 mg/m\^2 on Days 1, 8, 15, and 22 of Cycle 1 and Day 1 of Cycles 4, 6, 8, and 10.

Interventions: intervention 1: Cerdulatinib intervention 2: Rituximab
Intervention descriptions: intervention 1: Oral capsule intervention 2: IV infusion

Protocol document:
Prot_000.pdf: 
Portola
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 1 
A PHASE 1/2A OPEN-LABEL, MULTI-DOSE, MULTI-CENTER ESCALATION 
AND EXPLORATORY STUDY OF CERDULATINIB (PRT062070) IN PATIENTS 
WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA 
(CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL) OR B-CELL OR 
T-CELL NON-HODGKIN LYMPHOMA (NHL)
DRUG NAME: 
Cerdulatinib (PRT062070) 
PROTOCOL NUMBER: 
13-601
PHASE: 
1/2a 
IND NUMBER: 
118394 
EUDRACT NUMBER: 
2016-002182-65 
TRIAL SPONSOR: 
Portola Pharmaceuticals, Inc. 
270 East Grand Avenue 
South San Francisco, CA 94080 
MEDICAL MONITORS: 
 
Portola Pharmaceuticals, Inc. 
 
Syneos Health 
PROTOCOL DATE: 
Original: 
14 August 2013 
Amendment 1: 
26 September 2013 
Amendment 2: 
19 November 2013 
Amendment 3: 
02 April 2015 
Amendment 4: 
06 April 2016 
Amendment 5: 
12 October 2016 
Amendment 6: 
05 May 2017 
Amendment 7*: 06 March 2019 
Amendment 8: 
04 April 2019 
Amendment 9: 14 October 2019 
*Amendment 7 was superseded by Amendment 8 prior to
distribution/operationalization.
NCT #NCT01994382 
Clinical Study 13-601  
Pharmaceuticals, Inc. 


Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 2 
 
 
 
 
CONFIDENDIALITY STATEMENT 
This protocol is the property of Portola Pharmaceuticals, Inc. It is a confidential communication. 
Acceptance implies an agreement not to disclose information contained herein that is not otherwise publicly 
available, with the exception that it may be disclosed to an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) for the purpose of obtaining approval to conduct the study. The IRB/IEC is 
requested and expected to maintain confidentiality. This document may not be used or published without the 
consent of Portola Pharmaceuticals, Inc. 


Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 3 
 
 
 
 
INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for cerdulatinib. I have read Amendment 9 
to Protocol number 13-601 entitled A Phase 1/2A Open-Label, Multi-Dose, Multi-Center 
Escalation and Exploratory Study of Cerdulatinib (PRT062070) in Patients with 
Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma 
(SLL) OR B-Cell or T-Cell Non-Hodgkin Lymphoma. I agree to conduct the study as outlined. 
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Printed Name of Investigator 


 
 
Cerdulatinib 
Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
 
 
 
SPONSOR'S AGREEMENT 
I have read Amendment 9 to Protocol number 13-601 entitled A Phase 112A Open-Label, Multi­ 
Dose, Multi-Center Escalation and Exploratory Study of Cerdulatinib (PRT062070) in Patients 
with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma 
(SLL) ORB-Cell or T-Cell Non-Hodgkin Lymphoma and agree to abide by all provisions set 
forth therein. 
 
I agree to comply with the ICH Tripartite Guideline on Good Clinical Practice (GCP), applicable 
Food and Drug Administration (FDA) regulations set forth in 21 CFR Parts 11, 50, 54, 56, 
312 and all locally applicable laws. 
 
 
Portola Pharmaceuticals, Inc. 
South San Francisco, CA 
USA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
 
Protocol Amendment 9 
14 October 2019 
Page4 


Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 5 
 
 
 
 
STUDY CONTACT INFORMATION AND PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Study Contact Information and 24-Hour Emergency Contact 
 
Role in Study 
Name 
Contact Information 
Portola Responsible 
Physician/Medical Monitor 
 
Portola Pharmaceuticals, Inc. 
270 East Grand Avenue 
South San Francisco, CA 94080 
Phone: 
 
Email: 
 
Drug Safety Physician, 
Syneos Health Medical Monitor 
 
Phone: 
 
Email: 
 
24-Hour SAE Reporting 
Procedures 
Not applicable 
Report SAEs using the methods described on 
the SAE cover form, e.g., email 
to 
 
General Study Inquiries and 
Communication, Pre-screening 
Information, Enrollment Forms 
Cerdulatinib Clinical Study 
Mailbox 
 
IP Requests and Complaints 
13601 Drug Mailbox 
 
Lab Kit Requests and Lab 
Shipment Notifications 
13601 Lab Mailbox 
 


Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 6 
 
 
 
 
Table 2: 
Summary of Key Changes from Original Protocol (14 August 2013): 
Amendments 1 through 9 
 
Protocol Version: 
Date 
Key Changes 
Original: 
14 August 2013 
• 
The original version of Protocol Number 13-601, a clinical study that investigated 
PRT062070 (hereafter referred to as “cerdulatinib”), was entitled A Phase I Open- 
Label, Multi-Dose, Dose-Escalation Study of PRT062070 in Patients with 
Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic 
Lymphoma (SLL) or B-Cell Non-Hodgkin Lymphoma (NHL). 
Amendment 1: 
26 September 2013 
Incorporated changes to the protocol as recommended by FDA in response to the Original 
Investigational New Drug (IND) Application 118394 for PRT062070, as follows: 
• 
Changed starting dose from 15 mg BID to 15 mg QD. 
• 
Clarified DLT criteria regarding the exclusion of patients for DLT evaluation and AEs 
leading to treatment discontinuation. 
• 
Modified DLT hematologic criteria and made additional changes to DLT criteria. 
• 
Added of CBC and serum chemistry testing on Days 1 and 15 for Cycles 2 through 4. 
Amendment 2: 
19 November 2013 
• 
Added additional PK monitoring during the first cycle. In order to do this the cycle 
length was changed from 21 days to 28 days throughout. 
• 
Changed the schedule of tumor assessments from every 4 cycles after the first 
assessment at Cycle 3 to every 3 cycles.  This maintained tumor assessments at every 
12 weeks with the new cycle length of 28 days. 
• 
Started QD dosing and allowed for flexibility to test BID dosing, depending on 
available PK data from prior cohorts. 
• 
Added a list of strong CYP3A inhibitors and inducers and caution the Investigator as to 
their use. 
Amendment 3: 
02 April 2015 
• 
Changed the design of the study so as to conduct Part 2 (Dose Expansion phase) of the 
study using a 45 mg QD dose in 2 Groups of up to 40 patients each: 
o 
Group 1 was planned for patients with CLL/SLL who had progressed or relapsed 
on prior therapy with any Bruton’s tyrosine kinase (BTK) inhibitor (such as 
ibrutinib) or any phosphatidylinositide 3 kinase (PI3K) inhibitor 
(such as idelalisib) 
o 
Group 2 was planned for patients with FL who had progressed or relapsed on prior 
therapy. 
• 
Substituted the name cerdulatinib for PRT062070 throughout the protocol. Note: The 
title of the study was not changed and still read A Phase I Open-Label, Multi-Dose, 
Dose Escalation. 
Study of PRT062070 in Patients with Relapsed/Refractory Chronic Lymphocytic 
Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) or B-Cell Non-Hodgkin 
Lymphoma (NHL) 
1 
Patients with FL Grade 1 to 3A/iNHL who have received ≥ 1 prior treatment 
regimen. 
2 
Patients with FL Grade 1 to 3A/iNHL who have received ≥ 1 prior treatment 
regimen. In addition to receiving cerdulatinib, this cohort will also receive rituximab 
IV at 375 mg/m2 during Cycle 1 on Days 1, 8, 15, and 22 of Cycle 1 and during 
Cycles 4, 6, 8, and 10 on Day 1 only. 


Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 7 
 
 
 
 
Protocol Version: 
Date 
Key Changes 
3 
Patients with aggressive NHL (aNHL), defined as DLBCL, FL 3B, MCL, and 
transformed NHL. These patients have relapsed from ≥ 1 but ≤ 3 prior cytotoxic 
chemotherapy regimens with an anti CD20 antibody, (e.g., R-CHOP, BR). Patients 
must have received an anthracycline based therapy unless anthracyclines were 
deemed inappropriate in the judgement of the investigator. 
Patients must have either relapsed following ASCT or not be candidates (ineligible) 
for ASCT, defined as meeting any of the following criteria [1]: a) age ≥ 70 years; 
b) DLCO < 50% by pulmonary function tests; c) FEV1/FVC < 60% predicted by 
pulmonary function tests; d) LVEF < 45% by MUGA or echocardiogram; 
e) uncontrolled arrhythmia; f) calculated creatinine clearance (Cockcroft-Gault) 
≤ 60 mL/min; g) other comorbidities (e.g., medical conditions or psychosocial 
conditions) that would likely result in an unacceptably high probability of treatment/ 
transplant related morbidity and mortality in the judgement of the investigator (e.g., 
high HCT-CI, CIRS, scores); h) refusal of ASCT. 
(Note: Antibody drug conjugates (ADC) count as cytotoxic chemotherapy. Salvage 
chemotherapy prior to ASCT with or without maintenance therapy counts as one 
regimen.) 
4 
Patients with CLL/SLL who have received ≥ 1 prior treatment regimen. 
5 
Patients with PTCL NHL who have received ≥ 1 prior systemic treatment regimen 
for PTCL. 
6 
Patients with CTCL NHL who have received ≥ 1 prior systemic treatment regimen 
for CTCL. 
Amendment 4: 
06 April 2016 
• 
Changes to the study design: Updated the overall study design so that Protocol 13-601 
was described as an open-label, Phase 1/2a, multi-dose, multi-center trial of orally 
administered cerdulatinib with 2 distinct phases (note that at the time of implementation 
of Amendment 4, the Phase 1 portion of the study is closed to enrollment). 
o 
Expanded Phase 2a (Exploratory) portion to include 6 cohorts, each defined by 
cancer type and prior therapy: 
• 
Title Change: Changed title of protocol to A Phase I/2a Open-Label, Multi-Dose, 
Multi-Center Escalation and Exploratory Study of Cerdulatinib (PTR062070) In 
Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)/Small 
Lymphocytic Lymphoma (SLL) or B-Cell or T-Cell Non Hodgkin Lymphoma (NHL). 
• 
Updated/clarified Phase 2 objectives to address 6 cohorts. 
• 
Updated/clarified Phase 2 endpoints to address 6 cohorts. 
• 
Updated Phase 2a cancer-specific Inclusion Criteria. 
• 
Updated Exclusion Criteria to apply to patients in Phase 2a. 
• 
Updated the Statistical Analysis Plan to apply to Phase 2a. 
• 
Updated or added the following appendices: 
o 
Appendix 3, Eastern Cooperative Oncology Group (ECOG) Performance Status; 
Appendix 4, Table of Strong CYP3A4 Inhibitors and Inducers (and also added 
Table of CYP3A Sensitive Substrates); Appendix 5, added response definitions 
for B-cell NHL, PTCL, CLL, CTCL, and WM; Appendix 6, added prognostic 
indices for the following: Follicular Lymphoma International Prognostic Index-1 
(FLIPI) Criteria, International Prognostic Index (IPI) Criteria, Age-adjusted 
International Prognostic Index, Simplified Mantle-Cell Prognostic Index (MIPI), 
International Prognostic Scoring System for Waldenström’s Macroglobulinemia 
(IPSSWM); Appendix 7, added decision tree for differential of ABC vs. GCG 
type of DLCBL by ICH-Hans methodology; Appendix 8, added the following 
staging systems: Rai staging system for CLL, Binet staging system for CLL, 


Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 8 
 
 
 
 
Protocol Version: 
Date 
Key Changes 
Amendment 4: 
06 April 2016 
(Cont’d) 
Lugano Modification of Ann Arbor staging system for nodal lymphoma; and 
Appendix 9, updated to clarify Global Health Assessment scale for patients to 
report their level of health and added that patients could decline to answer. 
• 
Established a Study Committee for Protocol 13-601. 
Amendment 5: 
14 Oct 2016 
• 
Reduced starting dose of cerdulatinib from 35 mg BID to 30 mg BID, with subsequent 
reductions to 25 mg BID and then 20 mg BID permitted (Section 3.1.2.2.1 and 
throughout protocol). 
• 
Added pre- and post-study drug plasma sampling at C1D15 time point (Section 7.2.2.2). 
• 
Allowed unscheduled plasma samples for PK analyses to be collected at the discretion 
of the Investigator (e.g., in the event of an AE) (Section 9.1.2). 
• 
Added instruction to record date and time of last dose and last meal prior to PK 
sampling (Section 7.2.2.1 and throughout Section 7.2.2). 
• 
Modified Phase 2a General Inclusion Criteria, Section 4.1.2, item 5, to clarify the types 
of prior therapy allowed. 
• 
Modified Phase 2a General Inclusion Criteria, Section 4.1.2, item 7, to specify ANC 
and platelet criteria for CLL patients. 
• 
Modified Phase 2a General Inclusion Criteria, Section 4.1.2, item 8, to redefine 
adequate renal clearance. 
• 
Mandated prophylaxis for Pneumocystis carinii (PCP, aka Pneumocystis jirovecii 
Pneumonia) as well as prophylaxis for other opportunistic infections, per local standard 
of care or NCCN guidelines for all CLL enrolled patients; all other enrolled patients 
should receive prophylaxis described above (Section 7.6.2). 
• 
Identified AEs that may indicate potential drug toxicity (Section 10.1.3). 
• 
Updated routine chemistries to include assays for amylase and lipase (throughout 
Section 7.2.2 and Section 10.2.1). 
• 
Placed methodology applicable to the Phase 1 (Dose-Escalation) portion of the study 
(now closed to enrollment) in Appendix 12. 
• 
Added Table 2: Summary of Key Protocol Changes. 
• 
Made additional clarifications, deletions, and administrative corrections throughout the 
document and Appendices to improve clarity and consistency. 
Amendment 6: 
05 May 2017 
• 
Dose reductions to 15 mg BID permitted (after reducing from 30 mg BID starting dose 
to 25 mg BID and then 20 mg BID) (Section 3.1.2.2.1) 
• 
Dose escalations permitted after a dose reduction (up to a maximum dose of 30 mg 
BID) at the discretion of the investigator based upon clinical judgement and with 
Sponsor Medical Monitor approval. 
• 
Modified Study Methods to remove visit-by-visit instructions and instead provide 
details on each assessment (Section 7.0). The visit-by-visit instructions can be found in 
Appendix 1. 
• 
Added the option for patients to have a reduced on-site visit cycle after Cycle 12 in the 
event of a treatment response at Investigator’s discretion and with Sponsor Medical 
Monitor approval. The visit schedule can be reduced from on-site from Day 1 of every 
new cycle to every 3 cycles. Site staff should conduct phone visits for the cycles when 
the patient is not on-site (Section 7.3.2.1). 
• 
Clarified that patients should be on-site for Day 1 of all new cycles after Cycle 2 
(Section 7.3.2). 
• 
Modified Inclusion Criteria, Section 4.1.2, item 8 to decrease minimum creatinine 
clearance from ≥ 60 mL/min to ≥ 50 mL/min and allow for urine collection to measure 
creatinine clearance. 


Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 9 
 
 
 
 
Protocol Version: 
Date 
Key Changes 
Amendment 6: 
05 May 2017 
(Cont’d) 
• 
Modified Exclusion Criteria, Section 4.2, item 11 to prohibit any active infection 
requiring systemic treatment (not limited to IV treatment). 
• 
Changed overdose reporting requirements, including specifying the timeframe to 
require reporting within 24 hours of awareness (Section 10.2.4.11). 
• 
Addition of DNA and MRD sampling time points (Appendix 1). 
• 
Reduced post-dose Vital Signs collection to only 1 hour post-dose for all cohorts except 
Cohort 2 (Section 7.1.6). 
• 
Clarified that bone marrow biopsy and aspiration should only be repeated as clinically 
indicated in patients who were marrow-positive for lymphoma at baseline and to verify 
response in CLL patients (Section 7.1.12.1). 
• 
Removed the criteria governing cohort expansion (Section 11.2.2). 
• 
Changed long-term survival follow-up from “a minimum of 2 years” to “up to 2 years” 
(Section 7.3.2.3). 
• 
Clarified that serum protein electrophoresis (SPEP) and serum immunoelectrophoresis 
(SIEP) are required for Cohort 1 WM patients (Appendix 1) 
• 
Removed 60 mg cerdulatinib formulation as well as 50-count bottle packaging 
(Section 6.1.1). 
• 
Added visit windows and visit guideline clarification based upon previous Global 
Memo #2 (Section 7.3.3 and Appendix 1). 
• 
Clarified that PPIs are a prohibited medication (Section 7.5.1). 
• 
Made additional clarifications, deletions, and administrative corrections throughout the 
document and Appendices to improve clarity and consistency. 
Amendment 7: 
06 March 2019 
• 
Additional starting dose options were added for cerdulatinib. Starting doses are 30, 25, 
or 20 mg BID (Section 5.1.3). 
• 
Additional PK sampling was added at C1D1 and C1D8 at 1, 2, 4, 6, 8, and 24 hours 
post-dose, and the C1D15 post-dose sample was removed (Section 7.1.11). 
• 
Changes to Phase 2a general inclusion criteria (Section 4.1.2): 
o 
Prior therapy (IC #5) was updated to require patients with known 
CD30-expressing PTCL to have had at least one prior therapy that included a 
CD30-directed antibody (e.g., brentuximab vedotin). 
o 
Contraception requirements (IC #6) for Cohort 2 were aligned with the rituximab 
label, requiring patients use effective contraception during treatment with 
rituximab and for 12 months after the last dose of rituximab. 
o 
Adequacy of bone marrow reserves (IC #7) was updated to specify no limit on 
ANC or platelet count required for patients with leukemic forms of PTCL (ATLL, 
PLL, LGL) or hepatosplenic T-cell lymphoma (HSTCL). 
o 
Renal function inclusion (IC #8) was modified to require a creatinine clearance 
≥ 30 mL/min (previously: serum creatinine level ≤ 2 upper limit of normal [ULN] 
and a creatinine clearance ≥ 50 mL/min). 
o 
Cohort 1 will no longer enroll patients with marginal zone lymphoma (MZL) or 
Waldenström’s macroglobulinemia (IC #11). 
• Changes to Phase 2a exclusion criteria (Section 4.2): 
o 
Acid reducing agent (ARA) (EC #4) consumption was removed as an exclusion 
(e.g., ARAs are permitted), and it was clarified that intake of CYP3A4-sensitive 
substrates was also prohibited. 
o 
Prior therapy (EC #8) with alemtuzumab must have been greater than 3 weeks 
prior to C1D1 (previously: 8 weeks). 


Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 10 
 
 
 
 
Protocol Version: 
Date 
Key Changes 
Amendment 7: 
06 March 2019 
(Cont’d) 
o 
HIV and hepatitis (EC #10): positive/negative status must be known, with 
additional testing required if a patient does not have documentation of prior 
negative hepatitis panel or negative HIV history for patients. 
o 
Removed the directive to administer cerdulatinib under fasting conditons; 
cerdulatinib may be administered with food (Section 5.1.1). 
o 
Peripheral blood quantitative EBV polymerase chain reaction assay (PCR) was 
added to the baseline assessment and should be performed post-baseline for any 
unexplained fevers if there is clinical suspicion of EBV reactivation 
(Section 5.2.1.4). 
o 
Guidance on the management of Grade 1 and 2 diarrhea, nausea and vomiting was 
added (Sections 5.2.1.5 and 5.2.1.6). 
o 
The guidelines for dose reductions for cerdulatinib were updated (Table 8). 
• 
Clarified that rituximab is not provided by the Sponsor as it is considered standard of 
care (Section 5.3). 
• 
Added collection of molecular/mutation profile if obtained as standard of care 
(Section 7.1.9.2). 
• 
Clarified that patients may continue adjuvant hormonal therapy for prostate or breast 
cancer (Section 7.5.1). 
• 
Immunosuppressive agents was removed as a prohibited medication group (Section 
7.5.1). 
• 
Restrictions on the administration of anti-emetic agents were removed (Section 7.5.2). 
• 
Description of the Study Committee composition and function was revised to reflect 
current review practice (Section 7.6). 
• 
Assessement of Safety (Section 10.0) was revised for clarity. No new information was 
added. 
• 
For Cohort 1 iNHL patients only, whole blood sample collection for immune flow 
chemistry was removed from the protocol (Section 7.1.10.2 and Appendix 1). 
• 
Whole blood sample collection (all patients) for isolation of cell-free tumor DNA 
(ctDNA) was added (Section 7.1.10.1 and Appendix 1). 
• 
Post-dose vital signs assessments was removed from Cycle 2, Day 1 in the Schedule of 
Assessments (Appendix 1); a post-dose assessment was added in error to Cycle 2, 
Day 15. 
• 
Medical Monitor changed to 
 Syneos Health 
(previously: 
 Medical Monitor, INC Research). 
• 
Administrative Sections 12.0 – 16.0 were updated to align with company standard. 
• 
Appendix 12 was removed.  This appendix contained the methodology applicable to the 
Phase 1 portion of the study which is closed, but may be referenced in earlier versions 
of the protocol. 
Amendment 8: 
04 April 2019 
• 
Clarified instructions for the management of EBV reactivation (Section 5.2.1.4): in 
select cases, patients may continue to receive cerdulatinib with the Medical Monitor 
approval. 
• 
Clarified recording persistent versus recurrent adverse events (Section 10.2.4.3). 
• 
The Schedule of Assessments (Appendix 1) was updated for the following: 
a. 
Addition of a line item for HIV/HBV/HCV infection testing required as part of 
EC #10. 
b. Correction of pharmacodynamics sampling time point: removed at C1D9 and 
added at C1D8. 


Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 11 
 
 
 
 
Protocol Version: 
Date 
Key Changes 
Amendment 9: 
14 October 2019 
• 
Updated this Summary of Key Changes table (Amendment 7) based on omissions 
identified and communicated in Global Study Memo #14. 
• 
Added an exception to the statement that any patients with a dose interruption of > 28 
days should be permanently discontinued from cerdulatinib therapy (Section 5.2.1.3.1). 
• 
Updated Table 8 Guidelines for Dose Reductions for Cerdulatinib to state “may restart” 
instead of “restart” for consistency with language in Section 5.2.1.3.1 Dose 
Modifications to Cerdulatinib During Phase 2a. 
• 
Updated Section 5.2.1.5 Management of Diarrhea and Section 5.2.1.6 Management of 
Nausea and Vomiting to indicate that cerdulatinib can be restarted at the same dose 
level or at the next lower dose level. 
• 
Added details on new presentations of cerdulatinib that may be provided by Portola 
Pharmaceuticals, Inc. in Amendment 9 (Section 6.1.1). 
• 
Updated language in Section 7.1.6 Vital Signs for clarity and to allow post-dose vital 
sign measurements for Cohort 2 to be performed per standard of care. 
• 
Updated vital sign assessment window from ±5 minutes to ± 10 minutes in 
Section 7.1.6 Vital Signs for consistency with the Schedule of Assessments. 
• 
Deleted whole blood sample collection for pharmacodynamics and isolation of cell-free 
tumor DNA, as this is no longer needed (Section 7.1.10.1 and Schedule of Assessments 
[Appendix 1]) per Global Study Memo #15. 
• 
Deleted assessments for MRD (Sections 7.1.10.2, 7.1.12.2, 7.3.2.4, and 8.2.2; 
Schedule of Assessments [Appendix 1]) per Global Study Memo #15. 
• 
Updated Section 7.1.12.1 Bone Marrow Biopsy and Aspiration and the Schedule of 
Assessments (Appendix 1 ) for clarity and accuracy. 
• 
Removed the 2-year long-term follow-up from the study (Section 7.3.2.3; Schedule of 
Assessments [Appendix 1]), changed the definition of End of Study (Section 3.1.3) to 
reflect removal of the long-term follow-up, and changed the estimated study duration 
(Section 3.1.4; synopsis) to reflect removal of the long-term follow-up; removed 
references to long-term follow-up in Sections 5.2.1.3.1 and 5.2.1.3.2. 
• 
Updated language for flexibility in Section 7.6 Study Committee, since Principal 
Investigators may not be part of the Study Committee in Phase 2a. 
• 
Updated Section 3.1.5 Assessments, Section 9.2 Pharmacodynamic Assays, and 
Synopsis to accurately reflect sample collection. 
• 
Updated the causality categories and definitions of each category for adverse events 
(Section 10.2.3) 
• 
Updated the AE reporting term to “Disease Progression” for a death that is attributed 
solely to progression of the underlying malignancy (Section 10.2.4.7) to clearly 
distinguish between progression of an underlying malignancy (disease progression) and 
a new malignancy (new AE). 
• 
Corrected the rituximab infusion timepoints in the Schedule of Assessments 
(Appendix 1) for consistency with the protocol body and synopsis. 
• 
Deleted the post dose vital signs assessment at C2D15 in the Schedule of Assessments 
(Appendix 1) for consistency with the protocol body, as this was incorrectly added to 
the Schedule of Assessments in Amendment 7, but this assessment is not needed. 
• 
Added AE assessment at C1D9 and deleted AE assessment at long-term follow-up in 
the Schedule of Assessments in Appendix 1 (these were errors in Amendment 8). 


Clinical Study 13-601 
Portola Pharmaceuticals, Inc. 
Cerdulatinib 
Protocol Amendment 9 
14 October 2019 
Confidential 
Page 12 
 
 
 
 
SYNOPSIS 
 
Name of Sponsor/Company: Portola Pharmaceuticals, Inc. 
Name of Investigational Product: Cerdulatinib (PRT062070) 
Name of Active Ingredient: Cerdulatinib (PRT062070) 
Title: A Phase 1/2a Open-Label, Multi-Dose, Multi-Center Escalation and Exploratory Study of Cerdulatinib 
(PRT062070) in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic 
Lymphoma (SLL) or B-Cell or T-Cell Non-Hodgkin Lymphoma (NHL) 
Study Centers: Phase 1: 7 sites in the United States. Phase 2a: Approximately 40 sites in the United States. 
Phase of Development: 1/2a 
Study Duration: The duration of the study is approximately 6 years (Phase 1 and Phase 2a combined). 
Objectives and Endpoints: 
Phase 1 (Escalation portion) 
Primary Objective 
• To determine the maximum tolerated dose/maximum administered dose (MTD/MAD) of cerdulatinib in 
patients with relapsed/refractory chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) or 
B-cell non Hodgkin lymphoma (NHL). 
Secondary Objectives 
• To make a preliminary assessment of the antitumor activity of cerdulatinib in patients with relapsed/refractory 
CLL/SLL or B-cell NHL, as assessed by overall response rate (ORR), defined as complete response (CR) + 
partial response (PR). 
• To assess the safety and tolerability of cerdulatinib. 
• To determine the pharmacokinetic (PK) profile of cerdulatinib. 
• To evaluate the pharmacodynamics (PD) of cerdulatinib. 
Phase 2a (Exploratory portion) 
Primary Objective 
• To assess the antitumor activity of cerdulatinib in patients with specific subtypes of B-cell or T-cell NHL, or 
CLL/SLL, as a single agent and in combination with rituximab for B-cell NHL. 
Secondary Objectives 
• To assess the duration of antitumor activity of cerdulatinib, amount of time to achieve tumor response, and 
magnitude of response. 
• To further evaluate the PK profile of cerdulatinib in patients with specific subtypes of B-cell or T-cell NHL, 
alone or in combination with rituximab for B-cell NHL. 
• To further evaluate the PD of cerdulatinib in patients with specific subtypes of B-cell or T-cell NHL, alone or 
in combination with rituximab for B-cell NHL. 
• To assess tumor phenotype and genotype in relation to clinical response. 
• To further evaluate the safety and tolerability of cerdulatinib in patients with specific subtypes of B-cell or 
T-cell NHL or CLL/SLL. 
• To evaluate the safety and tolerability of the combination of cerdulatinib with rituximab for B-cell NHL. 


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Exploratory Objectives 
• To evaluate the relationship between markers of inflammation with clinical outcome and overall health as 
determined by the Global Health Assessment. 
• To assess Minimal Residual Disease (MRD) status in CLL patients achieving a complete response/complete 
response incomplete blood count recovery/partial response (CR/CRi/PR) by flow cytometry. MRD negativity 
(MRD-) is defined as < 1 CLL cell in 10,000 leucocytes. MRD+ (MR positivity) is defined as ≥ 1 CLL cell in 
10,000 leucocytes. 
Design and Methodology: This is an open-label, Phase 1/2a, multi-dose, multi-center trial of orally administered 
cerdulatinib with 2 phases: 
• Phase 1 (closed to enrollment): Dose-escalation, during which patients will receive single-agent cerdulatinib at 
their assigned dose level. 
− Patients will have histologically confirmed diagnosis of CLL/SLL or B-cell non-Hodgkin lymphoma. In 
addition, they will meet all other eligibility criteria as specified in Section 4.0 and applicable subsections. 
− The starting dose of cerdulatinib will be 15 mg once daily (15 mg QD). 
− Cerdulatinib will be administered in increasing dose levels until the MTD/MAD is identified (see 
definitions, Table 3). If the MTD is not achieved, the highest studied dose will be declared the MAD and 
become the recommended Phase 2 dose (RP2D). 
− To allow for a single-dose PK assessment, patients on a QD regimen will take their first dose of cerdulatinib 
on Day 1 and their second and subsequent doses daily beginning on Day 4. Patients will receive cerdulatinib 
once daily for a total of 28 days (one cycle) to assess the MTD/MAD, except on Days 2 and 3, when they 
will not take cerdulatinib. Patients in twice daily (BID) dosing regimens will start cerdulatinib on Day 1 and 
will not skip any days. 
− One patient will be enrolled in each dose cohort until the first report of a Grade 2 or greater adverse event 
(AE). 
 In the event of any Grade 2 or greater AE in a single patient, an additional 2 patients, for a total of 3, 
will be enrolled in that dose cohort, and all subsequent dose cohorts will follow a “3 + 3” design. 
 Dose escalation will be in 100% increments until a drug-related AE of Grade ≥ 2 occurs. Thereafter, 
dose escalation will be in increments of up to 50% as determined following review by the Study 
Committee. 
 If a dose-limiting toxicity (DLT) occurs in 1 of the first 3 patients in a cohort, that cohort will be 
expanded to at least 6 patients. 
o If ≤ 33% of 6 or more patients in a cohort experiences DLT, dose escalation may proceed. 
o If in any cohort 2 or more of the first 3 patients or ≥ 33% of patients in a cohort develop DLT, dose 
escalation will cease, and that dose level will be declared intolerable. The prior dose level will either 
be declared the MTD, and the cohort may be expanded to as many as 6 patients if fewer than 
6 patients had been treated previously at that dose level in order to further characterize the PK and 
PD at that level. 
• The study is currently in Phase 2a: Exploratory, consisting of 6 cohorts, each defined by cancer type and 
prior therapy 
− Under Amendment 7, the starting dose of orally administered cerdulatinib is either 30, 25, or 20 mg BID. 
Subsequent de-escalations to 25, 20, and then 15 mg BID are permitted. A patient who has been de- 
escalated may be re-escalated at the discretion of the Investigator based upon clinical judgement and with 
Sponsor Medical Monitor approval per the Dose Modification Guidelines for Phase 2a (Section 5.2.1.3). 
− The 6 cohorts are defined below: 
 Cohort 1: Patients with follicular lymphoma Grade 1 to 3A who have received ≥ 1 prior treatment 
regimen. 
 Cohort 2: Patients with FL Grade 1 to 3A who have received ≥ 1 prior treatment regimen. In addition 
to receiving cerdulatinib, this cohort will also receive rituximab IV at 375 mg/m2 during Cycle 1 on 
Days 1, 8, 15, and 22 and during Cycles 4, 6, 8, and 10 on Day 1 only. 


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 Cohort 3: Patients with aggressive NHL (aNHL), defined as diffuse large B-cell lymphoma (DLBCL), 
follicular lymphoma Grade B (FL 3B), Mantle Cell lymphoma (MCL), and transformed NHL. These 
patients have relapsed from ≥ 1 but ≤ 3 prior cytotoxic chemotherapy regimens with an anti CD20 
antibody, (e.g., R-CHOP, BR). Patients must have either relapsed following autologous stem cell 
therapy (ASCT) or not be candidates (ineligible) for ASCT, defined as meeting any of the following 
criteria [1]: a) age ≥ 70 years; b) DLCO < 50% by pulmonary function tests; c) forced expiratory 
volume in 1 second/forced vital capacity; (FEV1/FVC) < 60% predicted by pulmonary function tests; d) 
left ventricular ejection fraction (LVEF) < 45% by multiple gated acquisition (MUGA) or 
echocardiogram; e) uncontrolled arrhythmia, f) calculated creatinine clearance (Cockcroft-Gault) 
≤ 60 mL/min; g) other comorbidities (e.g., medical conditions or psychosocial conditions) that would 
likely result in an unacceptably high probability of treatment/transplant related morbidity and mortality 
in the judgement of the investigator (e.g., high Hematopoietic Cell Transplantation Co-Morbidity Index 
(HCT-CI), Cumulative Illness Rating Scale (CIRS) scores); h) refusal of ASCT. 
(Note: Antibody drug conjugates (ADC) count as cytotoxic chemotherapy. Salvage chemotherapy 
prior to ASCT with or without maintenance therapy counts as one regimen.) 
 Cohort 4: Patients with CLL/SLL who have received ≥ 1 prior treatment regimen. 
 Cohort 5: Patients with peripheral T-cell lymphoma (PTCL) NHL who have received ≥ 1 prior 
systemic treatment regimen for PTCL. In patients with CD30-expressing PTCL, prior treatment must 
include a CD30-directed antibody (e.g., brentuximab vedotin). 
 Cohort 6: Patients with cutaneous T-cell lymphoma (CTCL) NHL who have received 
≥ 1 prior systemic treatment regimen for CTCL. 
Number of Patients (Planned): 
Phase 1: 
43 patients were enrolled and dosed. Enrollment to Phase 1 is closed. 
Phase 2a: 
Approximately 240 patients. 
Total: 
Up to 283 patients dosed for the entire study 
Diagnosis and Main Criteria for Inclusion: 
Phase 1 Cancer-Specific Inclusion Criteria 
1. Patient must have a histologically confirmed diagnosis of 1 of the following: 
− CLL/SLL 
− B-cell non-Hodgkin lymphoma, any of the types specified below, all with relapsed or refractory disease: 
 Diffuse Large B-cell lymphoma (DLBCL) 
 Follicular lymphoma (FL) 
 Mantle cell lymphoma (MCL) 
 Mucosa Associated Lymphoid Tumor (MALT) 
 Marginal zone lymphoma (MZL) 
 Lymphoplasmacytic lymphoma (LPL) 
Phase 1 General Inclusion Criteria 
1. Patient has failed at least 1 prior established treatment regimen (e.g., progressed during, or refractory to), and no 
other standard therapy exists for that patient, or patient is intolerant of existing standard therapy or is not a 
candidate for such standard therapy. 
2. Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1. 
3. Patient must be 18 years or older, of either sex, and of any race. 
4. Patient (and/or parent/guardian for patients who otherwise are unable to provide independent consent) must be 
willing to give written informed consent and be able to adhere to dose and visit schedules. 


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5. Female patients of childbearing potential and male patients must agree to abstain from sexual intercourse or to 
use an effective method of contraception during the study and for 90 days following the last dose of protocol 
therapy (examples of effective methods of contraception include oral contraceptives or double barrier methods 
such as condom plus spermicide or condom plus diaphragm). 
6. Patient must have adequate bone marrow reserve as evidenced by an absolute neutrophil count 
(ANC) ≥ 1,000/µL AND platelet count ≥ 75,000/µL. 
7. Patient must have adequate renal function as evidenced by a serum creatinine level ≤ 1.5 × upper limit of 
normal (ULN) or a calculated creatinine clearance > 60 mL/min. 
8. Patient must have adequate hepatic function as evidenced by a serum bilirubin level ≤ 2.0 mg/dL AND serum 
aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels ≤ 2.5 × the ULN for the reference 
laboratory. Serum bilirubin must be ≤ 2.5 mg/dL when increase is clearly documented as due to 
Gilbert’s syndrome. 
Phase 2a Cancer-Specific Inclusion Criteria 
Patient must have a histologically confirmed diagnosis of 1 of the following: 
Note: Definitions for “relapsed” and “refractory” disease are provided in Table 3. 
• FL Grade 1 to 3A, with relapsed or refractory disease. 
• Aggressive NHL (aNHL), defined as DLBCL, FL Grade 3B, MCL, and transformed NHL with 
relapsed disease. 
• CLL/SLL, with relapsed or refractory disease. 
• PTCL, with relapsed or refractory disease. 
• CTCL with relapsed or refractory disease. Only CTCL patients with MF/SS are allowed. 
Patients who received any BCR pathway inhibitor (e.g., BTK inhibitors such as ibrutinib, or PI3 Kinase inhibitors 
such as idelalisib) and/or BCL2 pathway inhibitors (e.g., venetoclax), and were either intolerant to therapy or had 
relapsed/refractory disease following therapy are also eligible. 
Phase 2a General Inclusion Criteria 
1. Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1. 
2. Patient must be 18 years or older, of either sex, and of any race. 
3. Patient (and/or parent/guardian for patients who otherwise are unable to provide independent consent) must be 
willing to give written informed consent and be able to adhere to dose and visit schedules. 
4. Patient has had prior treatment for lymphoid malignancy requiring treatment for progressive disease/refractory 
disease (per guidelines for diagnosis and treatment of CLL [2] and revised response criteria for 
malignant lymphoma [3]). 
5. Patient has had ≥ 1 prior systemic treatment regimen administered for at least 2 cycles (unless the patient was 
intolerant or experienced documented progression on therapy) that must have involved either: (1) an anti-CD20 
agent (such as rituximab) WITH chemotherapy for B-cell NHL, unless contraindicated in the judgement of the 
investigator (e.g., the patient was not a candidate for chemotherapy and received ibrutinib as firstline treatment); 
(2) a cytotoxic chemotherapy drug for T-cell NHL; (3) an anti-CD20 agent (such as rituximab) with 
chemotherapy for CLL, unless contraindicated in the judgement of the investigator (e.g., the patient was not a 
candidate for chemotherapy and received ibrutinib as firstline treatment); or (4) in patients with 
CD30-expressing PTCL, a CD30-directed antibody (e.g., brentuximab vedotin). 
6. Female patients of childbearing potential and male patients must agree to abstain from sexual intercourse or to 
use an effective method of contraception during the study and for 90 days following the last dose of protocol 
therapy (examples of effective methods of contraception include oral contraceptives or double barrier methods 
such as condom plus spermicide or condom plus diaphragm). Patients enrolled into Cohort 2 should use 
effective contraception during treatment with rituximab and for 12 months after the last dose of rituximab. 


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7. Patient must have adequate bone marrow reserve as evidenced by an absolute neutrophil count 
(ANC) ≥ 1,000/µL, platelet count ≥ 75,000/µL. Platelet count must be without transfusion support within 
7 days of the first dose of cerdulatinib. 
Note: CLL patients only: ANC ≥ 750/µL and platelet count ≥ 30,000/µL are acceptable. There are no limits 
on ANC or platelet count required for patients with leukemic forms of PTCL (ATLL, PLL, LGL) or 
hepatosplenic T-cell lymphoma (HSTCL) as long as cytopenia, if present, is secondary to disease. 
8. Patient must have adequate renal function as evidenced by a creatinine clearance ≥ 30 mL/min (calculated using 
the Cockcroft-Gault equation or based on a 24-hour urine specimen). 
9. Patient must have adequate hepatic function as evidenced by a serum bilirubin level ≤ 2.0 mg/dL AND serum 
AST/ALT levels ≤ 2.5× the ULN for the reference lab. Serum bilirubin ≤ 2.5 mg/dL when increase clearly 
documented as due to Gilbert’s syndrome. 
10. Where available, ability to submit a formalin-fixed paraffin embedded tissue (FFPE) block or a minimum of 
10 unstained, freshly cut FFPE tissue slides from lymph node or other biopsies that were collected as part of 
patient diagnosis. If samples are unavailable the patient is still eligible for enrollment. 
11. Measureable disease for a given tumor type, defined as: 
a. The presence of ≥ 1 lesion that measures ≥ 1.5 cm in a single dimension as assessed by CT, CT/PET for 
patients with nodal or mass lesions (e.g., FL, DLBCL, other NHL), or 
b. Quantifiable circulating tumor cells for patients with circulating tumor (e.g., Sézary Syndrome [SS]), or 
c. For CTCL: mSWAT score > 0. 
12. Ability to provide redacted copies of pathology reports and radiology reports used for the diagnosis of NHL or 
CLL. In addition, for CTCL, ability to provide redacted photographs of skin responses. 
Phase 2a Cohort-Specific Inclusion Criteria 
• Cohort 1 (FL): Grades 1 to 3A (Single-Agent Cerdulatinib): Received ≥ 1 prior treatment regimen. 
• Cohort 2 (Combination): FL, Grades 1 to 3A (Cerdulatinib + Rituximab): Received ≥ 1 prior treatment 
regimen. 
• Cohort 3 (aNHL): aNHL (Single-Agent Cerdulatinib): Aggressive non-Hodgkin lymphoma (aNHL) is 
defined as DLBCL, FL Grade 3B, Mantle Cell Lymphoma (MCL), and transformed NHL. Patients had 
relapsed from ≥ 1 but ≤ 3 prior cytotoxic chemotherapy regimens with an anti CD20 antibody, (e.g., R-CHOP, 
BR). Patients must have received an anthracycline based therapy unless anthracyclines were deemed 
inappropriate in the judgement of the investigator. Patients must have either relapsed following autologous 
stem cell therapy (ASCT), or not be candidates (ineligible) for ASCT, defined as meeting any of the following 
criteria [1]: a) Age ≥ 70 years; b) DLCO < 50% by pulmonary function tests; c) FEV1/FVC < 60% predicted 
by pulmonary function tests; d) LVEF < 45% by MUGA or echocardiogram; e) uncontrolled arrhythmia; f) 
calculated creatinine clearance (Cockcroft-Gault) ≤ 60 mL/min; g) other comorbidities (e.g., medical 
conditions or psychosocial conditions) that would likely result in an unacceptably high probability of 
treatment/transplant related morbidity and mortality in the judgement of the investigator (e.g., high HCT-CI, 
CIRS, scores); h) Refusal of ASCT. 
• Note: Antibody drug conjugates (ADC) count as cytotoxic chemotherapy. Salvage chemotherapy prior to 
ASCT with or without maintenance therapy counts as one regimen. 
• Cohort 4 (CLL/SLL): CLL/SLL (Single-Agent Cerdulatinib): Received ≥ 1 prior treatment regimen. 
• Cohort 5 (PTCL NHL): Peripheral T-cell NHL (PTCL) (Single-Agent Cerdulatinib): Received ≥ 1 prior 
systemic treatment regimen for PTCL. In patients with CD30-expressing PTCL, prior treatment must include a 
CD30-directed antibody (e.g., brentuximab vedotin). 
• Cohort 6 (CTCL NHL): Cutaneous T-cell NHL (CTCL, MF/SS only) (Single-Agent Cerdulatinib): 
Received ≥ 1 prior systemic treatment regimen for CTCL. 
Phase 1 and Phase 2a Exclusion Criteria 
A patient meeting any 1 of the Exclusion Criteria listed below will be excluded from the trial, whether enrolled in 
Phase 1 or Phase 2a of the study. 


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1. Patient has Richter’s syndrome, Burkitt’s lymphoma, or Burkitt-like Lymphoma. Patients with transformed 
DLBCL from Follicular NHL are eligible. 
2. Patient has undergone prior allogeneic or autologous transplant with infusion of stem cells within 90 days 
before Cycle 1 Day 1 (C1D1), or on active immunosuppressive therapy for graft-versus-host disease (GVHD) 
or GVHD prophylaxis within 8 weeks before C1D1. 
3. Patient has received prior therapy with a spleen tyrosine kinase (SYK) inhibitor. 
4. Patient requires chronic treatment with a strong CYP3A4 inhibitor or inducer or CYP3A4-sensitive substrate 
(Appendix 3). 
5. Patient has known lymphomatous involvement of the central nervous system (CNS). 
6. Patient has a known hypersensitivity to any of the components of cerdulatinib. 
7. Patient has persistent, unresolved NCI CTCAE v5.0 ≥ Grade 2 clinically significant (in the judgement of the 
investigator) drug-related toxicity (except alopecia, erectile impotence, hot flashes, libido, neuropathy) 
associated with previous treatment. 
8. Prior monoclonal antibody (Mab) (including alemtuzumab), radioimmunoconjugate, antibody drug conjugate 
(ADC), phototherapy, radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any 
investigational agent for the purposes of treating cancer within 3 weeks before Cycle 1 Day 1. 
9. For CTCL patients only: total skin electron beam therapy (TSEBT) within 12 weeks, or initiation of topical 
steroid, nitrogen mustard, or topical retinoid within 2 weeks before Cycle 1 Day 1. Patients with CTCL who are 
on a stable topical regimen for ≥ 4 weeks prior to C1D1 are allowed. 
10. The patient has a known infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) or is a carrier 
of HBV or HCV. Patients who are seropositive for HCV antibody must test negative for HCV by polymerase 
chain reaction (PCR) assay to be eligible. Patients with an occult or prior HBV infection (defined as being 
seropositive for total hepatitis B core antibody [HBcAb] and seronegative for HBsAg) may be included if his or 
her HBV DNA is undetectable or if it is undetectable with antiviral therapy. These patients must be willing to 
undergo additional testing per local standard of care if this data is unavailable. Additional testing will be 
performed if the patient does not have documentation of a negative hepatitis panel and negative HIV history 
within the 12-week period prior to enrollment. 
11. Patient has an active infection requiring systemic treatment, defined as requiring antimicrobial, antifungal, or 
antiviral agents.  Prophylactic antimicrobial treatment is permitted. 
12. Patient has significant gastrointestinal disease that may interfere with absorption of the study drug or that 
predisposes him/her to GI adverse effects, or has had major gastric or bowel surgery. 
13. Patient has difficulty swallowing or malabsorption syndrome. 
14. Patient has any other medical, social, or psychiatric condition that might interfere with the patient’s 
participation in the trial or interfere with the interpretation of trial results. 
15. Patient has undergone major surgery within 4 weeks prior to first study drug administration. 
16. Patient has a history (within 2 years prior to first study drug administration) of another malignancy unless 
malignancy treated with curative intent and likelihood of relapse is small (< 5% in 2 years in the judgement of 
the investigator). Patients with a history of squamous or basal cell carcinoma of the skin or carcinoma in situ of 
the cervix may be enrolled. 
17. Patient is receiving systemic steroids at doses greater than the equivalent of prednisone, 20 mg daily, with the 
exception of intermittent use for the treatment of emesis. 
18. Patient is female and is breast-feeding, pregnant, or intends to become pregnant. 
19. Patient is participating in any other therapeutic clinical study (observational or registry trials are allowed). 


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Investigational Product, Dosage and Mode of Administration: 
Cerdulatinib, administered orally (po) during both phases: 
• Phase 1 (dose-escalation): Starting dose is 15 mg QD in increasing dose levels until the MTD/MAD is 
identified. 
• Phase 2a (exploratory): Six cohorts are planned. Five cohorts will receive single-agent cerdulatinib and 
1 cohort will receive cerdulatinib plus rituximab IV at 375 mg/m2 during Cycle 1 on Days 1, 8, 15, and 22 and 
during Cycles 4, 6, 8, and 10 on Day 1 only. 
• Cerdulatinib will be administered at the following starting dose levels: 30, 25, or 20 mg BID. 
Duration of Treatment for Individual Patients and Duration of Study: 
Patients enrolled under Phase 1 and Phase 2a portions of this study may continue to receive cerdulatinib in the 
absence of disease progression or intolerable toxicity or until they meet any other withdrawal criteria (Section 4.4). 
The total duration of the study (Phase 1 and Phase 2a) is expected to be ~6 years. 
Reference Therapy, Dosage, and Mode of Administration: None. 
Criteria for Evaluation: 
Efficacy (Primary and Secondary) 
Response Criteria: Response in NHL patients will be evaluated using The Lugano Classification [4]; in CLL 
patients using the Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines for the Diagnosis and 
Treatment of Chronic Lymphocytic Leukemia [2]; and in CTCL patients using the modified Severity Weighted 
Assessment Tool (mSWAT) and other measures as appropriate [5]. Appendix 4 provides definitions and detailed 
descriptions of response criteria as well as guidance on selection of lesions for evaluation. Redacted copies of 
radiology reports will be sent to the Sponsor for review. 
Tumor/Lymph Node Biopsies: If tumor or lymph node or skin biopsies (including CTCL patients) biopsies are 
obtained during the course of the patient’s treatment, redacted copies of the pathology reports should be sent to the 
Sponsor for review. In addition, a portion of the tumor block or at a minimum of 10 unstained slides should be sent 
for review as discussed in earlier sections of the protocol. 
Exploratory Efficacy: Global Health Questionnaire and detection of minimal residual disease in CLL patients 
achieving a CR or CRi or PR using 4-color flow cytometry. MRD negativity (MRD-) is defined as < 1 CLL cell in 
10,000 leucocytes. MRD positivity (MRD+) is defined as ≥ 1 CLL cell in 10,000 leucocytes. 
Pharmacokinetic Assessments: Phase 1: Blood samples will be obtained at frequent intervals for determination of 
cerdulatinib concentration. Parameters calculated for all patients will be: plasma half-life (t½); time to maximum 
observed plasma concentration (Tmax); maximum observed plasma concentration (Cmax); minimum observed plasma 
concentration (Cmin); area under the plasma concentration-time curve from 0 to last measurable concentration 
(AUC0-last) computed using the linear trapezoidal rule; total area under the plasma concentration-time curve from 
time 0 to infinity (AUC0-∞); clearance of cerdulatinib (CL/F); volume of distribution of cerdulatinib at steady state 
(Vss/F); amount of drug excreted in urine over the sampling interval (Ae) for those patients for whom total volume 
of urine was collected; accumulation ratio, calculated by AUC0-12 at steady-state/AUC0-12 following the first dose for 
those patients for whom the 12-hour sample was collected. 
Phase 2a: In order to further characterize the PK of cerdulatinib (specifically, Cmin), serial plasma PK samples will 
be collected on Cycle 1 Days 1 and 8 at pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. PK samples will also be 
taken pre-dose at Cycle 1 Day 15, Cycle 2 Day 1, and prior to Cycles 3, 6, 9, and every 3 cycles thereafter (to 
correspond with tumor assessment). Additional unscheduled PK plasma samples may be taken at the discretion of 
the Investigator (e.g., in the event of an AE or dose change). 
Pharmacodynamic Assessments: Serum will be obtained at various time points throughout the trial to determine 
the effects of cerdulatinib on markers of inflammation. DNA and RNA (DNA only for Phase 2a) will be isolated 
from optional tumor biopsy specimens to assess genetic mutations relevant to the disease and the mechanism of 
action of cerdulatinib. The following will be assessed: quantification of serum proteins, quantitative polymerase 
chain reaction (PCR) for tumor relevant transcripts; hybridization of RNA to gene arrays, and DNA sequencing to 
identify disease-relevant mutations. 


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Safety: Safety will be monitored by serial physical exams, vital signs, hematology and chemistry laboratory studies, 
concomitant medications, and reported AEs (including deaths and other serious adverse events [SAEs] and 
treatment-related AEs). 
Study Committee: Select study participants will comprise the Study Committee (e.g., selected Principal 
Investigators, Portola’s Medical Monitor, Clinical Study Manager, and Drug Safety Medical Monitor). Other 
Portola or outside personnel may be called or consulted as needed. The Study Committee composition and 
functions are fully defined in Section 7.6. During Phase 1, the Study Committee will meet after all patients in any 
cohort have completed Cycle 1 to determine whether it is safe to escalate to the next dose of cerdulatinib or whether 
the MTD/MAD dose has been reached. If it is safe to continue, the committee will determine the next dose level to 
be studied. During Phase 2a, the Study Committee will meet periodically to review available safety and efficacy 
data from the study. Following the first meeting of the Study Committee, subsequent meetings will be held 
periodically as needed. Data to be evaluated may include (but are not limited to): deaths, other SAEs, AEs, 
including treatment-related AEs; reasons for treatment discontinuation or dose modification/interruption, trends in 
laboratory evaluations, and efficacy. For the combination cohort with rituximab, the Study Committee will evaluate 
(using the assessments as outline above) the first 3 to 6 patients who have completed Cycle 1 before allowing further 
enrollment in the cohort. Afterwards, the cohort can be evaluated with the rest of the other cohorts as above. 
Statistical Methods: 
General Considerations: Statistical summaries are expected to be performed using SAS software Version 9.3 
(SAS Institute, Inc., Cary, NC, USA) or higher. Additional software may be used for the production of graphics. 
Analysis Populations: The safety analysis population will consist of all patients treated with at least 1 dose of study 
medication (cerdulatinib). Safety data will be summarized by dose level, based on the original assigned dose of 
study drug. The efficacy analysis population for the primary and secondary efficacy endpoints will consist of all 
patients who have taken at least 1 dose of study medication and have had at least 1 post-baseline tumor assessment. 
Efficacy will be summarized separately for Phase 1 and 2a, and within Phase 2a will be summarized by cohort and 
dose level. The PK and PD analysis populations will consist of all patients who have received the requisite 
treatments and have data at the required time points. In order to determine cohort comparability, baseline and 
demographic characteristics of the Phase 1 and 2a cohorts will be summarized by dose cohort and overall. No 
formal analyses of these data are planned, but descriptive statistics may be used to aid in interpreting results. 
Analysis of Efficacy Endpoints: Responses will be classified as complete response (CR), partial response (PR), 
stable disease (SD), disease progression (PD), or not evaluable. The overall response rate (ORR, defined as 
CR+PR) and clinical benefit rate (CR+PR+SD) will be summarized along with two-sided exact 95% confidence 
intervals. Responses will be based on computed tomography (CT) or computed tomography/positron emission 
tomography (CT/PET), evaluated per revised IWG Criteria [3] for patients with lymphoma and on peripheral 
lymphocyte counts and bone marrow biopsy results for patients with CLL [2]. Listings of tumor response for each 
patient will also be provided. Responses will be summarized separately for each dose level in Phase 1 and for each 
cohort and dose level in Phase 2a. Due to differences in underlying disease and prior treatment, response rates 
considered clinically significant and that would prompt further study will depend on the cohort. Such summaries 
will also depend on the safety and tolerability profile observed. While it is anticipated that a 30 to 40% response 
rate will be sufficient to support further investigation, no criteria for success in this study are specified. 
In addition to the tumor response rates described above, the following efficacy endpoints will be assessed: duration 
of response (DOR), progression-free survival (PFS), lymph node response (LNR), and time-to-treatment response 
(TTR) (see definitions in Table 3). 
Exploratory Efficacy – Phase 2a Only 
As an exploratory assessment, patients will be asked to complete a Global Health Assessment (Appendix 8) to 
assess whether patients feel their overall health is improving on this study. The correlation between markers of 
inflammation with clinical response and the overall health (Global Health Assessment) will be assessed. 
An additional exploratory assessment, detection of minimal residual disease (MRD) in CLL patients achieving a CR 
or CRi or PR will also be performed using at least 4 color flow cytometry by either local lab or a designated central 
lab in blood and/or marrow. MRD- (MRD negativity) defined as < 1 CLL cell in 10,000 leucocytes. MRD+ (MRD 
positivity) is defined as ≥ 1 CLL cell in 10,000 leucocytes. 


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Pharmacokinetic Analyses: PK parameters will be calculated for each patient for which adequate samples are 
available and summarized. 
Pharmacodynamic Analyses, Phase 1 and 2a: A number of PD parameters (described above) will be measured 
serially. At each time point, each of these parameters will be summarized by dose level. In addition, the parameters 
over time will be plotted for each patient and dose cohort. No formal statistical analyses are planned. 
Safety, Phase 1 and 2a: For the Phase 1 portion of the study, the primary safety endpoint is the incidence of DLT by 
dose level and the secondary safety endpoints are the AE profile (classified by NCI-CTCAE v5.0), clinically 
significant changes in vital signs and physical exams by dose level, and changes in hematology and chemistry 
laboratory parameters by dose level. The incidence of DLT will be summarized and listed by dose cohort for 
Phase 1. 
For the Phase 1 and Phase 2a portions of the study, AEs will be graded according to the National Cancer Institute 
Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v5.0 and coded according to the latest Medical 
Dictionary for Regulatory Activities (MedDRA) version available at the time of database creation. The number and 
percent of patients with any AE will be presented by System Organ Class (SOC) and preferred term for each cohort 
will be summarized by dose cohort for Phase 1 and by Cohort for Phase 2a. An additional summary will include all 
patients who received the dose used in Phase 2a. Vital signs, laboratory parameters, and ECG intervals will be 
summarized and listed by time point for each dose cohort for Phase 1 and by cohort for Phase 2a. No formal 
statistical analyses are planned. 
Sample Size Considerations 
Phase 1: The sample size is based on clinical judgment and is typical of studies of this type. A total of 
approximately 40 to 50 patients will be studied in Phase 1, depending on the number of dose levels evaluated. 
To date, 52 patients have been enrolled with 43 dosed in sites in North America. 
Phase 2a: For the initial opening of this portion of the study, patients will be enrolled into 3 cohorts only: 
Cohorts 1 (FL), 3 (aggressive NHL [aNHL]), and 4 (CLL/SLL). Further cohorts may be opened or closed and the 
starting dose for patients may be adjusted at the discretion of the Sponsor, and the Sponsor will notify the 
Investigators/site when the other cohorts will be open or closed to enrollment or when the starting dose is adjusted. 
Initial enrollment into any cohort will be up to 20 patients; cohorts may be expanded to 40-50 evaluable patients. 
A total of approximately 240 patients is planned in the Phase 2a portion of the study. If fewer than 2 responses are 
seen in the first 20 patients, enrollment in the cohort will be closed, as the upper bound (UB) of the 95% confidence 
interval would be approximately 25%. If 2 or more responses are seen, the cohort may be expanded. With 
40 patients in a cohort, an observed response rate of 30% will have a 2-sided exact 95% confidence interval (CI) of 
(16.6%, 46.5%); an observed response rate of 20% will have a 2-sided exact 95% CI of 9.1%, 35.7%. 


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TABLE OF CONTENTS 
Page 
INVESTIGATOR’S AGREEMENT ......................................................................................................... 3 
SPONSOR’S AGREEMENT ..................................................................................................................... 4 
STUDY CONTACT INFORMATION AND PROCEDURES IN CASE OF EMERGENCY ............. 5 
SYNOPSIS ................................................................................................................................................. 12 
1.0 
INTRODUCTION ........................................................................................................................ 34 
1.1. 
CERDULATINIB (PRT062070) .............................................................................................. 34 
1.2. 
PHARMACOLOGY STUDIES OF CERDULATINIB ........................................................... 34 
1.3. 
SAFETY PHARMACOLOGY STUDIES................................................................................ 36 
1.4. 
NONCLINICAL TOXICOLOGY STUDIES ........................................................................... 37 
1.5. 
CERDULATINIB PHASE 1 INTERIM RESULTS ................................................................. 40 
1.6. 
BACKGROUND ON THE NHL IN THE STUDY .................................................................. 42 
1.6.1. 
Aggressive B-cell Lymphomas ........................................................................................ 43 
1.6.2. 
Rituximab in the Treatment of B-cell NHL ..................................................................... 43 
1.6.3. 
T-cell NHL (PTCL, CTCL) ............................................................................................. 44 
1.6.4. 
Follicular Lymphoma and Other Indolent Lymphomas (iNHL); (FL/iNHL) .................. 45 
1.6.5. 
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)............ 46 
2.0 
OBJECTIVES AND ENDPOINTS ............................................................................................. 47 
2.1. 
OBJECTIVES ........................................................................................................................... 47 
2.1.1. 
Phase 1 Objectives (Escalation) ....................................................................................... 47 
2.1.1.1. 
Primary Objective ................................................................................................... 47 
2.1.1.2. 
Secondary Objectives.............................................................................................. 47 
2.1.2. 
Phase 2a Objectives (Exploratory) ................................................................................... 47 
2.1.2.1. 
Primary Objective ................................................................................................... 47 
2.1.2.2. 
Secondary Objectives.............................................................................................. 47 
2.1.2.3. 
Exploratory Objectives ........................................................................................... 48 
2.2. 
ENDPOINTS ............................................................................................................................ 48 
2.2.1. 
Phase 1 Endpoints ............................................................................................................ 48 
2.2.1.1. 
Primary Endpoint .................................................................................................... 48 
2.2.1.2. 
Secondary Endpoints .............................................................................................. 48 
2.2.2. 
Phase 2a Endpoints .......................................................................................................... 49 
2.2.2.1. 
Primary Endpoint .................................................................................................... 49 
2.2.2.2. 
Secondary Endpoints .............................................................................................. 49 
2.2.3. 
Exploratory Endpoints ..................................................................................................... 49 
3.0 
INVESTIGATIONAL PLAN ...................................................................................................... 50 
3.1. 
OVERALL STUDY DESIGN AND STUDY SCHEMA ......................................................... 50 
3.1.1. 
Phase 1 ............................................................................................................................. 50 
3.1.1.1. 
Overall Description ................................................................................................. 50 


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3.1.1.2. 
Rationale for Dose Selection in Phase 1 and Dose-Escalation Methods ................ 51 
3.1.2. 
Phase 2a ........................................................................................................................... 51 
3.1.2.1. 
Overall Description, Including Rationale for Inclusion of T-cell 
Malignancies ........................................................................................................... 51 
3.1.2.2. 
Rationale for Initial Starting Dose and Individual Dose Reductions ...................... 54 
3.1.3. 
End of Study .................................................................................................................... 60 
3.1.4. 
Total Number of Patients, Cessation of Treatment, and Total Duration of 
the Study .......................................................................................................................... 60 
3.1.5. 
Assessments ..................................................................................................................... 60 
3.2. 
RANDOMIZATION AND BLINDING ................................................................................... 60 
4.0 
SELECTION, ENROLLMENT, AND WITHDRAWAL OF PATIENTS ............................. 61 
4.1. 
INCLUSION CRITERIA .......................................................................................................... 61 
4.1.1. 
Phase 2a Cancer-specific Inclusion Criteria .................................................................... 61 
4.1.2. 
Phase 2a General Inclusion Criteria ................................................................................. 61 
4.1.3. 
Phase 2a Cohort-specific Inclusion Criteria ..................................................................... 63 
4.1.3.1. 
Cohort 1 (FL) – Grades 1 to 3A (Single-agent Cerdulatinib) ................................. 63 
4.1.3.2. 
Cohort 2 (Combination) – FL, Grades 1 to 3A (Cerdulatinib + Rituximab) ........... 63 
4.1.3.3. 
Cohort 3 (aNHL) – aNHL (Single-agent Cerdulatinib) .......................................... 63 
4.1.3.4. 
Cohort 4 (CLL/SLL) – CLL/SLL (Single-agent Cerdulatinib) ............................... 64 
4.1.3.5. 
Cohort 5 (PTCL NHL) – Peripheral T-cell NHL (PTCL) (Single-agent 
Cerdulatinib) ........................................................................................................... 64 
4.1.3.6. 
Cohort 6 (CTCL NHL)– Cutaneous T-cell NHL (CTCL, MF/SS only) 
(Single-agent Cerdulatinib) ..................................................................................... 64 
4.2. 
PHASE 1 AND PHASE 2A EXCLUSION CRITERIA ........................................................... 64 
4.3. 
ENROLLMENT PROCESS ..................................................................................................... 65 
4.4. 
WITHDRAWAL CRITERIA AND REPLACEMENT OF PATIENTS .................................. 66 
4.4.1. 
General Withdrawal Criteria ............................................................................................ 66 
4.4.2. 
Specific Withdrawal Criterion and Replacement Procedure for Phase 1 ......................... 67 
4.4.3. 
Specific Withdrawal Criteria and Replacement Procedure for Phase 2a ......................... 67 
4.5. 
WITHDRAWAL AND/OR REPLACEMENT CRITERIA FOR SITE OR PRINCIPAL 
INVESTIGATOR ..................................................................................................................... 67 
4.6. 
SPONSOR STUDY DISCONTINUATION ............................................................................. 67 
4.7 
PROTOCOL VIOLATIONS AND DEVIATIONS .................................................................. 67 
5.0 
TREATMENTS ADMINISTERED ........................................................................................... 68 
5.1. 
CERDULATINIB STUDY DRUG ADMINISTRATION ....................................................... 68 
5.1.1. 
General Instructions ......................................................................................................... 68 
5.1.2. 
Phase 1 Cerdulatinib Dosing ............................................................................................ 68 
5.1.2.1. 
Initial Dosing with Cerdulatinib ............................................................................. 68 
5.1.3. 
Phase 2a Cerdulatinib Dosing .......................................................................................... 70 
5.2. 
DOSE-LIMITING TOXICITY, DOSE MODIFICATIONS, AND OTHER 
DOSING/MONITORING GUIDANCE ................................................................................... 70 


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5.2.1. 
Cerdulatinib...................................................................................................................... 70 
5.2.1.1. 
Definitions of Dose-limiting Toxicity for Cerdulatinib during Phase 1.................. 70 
5.2.1.2. 
Phase 2a: Monitoring for Toxicity in Phase 2a ...................................................... 71 
5.2.1.3. 
Dose Modifications for Cerdulatinib ...................................................................... 71 
5.2.1.4. 
Management of Potential Epstein-Barr Virus Reactivation .................................... 73 
5.2.1.5. 
Management of Diarrhea ........................................................................................ 74 
5.2.1.6. 
Management of Nausea and Vomiting.................................................................... 74 
5.3. 
RITUXIMAB INFORMATION AND DOSE MODIFICATIONS .......................................... 74 
5.3.1. 
Prescribing Information ................................................................................................... 74 
5.3.2. 
Management of Rituximab Infusion Toxicity .................................................................. 74 
5.3.3. 
Dose Modifications to Rituximab .................................................................................... 75 
6.0 
STUDY MATERIALS AND MANAGEMENT......................................................................... 76 
6.1. 
CERDULATINIB ..................................................................................................................... 76 
6.1.1. 
Identity of Product ........................................................................................................... 76 
6.1.2. 
Dispensing and Accountability ........................................................................................ 76 
6.1.3. 
Dose Regimens ................................................................................................................ 76 
6.2. 
RITUXIMAB (FOR COMBINATION COHORT 2, RITUXIMAB AND 
CERDULATINIB) .................................................................................................................... 77 
6.2.1. 
Identity of Product ........................................................................................................... 77 
6.2.2. 
Dispensing and Accountability ........................................................................................ 77 
6.2.3. 
Rituximab Dose Regimen (Cohort 2 Only) ..................................................................... 77 
6.2.3.1. 
Premedication and Prophylactic Medication .......................................................... 77 
6.2.3.2. 
Dose Rationale ........................................................................................................ 77 
6.2.3.3. 
Dosage .................................................................................................................... 77 
7.0 
STUDY METHODS ..................................................................................................................... 78 
7.1. 
STUDY ASSESSMENTS ......................................................................................................... 78 
7.1.1. 
Informed Consent............................................................................................................. 78 
7.1.2. 
Global Health Assessment ............................................................................................... 78 
7.1.3. 
Medical History ............................................................................................................... 78 
7.1.4. 
Concomitant Medications ................................................................................................ 78 
7.1.5. 
Physical Examination, Height, and Weight ..................................................................... 78 
7.1.6. 
Vital Signs ........................................................................................................................ 79 
7.1.7. 
Eastern Cooperative Oncology Group (ECOG) Performance Status ............................... 79 
7.1.8. 
Electrocardiogram (ECG) ................................................................................................ 79 
7.1.9. 
Local Laboratory Tests and Response Assessments ........................................................ 79 
7.1.9.1. 
Serum Chemistry, Hematology, Urinalysis, Coagulation, and Pregnancy 
Tests ........................................................................................................................ 79 
7.1.9.2. 
Other Local Labs/Assessments for All Patients ...................................................... 80 
7.1.9.3. 
Other Local Labs/Assessments for Specific Patients .............................................. 80 
7.1.10. Central Laboratory Assessments ...................................................................................... 81 


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7.1.10.1. Central Laboratory Assessments for All Patients: .................................................. 81 
7.1.11. Pharmacokinetics ............................................................................................................. 81 
7.1.12. Biopsies ............................................................................................................................ 82 
7.1.12.1. Bone Marrow Biopsy and Aspiration ..................................................................... 82 
7.1.12.2. Skin Punch Biopsy (Cohort 6, CTCL Only) ........................................................... 82 
7.1.12.3. Optional Biopsies .................................................................................................... 82 
7.2. 
SCREENING VISIT ................................................................................................................. 82 
7.3. 
DOSING CYCLES ................................................................................................................... 83 
7.3.1. 
Phase 2a Dosing Cycles ................................................................................................... 83 
7.3.2. 
Patient Visits After Cycle 2 ............................................................................................. 83 
7.3.2.1. 
Visit Reduction for Response Patients after Cycle 12 ............................................ 84 
7.3.2.2. 
30 Days Post-Last Treatment .................................................................................. 84 
7.3.2.3. 
Unscheduled Assessments ...................................................................................... 84 
7.3.3. 
Visit Windows ................................................................................................................. 85 
7.3.3.1. 
Visit Window and Timeline Guidance ................................................................... 85 
7.4. 
BLOOD COLLECTION ........................................................................................................... 85 
7.5. 
CONCOMITANT MEDICATIONS AND OTHER GUIDANCE ........................................... 85 
7.5.1. 
Prohibited Medications/Procedures ................................................................................. 85 
7.5.2. 
Permitted or Mandated Medications ................................................................................ 86 
7.5.2.1. 
Antimicrobial Prophylaxis ...................................................................................... 86 
7.5.3. 
Cerdulatinib and CYP3A4 ............................................................................................... 86 
7.6. 
STUDY COMMITTEE ............................................................................................................. 87 
8.0 
ASSESSMENT OF EFFICACY ................................................................................................. 88 
8.1. 
RESPONSE CRITERIA ........................................................................................................... 88 
8.2. 
EXPLORATORY EFFICACY ................................................................................................. 88 
8.2.1. 
Global Health Questionnaire ............................................................................................ 88 
9.0 
PHARMACOLOGY ASSESSMENTS ....................................................................................... 89 
9.1. 
PHARMACOKINETIC ASSAYS ............................................................................................ 89 
9.1.1. 
Phase 1 Pharmacokinetic Analysis .................................................................................. 89 
9.1.2. 
Phase 2a Pharmacokinetic Analysis ................................................................................. 90 
9.2. 
PHARMACODYNAMIC ASSAYS ......................................................................................... 90 
10.0 
ASSESSMENT OF SAFETY ...................................................................................................... 91 
10.1. SAFETY PARAMETERS AND DEFINITIONS ..................................................................... 91 
10.1.1. Adverse Events ................................................................................................................ 91 
10.1.2. Serious Adverse Event (SAE) .......................................................................................... 91 
10.1.3. Suspected Unexpected Serious Adverse Reactions (SUSARs) ....................................... 92 
10.2. METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS ........................................................................................................................ 93 
10.2.1. Adverse Event Reporting Period ...................................................................................... 93 


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10.2.2. Assessment of Severity of Adverse Events ...................................................................... 94 
10.2.3. Assessment of Causality of Adverse Events .................................................................... 95 
10.2.4. Procedures for Recording AEs ......................................................................................... 96 
10.2.4.1. Diagnosis versus Signs and Symptoms ................................................................... 97 
10.2.4.2. Adverse Events that are Secondary to Other Events ............................................... 97 
10.2.4.3. Persistent or Recurrent Adverse Events .................................................................. 97 
10.2.4.4. Abnormal Laboratory Values ................................................................................. 98 
10.2.4.5. Abnormal Vital Sign Values ................................................................................... 98 
10.2.4.6. Abnormal Liver Function Tests .............................................................................. 99 
10.2.4.7. Deaths ..................................................................................................................... 99 
10.2.4.8. Lack of Efficacy or Worsening of Underlying Malignancy ................................. 100 
10.2.4.9. Preexisting Medical Conditions ............................................................................ 100 
10.2.4.10. Hospitalization or Prolonged Hospitalization ....................................................... 100 
10.2.4.11. Adverse Events Associated with an Overdose or Error in Drug 
Administration ...................................................................................................... 100 
10.2.4.12. Adverse Events in Individuals Not Enrolled in the Study .................................... 101 
10.2.4.13. Pregnancy Exposure and Birth Events .................................................................. 101 
11.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ........................................... 102 
11.1. GENERAL CONSIDERATIONS........................................................................................... 102 
11.1.1. Analysis Populations ...................................................................................................... 102 
11.1.2. Cohort Comparability .................................................................................................... 102 
11.1.3. Efficacy Endpoints and Analyses................................................................................... 102 
11.1.4. Pharmacokinetic Analyses, Phase 1 and 2a ................................................................... 103 
11.1.5. Pharmacodynamic Analyses, Phase 1 and 2a ................................................................ 103 
11.1.6. Safety Analyses, Phase 1 and 2a .................................................................................... 103 
11.2. SAMPLE SIZE CONSIDERATIONS .................................................................................... 104 
11.2.1. Phase 1 Sample Size ...................................................................................................... 104 
11.2.2. Phase 2a Sample Size ..................................................................................................... 104 
11.3. MISSING DATA .................................................................................................................... 104 
11.4. MULTIPLICITY ..................................................................................................................... 104 
11.5. DATA SAFETY MONITORING ........................................................................................... 104 
12.0 
INVESTIGATOR AND SPONSOR OBLIGATIONS ............................................................ 105 
12.1. DOCUMENTATION REQUIRED FOR STUDY INITIATION ........................................... 105 
12.2. DATA REPORTING AND CASE REPORT FORMS (CRF) ................................................ 105 
12.3. DEVIATION FROM THE PROTOCOL ................................................................................ 105 
12.4. STUDY MONITORING ......................................................................................................... 106 
12.5. AUDITS AND INSPECTIONS .............................................................................................. 106 
12.6. INSTITUTIONAL REVIEW BOARD (IRB) OR INDEPENDENT ETHICS 
COMMITTEE (IEC) ............................................................................................................... 107 
12.7. DRUG ACCOUNTABILITY ................................................................................................. 107 


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12.8. DISCLOSURE OF DATA ...................................................................................................... 107 
13.0 
QUALITY CONTROL AND ASSURANCE ........................................................................... 108 
14.0 
ETHICS ....................................................................................................................................... 109 
14.1. ETHICS REVIEW .................................................................................................................. 109 
14.2. ETHICAL CONDUCT OF THE STUDY .............................................................................. 109 
14.3. WRITTEN INFORMED CONSENT...................................................................................... 109 
15.0 
DATA HANDLING AND RECORD RETENTION ............................................................... 110 
15.1. INSPECTION OF RECORDS ................................................................................................ 110 
15.2. RETENTION OF RECORDS ................................................................................................. 110 
16.0 
PUBLICATION POLICY ......................................................................................................... 111 
17.0 
LIST OF REFERENCES .......................................................................................................... 112 
18.0 
APPENDICES ............................................................................................................................ 116 
APPENDIX 1. 
SCHEDULE OF ASSESSMENTS ─ PHASE 2A (EXPLORATORY) ............... 117 
APPENDIX 2. 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ................................................................................. 119 
APPENDIX 3. 
STRONG CYP3A4 INHIBITORS AND INDUCERS AND CYP3A 
SENSITIVE SUSBSTRATES ............................................................................... 120 
APPENDIX 4. 
RESPONSE DEFINITIONS FOR B-CELL NHL AND PTCL, CLL, AND 
CTCL ..................................................................................................................... 122 
APPENDIX 5. 
PROGNOSTIC FACTORS ................................................................................... 137 
APPENDIX 6. 
DIFFERENTIAL OF ABC VS. GCG TYPE OF DLBCL BY IHC-HANS 
METHODOLOGY ................................................................................................ 139 
APPENDIX 7. 
STAGING SYSTEMS FOR CLL AND NHL ....................................................... 140 
APPENDIX 8. 
GLOBAL HEALTH ASSESSMENT ................................................................... 142 
APPENDIX 9. 
COCKCROFT-GAULT METHOD FOR EVALUATING CREATININE 
CLEARANCE ....................................................................................................... 143 
APPENDIX 10. LIKERT SCALE ................................................................................................... 144 
APPENDIX 11. T-CELL LYMPHOMA CLASSIFICATIONS ...................................................... 145 
 
 
List of Tables 
Table 1: 
Study Contact Information and 24-Hour Emergency Contact ............................................ 5 
Table 2: 
Summary of Key Changes from Original Protocol (14 August 2013): 
Amendments 1 through 9 .................................................................................................... 6 
Table 3: 
Protocol-specific List of Specialist Terms and Terms Used for Response Criteria .......... 33 
Table 4: 
Grade ≥ 3 Adverse Events Related to Cerdulatinib by MedDRA Preferred Term: 
Phase 1 Portion (Completed) of Study 13-601 (N=43) ..................................................... 41 


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Table 5: 
All Serious Adverse Events Related to Cerdulatinib by MedDRA Preferred Term: 
Phase 1 Portion (Completed) of Study 13-601 (N=43) ..................................................... 42 
Table 6: 
By-Cohort Inclusion Criteria for Phase 2a Cohorts........................................................... 53 
Table 7: 
Estimated Concentrations of Twice Daily (BID) Doses from PK Modeling .................... 59 
Table 8: 
Guidelines for Dose Reductions for Cerdulatinib ............................................................. 73 
Table A3-9: 
Strong CYP3A4 Inhibitors and Inducers ................................................................. 120 
Table A3-10: 
CYP3A Sensitive Substrates ................................................................................... 120 
Table A4-11: 
Lugano Criteria (Revised Criteria) for Response Assessment in NHL ................... 123 
Table A4-12: 
Response Criteria for ATLL .................................................................................... 130 
Table A4-13: 
Response Criteria for LGL ...................................................................................... 131 
Table A4-14: 
Global Response Score ............................................................................................ 132 
Table A4-15: 
Response in Skin ..................................................................................................... 132 
Table A4-16: 
Response in Lymph Nodes ...................................................................................... 133 
Table A4-17: 
Response in Viscera ................................................................................................ 133 
Table A4-18: 
Response in Blood ................................................................................................... 134 
Table A4-19: 
Calculating Skin Scores ........................................................................................... 135 
Table A4-20: 
mSWAT Response Assessment .............................................................................. 136 
Table A5-21: 
Follicular Lymphoma International Prognostic Index -1 (FLIPI-1) Criteria ........... 137 
Table A5-22: 
International Prognostic Index (IPI) ........................................................................ 137 
Table A5-23: 
Age-Adjusted International Prognostic Index ......................................................... 137 
Table A5-24: 
Simplified Mantle-Cell Prognostic Index (MIPI) .................................................... 138 
Table A7-25: 
Rai Staging System for Chronic Lymphocytic Lymphoma ..................................... 140 
Table A7-26: 
Binet Staging System for Chronic Lymphocytic Lymphoma ................................. 140 
Table A7-27: 
Lugano Modification of Ann Arbor Staging System (for Primary Nodal 
Lymphomas) ............................................................................................................ 141 
Table A11-28: 
Mature T- and NK-cell Neoplasms in the 2008 WHO Classification 
of Lymphoid Tumors ............................................................................................... 145 
List of Figures 
Figure 1: 
Cerdulatinib Pathway Inhibition in Peripheral Blood ....................................................... 55 
Figure 2: 
Individual Trough Levels (Cmin) for Tolerated (40-65 mg QD) and Non-tolerated 
(45 mg BID) Dose Regimens of Cerdulatinib on Day 29 (First Day of Cycle 2) ............. 57 
Figure 3: 
Steady-State Cerdulatinib Plasma Concentrations and Treatment-related Grade 2 + 
Adverse Events .................................................................................................................. 58 
Figure 4: 
Change in Sum of Tumor Volumes from Computed Tomography Scans ......................... 58 
Figure A6-5: 
Decision Tree for Immunoperoxidase Tissue Microarray (TMA) .......................... 139 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations used in this study protocol are shown in the table below. Specialist 
terms, including response criteria, are defined in Table 3. 
 
Abbreviation 
Expansion 
ABC 
Activated B-cell like diffuse large B-cell lymphoma 
Ae 
Amount of drug excreted in urine over the sampling interval 
AE 
Adverse event 
ALKP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aNHL 
Aggressive non-Hodgkin lymphoma 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
ASCT 
Autologous stem cell therapy 
AST 
Aspartate aminotransferase 
Au 
Amount of drug excreted into urine 
AUC 
Area under the curve 
BCR 
B-cell Receptor 
BID 
Twice a day 
BR 
Bendamustine and rituximab 
BRAT 
bananas, rice, applesauce, toast 
BTK 
Bruton’s tyrosine kinase 
BUN 
Blood urea nitrogen (chemotherapy regimen) 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHOP 
Cyclophosphamide, doxorubicin hydrochloride, vincristine (formerly 
oncovin) and prednisolone (chemotherapy regimen) 
CIRS 
Cumulative Illness Rating Scale 
CL 
Clearance 
CLL 
Chronic lymphocytic leukemia 
CLr 
Renal clearance 
Cmax/min 
Maximum/minimum observed concentration 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CR 
Complete response 
CRP 
C-reactive protein 
CRF 
Case report forms 


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Abbreviation 
Expansion 
CRO 
Contract research organization 
CT 
Computed Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTCL 
Cutaneous T-cell lymphoma 
DSMB 
Data Safety Monitoring Board 
dL 
Deciliter 
DLBCL 
Diffuse Large B-cell Lymphoma 
DLCO 
Diffusion capacity of carbon monoxide 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic Acid 
EBV 
Epstein-Barr virus 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic Acid 
ESR 
Erythrocyte sedimentation rate 
FcR 
Fc Receptor 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FFPE 
Formalin-fixed paraffin embedded tissue 
FISH 
Florescence in situ hybridization 
FL 
Follicular Lymphoma 
FLIPI 
Follicular Lymphoma International Prognostic Index 
FVC 
Forced vital capacity 
GCB DLBCL 
Germinal center B-cell like Diffuse Large B-cell Lymphoma 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GLP 
Good Laboratory Practices 
HCO3 
Bicarbonate 
HCT-CI 
Hematopoietic Cell Transplantation Co-Morbidity Index 
HDPE 
High Density Polyethylene 
hERG 
human ether-à-go-go-related gene 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest Non-Severely Toxic Dose 
hr 
Hour 


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Abbreviation 
Expansion 
HSCT 
Hematopoietic stem cell transplant 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
IC90 
90% maximal inhibitory concentration 
ICH 
International Conference on Harmonisation 
ID 
Identification 
Ig 
Immunoglobulin 
IgE 
Immunoglobulin E 
IgM 
Immunoglobulin M 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
iNHL 
Indolent non-Hodgkin lymphoma 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IR 
Immediate Release 
ITP 
Immune Thrombocytopenic Purpura 
IV 
Intravenous 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IWG 
International Working Group 
JAK 
Janus kinase 
kg 
Kilogram 
LCMS 
Liquid Chromatography Mass Spectrometry 
LDH 
Lactic dehydrogenase 
LPL 
Lymphocytoplasmacytic lymphoma 
LLN 
Lower Limit of Normal 
LVEF 
Left ventricular ejection fraction 
MAD 
Maximum Administered Dose 
MALT 
lymphoma 
Mucosa Associated Lymphoid Tumor 
MCL 
Mantle Cell Lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Mycosis fungoides 
mSWAT 
Modified Severity Weighted Assessment Tool 
mg 
Milligram 
min 
Minute 
MITT 
Modified Intent to Treat 
mL 
Milliliter 


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Abbreviation 
Expansion 
MRD 
Minimal Residual Disease 
MTD 
Maximum Tolerated Dose 
MZL 
Marginal zone lymphoma 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin Lymphoma 
ng 
Nanogram 
NOAEL 
No Observed Adverse Effect Level 
ORR 
Overall response rate (CR + PR) 
PCP 
Pneumocystis carinii (aka Pneumocystis jirovecii) Pneumonia 
PTCL 
Peripheral T-cell lymphoma 
PCR 
Polymerase Chain Reaction 
PD 
Progressive disease or Pharmacodynamic 
PET 
Positron-Emission Tomography 
PK 
Pharmacokinetic 
PI 
Principal Investigator 
PMA 
Phorbol 12-myristate 13-acetate 
PO 
Orally 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
q12h 
Every 12 hours 
q24h 
Every 24 hours 
Q 
Every 
QD 
Once daily 
R-CHOP 
Rituximab + CHOP (defined earlier) 
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SIEP 
Serum immunoelectrophoresis 
SPEP 
Serum protein electrophoresis 
SLL 
Small lymphocytic lymphoma 


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Abbreviation 
Expansion 
SOC 
Standard of care or (MedDRA) system organ class 
SS 
Sézary Syndrome 
ss 
Steady state 
SPD 
Sum of the perpendicular diameters 
STD10 
Severely toxic dose in 10% of rodents 
SUSAR 
Suspected unexpected serious adverse reaction 
SYK 
Spleen Tyrosine Kinase 
t½ 
Half-life 
Tmax/min 
Time to maximum/minimum observed concentration 
TEAE 
Treatment emergent adverse event 
μL 
Microliter 
μM 
Micromolar 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
VS 
Vital signs 
Vss 
Volume at steady state 
WBC 
White blood cell(s) 
WM 
Waldenström's macroglobulinemia 


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Table 3: 
Protocol-specific List of Specialist Terms and Terms Used for 
Response Criteria 
 
Specialist Term 
Expansion and Definition 
aNHL 
Aggressive Non-Hodgkin lymphoma, defined as DLBCL, FL3B, MCL, and transformed 
NHL (definitions provided below). 
Clinical Benefit 
CR + PR + SD, PFS, and DOR. 
CR 
Complete response. Criteria vary by disease type. 
DLBCL 
Diffuse large B-cell lymphoma. 
DOR 
Duration of response: Time from the first documentation of PR or CR to the earlier of the 
first documentation of disease progression or death from any cause. 
Intolerant 
Discontinuation due to previous therapy due to a clinically significant adverse event. 
FL/iNHL 
Follicular lymphoma/indolent Non-Hodgkin lymphoma. 
FL Grade 3B 
Follicular lymphoma, Grade 3 B. 
LNR 
Lymph node response: The proportion of patients who achieve a ≥ 50% decrease from 
baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index 
lymph nodes. 
MAD 
Maximum administered dose: The MAD is defined as the highest dose level achieved in this 
study suitable for further investigation and will be declared the RP2D. If the MTD is not 
achieved, the highest studied dose will be declared the MAD and become the RP2D. 
MCL 
Mantle cell lymphoma. 
MRD- 
Minimum residual disease negativity: < 1 CLL cell in 10,000 leucocytes. 
MRD+ 
Minimum residual disease positivity: ≥ 1 CLL cell in 10,000 leucocytes. 
MTD 
Maximum tolerated dose: Per the National Cancer Institute (NCI) Dictionary of Cancer 
terms, the MTD is “the highest dose of a drug or treatment that does not cause unacceptable 
side effects [6].” 
ORR 
Overall response rate: Defined as CR+PR. 
PFS 
Progression-free survival time: Time from the start of cerdulatinib treatment to the earlier of 
the first documentation of disease progression or death from any cause. 
PR 
Partial response: Criteria vary by disease type. 
Relapsed Disease 
Progression or recurrence of disease after documentation of response (CR or PR) ≥ 6 months 
since last treatment. 
Refractory Disease 
Progression on treatment, SD, or PR, or better, with progression < 6 months after any prior 
treatment. 
RP2D 
Recommended Phase 2 dose: The RP2D is the beginning dose recommended for Phase 2 
clinical trials. For the purposes of this protocol, the MTD will be declared the RP2D. If the 
MTD is not declared, the MAD will be declared the RP2D. 
SD 
Stable disease: Criteria vary by disease type. 
TTR 
Time to treatment response: Time from the start of cerdulatinib treatment to the first 
documentation of CR or PR. 


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1.0 
INTRODUCTION 
 
1.1. 
Cerdulatinib (PRT062070) 
Cerdulatinib (PRT062070) is an orally available, reversible, small molecule ATP competitive 
inhibitor of Spleen Tyrosine Kinase (SYK) and the Janus kinase (JAK) family that will be 
developed for the treatment of patients with B-cell malignancies, including non-Hodgkin 
lymphoma (NHL) and chronic lymphocytic leukemia/small lymphocytic lymphoma CLL/SLL. 
 
SYK, as a key component of Fc receptor signaling and of the BCR signaling pathway, has been 
demonstrated to be an important target in the disruption of cell survival signals mediated through 
BCR. It has been suggested that SYK may mediate survival signals in DLBCL, Mantle Cell 
Lymphoma (MCL), and FL [7-9]. The JAK/STAT pathway, important in cytokine signaling has 
also been reported to be activated in B cell lymphomas and the resistance of some DLBCL 
appears related to mutations that drive NFkB-mediated JAK/pSTAT3 activation [10]. CLL is 
another B-cell malignancy that appears to be dependent on BCR and thus SYK signaling [11]. 
Additionally, several cytokines have been reported to be increased in CLL and may be important 
in promoting CLL cell survival and proliferation through interaction with the tumor 
microenvironment [12]. The cytokines, IL-2, IL 4, and INF-α have been shown to promote 
CLL cell survival through the anti-apoptotic effects of up-regulation of BCL2 family proteins 
[13-15]. Studies have also shown that disruption of cytokine signaling via inhibition of JAK has 
the potential to reverse the cytoprotection provided to CLL cells by the tumor 
microenvironment [16]. 
 
Please refer to the Investigator’s Brochure (IB) for more details. 
 
1.2. 
Pharmacology Studies of Cerdulatinib 
Multiple in vitro and in vivo pharmacology studies have been undertaken to evaluate the activity 
of cerdulatinib. Cerdulatinib was studied in vitro against a panel of purified kinase assays 
followed by specific cellular potency assays against SYK, JAK1, JAK2, JAK3, and TYK2. 
Significant potency was observed against signaling pathways utilizing SYK, JAK1, JAK3, and 
TYK2. SYK-dependent BCR signaling and functional responses were inhibited with a half 
maximal inhibitory concentration (IC50) in the range of 0.1 to 0.5 µM. In cytokine signaling and 
functional response assays, inhibition against pathways utilizing JAK1/3 (Interleukin (IL)-2, 
IL 4) and JAK1/JAK2/TYK2 (IL-6) was observed, with IC50 values ranging from 0.15 to 
0.9 µM. Cerdulatinib induces growth arrest and apoptosis in B-cell tumor cell lines and the 
viability of primary CLL cell cultures was also adversely affected in a dose dependent manner. 
 
The in vivo effects of cerdulatinib have been studied in B-cell tumor xenografts, in a rodent 
model of idiopathic thrombocytopenic purpura (ITP), and in rodent models of arthritis. In the 
subcutaneous xenograft study, Ramos (Burkitt’s lymphoma line) tumor growth was measured at 
various intervals. Inhibition of tumor growth was found to be comparable to that of vehicle 
controls. The lack of efficacy was likely the result of inadequate exposure of cerdulatinib, where 


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Cave plasma and tumor concentrations at the highest dose were below the level known to 
demonstrate inhibition of Ramos cell viability in vitro. 
 
In an effort to overcome the challenges of the poor pharmacokinetics (PK) in mice, an 
intravenous (IV) tumor model was utilized, in which mice received an IV injection of Ramos 
cells, followed by cerdulatinib after 3 days of tumor growth. Time to hind limb paralysis, a 
marker of tumor growth and the primary efficacy endpoint, was significantly delayed in animals 
treated with cerdulatinib at a dose of 30 mg/kg twice daily (BID). 
 
Cerdulatinib was also studied in a model of chronic BCR stimulation and splenomegaly. BCR 
stimulation and subsequent splenomegaly were induced in mice following injections of an 
anti-mouse BCR antibody. Doses of 15 mg/kg or greater were effective in reducing the 
splenomegaly compared to that observed in vehicle-treated animals. In a murine model of ITP, 
Fc receptor (FcR) mediated antibody-induced platelet clearance was significantly inhibited by 
treatment with cerdulatinib at a dose of 30 mg/kg, affirming the ability of this compound to 
interfere with SYK -dependent FcR signaling. 
 
Two rodent models of arthritis have demonstrated the ability of cerdulatinib to interfere with 
SYK and JAK-mediated inflammation. In the mouse passive anti-collagen antibody induced 
arthritis (CAIA) model, inflammation and swelling were completely inhibited following 
cerdulatinib treatment at 30 mg/kg BID. In the rat collagen-induced arthritis model (CIA), 
treatment with cerdulatinib was initiated following the observation of paw inflammation. 
Progression of the arthritis and inflammation were completely suppressed in animals treated with 
cerdulatinib at doses of 5 mg/kg BID or higher. 
 
The PK properties of cerdulatinib were evaluated in mouse, rat, dog, and monkey following IV 
and oral (po) dosing. Systemic clearance (CLss) was much higher in the mouse compared with 
CLss in rat, dog, and monkey. The volume of distribution (Vss) was also highest in the mouse 
compared to other species. The apparent terminal half-life (t½) ranged from 1.16 to 15.9 hours 
after IV administration. Cerdulatinib was well absorbed in rat and monkey (oral bioavailability; 
F = 22.3-30.9%) and completely absorbed in dog (F = 113%). 
 
In the rat, the PK of cerdulatinib was non-linear following both IV and po administration. 
Between 1 and 10 mg/kg IV, the clearance of cerdulatinib decreased from 14.4 mL/min/kg to 
7.81 mL/min/kg. Following po dosing at 1, 10, or 50 mg/kg, AUC0-∞ increased greater than 
dose-proportionally from 1 to 50 mg/kg. These data suggest that certain elimination pathways 
may be saturated at higher doses, resulting in a greater than dose-proportional increase 
in exposure. 


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In the dog, non-linear PK was observed following po dosing at 25 mg/kg. After 5 days of 
dosing, the exposure of cerdulatinib on Day 5 was higher than expected when comparing 
AUC0-24 on Day 5 to AUC0-∞ on Day 1. However, when compared to the exposure following 
administration of single po doses of 5, 15, or 50 mg/kg, the dose-normalized AUC0-∞ of the 
15 and 50 mg/kg were lower than that of the 5 mg/kg. Therefore, the PK of cerdulatinib in the 
dog is possibly influenced by both some type of saturation of clearance process(es) and the 
limited absorption of the compound. 
 
Protein binding for cerdulatinib in mouse, rat, dog, cynomolgus monkey, and human plasma was 
91.7, 95.6, 83.2, 88.1, and 89.5%, respectively. Studies of bile-duct cannulated rats have shown 
that the major route of elimination for cerdulatinib appears to be metabolism. Cerdulatinib can 
be metabolized by CYPs 1A1, 1B1, 2J2, and 3A4. Oxidative metabolism appears to be the 
major route of metabolism of cerdulatinib by rat, dog, monkey, and human liver microsomes 
and hepatocytes. 
 
The capacity of cerdulatinib to inhibit the major human liver CYP isozymes (CYPs 1A2, 2C8, 
2C9, 2C19, 2D6, and 3A4) was evaluated using pooled human liver microsomes and isozyme 
specific probe substrates. Cerdulatinib did not demonstrate significant inhibition at 
concentrations up to 50 µM. With respect to time-dependent inhibition, cerdulatinib 
demonstrated significant inhibition (≥ 30%) of CYP3A4 at 50 µM but not at 10 µM. 
Subsequently, it was found that cerdulatinib 0.3 to 1 µM decreased CYP3A4 mRNA and activity 
levels. Therefore, it is possible that cerdulatinib could affect the levels of co-administered drugs 
that are metabolized by CYP3A4 similar to a CYP inhibitor. 
 
1.3. 
Safety Pharmacology Studies 
The cardiovascular safety of cerdulatinib was assessed in both in vitro and in vivo studies. In a 
non-Good Laboratory Practices (GLP) human ether-à-go-go-related gene (hERG) radio-ligand 
binding displacement assay, cerdulatinib (10 and 50 μM) generated 10% and 34% inhibition of 
binding to the hERG receptor. In a non-GLP in vitro patch clamp study using transfected HEK 
293 cells, cerdulatinib (50 μM) inhibited the potassium channel by 42%, compared to 69% for 
the positive control. In the subsequent GLP patch clamp study, 30 μM cerdulatinib resulted in a 
38% inhibition of IKr tail current density. A non-GLP in vitro study of the effect of cerdulatinib 
on action potential duration was conducted in isolated Purkinje fibers from canine hearts. 
Cerdulatinib did not prolong action potential durations up to 50 µM concentration. Additionally, 
no changes were observed in action potential amplitude or resting membrane potential of the 
Purkinje fibers. These data suggest there is low potential for cerdulatinib to interact with the 
hERG or other cardiac ion channels. 


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In vivo studies included a non-GLP study of the effect of cerdulatinib on hemodynamic 
parameters in anesthetized rats. The IV infusion of cerdulatinib had no effect on heart rate and 
blood pressure up to plasma concentrations of 5 to 10 μM. In a non-GLP study telemetrized 
dogs received 25 mg/kg cerdulatinib or vehicle. Telemetry data for QT interval, heart rate, 
systolic, diastolic and mean arterial blood pressure were recorded from 17 hours pre- to 48 hours 
post study drug. Mean plasma levels at Cmax were 4.7 µM and were maintained > 2 μM for up to 
6 hours. No changes in QTc interval were observed, heart rate increased by ~20 beats per minute 
for 7 hours but remained within the normal range, diastolic and mean arterial blood pressure 
were unchanged, and systolic blood pressure showed sporadic decreases (3 and 20 hours) that 
were not considered biologically meaningful. A GLP cardiovascular safety study was also 
performed in dogs. Dogs maintained normal sinus rhythm and no consistent changes in QT 
morphology were observed. A number of changes in R-R interval and in diastolic, systolic, and 
mean arterial pressure were noted, however, although statistically significant these changes were 
generally considered incidental and not adverse. The no adverse effect level (NOAEL) for this 
study was determined to be 50 mg/kg. 
 
A GLP respiratory safety study was also conducted. Male rats received cerdulatinib at 0, 25, 30, 
or 60 mg/kg.  There were no statistically significant changes in respiratory rate for any group. 
Non dose-dependent but statistically significant changes in tidal volume between 1 to 6 hours 
post dose, and changes in minute volume 24 hours post dose were considered spurious, and the 
no observed adverse effect level (NOAEL) for this study was determined to be 60 mg/kg. 
 
A GLP central nervous system (CNS) safety pharmacology study was conducted in rats. Low 
arousal/reactivity to environment was observed at dose levels of 30 and 60 mg/kg. Statistically 
significant changes in motor activity were noted for males given 60 mg/kg. Similar but not 
statistically significant changes were observed in female rats. The NOAEL for cerdulatinib was 
considered to be 30 mg/kg in males and 60 mg/kg in females. 
 
A non-GLP Side Effect Panel screen was performed to assess the ability of cerdulatinib to 
interact with neurotransmitter related receptors, steroid receptors, ion channels, prostaglandins, 
growth factors/hormones, brain/gut peptides, and enzymes. Of the 63 tested, cerdulatinib at a 
concentration of 10 μM significantly inhibited ligand binding to only 2 (adenosine 
[non-selective] neurotransmitter receptor [58%] and sodium [site 2] ion channel [47%]). 
 
1.4. 
Nonclinical Toxicology Studies 
Single dose toxicity studies of cerdulatinib, given by oral gavage, were conducted in mouse, rat, 
and dogs. Deaths occurred in mice receiving 1,000 mg/kg or more, and in rats receiving 
300 mg/kg. Additional observations included scruffy coat, piloerection, and abnormal gait in 
mice receiving 300 mg/kg, and weight loss in rats receiving 100 mg/kg. Dogs developed 
vomiting, loose stools, and a transient decrease in neutrophils at a dose of 50 mg/kg; all 
symptoms/signs recovered within 24 hours. 


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Non-GLP repeat dose, dose-ranging studies were conducted in mouse, rat, and dog. In mice 
given 30, 100, or 300 mg/kg daily for 12 days, the NOAEL was 30 mg/kg/day. Body weight 
loss, bone marrow hypoplasia, enteropathy, lack of splenic germinal centers, and thymic 
depletion were noted at doses of 100 mg/kg or greater. In a similar study, rats received 4, 10, 30, 
or 100 mg/kg/day given in divided doses BID for 11 days. The NOAEL was determined to be 
30 mg/kg. Deaths occurred at 100 mg/kg/day. Additionally, AST/ALT increased by 2 to 3×, 
and animals given 100 mg/kg/day were observed to have myocardial necrosis, hepatic necrosis, 
thymic lymphoid depletion, and severe bone marrow hypoplasia. Bone marrow hypoplasia was 
also observed in 25% of animals given 30 mg/kg/day, along with mild thymic lymphoid 
depletion and a decrease in body weight gain. Two non-GLP studies were conducted in dogs. 
Dogs were given 25 mg/kg/day for 5 days or 10, 15, or 20 mg/kg/day for 11 days. In the 5-day 
study reversible decreases in neutrophils and total WBC were observed without clinical 
chemistry changes. In the 11-day study, dogs given 20 mg/kg/day had decreased WBC, without 
effects on other hematological parameters. 
 
GLP-compliant toxicology studies were conducted in the rat and dog. Sprague-Dawley rats were 
given 0, 2.5, 6.0, or 15 mg/kg/day of cerdulatinib by oral gavage for 28 days. Recovery animals 
were included in the 0 and 15 mg/kg/day groups; recovery group animals given 15 mg/kg/day 
died or were euthanized during the recovery period (Study Days 29 and 38), but the deaths were 
attributed to phlebotomy procedure. The primary finding in male rats receiving 15 mg/kg/day 
was a statistically significant decrease in body weight gain. All dose groups had fewer mean 
WBC, lymphocyte, neutrophil, monocyte, eosinophil, basophil, and reticulocyte numbers 
compared to vehicle treated animals, however the changes were within the reference range and 
thus not considered biologically meaningful. Both male and female rats had statistically 
significant increases in alanine transaminase (ALT), aspartate transaminase (AST), and alkaline 
phosphatase (ALKP), however the magnitude of the change was < 2x and findings did not 
correlate with gross or microscopic findings. All cerdulatinib-treated rats had spleen and thymus 
weights less than vehicle-treated rats. Changes related to the pharmacologic activity of 
cerdulatinib, or that were not dose-dependent or associated with gross or microscopic pathologic 
findings were considered not adverse. T-cell immune response was also assessed in this study. 
All main study animals were immunized with 0.5 mg Keyhole Limpet Hemocyanin (KLH) on 
Day 12. Analysis for Immunoglobulin G (IgG) and Immunoglobulin M (IgM) showed both an 
IgM and IgG response that did not appear to be affected by administration of cerdulatinib. The 
NOAEL was considered to be 6.0 mg/kg in male rats and > 15 mg/kg in female rats. Mean 
Cmax/AUC for male rats at 6.0 mg/kg/day was 445 ng/mL/4,886 ng*hr/mL, while the mean 
Cmax/AUC for female rats at 15 mg/kg/day was 2,737 ng/mL/31,391 ng*hr/mL. 
A 28-day repeat dose study was also conducted in dogs. Dogs received 0, 0.75, 2.5, 5.0, or 
50/20/15 (multiple dose reductions) mg/kg/day of cerdulatinib by oral gavage. One death 
occurred on Day 7 in the 50 mg/kg/day group; the remaining animals in this group were dose 
reduced to 20 mg/kg/day on Day 10, then again to 15 mg/kg/day on Day 13 and Days 16 to 22. 


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This group was terminated on Day 22. Vomiting and fecal changes were present in dogs treated 
at 2.5 mg/kg/day or more. Decreased activity was observed in animals receiving 5.0 mg/kg/day 
or more. T-lymphocyte counts were decreased in a dose-dependent fashion in all animals 
receiving cerdulatinib at doses of 0.75 mg/kg/day or more. B-lymphocyte counts were also 
generally lower. Reductions in indicators of erythroid mass and in reticulocyte counts were 
observed in the high dose group and in animals from the 2.5 and 5.0 mg/kg dose groups. 
Reductions in WBC, including neutrophil and lymphocyte counts were also seen in these 3 dose 
groups. All hematologic changes showed complete recovery by the end of the recovery period. 
Thymus and spleen weights were decreased in the 2.5 and 5.0 mg/kg dose groups. Microscopic 
findings considered related to cerdulatinib included hypertrophy of the zona fasciculata of the 
adrenal glands; changes, including atrophy of the submucosal glands, of the esophagus; 
multifocal necrosis of the epithelium of the kidney proximal convoluted tubules and basophilia 
of the proximal tubules (5.0 and 50/20/15 mg/kg); lymphoid depletion of the cervical lymph 
nodes, thymus, and spleen; multifocal degeneration of the epithelium of the seminiferous tubules 
of the testes, and multinucleated spermatids of the seminiferous tubules (2.5, 5.0, and 
50/20/15 mg/kg). Changes in the bone marrow, including hypocellularity, increased myeloid to 
erythroid ratio, and reduced total erythroid counts were observed in animals from the 5.0 and 
50/20/15 mg/kg dose groups. The NOAEL for cerdulatinib was determined to be 2.5 mg/kg/day 
for females and 0.75 mg/kg/day for males. The NOAEL was determined to be 0.75 mg/kg/day. 
At 0.75 mg/kg mean Cmax ranged from 216 to 231 ng/mL while AUC ranged from 1,219 to 
1,751 ng*hr/mL. At 2.5 mg/kg, the mean Cmax in females was 733 ng/mL and AUC was 
4,430 ng*hr/mL. 
 
The genotoxic/mutagenic potential of cerdulatinib was studied in both a GLP-compliant AMES 
assay and in a GLP-compliant rat bone marrow micronucleus assay with Liver Comet Assay. 
Cerdulatinib showed a low potential for mutagenicity in the AMES assay. Similarly, results of 
the rat bone marrow micronucleus assay showed a low probability that cerdulatinib is genotoxic 
or mutagenic (no DNA breaks or increased nuclear fragments). 
 
For the Phase 1 trial, a starting dose of 15 mg QD has been proposed based on the STD10 in rats 
of 15 mg/kg. This dose is predicted to provide a steady state Cmax and AUC of approximately 
28 ng/mL (0.06 µM) and 225 ng*hr/mL, respectively, which is expected to yield Cmax and AUC 
exposures of 8-fold and 7-fold lower than the no observed adverse effect level (NOAEL) in the 
dog of 0.75 mg/kg/day. 
 
Thus, the pharmacology and nonclinical safety data described above support this initial proposed 
clinical trial of cerdulatinib, which is designed to identify the maximum tolerated dose (MTD), 
evaluate the safety profile, and assess the pharmacokinetic (PK) profile of cerdulatinib in patients 
with relapsed/refractory lymphoid malignancies. 


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1.5. 
Cerdulatinib Phase 1 Interim Results 
The Phase 1 portion of the study is closed to enrollment. 
 
Cerdulatinib data were presented at the 2015 American Society of Clinical Oncology meeting in 
June 2015 [17]. Doses studied included 15 to 65 mg po daily. Data for 30 patients demonstrated 
multiple nodal responses, and 4 patients demonstrated partial responses (PRs): at 30 mg in 
1 patient with del 17p CLL who had relapsed after 6 prior therapies; at 45 mg in 1 patient with 
CLL who had received 4 prior therapies and 1 patient with follicular lymphoma (FL) who had 
received 3 prior therapies; and at 65 mg in 1 patient with a transformed diffuse large B-cell 
lymphoma (DLBCL; MYC, BCL2, and BCL6 expression by immunohistochemistry [IHC]) who 
had relapsed approximately 1 year after 1 prior therapy. No dose-limiting toxicities (DLTs) were 
observed as of that time. The PK parameters, specifically the half-life (t½ of ~24 hours) and a 
2:1 peak-trough ratio, indicated the suitability of once-daily dosing with cerdulatinib. Evidence 
of pharmacodynamic (PD) activity was observed for multiple markers of inflammation and 
cytokines, as well as complete inhibition of peripheral blood SYK and JAK signaling pathways. 
 
After evaluation of the 65 mg dose cohort was completed, dose escalation proceeded to the 
100 mg dose level.  Pharmacokinetic (PK) findings from the 100 mg daily dose level were 
consistent with those from the 40 to 65 mg dose levels, indicating a plateau in exposure. Further 
analysis indicated the likely cause of this was cerdulatinib solubility. 
 
A 45 mg twice daily (BID) dosing cohort was studied, which showed an increase in AUC and 
minimum and maximal concentrations (Cmin and Cmax, respectively). The 45 mg BID level 
roughly doubled the exposure relative to the 40 to 100 mg once daily (QD) average, achieving 
steady-state Cmin and Cmax of 1.5 and 1.8 µM, respectively. Under this dose regimen, 1 patient 
with FL achieved a PR, with what appeared to be a rapid (within 1 week) onset of palpable 
tumor reduction. Another patient with CLL experienced rapid lymphocytosis, whereas a 
refractory FL patient demonstrated stable disease (SD). The 45 mg BID dose regimen, however, 
resulted in 2 DLTs: 1 patient experienced pancreatitis within 2 weeks of dosing, and a second 
patient experienced Grade 3 fatigue. These findings were discussed at regularly scheduled 
conferences with the Investigator, during which it was determined that this dose regimen was not 
tolerated. Of note, the 2 patients with DLTs at 45 mg BID did not achieve the highest exposures 
at this dose level. Thus, we aggregated all data from the escalation portion of the study to date to 
explore the PK profile. 
 
All AEs of Grade 3 or higher and all SAEs (including 2 fatal SAEs) considered to be related to 
cerdulatinib reported during the Phase 1 portion of the study in 43 dosed patients are summarized 
in Table 4 and Table 5, respectively. (Data cutoff is of 25 March 2016; although Phase 1 is 
closed to enrollment, dosing with cerdulatinib is still ongoing in several patients enrolled under 
Phase 1 who have been rolled over into the Phase 2a portion of the study.) 


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Table 4: 
Grade ≥ 3 Adverse Events Related to Cerdulatinib by MedDRA Preferred 
Term: Phase 1 Portion (Completed) of Study 13-601 (N=43) 
 
AEs by MedDRA Preferred Term 
Total Number of Patients (N=43) 
Number (%) of Patients with 
Grade ≥ 3 AE (N=43) 
Number (%) of Patients with AE 
Any Grade (N=43) 
Diarrhea 
4 (9.3) 
27 (46.5) 
Nausea 
1 (2.3) 
11 (25.6) 
Abdominal pain 
2 (4.7) 
8 (18.6) 
Pancreatitis 
1 (2.3) 
1 (2.3) 
Fatigue 
5 (11.6) 
15 (34.9) 
Anemia 
3 (7) 
5 (11.6) 
Neutropenia 
3 (7) 
5 (11.6) 
Thrombocytopenia 
1 (2.3) 
3 (7) 
Febrile Neutropenia 
1 (2.3) 
1 (2.3) 
Pancytopenia 
1 (2.3) 
1 (2.3) 
Neutrophil count decreased 
2 (4.7) 
3 (7) 
LDH increased 
1 (2.3) 
2 (4.7) 
AST increased 
1 (2.3) 
1 (2.3) 
Decreased appetite 
1 (2.3) 
7 (16.3) 
Hyponatremia 
1 (2.3) 
2 (4.7) 
Pneumonia 
2 (4.7) 
2 (4.7) 
Lung infection 
1 (2.3) 
1 (2.3) 
Pneumocytsis jirovecii pneumonia a 
1 (2.3) 
1 (2.3) 
Macular rash 
1 (2.3) 
1 (2.3) 
Hypotension 
1 (2.3) 
2 (4.7) 
AE = Adverse event; MedDRA = Medical dictionary for regulatory activities 
Note: Data cutoff:  25 March 2016. 
a Fatal. 
Source: Data on file at Portola (clinical study database). The Phase 1 portion of the study is closed to enrollment; 
however, some patients enrolled under Phase 1 are still receiving cerdulatinib in Phase 2a. 


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Table 5: 
All Serious Adverse Events Related to Cerdulatinib by MedDRA Preferred 
Term: Phase 1 Portion (Completed) of Study 13-601 (N=43) 
 
Serious Adverse Event by MedDRA Preferred Term 
Number (%) of Patients (N=43) 
Anemia 
1 (2) 
Blood and Lymphatic System Disorders - Other, specify: Pancytopenia 
1 (2) 
Diarrhea 
1 (2) 
Febrile Neutropenia 
1 (2) 
Fever 
1 (2) 
Hypotension 
1 (2) 
Lung infection a 
1 (2) 
Nausea 
1 (2) 
Pancreatitis 
1 (2) 
Pneumonia 
1 (2) 
Pneumocytsis jirovecii pneumonia a 
1 (2) 
AE = Adverse event; MedDRA = Medical dictionary for regulatory activities 
Note: Data cutoff: 25 March 2016. 
a Fatal. 
Source: Data on file at Portola (clinical study database). The Phase 1 portion of the study is closed to enrollment; 
however, some patients enrolled under Phase 1 are still receiving cerdulatinib in Phase 2a. 
 
 
Pharmacokinetic modeling and exploration of the PK/PD and PK/AE data from the Phase 1 
portion indicated that a dose of 35 mg BID should provide adequate exposure as well as 
inhibition of the desired targets of cerdulatinib.  Further explanation of the data and rationale for 
dosing during Phase 2a portion of the study is provided in Section 3.1.2.2. 
 
During Phase 1, PRs have been observed in CLL (including 17p deleted CLL), FL, and 
transformed follicular lymphoma. CR was observed in 2 FL patients. Responses typically 
occurred after 2 cycles and have been durable in several patients [18]. 
 
1.6. 
Background on the NHL in the Study 
The non-Hodgkin lymphomas (NHLs) are a diverse group of disorders of proliferating B, T, or 
NK cells, and collectively, NHL is the seventh leading site of new cancer cases in the United 
States (US) in men and women [19]. In the US, B-cell lymphomas are diagnosed in 
approximately 85 to 90% of people, and T-cell NHL comprises the majority of the remaining 
10 to 15%. In 2015, approximately 72,000 people in the US will be diagnosed with NHL, and 
there will be nearly 20,000 deaths. 
 
The overall incidence of NHL has increased since the 1970s through the 1990s, partially due to 
human immunodeficiency virus (HIV). However, the incidence of NHL in older individuals is 
also increasing, and thus the median age of patients with NHL has increased as well. Many of 
these older patients have multiple comorbid conditions that complicate NHL treatment [19, 20]. 


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In the past 10 to 15 years, the treatment of NHL and CLL/SLL has changed from treatment 
regimens comprising a variety of combinations of cytotoxic therapeutics to the introduction of 
multiple novel therapeutic modalities. Perhaps the most significant of these have been the anti- 
CD20+ antibodies (most prominently rituximab); however, novel purine/pyrimidine analogues 
(fludarabine) and alkylating agents (bendamustine) have also resulted in significant changes to 
the treatment paradigms for both NHL and CLL/SLL. More recently, novel tyrosine kinase 
inhibitors targeting components of the B-cell receptor (BCR) signaling pathway (fostamatinib, 
idelalisib, ibrutinib) have entered clinical trials. Response rates have demonstrated the 
dependency of many of the NHL subtypes, and particularly CLL/SLL, on BCR signaling 
for survival [20-23]. 
 
1.6.1. 
Aggressive B-cell Lymphomas 
Diffuse large B-cell lymphoma (DLBCL) accounts for 30 to 40% of B-cell NHL [19, 24]. 
Follicular lymphoma, Grade 3B (FL3B), accounts for < 10% of all FLs and behaves similarly to 
DLBCL [25]. Similarly, transformed NHL refers to a typically more indolent lymphoma that has 
transformed to a more aggressive lymphoma, with varying reported rates of transformation [26]. 
Mantle cell lymphoma (MCL) accounts for 6% of NHL and often can have a more aggressive 
course [19]. The underlying biology behind the various aggressive lymphomas is diverse and 
may involve mutations or overexpression of MYC, BCL2, and other oncogenes [19, 24, 26, 27]. 
SYK inhibition, as well as inhibition of various cytokines in the JAK-STAT pathway, 
demonstrated activity against various B-cell lymphoma cell lines [1]. 
 
The typical treatment for the more aggressive lymphoma consists of an anti-CD20 antibody, 
rituximab, combined with cytotoxic chemotherapy such as cyclophosphamide, doxorubicin 
hydrochloride, vincristine (formerly oncovin), and prednisolone (CHOP; i.e., the R-CHOP 
regimen). This can produce durable remissions in a number of patients and lead to cure. 
Patients who relapse are often treated with a variety of salvage regimens and may receive 
high-dose chemotherapy with stem cell rescue, which in some cases may also be curative 
[19, 24-26]. Unfortunately, not all patients are candidates for high-dose chemotherapy with stem 
cell rescue due to a variety of factors such as age and organ dysfunction (cardiac, pulmonary, 
renal, hepatic); thus, these patients are in need of alternative therapies [28]. 
 
Unfortunately, limited treatment options exist for the patient who has a disease relapse or is 
refractory to therapy. In the case of MZL, ibrutinib, an inhibitor of BTK, has been approved for 
relapsed/refractory patients [29]. There are limited treatment options for patients with 
relapsed/refractory DLBCL, transformed NHL, MCL, cell lymphoma, or FL3B [19, 26, 30, 31]. 
Newer agents are needed. 
 
1.6.2. 
Rituximab in the Treatment of B-cell NHL 
Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen expressed on 
normal and malignant B-cells [32, 33]. Rituximab’s mechanism of action involves antibody 


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dependent cellular cytotoxicity (ADCC), complement mediated cytotoxicity (CDC), and direct 
induction of apoptosis [33]. 
 
Rituximab was originally approved by the US FDA in 1997 for the treatment of relapsed or 
refractory low-grade NHL. Subsequently, it was approved in combination with chemotherapy 
for both front-line follicular NHL, diffuse large B-cell NHL, and as chemotherapy in previously 
treated or untreated CLL [32, 34, 35]. Rituximab is also approved as a maintenance therapy for 
low-grade NHL. It has also been used in the treatment of other B-cell NHL such as relapsed 
Waldenstrom’s macroglobulinemia (WM) and MCL [19, 32, 36]. 
 
The drug is given in a variety of doses and schedules and is generally well tolerated. Several 
types of adverse events (AEs) have been observed with rituximab administration when used for 
the treatment of NHL, including infusion reactions, tumor lysis syndrome, hematotoxicity, and 
increased incidence of infections [33, 34]. 
 
In combination with chemotherapy, rituximab-containing regimens have consistently 
demonstrated improvements in overall survival (OS), and overall response rate (ORR) vs. 
chemotherapy alone. It is now a mainstay of B-cell NHL therapy [19, 37]. 
 
1.6.3. 
T-cell NHL (PTCL, CTCL) 
T-cell NHL comprises approximately 10 to 15% of the total cases of NHL, resulting in 
approximately 7,000 to 10,000 cases/year in the US [19, 38]. The 2008 World Health 
Organization (WHO) classification has a multitude of subtypes of PTCL, and the majority of 
them are peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell 
lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma. In general, patients with PTCL 
have an inferior survival rate as compared to patients with B-cell NHL [19, 38, 39]. SYK is 
expressed in PTCL samples, a SYK-ITK fusion gene has been identified in PTCL, and the 
JAK/STAT pathway has been implicated in this disease as well [40-42]. 
 
Typical front-line treatment of PTCL consists of CHOP or other intense chemotherapy, albeit 
with inferior outcomes as mentioned above. There are several agents approved for treatment in 
the relapsed/refractory setting, but all have response rates of 25 to 30% and response durations of 
approximately 1 year or less [19, 38, 39, 43-45]. Both autologous and allogeneic stem cell 
transplantation have also been used as salvage therapy for relapsed patients with PTCL with 
some evidence of efficacy, but little, if any randomized data exists [46, 47]. 
 
For patients who relapse after, or are refractory to multiple therapies, the prognosis is dismal and 
new therapies are needed. 
 
The cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of skin-homing 
lymphomas. The majority of CTCLs comprise Mycosis Fungoides (MF) and Sézary Syndrome 
(SS) [19, 48]. In the early stages of CTCL, skin directed therapies such as phototherapy, 


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steroids, or nitrogen mustard are administered [19, 48, 49]. For patients whose disease has 
progressed after treatment with the skin-directed therapies mentioned above, systemic therapies 
are used. Several therapies are currently approved or used for CTCL and include bexarotene, 
vorinostat, and romidepsin [19, 43, 48, 50]. Systemic chemotherapy is also used as a treatment 
for patients with advanced disease and SS [19]. Patients with CTCL have a number of 
supportive care concerns and comorbid conditions, including pruritus and infectious 
complications. Pruritus can have a major impact on patients’ quality of life and may be related 
to several cytokines [51-53]. Multiple genomic aberrations have been described in CTCL that 
involve the JAK/STAT pathways [54]. 
 
There is no standard agreed upon algorithm for the treatment of advanced CTCL, and for patients 
with advanced disease whose disease relapses after standard therapy, newer therapies are needed. 
 
1.6.4. 
Follicular Lymphoma and Other Indolent Lymphomas (iNHL); (FL/iNHL) 
Follicular lymphoma is the most common indolent NHL (iNHL), accounting for about 20 to 30% 
of all B-cell NHL [19, 55]. Nearly 90% of cases have a translocation [15, 19], resulting in 
deregulated expression of BCL2. Follicular lymphoma has several grades depending on various 
histologic features; however, Grade 3B is usually treated like DLBCL [19, 25, 55]. Although 
they have differing histologies, the other iNHLs such as SLL (discussed below), Waldenström's 
macroglobulinemia (WM), and marginal zone lymphoma (MZL) often have similar clinical 
presentations, histories, and treatments as does FL, and are often included in the iNHL category 
along with FL [56]. 
 
Although advanced disease is not curable, effective therapy is available for this disease. Therapy 
is usually initiated when symptoms are present or certain criteria are met [55]. Rituximab has 
had a major influence on the treatment of follicular lymphoma and other iNHLs. Typical 
front-line treatments include rituximab as a single agent, or combined with chemotherapy such as 
CHOP, bendamustine, or other agents [19, 55, 57]. These agents may also be used in the 
relapsed setting. High dose chemotherapy with autologous or allogenic stem cell rescue has also 
been used as a salvage therapy with some success as well [57, 58]. 
 
A certain percentage of FLs will transform into DLBCL, which is associated with a poor clinical 
outcome. The underlying reasons for transformation are unknown, and the risk of transformation 
is about 2 to 3% per year [26]. These patients are treated like patients with DLBCL. 
 
For patients whose disease has progressed after multiple therapies, several agents have been 
used, and the PI3 kinase inhibitor, idelalisib, has been approved by the US FDA and other 
regulatory agencies for use in patients with FL whose disease has progressed after 2 prior 
therapies [19, 58, 59]. This agent has a response rate of over 50% and a median duration of 
response of 12.5 months [59]. Further agents are needed for patients with multiple relapsed 
and/or refractory FL and other iNHLs. 


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1.6.5. 
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) 
CLL is the most prevalent leukemia in the western world. SLL is essentially a more nodal form 
of the disease without peripheral blood involvement [19, 55]. In 2015, there were an estimated 
14,620 cases and 4,650 deaths from CLL/SLL. 
 
CLL/SLL is grouped with the indolent lymphomas and is incurable; however, typically it is 
treatable. Depending on the stage, genetic/other prognostic factors and symptoms at diagnosis, 
patients may be observed initially and only treated when symptoms such as adenopathy or 
cytopenias develop [19, 55, 60]. 
 
There are a multitude of regimens available for therapy and the choice of 1 regimen or agent 
over another depends on the patient’s prognostic factors, performance status, and symptoms. For 
more elderly patients with comorbidities, chlorambucil (alone or in combination with 
obinituzumab or ofatumumab, both anti-CD20 antibodies) can be used. The combinations have 
shown superior outcomes vs. single-agent chlorambucil [19, 60, 61]. Alternatively, 
bendamustine with rituximab can also be used. For more fit patients, fludarabine may be used in 
combination with rituximab and cyclophosphamide (for both upfront and relapsed/refractory 
patients) [19, 60, 61]. 
 
Unfortunately, patients will ultimately relapse or become refractory to most therapies. In some 
cases, patients may have a histologic transformation of their CLL to DLBCL (Richter’s 
syndrome), and these patients have a poor prognosis [19, 62, 63]. For patients who relapse from 
previous cytotoxic therapies, such as bendamustine and rituximab, or fludarabine, 
cyclophosphamide and rituximab, the options are limited especially if the duration of response is 
fewer than 2 to 3 years [64]. Newer agents are available: Ibrutinib, an inhibitor of Bruton’s 
tyrosine kinase (BTK) was recently approved for the treatment of CLL for patients with 
relapsed/refractory disease [21, 61, 65]. In addition, idelalisib, an inhibitor of PI3 kinase, was 
also approved for the treatment of CLL in combination with rituximab for patients with relapsed 
CLL with comorbidities [49, 66]. Lastly, venetoclax, an inhibitor of BCL2, has shown dramatic 
activity in relapsed/refractory CLL, although the patients treated in this study had CLL that was 
relapsed/refractory to fludarabine or alkylator-based therapy [67]. However, patients will relapse 
from or be refractory to these newer agents, and in the case of relapse from ibrutinib, the 
prognosis is dismal, with a median survival of approximately 3 months [68]. New therapies are 
needed for patients who progress or are refractory to the current ones. 
 
In CLL, the detection of minimal residual disease (MRD) is an independent predictor of OS and 
PFS in patients treated with chemoimmunotherapy [69]. The prognostic value of achieving 
MRD negativity is unknown with newer pathway inhibitors, and it remains a patient of clinical 
investigation. MRD assessment has traditionally been done by flow cytometry (typical limit of 
detection at 1 in 10,000 cells), although other assessments that are perhaps more sensitive are 
being studied [69-71]. 


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2.0 
OBJECTIVES AND ENDPOINTS 
See Table 3 for definitions of the specialist terms and response criteria used in the sections 
that follow. 
 
2.1. 
Objectives 
2.1.1. 
Phase 1 Objectives (Escalation) 
2.1.1.1. 
Primary Objective 
• 
To determine the maximum tolerated dose/maximum administered dose (MTD/MAD) of 
cerdulatinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), 
small lymphocytic lymphoma (SLL) or B-cell non-Hodgkin lymphoma (NHL). 
 
2.1.1.2. 
Secondary Objectives 
• 
To make a preliminary assessment of the antitumor activity of cerdulatinib in patients 
with relapsed/refractory CLL/SLL or B-cell NHL, as assessed by overall response rate 
(ORR), defined as complete response (CR)+ partial response (PR). 
• 
To assess the safety and tolerability of cerdulatinib. 
• 
To determine the pharmacokinetic (PK) profile of cerdulatinib. 
• 
To evaluate the pharmacodynamics (PD) of cerdulatinib. 
 
2.1.2. 
Phase 2a Objectives (Exploratory) 
2.1.2.1. 
Primary Objective 
• 
To assess the antitumor activity of cerdulatinib in patients with specific subtypes of 
B-cell or T-cell NHL, or CLL/SLL, as a single agent and in combination with rituximab 
for B-cell NHL. 
 
2.1.2.2. 
Secondary Objectives 
• 
To assess the duration of antitumor activity of cerdulatinib, amount of time to achieve 
tumor response, and magnitude of response. 
• 
To further evaluate the PK profile of cerdulatinib in patients with specific subtypes of 
B-cell or T-cell NHL, alone or in combination with rituximab for B-cell NHL. 
• 
To further evaluate the PD of cerdulatinib in patients with specific subtypes of B-cell or 
T-cell NHL, alone or in combination with rituximab for B-cell NHL. 
• 
To assess tumor phenotype and genotype in relation to clinical response. 
• 
To further evaluate the safety and tolerability of cerdulatinib in patients with specific 
subtypes of B-cell or T-cell NHL, or CLL/SLL. 


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• 
To evaluate the safety and tolerability of the combination of cerdulatinib with rituximab 
for B-cell NHL. 
 
2.1.2.3. 
Exploratory Objectives 
• 
To evaluate the relationship between markers of inflammation with clinical outcome and 
overall health as determined by the Global Health Assessment. 
• 
To assess Minimal Residual Disease (MRD) status in CLL/SLL patients achieving a 
complete response/complete response incomplete blood count recovery/partial response 
(CR/CRi/PR) by flow cytometry. MRD negativity (MRD-) is defined as < 1 tumor cell 
in 10,000 leucocytes. MRD+ (MRD positivity) is defined as ≥ 1 tumor cell in 
10,000 leucocytes. 
 
2.2. 
Endpoints 
2.2.1. 
Phase 1 Endpoints 
2.2.1.1. 
Primary Endpoint 
• 
The primary safety endpoint will be the incidence of DLT by dose level. 
 
2.2.1.2. 
Secondary Endpoints 
• 
ORR, defined as CR+PR. 
• 
Clinical benefit rate, defined as CR + PR + SD, PFS, and DOR. 
• 
Adverse event profile (classified by National Cancer Institute Common Toxicity Criteria 
for Adverse Events [NCI-CTCAE v4.0]) by dose level. 
• 
Clinically significant changes in vital signs, physical exams by dose level. 
• 
Changes in hematology and chemistry laboratory parameters by dose level. 
• 
PK endpoints: PK profile at each dose level and overall, including Cmax, AUC, and t½. 
• 
PD endpoints: Changes in biomarker data for a range of ex vivo assays. 


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2.2.2. 
Phase 2a Endpoints 
2.2.2.1. 
Primary Endpoint 
• 
The primary efficacy endpoint is ORR, defined as CR+PR. 
 
2.2.2.2. 
Secondary Endpoints 
• 
Duration of response (DOR), progression-free survival (PFS), time to treatment response 
(TTR), and lymph node response (LNR). 
• 
Clinical benefit rate, defined as CR + PR + SD. 
• 
Adverse event profile (classified by NCI-CTCAE v5.0) by dose level. 
• 
Clinically significant changes in vital signs, physical exams by dose level. 
• 
Changes in hematology and chemistry laboratory parameters by dose level. 
• 
PD endpoints: Changes in biomarker data for a range of ex vivo assays. 
 
2.2.3. 
Exploratory Endpoints 
• 
Correlation in markers of inflammation with clinical response and overall health 
(Global Health Assessment). 
• 
Assessment of percentage of CLL/SLL patients with status of MRD- in CLL/SLL 
patients achieving a CR/CRi/PR by flow cytometry. 


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3.0 
INVESTIGATIONAL PLAN 
 
3.1. 
Overall Study Design and Study Schema 
This is an open-label, Phase 1/2a, multi-dose, multi-center trial of orally administered 
cerdulatinib with 2 phases: 
• 
Phase 1: Dose-escalation portion, during which patients will receive single-agent 
cerdulatinib at their assigned dose level. The starting dose for this portion of the study 
will be 15 mg QD, administered in increasing doses until the MTD/MAD is identified. 
• 
Phase 2a: Exploratory portion, consisting of 6 cohorts, defined by cancer type and prior 
therapy. Five cohorts will receive single-agent cerdulatinib, and 1 cohort will receive 
cerdulatinib plus rituximab administered IV during Cycle 1 on Days 1, 8, 15, and 22 and 
during Cycles 4, 6, 8, and 10 on Day 1 only. The starting dose of cerdulatinib during this 
portion of the study will be 30, 25, or 20 mg BID. 
 
The Schedule of Assessments for Phase 2a is provided in Appendix 1. 
 
3.1.1. 
Phase 1 
3.1.1.1. 
Overall Description 
Patients: The Phase 1 portion of the study will include patients with a histologically confirmed 
diagnosis of CLL/SLL or B-cell non-Hodgkin lymphoma. 
 
Design: Eligible patients enrolled in sequential dose cohorts will receive once-daily, orally 
administered single-agent cerdulatinib at starting dose of 15 mg (15 mg po QD) in increasing 
dose levels until the MTD/MAD is identified. An exception occurs on Days 2 and 3, during 
which patients on a QD schedule will not take study drug (see next paragraph). If the MTD 
is not achieved, the highest studied dose will be declared the MAD and become the RP2D. 
(See Table 3 for definitions of cancer types.) 
 
To allow for a single-dose PK assessment, patients on a QD dosing regime will take their first 
dose of cerdulatinib on Day 1 and their second and subsequent doses daily beginning on Day 4. 
They will not take cerdulatinib on Days 2 or 3. Starting with Day 4, patients will receive 
cerdulatinib once daily for a total of 28 days (one cycle) to assess the MTD/MAD. Patients on 
BID dosing schedules can dosing begin on Day 1 and continue cerdulatinib without interruption 
(i.e., these patients will not skip any days of the cycle). If cerdulatinib is well tolerated, patients 
may continue to receive cerdulatinib at their assigned dose in the absence of disease progression, 
unacceptable toxicity, or meeting of any other withdrawal criteria (Section 4.4). 


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One patient will be enrolled in each dose cohort until the first report of a Grade 2 or greater 
adverse event (AE). In the event of any Grade ≥ 2 AE in the single patient, an additional 
2 patients, for a total of 3, will be enrolled in that dose cohort, and all subsequent dose cohorts 
will follow a “3 + 3” design. Dose escalation will be in 100% increments until a drug-related AE 
of Grade 2 or greater severity occurs. Thereafter, dose escalation will be in increments of up to 
50% as determined following review by the Study committee. If a dose-limiting toxicity (DLT) 
occurs in 1 of the first 3 patients in a cohort, that cohort will be expanded to at least 6 patients. 
If ≤ 33% of six or more patients in a cohort experiences DLT, dose escalation may proceed. If in 
any cohort 2 or more of the first 3 patients or ≥ 33% of patients in a cohort develop DLT, dose 
escalation will cease, and that dose level will be declared intolerable. The prior dose level will 
be declared the MTD, and the cohort may be expanded to as many as 6 patients if fewer than 
6 patients had been treated previously at that dose level in order to further characterize the PK 
and PD at that level. A total of 43 patients have been dosed. The study is closed to Phase 1 
enrollment. 
 
3.1.1.2. 
Rationale for Dose Selection in Phase 1 and Dose-Escalation Methods 
The starting dose for the Phase 1 portion of the study was based on the severely toxic dose in 
10% of rodents (STD10) from a 28-day toxicology study in the rat, the most sensitive species, as 
defined by the S9 Guidance to Industry “Nonclinical Evaluation for Anticancer 
Pharmaceuticals.” One-tenth of the STD10 of 15 mg/kg is recommended by the guidance to be 
the appropriate starting dose. After allometric scaling, and accounting for the average weight of 
human patients (70 kg), the total daily starting dose for cerdulatinib was determined to be 15 mg 
po once daily (QD). The dose-escalation methods accord with the principles described by 
Le Tourneau et al., for Phase 1 clinical trials [6]. 
 
3.1.2. 
Phase 2a 
3.1.2.1. 
Overall Description, Including Rationale for Inclusion of T-cell Malignancies 
Patients: The Phase 2a portion of the study will include patients with B-and T-cell malignancies 
(Table 6) who are believed to be able to tolerate therapy and who will provide interpretable 
results to further guide the development of cerdulatinib. In general, the malignancies being 
studied in this portion of the study were chosen based on the role of BCR signaling and/or the 
role of the JAK/STAT pathway in their disease as discussed in Section 1.0. The decision to 
include T-cell malignancies in the Phase 2a cohorts was based on SYK expression in PTCL, as 
well as the role of the JAK/STAT pathway in PTCL described in Section 1.6.3. A rituximab 
combination cohort (Cohort 2, see Table 6) was added to explore the activity of cerdulatinib with 
a known effective agent in the treatment of B-cell NHL. 


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Design: The Phase 2a portion will investigate 6 cohorts, each defined by cancer type and 
therapy (Table 6). Five cohorts will receive single-agent cerdulatinib administered orally, and 
1 cohort with B-cell NHL (No. 2) will receive orally administered cerdulatinib and rituximab 
administered IV at 375 mg/m2 during Cycle 1 on Days 1, 8, 15, and 22 and during Cycles 4, 6, 8, 
and 10 on Day 1 only. 
 
Initial enrollment into any of the 6 cohorts will be up to 20 patients; each cohort may be 
expanded for a total of approximately 240 patients in the Phase 2a portion of the study. 
 
Throughout the duration of the study, Portola will inform Investigators and sites regarding which 
cohorts are open and what starting dose of cerdulatinib (i.e., 30, 25, or 20 mg BID) should be 
administered to patients at the time of enrollment. Dose Modification Guidelines for Phase 2a 
are provided in Section 5.2.1.3. 


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Table 6: 
By-Cohort Inclusion Criteria for Phase 2a Cohorts 
 
Cohort Number 
(short descriptor) 
Inclusion Criteria 
1 
(FL) 
Patients with FL Grade 1 to 3A who have received ≥ 1 prior treatment regimen. 
2 
(Combination 
Cohort) 
Patients with FL Grade 1 to 3A who have received ≥ 1 prior treatment regimen. In addition 
to receiving cerdulatinib, this cohort will also receive rituximab IV at 375 mg/m2 during 
Cycle 1 on Days 1, 8, 15, and 22 and during Cycles 4, 6, 8, and 10 on Day 1 only. 
3 
(aNHL) 
Patients with aggressive NHL (aNHL), defined as DLBCL, FL 3B, MCL, and transformed 
NHL. These patients have relapsed from ≥ 1 but ≤ 3 prior cytotoxic chemotherapy regimens 
with an anti CD20 antibody, (e.g., R-CHOP, BR). Patients must have received an 
anthracycline based therapy unless anthracyclines were deemed inappropriate in the 
judgement of the investigator. 
Patients must have either relapsed following ASCT or not be candidates (ineligible) for 
ASCT, defined as meeting any of the following criteria [1]: a) age ≥ 70 years; b) DLCO 
< 50% by pulmonary function tests; c) FEV1/FVC < 60% predicted by pulmonary function 
tests; d) LVEF < 45% by MUGA or echocardiogram; e) uncontrolled arrhythmia; 
f) calculated creatinine clearance (Cockcroft-Gault) ≤ 60 mL/min; g) other comorbidities 
(e.g., medical conditions or psychosocial conditions) that would likely result in an 
unacceptably high probability of treatment/transplant related morbidity and mortality in the 
judgement of the investigator (e.g., high HCT-CI, CIRS, scores); h) refusal of ASCT. 
(Note: Antibody drug conjugates (ADC) count as cytotoxic chemotherapy. Salvage 
chemotherapy prior to ASCT with or without maintenance therapy counts as one regimen.) 
4 
(CLL/SLL) 
Patients with CLL/SLL who have received ≥ 1 prior treatment regimen. 
5 
(PTCL NHL) 
Patients with PTCL NHL who have received ≥ 1 prior systemic treatment regimen 
for PTCL. In patients with CD30-expressing PTCL, prior treatment must include a CD30- 
directed antibody (e.g., brentuximab vedotin). 
6 
(CTCL NHL) 
Patients with CTCL NHL who have received ≥ 1 prior systemic treatment regimen 
for CTCL. 
ADC = Antibody drug conjugate; ASCT = Autologous stem cell therapy; aNHL = Aggressive non-Hodgkin 
lymphoma; BCR = B-cell receptor; BR = Bendamustine and rituximab; BTK = Bruton tyrosine kinase; 
CLL = Chronic lymphocytic leukemia; CIRS = Cumulative Illness Rating Scale; CTCL = Cutaneous T-cell 
lymphoma; DLBCL = Diffuse Large B-cell lymphoma; DLCO = Carbon monoxide diffusion capacity; 
FEV1/FVC = Forced expiratory volume in 1 second/forced vital capacity; FL = Follicular lymphoma; 
FL 3B = Follicular lymphoma, Grade 3B; HCT-CI = Hematopoietic cell transplantation co-morbidity index; 
HSCT = Hematopoietic stem cell transplant; LEVF = Left ventricular ejection fraction; MUGA = Multiple gated 
acquisition; PR = Partial response; PTCL = Peripheral T-cell lymphoma; R-CHOP = Rituximab + 
cyclophosphamide, doxorubicin hydrochloride, vincristine (formerly oncovin), and prednisolone; SLL = Small 
lymphocytic lymphoma 
Note: Patients who received any BCR pathway inhibitor (e.g., BTK inhibitors such as ibrutinib, or PI3 Kinase 
inhibitors such as idelalisib) and/or BCL2 pathway inhibitors (e.g., venetoclax), and were either intolerant to therapy 
or had relapsed/refractory disease following therapy are also eligible. 


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3.1.2.2. 
Rationale for Initial Starting Dose and Individual Dose Reductions 
3.1.2.2.1. Rationale for Starting Dose 
Under Amendment 4 the starting dose of cerdulatinib in the Phase 2a portion of the study was 
35 mg BID based on the PK/PD and PK/AE relationships and PK modeling of the Phase 1 study 
(Section 1.5). Clinical PK/PD evaluations demonstrated that IC50s in the 0.2 to 0.6 µM range 
suppress BCR and cytokine JAK/STAT signaling pathways (Figure 1). However, under 
Amendment 5, the starting dose was changed to 30 mg BID (rationale below), with subsequent 
dose reductions to 25 mg BID, 20 mg BID, and then 15 mg BID permitted (the rationale for 
individual dose titration strategy is in Section 3.1.2.2.2). Under Amendent 7 starting doses of 30, 
25, or 20 mg BID may be explored to further investigate the relationships between cerdulatinib 
exposure, extent of SYK/JAK pathway inhibition, anti-inflammatory response, clinical response, 
and safety. The data overall will be used in the final determination of the appropriate dose for 
registration studies. 
 
IC90 for BCR signaling is approximately 0.8 µM, and for JAK/STAT signaling ranges from 
0.75 to 1.25 µM. The pathway inhibition is selective, as no inhibition of JAK2- or 
PKC-dependent signaling was observed. These data reflect pathway inhibition in peripheral 
blood, and therefore do not predict the level of inhibition in solid tumor. 


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Figure 1:       Cerdulatinib Pathway Inhibition in Peripheral Blood 
Conc = Concentration; IC50 = Half maximal inhibitory concentration; PK/PD = Pharmacokinetic/pharmacodynamic
Notes: PK/PD relationships are shown from peripheral whole blood assays. Percent inhibition relative to pre-dose
signaling on Day 1 is plotted on the Y-axis, cerdulatinib plasma concentration in molar on the X-axis. Clinical
PK/PD evaluations have demonstrated IC50s in the 0.2 to 0.6 µM range to suppress BCR and cytokine JAK/STAT
signaling pathways. IC90 for BCR signaling is approximately 0.8 µM, and for JAK/STAT signaling ranges from
0.75 to 1.25 µM.


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Cerdulatinib was studied at multiple QD and BID dose levels and exhibited nonlinear PK at 
doses higher than 30 mg QD, with the exposure increasing approximately 3-fold as the dose was 
increased from 30 to 40 mg QD. Daily dose levels ranging from 40 to 65 mg demonstrated an 
exposure plateau above 30 mg QD, resulting in average steady-state Cmin and Cmax 
concentrations of 0.8 and 1.6 µM, respectively. The 100 mg QD dose resulted in lower overall 
exposure, possibly a consequence of drug precipitation in the gut. The 40 to 65 mg dose levels 
resulted in greater than 90% inhibition of the BCR signaling pathway, and greater than 75% 
inhibition of various JAK/STAT pathways (IL2, IL4, IL6) at steady-state Cmin. Two PRs were 
observed at the 45 mg QD dose level, and a third at the 65 mg QD dose. The t½ at these doses 
was approximately 24 hours. Hence, the drug properties are suitable for once daily dosing. 
 
Based on pre-clinical tumor models, 1 µM cerdulatinib is sufficient to reduce viability in the 
majority of cell lines and primary leukemia samples tested. Therefore, a method was sought to 
increase steady-state Cmin concentrations in humans to 1 µM or above. Given the saturated 
exposure achieved with QD dosing, we utilized a physiological-based PK model to determine the 
potential reasons for the plateau in the QD schedule. This model indicated that pH-dependent 
drug solubility was likely the limiting factor and that BID dosing should overcome this plateau, 
resulting in higher exposures. 
 
The 45 mg BID regimen roughly doubled the exposure relative to the 40 to 65 mg QD average, 
achieving steady-state Cmin and Cmax of 1.5 and 1.8 µM, respectively. One PR was observed in a 
patient with FL, with what appeared to be a rapid (within 1 week) onset of palpable tumor 
reduction. Another patient with CLL experienced rapid lymphocytosis, whereas a refractory 
FL patient demonstrated stable disease. This exposure level, however, resulted in 2 DLTs: 
1 patient experienced pancreatitis within 2 weeks of dosing, and a second experienced Grade 3 
fatigue. Therefore, it was determined that the exposure range was not tolerated. Of note, the 
2 patients with DLT did not achieve the highest exposures at this dose level. We, therefore, 
aggregated all data from the escalation study to explore PK/AE relationships. 
 
The major difference in exposure between tolerated (40-65 mg QD) and non-tolerated (45 mg 
BID) doses was the Cmin, increasing from 0.8 µM to 1.5 µM (steady-state Cmin by dose level is 
summarized in Figure 2). Therefore, we explored the relationship between incidences of all 
treatment-related Grade ≥ 3 AEs with steady-state Cmin. No relationship was observed up to 
1.25 µM steady-state Cmin. However, above this concentration, there appeared to be some 
evidence (in the limited number of patients) for increased incidence of Grade 3 AEs (Figure 3). 
In the context of tumor response, we have observed more consistent anti-tumor activity in the 
0.75 to 1.25 µM steady-state Cmin concentration range, including 3 patients achieving PR 
(Figure 4). Hence, it appears that steady-state Cmin of 0.75 to 1.25 µM is likely to be efficacious 
and well tolerated. Furthermore, our dosing experience thus far indicates that a more consistent 
steady-state Cmin is obtained across patients with BID dosing. Thus, under Amendment 4 we 
recommended a 35 mg BID dosing schedule that targets steady-state Cmin within the range of 


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0.75 to 1.25 µM. Following an initial safety review of 12 patients dosed in the Phase 2a study, it 
was observed that whereas the majority of patients did achieve steady-state Cmin in the desired 
exposure range, 3 patients (25%) continued to accumulate plasma exposure to drug beyond Day 
8 (the expected time to steady-state); this resulted in exposures greater than originally modeled 
from the data gathered during once-daily dosing (i.e., in the 2-4 µM range and exceeded the 
modeled Cmax target by 1.5- to 2.5-fold). Of these 3 patients, 2 experienced Grade 5 infections 
(i.e., with fatal outcomes), and 1 patient experienced Grade 3 chemical pancreatitis. Although 
causality between cerdulatinib exposure and the observed SAEs cannot be determined, as of 
Amendment 5 the starting dose was lowered from 35 mg BID to 30 mg BID to correct for this 
unexpected accumulation in cerdulatinib exposure and to provide an extra margin of safety 
for patients. 
 
Figure 2: 
Individual Trough Levels (Cmin) for Tolerated (40-65 mg QD) and 
Non-tolerated (45 mg BID) Dose Regimens of Cerdulatinib on Day 29 
(First Day of Cycle 2) 
 
BID = Twice daily; Cmin = Minimum concentration (i.e., trough level); PK = Pharmacokinetic; QD = Once daily 
Notes: Individual trough (pre-dose) concentrations are shown for patients on Day 29, the first day of Cycle 2. The 
horizontal bar is the mean value and the longitudinal bar shows the range for each dose cohort. The PK-modeled 
estimates for trough (Cmin) concentrations are shown as dashed lines for reference purposes. The predicted mean for 
the 45 mg BID dose is very close to the actual mean value. The QD dose cohorts of 40, 45, 50, and 65 mg had mean 
values close to the predicted Cmin for 30 mg BID. The predicted Cmin level for the 35 mg BID schedule is slightly 
higher, and if tolerated, should provide the best opportunity to minimize variability and increase the number of 
observed responses. 


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0.25
0.50
1.25
Figure 3: 
Steady-State Cerdulatinib Plasma Concentrations and Treatment-related
Grade 2 + Adverse Events
5
4
3
2
1
0
AE = Adverse event; Cmin = Minimum concentration (i.e., trough level)
Notes: Treatment-related Grade 2+ AEs are shown on y-axis, with steady-state cerdulatinib
plasma concentration at Cmin on the x-axis. The red dashed line depicts the exposure (~1.25 µM)
at which there may be a concentration-effect on AE profile.
Figure 4: 
Change in Sum of Tumor Volumes from Computed Tomography Scans
100
50
0 
-50
-100
Cerdulatinib SS Cmin (µM)
Cmin = Minimum concentration (i.e., trough level); CT = Computed tomography; SS = Steady state
Notes: The best percent change in sum of tumor volumes from CT scans is shown on the y-axis.
Cerdulatinib steady-state plasma concentrations at Cmin are on the x-axis. The red dashed
box highlights the greater consistency in anti-tumor activity in the 0.75-1 µM range.
0.75
1.00
0.00
0.50
1.00
1.50
2.00
Steady-State Cmin (µM)
Grade of Related AEs
% Change in Tumor Volume


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An estimate of cerdulatinib concentrations from PK modeling for the proposed doses is detailed 
in Table 7. 
 
Table 7: 
Estimated Concentrations of Twice Daily (BID) Doses from PK Modeling 
 
BID Dose 
(mg) 
Cmin 
(µM) 
Cmax 
(µM) 
Cave 
(µM) 
20 a 
0.38 ± 0.02 
0.89 ± 0.16 
0.52 ± 0.09 
25 
0.66 
0.89 
0.75 
30 
0.83 
1.09 
1.0 
35 a 
1.06 ± 0.50 
1.26 ± 0.70 
NA 
45 
1.43 
1.78 
1.6 
BID = Twice daily; Cave = Average concentration; Cmax = Maximum 
concentration; Cmin = Minimum concentration (i.e., trough level); 
PK = Pharmacokinetic 
a Observed concentrations. 
 
 
A PK model was developed to estimate steady-state concentration for BID dosing. This model 
used the average steady-state concentrations for previous BID dose cohorts at dose levels 15, 20, 
and 45 mg. In addition, the plasma concentrations from the patient who received 30 mg BID as 
part of a dose reduction was included in the model. The model incorporated the saturated 
clearance previously observed for cerdulatinib. The results are consistent with the data obtained 
to date for the 45 mg BID dose and are close to that observed with the single patient who 
received 30 mg BID. 
 
3.1.2.2.2. Rationale for Individual Dose Titration in Phase 2a 
Given the variability of cerdulatinib levels investigated to date, it is possible that some patients 
may be able to tolerate higher doses of cerdulatinib than others. Therefore, under Amendment 4 
patients were allowed to escalate to 40 mg BID after undergoing one 28-day cycle without 
Grade 3 or higher clinically significant toxicity. In addition, modeling data in Table 7 suggested 
that this dose regimen would provide Cmin in the acceptable range of between 0.75 and 1.25 μM. 
As shown in the literature, this dose titration approach based on clinical tolerability has been 
used with other tyrosine kinase inhibitors, and patients who tolerated the higher doses often 
achieved higher response rates [72]. However given the SAEs observed in the first 12 patients 
dosed at 35 mg BID (the starting dose under Amendment 4), both the starting dose and dose 
titration strategy were modified. The starting doses are 30, 25, or 20 mg BID. 
 
Dose reductions and subsequent dose escalations back to a maximum dose of 30 mg BID may be 
permitted per the Dose Modification Guidelines for Phase 2a (Section 5.2.1.3). As indicated in 
Table 6, the dose reductions are expected to lower overall exposure in a step-wise fashion. 
The dose of 20 mg BID was studied in 3 patients in the Phase 1 portion of this study and was 
well tolerated. 


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3.1.3. 
End of Study 
The end of study will occur when all patients have completed the follow-up visit at 30 days post- 
treatment, or until all patients have died, have been discontinued (under advice of the physician, 
at the request of the Sponsor), have withdrawn consent, or are lost to follow-up, whichever 
occurs first. 
 
3.1.4. 
Total Number of Patients, Cessation of Treatment, and Total Duration of 
the Study 
Under Phase 1 (closed to enrollment), 52 patients were enrolled, and 43 were dosed. Under 
Phase 2a, approximately 240 patients can be enrolled. Thus, a total of up to 283 patients can be 
dosed in the study. 
 
Patients enrolled under Phase 1 and Phase 2a may continue to receive cerdulatinib or cerdulatinib 
in combination with rituximab (in the combination cohort No. 2; see Table 6) in the absence of 
disease progression or intolerable toxicity, until they meet any other withdrawal criteria, 
(Section 4.4) or until the end of study (defined in Section 3.1.3). 
 
The total duration of the study is expected to be approximately 6 years. 
 
3.1.5. 
Assessments 
Safety will be monitored by serial physical exams, vital signs, hematology, and chemistry 
laboratory studies, and by reported AEs. 
 
Blood samples will be obtained at frequent intervals for determination of cerdulatinib 
concentration. 
 
Serum will be obtained for analysis of the PD effects of cerdulatinib. 
 
Antitumor activity will be assessed every 8 to 12 weeks according to the revised International 
Working Group (IWG) criteria [3] or the International Workshop on Chronic Lymphocytic 
Leukemia (IWCLL) criteria [2]. 
 
3.2. 
Randomization and Blinding 
This is an open-label, unblinded study. 


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4.0 
SELECTION, ENROLLMENT, AND WITHDRAWAL OF PATIENTS 
During the Phase 1 portion (now closed to enrollment), the study was conducted in patients with 
relapsed or refractory CLL/SLL or B-cell NHL. During the Phase 2a portion, the study will be 
conducted in patients with various B- and T-cell NHL (see Section 3.1.2 for the rationale for 
including patients with T-cell malignancies). 
 
4.1. 
Inclusion Criteria 
4.1.1. 
Phase 2a Cancer-specific Inclusion Criteria 
1. Patient must have a histologically confirmed diagnosis of 1 of the following: 
○ (Note: Definitions for “relapsed” and “refractory” disease are provided in Table 3). 
○ FL Grade 1 to 3A, with relapsed or refractory disease. 
○ Aggressive NHL (aNHL) defined as DLBCL, FL Grade 3B, MCL, and transformed 
NHL with relapsed disease, relapsed and refractory after 1 to 3 prior 
chemotherapy regimens. 
○ CLL/SLL, with relapsed or refractory disease. 
○ PTCL, with relapsed or refractory disease. 
○ CTCL with relapsed or refractory disease. Only CTCL patients with MF/SS 
are allowed. 
 
Patients who received any BCR pathway inhibitor (e.g., BTK inhibitors such as ibrutinib, or PI3 
Kinase inhibitors such as idelalisib) and/or BCL2 pathway inhibitors (e.g., venetoclax), and were 
either intolerant to therapy or had relapsed/refractory disease following therapy are also eligible. 
 
4.1.2. 
Phase 2a General Inclusion Criteria 
1. Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Score 
of 0 or 1. 
2. Patient must be 18 years or older, of either sex, and of any race. 
3. Patient (and/or parent/guardian for patients who otherwise are unable to provide 
independent consent) must be willing to give written informed consent and be able to 
adhere to dose and visit schedules. 
4. Patient has had prior treatment for lymphoid malignancy requiring treatment for 
progressive disease/refractory disease (per guidelines for diagnosis and treatment of 
CLL [2] and revised response criteria for malignant lymphoma [3]). 
5. Patient has had ≥ 1 prior systemic treatment regimen administered for at least 2 cycles 
(unless the patient was intolerant or experienced documented progression on therapy) that 
must have involved either: 1) an anti-CD20 agent (such as rituximab) WITH 
chemotherapy for B-cell NHL, unless contraindicated in the judgement of the investigator 


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(e.g., the patient was not a candidate for chemotherapy and received ibrutinib as first-line 
treatment); 2) a cytotoxic chemotherapy drug for T-cell NHL; 3) an anti-CD20 agent 
(such as rituximab) with chemotherapy for CLL, unless contraindicated in the judgement 
of the investigator (e.g., the patient was not a candidate for chemotherapy and received 
ibrutinib as first-line treatment); or 4) in patients with CD30-expressing PTCL, a 
CD30-directed antibody (e.g., brentuximab vedotin). 
6. Female patients of childbearing potential and male patients must agree to abstain from 
sexual intercourse or to use an effective method of contraception during the study and for 
90 days following the last dose of protocol therapy (examples of effective methods of 
contraception include oral contraceptives or double barrier methods such as condom plus 
spermicide or condom plus diaphragm). Patients enrolled into Cohort 2 should use 
effective contraception during treatment with rituximab and for 12 months after the last 
dose of rituximab. 
7. Patient must have adequate bone marrow reserve as evidenced by an absolute neutrophil 
count (ANC) ≥ 1,000/µL, platelet count ≥ 75,000/µL. Platelet count must be without 
transfusion support within 7 days of the first dose of cerdulatinib. 
Note: CLL patients only: ANC ≥ 750/µL and platelet count ≥ 30,000/µL are 
acceptable. There are no limits on ANC or platelet count required for patients with 
leukemic forms of PTCL (ATLL, PLL, LGL) or HSTCL as long as cytopenia, if present, 
is secondary to disease. 
8. Patient must have adequate renal function as evidenced by a creatinine clearance 
≥ 30 mL/min (calculated using the Cockcroft-Gault equation or based on a 24-hour 
urine specimen). 
9. Patient must have adequate hepatic function as evidenced by a serum bilirubin level 
≤ 2.0 mg/dL AND serum AST/ALT levels ≤ 2.5× the ULN for the reference lab. Serum 
bilirubin ≤ 2.5 mg/dL when increase clearly documented as due to Gilbert’s syndrome. 
10. Where available, ability to submit a formalin-fixed paraffin embedded tissue (FFPE) 
block or a minimum of 10 unstained, freshly cut FFPE tissue slides from lymph node or 
other biopsies that were collected as part of patient diagnosis. If samples are unavailable 
the patient is still eligible for enrollment. 
11. Measureable disease for a given tumor type, defined as: 
a. The presence of ≥ 1 lesion that measures ≥ 1.5 cm in a single dimension as assessed 
by CT, CT/PET for patients with nodal or mass lesions (e.g., FL, DLBCL, other 
NHL), or 
b. Quantifiable circulating tumor cells for patients with circulating tumor (e.g., Sézary 
Syndrome [SS]), or 
c. For CTCL: mSWAT score > 0. 


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12. Ability to provide redacted copies of pathology reports and radiology reports used for the 
diagnosis of NHL or CLL. In addition, for CTCL, ability to provide redacted 
photographs of skin responses. 
 
4.1.3. 
Phase 2a Cohort-specific Inclusion Criteria 
4.1.3.1. 
Cohort 1 (FL) – Grades 1 to 3A (Single-agent Cerdulatinib) 
1. Received ≥ 1 prior treatment regimen. 
 
4.1.3.2. 
Cohort 2 (Combination) – FL, Grades 1 to 3A (Cerdulatinib + Rituximab) 
1. Received ≥ 1 prior treatment regimen. 
 
4.1.3.3. 
Cohort 3 (aNHL) – aNHL (Single-agent Cerdulatinib) 
Aggressive non-Hodgkin lymphoma (aNHL) is defined as DLBCL, FL Grade 3B, Mantle Cell 
Lymphoma (MCL), and transformed NHL. 
1. Relapsed from ≥ 1 but ≤ 3 prior cytotoxic chemotherapy regimens with an anti CD20 
antibody, (e.g., R-CHOP, BR). Patients must have received an anthracycline based 
therapy unless anthracyclines were deemed inappropriate in the judgement of the 
investigator. Patients must have either relapsed following autologous stem cell therapy 
(ASCT), or not be candidates (ineligible) for ASCT, defined as meeting any of the 
following criteria [1]: 
a. Age ≥ 70 years. 
b. Carbon monoxide diffusion capacity (DLCO) < 50% by pulmonary function tests. 
c. Forced expiratory volume in 1 second/forced vital capacity FEV1/FVC < 60% 
predicted by pulmonary function tests. 
d. Left ventricular ejection fraction (LVEF) < 45% by multiple gated acquisition 
(MUGA) or echocardiogram. 
e. Uncontrolled arrhythmia. 
f. Calculated creatinine clearance (Cockcroft-Gault) ≤ 60 mL/min. 
g. Other comorbidities (e.g., medical conditions or psychosocial conditions) that would 
likely result in an unacceptably high probability of treatment/transplant related 
morbidity and mortality in the judgement of the investigator (e.g., high Hematopoietic 
Cell Transplantation Co-Morbidity Index [HCT-CI], Cumulative Illness Rating Scale 
[CIRS] scores). 
h. Refusal of ASCT. 
Note: Antibody drug conjugates (ADC) count as cytotoxic chemotherapy. Salvage 
chemotherapy prior to ASCT with or without maintenance therapy counts as one 
regimen. 


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4.1.3.4. 
Cohort 4 (CLL/SLL) – CLL/SLL (Single-agent Cerdulatinib) 
1. Received ≥ 1 prior treatment regimen. 
 
4.1.3.5. 
Cohort 5 (PTCL NHL) – Peripheral T-cell NHL (PTCL) (Single-agent 
Cerdulatinib) 
1. Received ≥ 1 prior systemic treatment regimen for PTCL. In patients with CD30- 
expressing PTCL, prior treatment must include a CD30-directed antibody (e.g., 
brentuximab vedotin). 
 
4.1.3.6. 
Cohort 6 (CTCL NHL)– Cutaneous T-cell NHL (CTCL, MF/SS only) 
(Single-agent Cerdulatinib) 
1. Received ≥ 1 prior systemic treatment regimen for CTCL. 
 
4.2. 
Phase 1 and Phase 2a Exclusion Criteria 
A patient meeting any 1 of the Exclusion Criteria listed below will be excluded from the trial. 
1. Patient has Richter’s syndrome, Burkitt’s lymphoma, or Burkitt-like Lymphoma. 
Patients with transformed DLBCL from Follicular NHL are eligible. 
2. Patient has undergone prior allogeneic or autologous transplant with infusion of stem 
cells within 90 days before Cycle 1 Day 1 (C1D1), or on active immunosuppressive 
therapy for graft-versus-host disease (GVHD) or GVHD prophylaxis within 8 weeks 
before C1D1. 
3. Patient has received prior therapy with a spleen tyrosine kinase (SYK) inhibitor. 
4. Patient requires chronic treatment with a strong CYP3A4 inhibitor or inducer or 
CYP3A4-sensitive substrate (Appendix 3). 
5. Patient has known lymphomatous involvement of the central nervous system (CNS). 
6. Patient has a known hypersensitivity to any of the components of cerdulatinib. 
7. Patient has persistent, unresolved NCI-CTCAE v5.0 ≥ Grade 2 clinically significant 
(in the judgement of the investigator) drug-related toxicity (except alopecia, erectile 
impotence, hot flashes, libido, neuropathy) associated with previous treatment. 
8. Prior monoclonal antibody (mAb) (including alemtuzumab), radioimmunoconjugate, 
antibody drug conjugate (ADC), phototherapy, radiotherapy, chemotherapy, 
immunotherapy, immunosuppressive therapy, or any investigational agent for the 
purposes of treating cancer within 3 weeks before Cycle 1 Day 1. 
9. For CTCL patients only: total skin electron beam therapy (TSEBT) within 12 weeks, or 
initiation of topical steroid, nitrogen mustard, or topical retinoid within 2 weeks before 
Cycle 1 Day 1. Patients with CTCL who are on a stable topical regimen for ≥ 4 weeks 
prior to C1D1 are allowed. 


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10. The patient has a known infection with HIV, HBV, or HCV or is a carrier of HBV or 
HCV. Patients who are seropositive for HCV antibody must test negative for HCV by 
PCR assay to be eligible. Patients with an occult or prior HBV infection (defined as 
being seropositive total hepatitis B core antibody [HBcAb] and seronegative for HBsAg) 
may be included if his or her HBV DNA is undetectable or if it is undetectable with 
antiviral therapy. These patients must be willing to undergo additional testing per local 
standard of care if this data is unavailable. Additional testing will be performed if the 
patient does not have documentation of a negative hepatitis panel and a negative HIV 
history within the 12-week period prior to enrollment. 
11. Patient has an active infection requiring systemic treatment, defined as requiring 
antimicrobial, antifungal, or antiviral agents. Prophylactic antimicrobial treatment is 
permitted. 
12. Patient has significant gastrointestinal disease that may interfere with absorption of the 
study drug or that predisposes him/her to GI adverse effects, or has had major gastric or 
bowel surgery. 
13. Patient has difficulty swallowing or malabsorption syndrome. 
14. Patient has any other medical, social, or psychiatric condition that might interfere with 
the patient’s participation in the trial or interfere with the interpretation of trial results. 
15. Patient has undergone major surgery within 4 weeks prior to first study drug 
administration. 
16. Patient has a history (within 2 years prior to first study drug administration) of another 
malignancy unless malignancy treated with curative intent and likelihood of relapse is 
small (< 5% in 2 years in the judgement of the investigator). Patients with a history of 
squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix may be 
enrolled. 
17. Patient is receiving systemic steroids at doses greater than the equivalent of prednisone, 
20 mg daily, with the exception of intermittent use for the treatment of emesis. 
18. Patient is female and is breast-feeding, pregnant, or intends to become pregnant. 
19. Patient is participating in any other therapeutic clinical study (observational or registry 
trials are allowed). 
 
4.3. 
Enrollment Process 
After informed consent is obtained, the required screening procedures are performed, and the 
results known, the site PI/designee will complete the enrollment form and send it to the 
Sponsor/designee, along with supporting documentation as listed in the study manual. After 
Sponsor/designee review, if eligible, the Sponsor/designee will assign a patient study number to 
the patient and inform the site PI/designee. 


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4.4. 
Withdrawal Criteria and Replacement of Patients 
Patients are free to withdraw from the study at any time for any reason; however, to the extent 
possible, all patients should continue to participate in the study once they have enrolled, even if 
they discontinue study drug. The Investigator also has the right to withdraw a patient from the 
study in case of events such as inter-current illness, AEs, progression, protocol violation, other 
procedures needed for treatment of their disease, or other medical conditions, administrative 
reasons or for other reasons (detailed in Section 4.4.1). 
 
An excessive rate of withdrawals can render the study un-interpretable; therefore, unnecessary 
withdrawal of patients should be avoided. Should a patient decide to withdraw, all efforts will be 
made to complete and report the observations as thoroughly as possible. Reasons for all 
discontinuation of study drug and withdrawals from the study will be recorded. If a patient 
discontinues the study drug due to an AE, that AE must be evaluated to determine if it is a 
serious adverse event (SAE; see Section 10.1.2). The Investigator must report all SAEs to the 
Syneos Safety Department (the Sponsor’s Safety Designee) on the SAE form within 24 hours 
from the point in time when the Investigator becomes aware of the SAE. The procedures 
described under 30 Days Post-Last Treatment (Section 7.3.2.2) will be performed upon 
discontinuation/withdrawal, whenever possible. If a patient withdraws consent, no further 
information will be collected after the study termination visit. 
 
Normal study termination is defined as the 30 Days Post-Last Treatment visit in Section 7.3.2.2. 
 
4.4.1. 
General Withdrawal Criteria 
Discontinuation of study drug and/or withdrawal from the study will occur if any of the 
following apply: 
• 
The patient experiences disease progression requiring other therapy. 
• 
The patient develops intolerable toxicity. 
• 
The patient develops an intercurrent condition precluding further administration 
of cerdulatinib. 
• 
The patient withdraws consent for further participation in the trial. 
• 
The patient becomes pregnant. 
• 
The patient fails to comply with study drug administration, dosing evaluations, or other 
requirements of the study. 
• 
The patient needs a concomitant medication that makes the patient ineligible for further 
participation in the study. 
• 
The Investigator believes it is no longer in the best interest of the patient to 
receive cerdulatinib. 
• 
The Sponsor discontinues the trial. 


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4.4.2. 
Specific Withdrawal Criterion and Replacement Procedure for Phase 1 
• 
Patients who discontinue from treatment prior to the completion of Cycle 1 or who do not 
receive at least 80% of the intended dose in Cycle 1 for reasons other than toxicity will be 
replaced. Dose escalation will not take place until the appropriate number of patients has 
completed Cycle 1 at the designated dose level. 
 
4.4.3. 
Specific Withdrawal Criteria and Replacement Procedure for Phase 2a 
• 
Patients who do not have at least 1 post baseline assessment for efficacy will be 
withdrawn from the study and may be replaced. 
• 
Patients who are found to have protocol violations that substantially impair the evaluation 
of safety and efficacy may be replaced. 
 
4.5. 
Withdrawal and/or Replacement Criteria for Site or Principal Investigator 
The site or Principal Investigator may be withdrawn or replaced from the study due to poor 
compliance with the study protocol or poor accrual. 
 
4.6. 
Sponsor Study Discontinuation 
The Sponsor has the right to terminate the entire study or study cohorts at any time. Reasons for 
terminating the study or study cohorts may include, but are not limited to, the following: 
• 
Excessive toxicity indicating a potential health hazard to patients. 
• 
Poor patient enrollment. 
 
The Sponsor will notify the Investigator if the study is placed on hold (or if individual cohorts 
are placed on hold), or if the Sponsor decides to discontinue the study or program. 
 
4.7 
Protocol Violations and Deviations 
Protocol violations are defined as significant departures from protocol-required processes or 
procedures that affect patient safety or benefit potential, or confound assessments of safety or 
clinical activity. A protocol deviation is a departure from the protocol that does not meet the 
above criteria. Protocol violations or deviations may be grouped into the following categories: 
• 
Enrollment criteria. 
• 
Study activities (e.g., missed evaluations or visits, data verification issues). 
• 
Noncompliance with dose or schedule, including dose calculation, administration, 
interruption, reduction, or delay, or discontinuation criteria. 
• 
Investigational product handling, including storage and accountability. 
• 
Informed consent and ethical issues. 


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5.0 
TREATMENTS ADMINISTERED 
Treatments administered during the study are listed below. Administration of study drug and 
related dose modifications are described in Sections 5.1 and 5.2 for cerdulatinib and in 
Section 6.2 for rituximab. 
• 
Phase 1 (closed): single-agent cerdulatinib 
• 
Phase 2a: 
○ Cohorts 1, 3, 4, 5, and 6: single-agent cerdulatinib 
○ Cohort 2: cerdulatinib and rituximab 
 
5.1. 
Cerdulatinib Study Drug Administration 
5.1.1. 
General Instructions 
Cerdulatinib may be taken with food, unless otherwise specified. Missed doses may be made up 
if given within 4 hours of the missed scheduled dosing time. Cerdulatinib may not be taken 
fewer than 8 hours prior to the next scheduled dose. Patients who vomit following 
administration of cerdulatinib should not repeat that dose of cerdulatinib but should resume study 
drug with the next scheduled dose. In the event of toxicity, dosing may be interrupted at the 
discretion of the treating physician until sufficient resolution of the toxicity is attained and then 
may be restarted at a lower dose level (see Section 5.2 for guidelines for cerdulatinib toxicity and 
subsequent dose modifications). 
 
In order to assess cerdulatinib compliance, patients will be instructed to keep patient diaries to 
document self-administration of study drug doses, and will include documentation of time study 
dose was taken, any missed doses and reason(s) why missed, and/or any wasted doses and 
reason(s) why. The diary will be reviewed by the appropriate study staff during study visits. 
 
5.1.2. 
Phase 1 Cerdulatinib Dosing 
5.1.2.1. 
Initial Dosing with Cerdulatinib 
Following screening and confirmation of eligibility, patients will be sequentially assigned to the 
next open dose cohort. For QD dosing regimens, to allow for single-dose PK assessments during 
the Phase 1 portion of the study, patients will take their first dose of cerdulatinib on Day 1 and 
their second and subsequent doses daily beginning on Day 4. During Part 1 of the study, 
cerdulatinib will be taken orally once daily in the AM. For BID dosing regimens, BID dosing 
can begin on Day 1. 
 
The initial dose cohort will begin treatment at a dose of 15 mg po QD. Subsequent total daily 
dose levels that may be studied include 30 mg, 60 mg, 90 mg, 120 mg, and 150 mg daily. 
Intermediate or higher dose levels may be studied, as appropriate, given the safety and 
PK profiles of cerdulatinib observed during the ongoing conduct of this study.  Depending on the 


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PK profile, twice-daily administration (BID) may be considered during the course of dose 
escalation. Single-dose PK assessment will not be conducted for BID cohorts. Increments of 
dose escalation will be adjusted as needed to accommodate available capsule strengths. Every 
effort should be made to administer study drug at the same times each day. 
 
Patients who do not receive at least 80% of their cerdulatinib doses in the first 28 days of 
treatment (Cycle 1) due to non-compliance will be withdrawn from the study. Beyond Cycle 1, 
dose holds may be permitted for reasons not related to disease progression or drug-related 
toxicity (e.g., elective procedures, vacations) with the permission of the Sponsor’s 
Medical Monitor. 
 
Intra-patient dose escalation will not be permitted during Phase 1. 
 
The dose-escalation scheme described in this and the following paragraph accords with the 
principles described by Le Tourneau et al [6]. One patient will be enrolled in each dose cohort 
until the first report of a Grade 2 or greater adverse event (AE). In the event of any Grade 2 or 
greater AE in the single patient, an additional 2 patients, for a total of 3, will be enrolled in that 
dose cohort, and all subsequent dose cohorts will follow a “3 + 3” design. Dose escalation will 
be in 100% increments until a drug-related adverse event of Grade 2 or greater severity occurs. 
Thereafter, dose escalation will be in increments of up to 50% as determined following review 
by the safety committee. If a dose-limiting toxicity (DLT) occurs in 1 of the first 3 patients in a 
cohort, that cohort will be expanded to at least 6 patients. If ≤ 33% of six or more patients in a 
cohort experiences DLT, dose escalation may proceed. If in any cohort 2 or more of the first 
3 patients or ≥ 33% of patients in a cohort develop DLT, dose escalation will cease. That dose 
level will be declared intolerable, and either the prior dose level will be declared the MTD, 
and/or the cohort may be expanded to as many as 6 patients if fewer than 6 patients had 
previously been treated at that dose level in order to further characterize the PK and PD at that 
level. A total of 43 patients have been enrolled in the Phase 1 (escalation) portion of this study, 
and Phase 1 is now closed to enrollment. 
 
All patients in a cohort must have been treated for 28 days (one cycle) prior to treatment of 
patients at the next higher dose level. In addition to DLTs defined below, the safety committee 
will also take into consideration the totality of available safety data in determining whether a 
given dose level should be deemed tolerable. Additional patients may be enrolled in individual 
cohorts if the Sponsor’s Medical Monitor or safety committee deems it necessary to obtain 
additional safety information prior to proceeding with dose escalation. In addition, intermediate 
dose levels may be used to allow for further exploration of safety. 
 
As of Amendment 4, Phase 1 dose escalation has concluded at 45 mg po BID (per Sections 1.5 
and 3.1.2.2). The dose selected for Phase 2a is 35 mg po BID based on PK modeling and 
accumulated safety data (Section 3.1.2.2). 


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5.1.3. 
Phase 2a Cerdulatinib Dosing 
Following confirmation of eligibility, patients will receive oral cerdulatinib at a starting dose of 
30, 25, or 20 mg BID. Every effort should be made to administer study drug at the same time 
each day. The drug will be administered in cycles of 28 days with no days off therapy 
between cycles. 
 
In the event of toxicity (see Section 5.2.1 for the definition of toxicity), dosing may be 
interrupted at the discretion of the Investigator until sufficient resolution of the toxicity is 
attained and then restarted at a lower dose level (dose modifications to cerdulatinib are 
summarized in Table 8). The lowest dose of cerdulatinib that may be administered is 
15 mg BID. 
 
Dosing information for rituximab is described in Section 6.2 (for Cohort 2, the combination 
cohort of cerdulatinib and rituximab). 
 
5.2. 
Dose-limiting Toxicity, Dose Modifications, and other Dosing/Monitoring 
Guidance 
5.2.1. 
Cerdulatinib 
5.2.1.1. 
Definitions of Dose-limiting Toxicity for Cerdulatinib during Phase 1 
 
DLT will be defined as any of the following toxicities, possibly or probably related to 
cerdulatinib, and clinically significant (in the judgement of the investigator) that occurs in the 
first 28 days (one cycle) of treatment. For patients to be evaluable for DLT, they must have 
received 80% of the doses in the first 28 days of Cycle 1, or been withdrawn from study therapy 
due to a drug-related toxicity. Patients who withdraw without meeting these criteria should be 
replaced. Toxicity will be graded according to the NCI-CTCAE v4.0. 
 
Hematologic 
• 
Febrile neutropenia (ANC < 1,000/μL and temperature ≥ 38.5°C). 
• 
Grade 4 neutropenia for > 5 days. 
• 
Grade 4 thrombocytopenia with or without bleeding. 
• 
Grade 3 thrombocytopenia with bleeding. 
• 
Grade 4 anemia, unexplained by underlying disease. 
 
Non-hematologic 
• 
Grade 3 or greater nausea, vomiting, or diarrhea if persistent despite optimal antiemetic 
or anti-diarrheal therapy. 


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• 
Grade 3 or greater increase in transaminases lasting > 5 days. 
• 
Grade 3 or greater fatigue persisting > 7 days in the absence of any other 
underlying cause. 
• 
Any other Grade 3 or greater non-hematologic toxicity (except fatigue as noted above) 
considered clinically significant by the investigator. 
• 
Toxicity of any grade resulting in dose delay of more than 7 days. 
• 
Toxicity resulting in study drug discontinuation prior to the completion of Cycle 1. 
 
5.2.1.2. 
Phase 2a: Monitoring for Toxicity in Phase 2a 
Patients will be monitored for toxicity throughout Phase 2a. For the purposes of this protocol, 
toxicity is defined as any Grade 3 or higher adverse event (AE) and/or any clinically significant 
AE (refer to Table 8). Patients experiencing a toxicity may be considered for a dose interruption 
or reduction. Enrollment in a cohort may be suspended at any time depending on the overall 
toxicity profile within that cohort, pending a review by the Study Committee, and consideration 
will be given to discontinuing enrollment in that cohort or providing a global dose reduction for 
that cohort. 
 
Physicians should monitor for infections and clinically significant decreases in leukocyte counts 
(e.g., ALC, ANC) and should consider holding cerdulatinib and/or dose modifications per 
Section 5.2.1.3 if clinically significant toxicity occurs. Also see Section 10.1.3, Adverse Events 
that May Indicate Potential Drug Toxicity. 
 
5.2.1.3. 
Dose Modifications for Cerdulatinib 
5.2.1.3.1. Dose Modifications to Cerdulatinib During Phase 2a 
Dose reductions and interruptions are permitted during all cycles. Guidelines for dose 
modifications are provided in Table 8. 
 
In general, for Grade 1 or 2 adverse events that are medically manageable, the Investigator is 
encouraged to continue dosing and institute standard of care support or hold dosing and institute 
standard of care support, and then restart dosing at the same dose after the event has resolved to 
baseline. Specific guidance for management of Grade 1 and 2 diarrhea and nausea and vomiting 
is provided in Sections 5.2.1.5 and 5.2.1.6. 
 
For adverse events ≥ Grade 3, rather than dose interruption or dose reduction, the Investigator is 
encouraged to hold dosing and institute standard of care support, and then restart dosing at the 
same dose after the event has resolved to baseline, as clinically appropriate. Table 8 provides 
further guidance on Grade 3 toxicities. A dose interruption does not necessitate a subsequent 
dose reduction. In the case of a dose interruption, once the toxicity has resolved to Grade < 2 or 


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baseline, the Investigator should use clinical judgement when deciding to restart the patient at the 
same dose level or at a reduced dose. 
 
Patients may be dose-reduced in increments from their starting dose, one level at a time, to the 
lowest dose level of 15 mg BID. A patient experiencing a toxicity at 15 mg BID should be 
discontinued from cerdulatinib and removed from the study (after completing the 30 Day 
Post-Last Treatment Visit in Section 7.3.2.2). 
 
Patients who experience dose interruptions > 28 days in duration should be permanently 
discontinued from cerdulatinib therapy (after completing the 30 Day Post-Last Treatment Visit in 
Section 7.3.2.2). Exceptions that would allow such patients to continue study treatment may be 
allowed at the discretion of the Investigator based upon clinical judgement and with Sponsor 
Medical Monitor approval. 
 
5.2.1.3.2. Dose Re-escalations During Phase 2a 
In Phase 2a, a patient who has been dose reduced from their starting dose may be re-escalated 
incrementally to the next higher dose level at the discretion of the Investigator based upon 
clinical judgement and with Sponsor Medical Monitor approval. Dose re-escalation to the next 
higher dose level should occur at the start of the next cycle. 


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Table 8: 
Guidelines for Dose Reductions for Cerdulatinib 
 
Toxicity 
Occurrence 
Action 1 
Hematologic 
Grade 3 or 4 febrile neutropenia 
Grade 4 neutropenia for ≥ 7 days, or 
Grade 4 thrombocytopenia 
1st 
Hold study drug. Once toxicity has resolved to 
Grade < 2 or baseline, may restart cerdulatinib at 
the next lower dose level. 
2nd 
Hold study drug. Once toxicity has resolved to 
Grade < 2 or baseline, may restart cerdulatinib at 
two dose levels below the starting dose. 
3rd 
Discontinue cerdulatinib 
Gastrointestinal 
Grade 3 or 4 nausea, vomiting, or diarrhea if 
persistent despite optimal antiemetic or 
antidiarrheal therapy 
Grade 3 or greater increase in ALT/AST, total 
bilirubin 
1st 
Hold study drug. Once toxicity has resolved to 
Grade < 2 or baseline, may restart cerdulatinib at 
the next lower dose level. 
2nd 
Hold study drug. Once toxicity has resolved to 
Grade < 2 or baseline, may restart cerdulatinib at 
two dose levels below the starting dose. 
3rd 
Discontinue cerdulatinib 
Other 
Any other related Grade 3 or 4 non-laboratory 
toxicity 
Any other related Grade 3 or 4 laboratory 
toxicity considered clinically significant by the 
Investigator (e.g., symptomatic) 
(Do not dose reduce or hold study drug for 
asyptomomatic amylase or lipase elevations 2) 
1st 
Hold study drug. Once toxicity has resolved to 
Grade < 2 or baseline, may restart cerdulatinib at 
the next lower dose level. 
2nd 
Hold study drug. Once toxicity has resolved to 
Grade < 2 or baseline, may restart cerdulatinib at 
two dose levels below the starting dose. 
3rd 
Discontinue cerdulatinib 
AE = Adverse event; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase 
Note: Grading is NCI CTCAE v5.0. 
1 Do not dose reduce below 15 mg BID. At 15 mg BID, if any toxicity (Grade 3 or greater AE and/or any clinically 
significant AE) occurs, discontinue cerdulatinib (and rituximab for the combination cohort of cerdulatinib and 
rituximab) after completing the 30 Day Post-Last Treatment Visit in Section 7.3.2.2. 
2 ≥ Grade 3 asymptomomatic elevations in amylase and lipase have been observed in this study without 
clinical pancreatitis. 
 
 
5.2.1.4. 
Management of Potential Epstein-Barr Virus Reactivation 
EBV reactivation has been observed in connection with cerdulatinib administration and should 
be viewed as a potential adverse effect of treatment. For this reason, peripheral blood 
quantitative EBV polymerase chain reaction assay (PCR) has been added to the baseline 
assessment of subjects and should be performed post-baseline for any unexplained fevers if there 
is clinical suspicion of EBV reactivation. 
 
If unexplained fever and increased EBV PCR raise clinical suspicion of EBV reactivation or 
infection, the investigator should take the following action *: 
1. Hold cerdulatinib dosing. 
2. Continue monitoring the patient’s EBV viral load with quantitative PCR per local 
standard of care (typically weekly). 


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3. Administer symptomatic treatment per local standard of care. 
4. Consider therapy with rituximab at a dose of 375 mg/m2 once weekly until normalization 
of the patient’s viral load. Typically, one to four doses of rituximab are used [73, 74]. 
The use of rituximab does not require study discontinuation. 
5. After symptoms resolve, resume cerdulatinib treatment at the same dose level or one dose 
level below the current dose level and continue monitoring the patient’s EBV viral load 
with quantitative PCR per local standard of care (typically monthly). 
 
* Cerdulatinib dosing may continue while rituximab therapy is administered, with the Medical 
Monitor approval. For asymptomatic increased EBV PCR, consider treatment with rituximab 
(per local standard of care) and continuing cerdulatinib. 
 
5.2.1.5. 
Management of Diarrhea 
Grade 1 or 2: The patient may continue receiving study drug. Institute anti-diarrheal treatment 
(e.g., loperamide [Imodium®] or diphenoxylate/atropine [Lomotil®]) and consider BRAT 
(bananas, rice, applesauce, and toast) diet. Persistent Grade 2 diarrhea despite optimal therapy 
may be managed with dose reduction. 
 
Grade ≥ 3: Hold study drug. Once toxicity has resolved to Grade < 2 or baseline, restart 
cerdulatinib at the same dose level or at the next lower dose level. 
 
Also, if clinically indicated, the patient should be assessed for C. difficile infection. 
 
5.2.1.6. 
Management of Nausea and Vomiting 
Grade 1 or 2: The patient may continue receiving study drug. Institute anti-emetic treatment 
(e.g., ondansetron [Zofran®] or prochlorperazine [Compazine®]), consider sucralfate (Carafate®), 
and institute standard of care support. Persistent Grade 2 nausea/vomiting despite optimal 
therapy may be managed with dose reduction. 
 
Grade ≥ 3: Hold study drug. Once toxicity has resolved to Grade < 2 or baseline, restart 
cerdulatinib at the same dose level or at the next lower dose level. 
 
5.3. 
Rituximab Information and Dose Modifications 
For patients enrolled in Cohort 2, rituximab will be provided as standard of care by the 
Investigator. Rituximab will not be provided by the Sponsor. 
 
5.3.1. 
Prescribing Information 
Please refer to local prescribing information for further details on rituximab (e.g., USPI, SmPC). 
 
5.3.2. 
Management of Rituximab Infusion Toxicity 
Please refer to local prescribing information for further details on rituximab (e.g., USPI, SmPC). 


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5.3.3. 
Dose Modifications to Rituximab 
Please refer to local prescribing information for further details on rituximab (e.g., USPI, SmPC). 
 
Escalations and reductions in rituximab dosing are not planned nor permitted. Repeat rituximab 
administrations may be delayed to allow patients to recover from rituximab-related AEs or 
intercurrent illness. 


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6.0 
STUDY MATERIALS AND MANAGEMENT 
 
6.1. 
Cerdulatinib 
6.1.1. 
Identity of Product 
Cerdulatinib, an investigational drug, is supplied by Portola Pharmaceuticals, Inc. (Portola), as 
an immediate release (IR) capsule for oral administration in 2 strengths: 5 mg and 15 mg. Each 
gelatin capsule will contain cerdulatinib HCl, microcrystalline cellulose, croscarmellose sodium, 
silicon dioxide, and magnesium stearate. The 5 mg capsules will be size 4 and dark green 
opaque in color, the 15 mg capsules will be size 4 and Swedish orange opaque in color. The 
study product will be supplied in 35 capsules/bottle in 60 cc high density polyethylene (HDPE) 
bottles and should be stored at room temperature. 
 
In Amendment 9, additional drug will be provided in the following new presentations: 
 
Cerdulatinib Dose (mg) 
Capsule Size 
Capsule Color 
Bottle 
configuration 
15 
Size 3 
Blue opaque 
30 capsules/bottle 
in 40 cc HDPE 
bottles 
20 
Size 3 
White opaque 
25 
Size 2 
Swedish orange 
opaque 
 
 
6.1.2. 
Dispensing and Accountability 
The dispensing pharmacist or designated qualified individual will write the date dispensed, dose 
dispensed, and the patient’s identification number or initials on the Drug Accountability Source 
Documents. All medication supplied will be accounted for on the Drug Accountability Record. 
All partially used or unused drug supplies will be destroyed at the site in accordance with 
approved written site procedures, or returned to the drug depot as described in the Study Drug 
Supply Process Manual. The Investigator will maintain a record of the amount, reason, and dates 
when unused supplies were either destroyed or returned to Portola.  All records will be retained 
as noted in Section 15.2. 
 
6.1.3. 
Dose Regimens 
Patients will receive cerdulatinib at a starting dose of 30, 25, or 20 mg BID (Section 3.1.2.2). 
Patients may be dose-reduced to a minimum dose of 15 mg BID (Section 5.2.1.3.1). Missed 
doses may be made up if given within 4 hours of the scheduled dosing time. Cerdulatinib may 
not be taken fewer than 8 hours prior to the next scheduled dose. Patients who vomit following 
administration of cerdulatinib should not repeat that dose of cerdulatinib but should resume study 
drug with the next scheduled dose. 


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6.2. 
Rituximab (for Combination Cohort 2, Rituximab and Cerdulatinib) 
6.2.1. 
Identity of Product 
Rituximab is commercially available. Please refer to local prescribing information for further 
details on rituximab (e.g., USPI, SmPC). 
 
6.2.2. 
Dispensing and Accountability 
Please refer to local prescribing information for further details on rituximab (e.g., USPI, SmPC). 
 
Acquisition, storage, control, and disposal of rituximab used in the study should be performed 
according to institutional procedures and policies. The dispensing pharmacist or designated 
qualified individual will write the lot number, date dispensed, dose/amount dispensed, and the 
patient’s identification number or initials on the Drug Accountability Source Documents. All 
medication supplied will be accounted for on the Drug Accountability Record. All partially used 
or unused drug supplies will be destroyed at the site in accordance with approved written site 
procedures. The Investigator will maintain a record of the amount and dates when unused 
supplies were either destroyed or returned to Portola. All records will be retained per 
Section 15.2 of the protocol. 
 
6.2.3. 
Rituximab Dose Regimen (Cohort 2 Only) 
6.2.3.1. 
Premedication and Prophylactic Medication 
Please refer to local prescribing information for further details on rituximab (e.g., USPI, SmPC). 
 
6.2.3.2. 
Dose Rationale 
Please refer to local prescribing information for further details on rituximab (e.g., USPI, SmPC). 
 
6.2.3.3. 
Dosage 
Please refer to local prescribing information for further details on rituximab (e.g., USPI, SmPC). 
 
Cerdulatinib should be taken before the rituximab infusion. 
 
Rituximab will be administered intravenously (IV) in the clinic. Dosing will be based on mg/m2 
of body surface area (BSA). The dose calculation of BSA will be based on the patient’s height 
and actual body weight prior to therapy. After establishment of BSA based on the patient’s 
pretreatment body weight, do not alter the total dose of rituximab for the patient, despite 
fluctuations in the patient’s body weight. 
 
Rituximab will be administered IV at 375 mg/m2 on Days 1, 8, 15, and 22 of Cycle 1, and during 
Cycles 4, 6, 8, and 10 on Day 1 only. 


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7.0 
STUDY METHODS 
A summary of the patient visits and clinical evaluations for Phase 2a is provided in Appendix 1. 
Please refer to the Study Laboratory Manual for further instructions on specimen processing 
and shipping. 
 
7.1. 
Study Assessments 
7.1.1. 
Informed Consent 
Written informed consent for participation in the study must be obtained before performing any 
study-specific screening procedures. Informed Consent Forms for all consented patients will be 
maintained at the study site. 
 
7.1.2. 
Global Health Assessment 
The Global Health Assessment should be administered after obtaining informed consent but prior 
to any other protocol procedures. It should be performed before any protocol-related information 
is communicated to the patient. 
 
7.1.3. 
Medical History 
Medical history should include previously determined prognostic factors, including (but not 
limited to): 
• 
Follicular Lymphoma International Prognostic Index (FLIPI) 
• 
International Prognostic Index (IPI) score for NHL 
• 
Mantle Cell International Prognostic Index (MIPI) 
• 
Others (see Appendix 4, Appendix 5, Appendix 6, and Appendix 7) 
 
Medical history should also include a redacted copy of the pathology report and any supporting 
pathology information, including the original pathology report from the diagnosis (which may 
include additional mutational analysis by sequencing, FISH, IHC, cytogenetics, etc.) to be 
available for Sponsor review. 
 
7.1.4. 
Concomitant Medications 
All medications, including over-the-counter preparations, herbals, and vitamins taken within 
14 days prior to Day 1 and throughout the study should be recorded. Additional information 
about prohibited and allowed concomitant medications can be found in Section 7.5. 
 
7.1.5. 
Physical Examination, Height, and Weight 
Physical examinations should include heart, lungs, and abdomen. Height and weight may also 
be required at certain visits (as defined in Appendix 1). In patients with CLL, the physical exam 
should include bi-dimensional measurements of all lymph nodes and measurement of 
spleen size. 


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7.1.6. 
Vital Signs 
Vital signs (temperature, respiratory rate, blood pressure, and heart rate) should be obtained after 
at least 5 minutes in the sitting or semi-recumbent position. Vital signs should be obtained 
pre-dose at the visits defined in Appendix 1. 
 
Vital signs should also be obtained post-dose at the visits defined in Appendix 1 at the following 
time points: 
• 
Cohorts 1, 3, 4, 5, 6 (cerdulatinib only): obtain vital signs at 1.0 hour post-cerdulatinib 
administration 
• 
Cohort 2 (cerdulatinib + rituximab) on visits rituximab is administered: obtain additional 
vital signs at 0.5, 1.0, 2.0, 3.0, and 4.0 hours post-cerdulatinib administration (or per 
standard of care), and then as clinically indicated. 
 
The window for collection of vital signs is ± 10 minutes. 
 
7.1.7. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
The ECOG performance status scale can be found in Appendix 2. 
 
7.1.8. 
Electrocardiogram (ECG) 
12-lead ECG will be required for all patients (single tracing acceptable, or triplicate ECGs as 
clinically indicated). 
 
7.1.9. 
Local Laboratory Tests and Response Assessments 
7.1.9.1. 
Serum Chemistry, Hematology, Urinalysis, Coagulation, and Pregnancy Tests 
Serum chemistry, hematology, urinalysis, and PT/PTT/INR assessments should be performed at 
the local lab. Urine or serum for pregnancy testing should be performed for women of child- 
bearing potential only. During Screening, these assessments should be completed within 7 days 
prior to Day 1. The results should be obtained and reviewed prior to enrollment to confirm 
eligibility. 
• 
Hematology - hemoglobin, hematocrit, WBC, platelet count, CBC with differential. 
• 
Serum Chemistry - sodium, potassium, chloride, magnesium, CO2 (HCO3), glucose, 
BUN, creatinine, aspartate aminotransferase (AST, i.e., serum glutamic-oxaloacetic 
transaminase [SGOT]), alanine aminotransferase (ALT, i.e., serum glutamic pyruvic 
transaminase [SGPT]), lactate dehydrogenase (LDH), total protein, albumin, alkaline 
phosphatase, calcium, phosphorous, bilirubin, uric acid, amylase, and lipase. 
o Grade 3 or greater increases in ALT or AST require liver function testing to be 
repeated within 72 hours of initial test. 
• 
Complete urinalysis - urine will be obtained at selected time points for the following 
laboratory tests: specific gravity, pH, glucose, protein, and hemoglobin. 


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○ Microscopic analysis for urine sediment to be performed as clinically indicated. 
○ Urinalysis will be analyzed at the local laboratory. Analysis results will be captured 
on study case report forms (CRF). 
• 
Pregnancy Test - Urine or serum will be obtained at Screening and on Day 1 of all cycles 
from all female patients of child-bearing potential and analyzed at the local laboratory to 
determine their pregnancy status. 
 
7.1.9.2. 
Other Local Labs/Assessments for All Patients 
The following additional assessments should also be performed locally for all patients: 
• 
Pre-dose blood sample for C-reactive protein (CRP) and ESR-Westergren. 
• 
Whole blood for Beta-2-microglobulin, lymphocyte subsets, and immunoglobulin 
levels including: 
○ Quantitative immunoglobulins - quantitative levels of IgA, IgE, IgG, and IgM. 
○ Lymphocyte subsets - quantitation of absolute numbers (or %) of CD3+, CD4+, 
CD8+, CD16/56+, and CD19+ by flow cytometry, WBCs, and lymphocyte count. 
• 
CT or CT/PET of chest, abdomen, pelvis, plus any other areas of lymphoma/CLL 
involvement (within 28 days prior to Day 1) and then as indicated in Appendix 1. 
○ Note: for CTCL patients, if baseline scan is negative for nodal/visceral/other disease 
a repeat CT or CT/PET is not necessary except to confirm CR and may be done as 
clinically indicated. 
○ For all patients, redacted copies of radiology reports should be sent to the Sponsor 
for review. 
○ Copies of scans should be made available to Sponsor upon request. 
• 
Obtain copy of molecular/mutation profile if obtained as standard of care. 
○ Examples of molecular/mutation profiles: FoundationOne, Caris, MSKCC IMPACT, 
or other local or commercial profiles. 
7.1.9.3. 
Other Local Labs/Assessments for Specific Patients 
The following additional assessments should be performed locally for specific patients 
as indicated: 
• 
For Cohort 4 CLL/SLL patients only, samples should be obtained at Day 1 for prognostic 
factor determination including: 
○ Cytogenetics (FISH) del(13q), del(11q), del(17p), del(6q) 
○ IgVH mutational status; results obtained within 3 months prior to C1D1 
are acceptable 
○ Zap70 


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○ CD38 
• 
If these tests were completed prior to Screening, the historic results should be recorded in the 
database within the appropriate eCRF.  The tests should then be repeated locally at Day 1. 
• 
For Cohort 6 CTCL patients only: 
○ Skin punch biopsy – 1, ≥ 5 mm punch biopsy of a representative lesion. A biopsy 
should be obtained from 2 different areas of disease, if possible (e.g., plaque and 
nodular lesions) 
○ Peripheral blood flow cytometry – for assessment of Sézary cells 
○ Modified Severity Weighted Assessment Tool (mSWAT) 
○ Likert Scale assessment 
○ Photographs of skin involvement per local standard of care (SOC) 
 
7.1.10. 
Central Laboratory Assessments 
• 
Details regarding the central laboratory collection procedures can be found in the Study 
Laboratory Manual. All post-dose central laboratory samples should be collected 
2.0 hours after administration of cerdulatinib unless otherwise specified. Before 
obtaining lab samples, date and time of patient’s last mean should be recorded. 
7.1.10.1. Central Laboratory Assessments for All Patients: 
• 
Serum sample for cytokine biomarker analysis. 
 
7.1.11. 
Pharmacokinetics 
Plasma samples for cerdulatinib pharmacokinetic (PK) assessments should be obtained at the 
time points as indicated in Appendix 1. Serial PK samples will be collected at the following 
time points: 
• 
Cycle 1 Day 1: pre-dose (i.e., within 60 minutes prior to the dose), and 1, 2, 4, 6, 8, and 
24 hours post-dose (collection window is ± 10 minutes, except for the 24-hour post-dose 
timepoint [± 30 minutes]). Collect the C1D1 24-hour post-dose sample prior to 
administering the C1D2 dose. 
• 
Cycle 1 Day 8: pre-dose (i.e., within 60 minutes prior to the dose), and 1, 2, 4, 6, 8, and 
24 hours post-dose (collection window is ± 10 minutes, except for the 24-hour post-dose 
timepoint [± 30 minutes]). Collect the C1D8 24-hour post-dose sample prior to 
administering the C1D9 dose. 
 
If a patient is not dosed at a particular visit but is due to be dosed, a trough PK assessment should 
still be performed. 


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7.1.12. 
Biopsies 
7.1.12.1. Bone Marrow Biopsy and Aspiration 
For CLL patients only, a bone marrow biopsy and aspiration will be completed before Day 1 
(within 6 weeks/42 days prior to Day 1) through the local lab and be repeated as clinically 
indicated. For all other patients with a history of bone marrow involvement prior to entering the 
study, a repeat biopsy should be performed to confirm a complete response or as 
clinically indicated. 
 
7.1.12.2. Skin Punch Biopsy (Cohort 6, CTCL Only) 
Skin punch biopsy is mandatory for all patients with CTCL and should be a ≥ 5 mm punch 
biopsy of a representative lesion. A biopsy should be obtained from 2 different areas of disease 
if possible (e.g., plaque and nodular lesions). Subsequent biopsies should be from the same 
general site if possible. At least 10 unstained slides or a FFPE tissue block should be submitted. 
 
7.1.12.3. Optional Biopsies 
The following optional biopsies may be obtained from all patients at the discretion of the 
Investigator or as clinically indicated: 
• 
Optional tumor Block/Unstained Slides (Screening) – During Screening, obtain tumor 
block/unstained slides that were previously collected as part of patient diagnosis if 
consent given (in selected patients, once eligibility is confirmed). A minimum of 
10 (preferably 20) unstained slides or Formalin-fixed paraffin embedded tissue (FFPE) 
block should be sent to Portola. A fresh tumor biopsy is not required; archival tissue may 
be used. 
• 
Optional Fresh Tumor Biopsy (Any time during study) – obtain a fresh lymph node or 
tumor biopsy. Submit a formalin-fixed paraffin embedded tissue (FFPE) block or a 
minimum of 10 (preferably 20) unstained, freshly cut FFPE tissue slides from lymph 
node or other biopsies. 
 
If tumor or lymph node or skin biopsies (including CTCL patients) are obtained during the 
course of the patient’s treatment, redacted copies of the pathology reports should be sent to the 
Sponsor for review.  Biopsy processing instructions can be found in the Study 
Laboratory Manual. 
 
7.2. 
Screening Visit 
All screening assessments will be conducted within 21 days prior to the first dose of study drug. 
Redacted copies of pathology reports used for the diagnosis of NHL or CLL/SLL, or other 
documents noted in the enrollment form, should be obtained during Screening. 


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Additionally, the patient’s pathology reports used to make the original diagnosis or diagnosis of 
relapse/progression should be examined to determine if the markers below were assessed: 
• 
For patients with DLBCL, assessment of germinal center B-cell-like DLBCL (GCB) vs. 
non-GCB by Hans methodology [75]; MYC, BCL2, and BCL6 if previously assessed; 
assessment of mutational profiling if previously assessed. 
• 
For patients with FL, assessment of t(14;18), BCL2, BCL6, and MYC if previously 
assessed; assessment of mutational profiling if previously assessed. 
• 
For patients with MCL, assessment of t(11;14), Cyclin D1 expression, and BCL2 if 
previously assessed; assessment of mutational profiling if previously assessed. 
• 
For patients with CLL, assessment of del (17p), del(13q), del (11q), del (6q), trisomy 12, 
IgVH, CD38, and Zap70 if previously assessed; assessment of mutational profiling if 
previously assessed (e.g., mutations that confer resistance to BTK inhibitors/ibrutinib 
such as Cys-481 or phospholipase C gamma 2 [PLCG2]). 
• 
For patients with PTCL, assessment of SYK by IHC, SYK-ITK fusion, or presence of 
t(5;9)(q33;q22) by cytogenetics or other methodology if previously assessed; assessment 
of mutational profiling if previously assessed. 
 
7.3. 
Dosing Cycles 
7.3.1. 
Phase 2a Dosing Cycles 
On days where pre-dose assessments are completed, patients should wait to take the study drug 
until they are on-site. 
 
Patients receiving ibrutinib should continue ibrutinib for 5 days after the start of cerdulatinib, 
with both drugs administered at the same time. Patients should discontinue ibrutinib after the 
first 5 days. 
 
7.3.2. 
Patient Visits After Cycle 2 
All patients enrolled in the Phase 2a portion of the study are expected to be on-site for Day 1 of 
every cycle (e.g., C3D1, C4D1, C5D1, C6D1) except with Sponsor permission described in 
Section 7.3.2.1. 
 
Certain assessments will be performed on Day 1 of every cycle throughout the duration of the 
study, as indicated in Appendix 1 under “All Other Cycles.” These include assessment of AEs 
and con meds, cerdulatinib administration, and local safety labs (e.g., chemistry, hematology, 
urinalysis, urine or serum pregnancy as required). Study drug dispensation and accountability by 
site staff will also occur at these Day 1 visits, as well as the distribution and collection of 
completed patient diaries and other study materials. 


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Additional assessments will be performed every 3 cycles only, as indicated in Appendix 1 under 
“Additional Tests Every 3 Cycles.” These include (but are not limited to) central labs and 
disease response assessments. 
 
7.3.2.1. 
Visit Reduction for Response Patients after Cycle 12 
If a patient experiences a treatment response while on study treatment, the patient may be 
eligible for a reduced visit schedule after Cycle 12 or at the discretion of the Sponsor. At the 
discretion of the Investigator based upon clinical judgement and with Medical Monitor approval, 
the patient’s visit cycle may be reduced from every cycle (e.g., C12D1, C13D1, C14D1) to every 
3 cycles (C12D1, C15D1, C18D1), corresponding with the “Additional Tests Every 3 Cycles” 
schedule in Appendix 1. 
 
If a patient experiences a response and their visit reduction is approved by the Medical Monitor 
to every 3 cycles, the site will call the patient and conduct a telephone visit for every cycle when 
the patient is not on-site. During this call, site staff should obtain information about the patient’s 
overall health, any reportable adverse events, or other relevant clinical information that would 
normally be collected on-site. 
 
In these cases, patients may be dispensed enough study drug and study materials (e.g., patient 
diaries) to accommodate the reduced visit frequency. 
 
7.3.2.2. 
30 Days Post-Last Treatment 
30 days after the last cerdulatinib dose administered, patients should return to the site for a 
follow-up visit consisting of a number of safety and response assessments as indicated 
in Appendix 1. 
 
7.3.2.3. 
Unscheduled Assessments 
At any time throughout the study, the following asssessments may be performed as 
clinically indicated: 
• 
Unscheduled plasma PK samples may be obtained at the discretion of the Investigator 
upon the decision to reduce dose, interruption or discontinuation of study drug, or other 
(e.g., AEs that may indicate potential drug toxicity [see Section 10.1.3]). When taking 
unscheduled samples for PK, please note the time since the last dose and last meal in 
source documents. 
○ In the event of a study drug interruption or dose-change, pre-dose PK samples should 
be collected the day study drug is restarted or a new dose is started, as well as 
7 days later. 
• 
Cohort 6 - CTCL patients only (local laboratory): 1, ≥ 5 mm skin punch biopsy of a 
representative lesion as clinically indicated may be performed; subsequent biopsies 
should be from the same general site, if possible. 


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7.3.3. 
Visit Windows 
Due to scheduling conflicts and the burden of study visits, patients may attend their scheduled 
visits within a visit window as indicated in Appendix 1. 
 
7.3.3.1. 
Visit Window and Timeline Guidance 
• 
A standard treatment cycle is defined as 28 days of treatment, and each new cycle should 
start 29 days from the previous Day 1 visit (e.g., C2D1 starts 29 days from C1D1). 
• 
Each new cycle “resets” the timeline. This means that C2D15 is measured from C2D1. 
• 
Dose interruptions that extend beyond the end of a cycle (e.g., after Day 28 of that cycle) 
will delay the start of the next cycle. Cycles should not be started during an interruption. 
• 
Subjects should continue to administer study drug daily until the new cycle is started. 
• 
For safety monitoring purposes, if a scheduled visit must be changed it is preferred that a 
patient comes in for a visit early instead of late. 
 
7.4. 
Blood Collection 
The maximum amount of blood to be drawn at a visit is ~104 mL and the total amount of blood 
to be drawn over a 50-week study period (including the 2-week screening period and through 
Week 48 of the study including a possible end-of-therapy visit) is ~548.5 mL. For a 40-kg 
person (the smallest participant expected to enroll in the study), this equates to maximum blood 
volume per body weight per visit of ~2.4 mL/kg and a total blood volume per body weight per 
average 6-week period of ~1.6 mL/kg. These quantities of blood are within accepted limits of 
3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of body weight for a 
6-week period [76]. 
 
7.5. 
Concomitant Medications and Other Guidance 
All concomitant medications used during the study and within 14 days prior to Screening must 
be reported on the appropriate CRF. 
 
7.5.1. 
Prohibited Medications/Procedures 
• 
Chemotherapy, radiation therapy, hormonal therapy or any investigational anti-neoplastic 
agent for the active treatment of cancer are prohibited. Patients may continue on 
adjuvant hormonal therapy for prostate or breast cancer, as long as there is no detectable 
disease at study entry. 
• 
Systemic steroids, at doses greater than the equivalent of 20 mg prednisone daily, with 
the exception of intermittent use for the treatment of emesis, are prohibited. Steroid 
inhalers for medical conditions are permitted. Patients needing pulse corticosteroids for 
other medical conditions should be discussed with the Sponsor’s Medical Monitor. 


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• 
Nasal flu vaccine is prohibited because the nasal vaccine is a live, attenuated virus; 
however, flu injections, which are nonviable antigens, are permitted (see Section 7.5.2). 
 
7.5.2. 
Permitted or Mandated Medications 
• 
Anti-emetic agents for the treatment of nausea and vomiting are permitted. 
○ No constraint will be placed on the use of growth factors during subsequent 
treatment; however, prophylactic use is discouraged and adherence to American 
Society of Clinical Oncology (ASCO) guidelines is recommended. 
 
7.5.2.1. 
Antimicrobial Prophylaxis 
• 
Pneumocystis prophylaxis is required in all patients receiving cerdulatinib, and study 
patients should be monitored closely with frequent cell counts for evidence of infection 
or bone marrow suppression. Bactrim™ (sulfamethoxozole/trimethoprim) 1 DS tab/day 
is the recommended prophylaxis regimen and will cover both Pneumocystis jirovecii and 
Nocardia. Other recommendations may be found in the National Comprehensive Cancer 
Network (NCCN) guidelines [77]. For patients unable to take Bactrim, atovaquone, or 
pentamadine (inhaled or IV) may be considered. Dapsone is not recommended because 
of the potential for drug interactions and methemoglobinemia. 
• 
Patients should also receive prophylaxis for herpes simplex virus infection per 
NCCN guidelines [77]. 
• 
Immunizations or vaccinations (for such things as influenza or pneumonia) are 
encouraged prior to study entry. Note that nasal flu vaccines should not be administered 
to patients because the nasal vaccine is a live, attenuated vaccine, whereas flu shots are 
nonviable antigens (see Section 7.5.1). 
• 
Prophylaxis for tumor lysis syndrome is permitted at the discretion of the treating 
physician, based on clinical characteristics. 
 
7.5.3. 
Cerdulatinib and CYP3A4 
Cerdulatinib is a substrate for CYP3A4 and may also decrease expression levels of CYP3A4 
enzyme activity in patients, thus potentially augmenting the AE profile of other drugs. To avoid 
possible drug-drug interactions, strong inhibitors, CYP3A sensitive substrates, and inducers of 
CYP3A4 should be avoided in patients receiving cerdulatinib. An inhibitor of CYP3A4 would 
reduce the metabolism of cerdulatinib and could result in high concentrations that could cause 
AEs. An inducer of CYP3A4 could result in lower than desired levels of cerdulatinib and lessen 
the likelihood of efficacy. Additionally, cerdulatinib can cause other medications to accumulate 
to levels that result in toxicity due to lower levels of CYP3A4 being expressed. Because of this 
effect CYP3A sensitive substrates need to be considered. If the Investigator feels that use of a 
strong inhibitor or strong inducer of CYP3A4 is necessary, this should be discussed with the 
Sponsor’s Medical Monitor. Appendix 3 provides a list of such CYP3A4 substrates and strong 


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inhibitors/inducers. Physicians should monitor for potential drug-drug interactions, and a dose 
adjustment (lowering) for CYP3A sensitive substrates should be considered on a case-by-case 
basis by the treating physician. 
 
7.6. 
Study Committee 
Select study participants will comprise the Study Committee (e.g., the selected Principal 
Investigators, Portola’s Medical Monitor, Clinical Study Manager, and/or Drug Safety Medical 
Monitor). Other Portola or outside personnel may be called or consulted as needed. 
• 
Phase 1: Upon the completion of the initial 28-day treatment period (Cycle 1) for all 
patients in any cohort, the Study Committee will convene via teleconference or in person 
to review all available DLT, AE, and any other clinical or laboratory data for the patients 
in that cohort. The Study Committee will determine whether it is safe to escalate to the 
next dose level of cerdulatinib or whether the MTD or MAD has been reached. If it is 
safe to continue, the Study Committee will determine the next dose level to be studied. 
• 
Phase 2a: The Study Committee will meet periodically to review available safety and 
efficacy data from the study. Following the first meeting of the Study Committee, 
subsequent meetings will be held periodically as needed. Members of the Portola study 
team, such as representatives from Biostatistics, Drug Safety, Clinical Development, and 
Clinical Operations may participate in the meetings as needed. Data to be evaluated may 
include (but are not limited to): deaths, other SAEs; AEs, including treatment-related 
AEs; reasons for treatment discontinuation or dose modification/ interruption, trends in 
laboratory evaluations, and efficacy. 
• 
For the combination cohort with rituximab, the Study Committee will evaluate (using the 
assessments as outline above) the first 3 to 6 patients who have completed Cycle 1 before 
allowing further enrollment in the cohort. Afterwards, the cohort can be evaluated with 
the rest of the other cohorts as above. 


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8.0 
ASSESSMENT OF EFFICACY 
 
8.1. 
Response Criteria 
Response in NHL patients will be evaluated using The Lugano Classification [4]; in CLL 
patients using the Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines for the 
Diagnosis and Treatment of Chronic Lymphocytic Leukemia [2]; in leukemic forms of PTCL 
(ATLL, PLL, LGL) using disease appropriate response criteria [77]; and in CTCL patients using 
the modified Severity Weighted Assessment Tool (mSWAT) and other measures as appropriate 
[5]. Appendix 4 provides definitions and detailed descriptions of response criteria as well as 
guidance on selection of lesions for evaluation. Redacted copies of radiology reports will be sent 
to the Sponsor for review. 
 
8.2. 
Exploratory Efficacy 
8.2.1. 
Global Health Questionnaire 
Patients will be asked to complete a Global Health Questionnaire (Appendix 8) to assess whether 
patients feel their overall health is improving on this study. The correlation between markers of 
inflammation with clinical response and the Global Health Assessment will be evaluated. 


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9.0 
PHARMACOLOGY ASSESSMENTS 
9.1. 
Pharmacokinetic Assays 
Plasma samples will be obtained at selected time points (detailed in Appendix 1) and analyzed 
for the concentration of cerdulatinib and possible metabolite identification. Sample assay for 
drug concentrations will be performed using a validated LCMS method. Details on the 
collection, processing, storage, and shipment of samples are contained in the Study 
Laboratory Manual. 
 
9.1.1. 
Phase 1 Pharmacokinetic Analysis 
The following PK parameters of cerdulatinib will be calculated for all patients: 
• 
Plasma half-life (t½), determined by linear regression of the log concentration on the 
terminal portion of the plasma concentration-time curve. Terminal half-life is calculated 
as ln(2)/(-β), where β is the slope of the terminal portion of the log concentration-time 
curve. 
• 
Time to maximum observed plasma concentration (Tmax). 
• 
Maximum observed plasma concentration (Cmax). 
• 
Minimum observed plasma concentration (Cmin). 
• 
Area under the plasma concentration-time curve from 0 to last measurable concentration 
(AUC0-last) computed using the linear trapezoidal rule. 
• 
Total area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞), 
computed as: 
AUC0-∞ = AUC0-last + Cplast /(- β) 
 
where AUC0-last is the area under the curve from time 0 to the time point of the last 
measurable concentration above the quantitation limit; Cplast is the last measurable 
concentration above the quantitation limit; and β is defined as above. 
• 
Clearance of cerdulatinib (CL/F). 
• 
Volume of distribution of cerdulatinib at steady state (Vss/F). 
• 
Amount of drug excreted in urine over the sampling interval (Ae) for those patients for 
whom total volume of urine was collected. 
• 
Accumulation ratio, calculated by AUC0-12 at steady-state/AUC0-12 following the first 
dose for those patients for whom the 12 hour sample was collected. 


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9.1.2. 
Phase 2a Pharmacokinetic Analysis 
In order to further characterize the PK of cerdulatinib (specifically, Cmin), plasma samples during 
the Phase 2a portion of the study will be taken pre- and post-dose at various visits during the 
study as described in Appendix 1. 
 
The date and time of last cerdulatinib dose prior to any PK assessment should be recorded. 
 
Unscheduled plasma samples may also be collected at the discretion of the Investigator (e.g., in 
the event of an AE) as described in Section 7.3.2.3. 
 
9.2. 
Pharmacodynamic Assays 
Serum will be obtained at various time points throughout the trial (detailed in Appendix 1) to 
determine the effects of cerdulatinib on markers of inflammation. DNA and RNA will be 
isolated from optional tumor biopsy specimensto assess genetic mutations relevant to the disease 
and the mechanism of action of cerdulatinib (see Appendix 1 and the Study Laboratory Manual). 
• 
Quantification of serum proteins. 
• 
Quantitative PCR for tumor relevant transcripts. 
• 
Hybridization of RNA to gene arrays. 
• 
DNA sequencing to identify disease-relevant mutations. 


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10.0        ASSESSMENT OF SAFETY 
Safety and tolerability will be monitored and determined by serial physical exams, vital signs, 
hematology and chemistry laboratory studies, and reported AEs (including deaths and other 
serious adverse events [SAEs] and treatment-emergent AEs). 
 
10.1. 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording adverse events, including serious 
adverse events and pregnancies; performing protocol-specified safety laboratory assessments; 
measuring protocol-specified vital signs; and conducting other protocol-specified tests that are 
deemed critical to the safety evaluation of the study. 
 
Certain types of events require immediate reporting to the Syneos Safety Department, as outlined 
in Section 10.2.1. 
 
10.1.1. 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any 
untoward medical occurrence in a patient administered a pharmaceutical product, which may or 
may not have a causal relationship with the treatment.  An AE can be any of the following: 
• 
Unfavorable and unintended sign (e.g., including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the study drug, whether or not 
it is considered to be study drug-related 
• 
Any newly occurring event or exacerbation of previous condition (e.g., increase in 
severity or frequency) since the administration of study drug 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug. 
• 
AEs that are related to a protocol-mandated intervention, including those that occur prior 
to assignment of study treatment (e.g., screening invasive procedures such as biopsies). 
 
10.1.2. 
Serious Adverse Event (SAE) 
An SAE is any AE, occurring at any dose of any study medication, regardless of causality that: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death). 
• 
Is life-threatening (i.e., in the opinion of the Investigator or Study Sponsor, the patient 
was at immediate risk of death from the reaction as it occurred). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 


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• 
Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother who was 
exposed to study drug or where the father was exposed to study drug before conception. 
Is an important medical event in the investigator's judgment (i.e., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes listed 
above). Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
 
Clarification should be made between the terms “serious” and “severe,” since these terms are 
NOT synonymous. The term “severe” is often used to describe the intensity (severity) of a 
specific event (according to NCI CTCAE criteria per section 10.2.2); the event itself, however, 
may be of relatively minor medical significance. This is NOT the same as “serious,” which is 
based on the strict regulatory definitions listed above and serves as a guide for defining 
regulatory reporting obligations. A severe adverse event does not necessarily need to be 
considered serious. For example, persistent nausea of several hours duration may be considered 
severe nausea but not an SAE if the event does not meet the serious criteria. On the other hand, a 
stroke resulting in only a minor degree of disability may be considered mild, but would be 
defined as an SAE based on the above noted serious criteria. Thus, severity and seriousness need 
to be independently assessed for each AE recorded on the eCRF. 
 
10.1.3. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
SUSARs are serious AEs that are both unexpected (i.e., the nature or severity is not expected 
from the information provided in the IB) and assessed by the Investigator or Portola Medical 
Monitor to have a reasonable possibility of a causal relationship to the investigational medical 
product(s). SUSARs require reporting to the Competent Authorities, and Ethics Committees 
within an expedited timeline (7 calendar days for fatal / life-threatening SUSARs, 15 calendar 
days for all other SUSARs). Thus it is required that the Investigator complete the SAE form and 
report all SAEs within 24 hours of his/her awareness of the event to the Syneos Safety 
Department. Additionally, Syneos Safety Department, on behalf of Portola, will immediately 
notify the Investigator if any additional safety or toxicology information that impacts patient 
safety becomes available during the study. All SUSARs will be provided to all Investigators for 
submission to their respective IRBs per local requirements and when information that impacts 
patient safety becomes available during the study. It is the responsibility of the Investigator to 
promptly notify the IRB/Independent Ethics Committee (IEC) of all SUSARs involving risk to 
human patients. 


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10.2. 
Methods and Timing for Capturing and Assessing Safety Parameters 
The investigator is responsible for ensuring that all AEs (Section 10.1.1 for definition) are 
recorded on the Adverse Event eCRF and reported to the Sponsor in accordance with instructions 
provided in this section. 
 
For each AE recorded on the Adverse Event eCRF, the investigator will make an assessment of 
seriousness (Section 10.1.2), severity (Section 10.2.2), and causality (Section 10.2.3). 
 
10.2.1. 
Adverse Event Reporting Period 
To comply with regulatory requirements, all SAEs, regardless of causality, that occur from the 
date of signing of informed consent until 30 days after the last study drug treatment (or initiation 
of the next therapeutic regimen prior to the 30 days), must be reported to Syneos Safety 
Department within 24 hours from Investigator awareness of the SAE. 
 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported to Syneos Safety Department. These 
pre-dose adverse events will be collected on the AE eCRF and assessed as not related to study 
drug, but will be assessed for relationship to study procedures/tests and interventions. 
 
After initiation of study drug, all treatment emergent adverse events (TEAE), regardless of 
relationship to study drug, will be reported until 30 days after the last dose of study drug. Any 
SAE that occurs with an onset date later than 30 days after completion of the study and that the 
Investigator considers to be related to study medication must be reported to the Syneos Safety 
Department. 
 
To report any SAEs, the SAE Report Form provided to the clinical study site must be completed 
with the available information. The information collected must include at minimum the 
following: patient number, study drug(s) received, the event term, the serious criteria met for the 
AE, a narrative description of the event, and an assessment by the Investigator of the 
severity/intensity of the event and relationship to study drug(s). The SAE report should be sent 
to Syneos Safety Department by email (see contact information below). Follow-up information 
on the SAE should be sent promptly by the Investigator to Syneos Safety Department when any 
additional relevant information about the SAE becomes known to the Investigator, or as 
requested by Syneos Safety Department. 


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All AEs and SAEs should be monitored until they are resolved or the patient dies. 
Additionally, the Investigator must determine both the severity of the event and the 
relationship of the event to study drug. 
 
10.2.2. 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v5.0) will be used for assessing AE severity. 
The table below will be used for assessing severity for AEs that are not specifically listed in the 
NCI CTCAE. 
 
 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the most recent version of NCI CTCAE (v5.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event, per the definition of serious adverse event in Section 10.1.2. 
d Grade 4 and 5 events must be reported as serious adverse events, per the definition of serious 
adverse event in Section 10.1.2. 
SAE Reporting Contact Information 
Syneos Safety Department 
 
Please refer to the SAE reporting form for 
more information. 


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10.2.3. 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether or not an adverse 
event is considered to be related to the study drug, indicating "yes" or "no" accordingly. The 
following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, discontinuation 
of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
 
The following categories should be used in the causality assessment of adverse events: 
Related 
The AE: 
• 
Follows a reasonable temporal sequence from the time of study drug administration; 
and/or 
• 
Follows a known response pattern to the study drug; and 
• 
Cannot be explained by other factors, such as the subject’s clinical state, therapeutic 
intervention, or concomitant therapy. 
• 
The response to withdrawal of the drug (dechallenge) should be clinically plausible and 
the event reoccurs on rechallenge if patient is re-exposed. 
 
Probably Related 
The AE: 
• 
Follows a reasonable temporal sequence from the time of study drug administration; 
and/or 
• 
Follows a known response pattern to the study drug; and 
• 
Was unlikely to have been produced by other factors, such as the subject’s clinical state, 
therapeutic intervention, or concomitant therapy. 


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Possibly Related 
The AE: 
• 
Follows a reasonable temporal sequence from the time of study drug administration; 
and/or 
• 
Follows a known response pattern to the study drug; but 
• 
Could have been produced by other factors, such as the subject’s clinical state, 
therapeutic intervention, or concomitant therapy. 
 
Unlikely 
The AE: 
• 
Does not follow a reasonable temporal sequence from the time of study drug 
administration; and 
• 
Was most likely produced by other factors, such as the subject’s clinical state, therapeutic 
intervention, or concomitant therapy. 
 
Unrelated 
This category is applicable to those AEs that are judged to be clearly and incontrovertibly due 
only to extraneous causes (e.g., the patient’s clinical state, therapeutic intervention or 
concomitant therapy) and do not meet the criteria for study drug relationship listed under 
Probable, Possible, or Unlikely. 
 
An AE with causal relationship not initially determined will require follow-up to assign 
causality. 
 
10.2.4. 
Procedures for Recording AEs 
Investigators should use correct medical terminology/concepts when recording AEs on the 
Adverse Event eCRF. Avoid colloquialisms and abbreviations. Only one AE term should be 
recorded in the event field on the Adverse Event eCRF. 
 
All AEs spontaneously reported by the patient and/or in response to an open-ended question 
from study personnel or revealed by observation, physical examination or other diagnostic 
procedures will be recorded on the appropriate forms in the eCRF. 
 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. When 
possible, a unifying diagnosis, or signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event. For example, the combination of 
general malaise, mild fever, headache and rhinitis should be described as a “common cold” 
rather than listing each symptom separately. 


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10.2.4.1. Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases; record Tumor Lysis Syndrome rather than hypocalcemia, hyperkalemia, 
hyperuricemia, etc.). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded on the Adverse Event eCRF. If a diagnosis is subsequently established, all 
previously reported AEs based on signs and symptoms should be nullified and replaced by one 
AE report based on the single diagnosis, with a starting date that corresponds to the starting date 
of the first symptom of the eventual diagnosis. 
 
10.2.4.2. Adverse Events that are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious secondary 
events. A medically significant secondary AE that is separated in time from the initiating event 
should be recorded as an independent event on the Adverse Event eCRF. For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF 
• 
If vomiting results in severe dehydration, both events should be reported separately on 
the eCRF 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF 
• 
If dizziness leads to a fall and consequent fracture, all three events should be reported 
separately on the eCRF 
• 
If neutropenia is accompanied by an infection, both events should be reported separately 
on the eCRF 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to whether 
the events are associated. 
 
10.2.4.3. Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points. Such events should only be recorded once on the Adverse Event eCRF with the 
severity (intensity or grade) of the events recorded at the time the event is first reported. 


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A recurrent AE is one that resolves between patient evaluation time points and subsequently 
recurs, or notes a change in severity or seriousness. Each recurrence of an AE should be 
recorded as a separate event on the Adverse Event eCRF. For example: 
• 
If Grade 1 vomiting has worsened to Grade 2 five days after onset, the Grade 1 vomiting 
is resolved on the date when this severity changed, and Grade 2 vomiting is recorded as a 
new event on the eCRF with onset date reflecting the change in severity. 
• 
If non-serious event of neutropenia required hospitalization five days after onset, the 
event is resolved on the hospitalization date, and a new SAE of neutropenia is recorded 
on the eCRF with start date reflecting when the event required hospitalization. 
 
10.2.4.4. Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE. A laboratory test result must be reported as 
an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• 
Is clinically significant in the investigator’s in the investigator’s judgment 
○ Note: For oncology trials, certain abnormal values may not qualify as AEs. 
 
It is the investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 × ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
 
10.2.4.5. Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE. A vital sign result must be reported as an 
AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment 


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It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE. 
 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse 
Event eCRF. 
 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF (Section 10.2.4.3 provides details on 
recording persistent AEs). 
 
10.2.4.6. Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either an 
elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total bilirubin 
> 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with 
clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory 
values should be recorded on the Adverse Event eCRF and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event). 
 
10.2.4.7. Deaths 
Death should be considered an outcome and not a distinct event. All deaths (including deaths 
due to progression of the underlying malignancy) that occur during the protocol-defined adverse 
event period should be reported as SAEs, regardless of attribution to study drug. The event or 
condition that caused or contributed to the fatal outcome should be recorded as the single 
medical concept (e.g., respiratory failure) with a fatal outcome. When the event that led to death 
cannot be identified (e.g., sudden death of unknown origin) report “sudden death” as the adverse 
event and update it when new information clarifies the event that led to death. Only one AE can 
be reported with a fatal outcome for each patient who dies. Other AEs that continued up to time 
of death should be reported with an outcome of not recovered/resolved. In the event that the 
death is attributed solely to progression of the underlying malignancy, the AE term should be 
reported as “Disease Progression.” 


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10.2.4.8. Lack of Efficacy or Worsening of Underlying Malignancy 
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be recorded as AEs (except deaths; see Section 10.2.4.7). Example: a patient 
with disease progression documented by metastatis/new tumors in the liver also has concurrent 
increases in transaminases. Every effort should be made to document progression through use of 
objective criteria. If there is any uncertainty as to whether a change in the patients condition, is 
due to disease progression, it should be reported as an AE. Example: a patient with disease 
progression documented by metastatis/new tumors in the liver also has concurrent new onset 
kidney failure (scan does not reveal kidney metastasis). 
 
10.2.4.9. Preexisting Medical Conditions 
A preexisting medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study. When recording such events on the Adverse 
Event eCRF, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (e.g., "more frequent headaches"). 
 
10.2.4.10. Hospitalization or Prolonged Hospitalization 
The following hospitalizations are not considered SAEs in this clinical trial: 
• 
Admissions per protocol for a planned medical/surgical procedure. Planned hospital 
admissions or planned surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial or before study drug was given are not to be considered 
AEs, unless they occur at a time other than the planned date for a reason such as a 
worsening of the underlying disease/illness/symptoms. 
• 
Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy). 
• 
Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study.  Appropriate documentation is required in 
these cases. 
• 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
 
10.2.4.11. Adverse Events Associated with an Overdose or Error in Drug Administration 
Overdose is defined as any dose in excess of the assigned dose of cerdulatinib greater than or 
equal to 90 mg total dose in one day or greater than 375 mg/m2 of rituximab per day. 
All overdoses meeting the above criteria must be recorded as an AE (Verbatim term = accidental 
overdose) on the eCRF. All overdoses must be reported to the Syneos Safety Department within 
24 hours of awareness including information for dose received vs. dose assigned, and treatment 


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given to the patient whether or not there are any signs or symptoms.  Any signs or symptoms 
resulting from an overdose must also be recorded as an AE on the eCRF and reported on the 
SAE form (medically important event) as separate adverse event(s) (see Section 10.2). 
 
Any dose that exceeds the assigned dose of cerdulatinib but is less than the 90 mg total dose in 
one day threshold for Overdose should be reported to the Sponsor Medical Monitor and captured 
appropriately in the Cerdulatinib Administration eCRF. 
 
All other significant dosing or medication errors that may not meet AE criteria (e.g., inadvertent 
dosing of non-study subject) should be reported to the Syneos Safety Department within 
24 hours of awareness. 
 
10.2.4.12. Adverse Events in Individuals Not Enrolled in the Study 
If an AE inadvertently occurs in an individual not enrolled in the study (e.g., during 
administration of study drug), the Adverse Event Form provided to investigators should be 
completed and submitted to Syneos SafetyDepartment, by scanning and emailing the form using 
the email address provided to investigators. 
 
10.2.4.13. Pregnancy Exposure and Birth Events 
If a female study patient becomes pregnant during study drug administration or within 16 weeks 
after date of last dose, the Investigator should be informed immediately and study treatment must 
be discontinued if not already terminated. The Investigator must urgently email a completed 
Pregnancy Form to Syneos Safety Department (Section 10.2). 
 
If a female partner of a male study patient is pregnant or suspects she is pregnant by the male 
study patient (between study drug administration and up to 16 weeks after the termination visit), 
the Investigator should be informed immediately. The Investigator must advise the male patient 
to have his female partner inform her treating physician immediately, and the Investigator must 
urgently email a completed Pregnancy Report Form to Syneos Safety Department. 
 
In all cases, the pregnancy must be followed up through delivery or other fetal outcome. 
Newborns should be monitored until at least 8 weeks of age for any potential congenital 
anomalies. The Investigator should promptly report any abnormal fetal outcome (i.e., congenital 
anomaly or birth defect, spontaneous or therapeutic abortion, stillbirth, pre-mature birth or 
outcome other than live normal birth) on an SAE form. 


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11.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
 
11.1. 
General Considerations 
It is anticipated that all statistical summaries will be performed using SAS software Version 9.3 
(SAS Institute, Inc., Cary, NC, USA) or higher. Additional software may be used for the 
production of graphics. 
 
11.1.1. 
Analysis Populations 
The safety analysis population will consist of all patients treated with at least 1 dose of study 
medication (cerdulatinib). Safety data will be summarized by dose level, based on the original 
assigned dose of study drug. 
 
The efficacy analysis population for the primary and secondary efficacy endpoints will consist of 
all patients who have taken at least 1 dose of study medication and have had at least 1 
post-baseline tumor assessment. Efficacy will be summarized separately for Phase 1 and 2a, and 
within Phase 2a, efficacy will be summarized by cohort and dose level. 
 
The PK and PD analysis populations will consist of all patients who have received the requisite 
treatments and have data at the required time points. Any windows for timing of measurements, 
etc., will be specified in the SAP. 
 
11.1.2. 
Cohort Comparability 
Baseline and demographic characteristics will be summarized for Phase 2a by dose cohort and 
overall. No formal statistical analyses of these data are planned, but descriptive statistics may be 
used to aid in interpreting results. 
 
11.1.3. 
Efficacy Endpoints and Analyses 
Responses will be summarized with patients classified as CR, PR, SD, PD, or not evaluable. 
The overall response rate (CR+PR) and clinical benefit rate (CR+PR+SD) will be summarized 
along with 2-sided exact 95% confidence intervals.  Responses will be based on CT or CT/PET, 
evaluated per IWG Criteria [3] for patients with lymphoma and on peripheral lymphocyte counts 
and bone marrow biopsy results for patients with CLL [2]. Listings of tumor response for each 
patient will also be provided. Responses will be summarized separately for each dose level in 
Phase 1 and for each cohort and dose level in Phase 2a. Due to differences in underlying disease 
and prior treatment, response rates considered clinically significant and that would prompt 
further study will depend on the cohort. Such summaries will also depend on the safety and 
tolerability profile observed. While it is anticipated that a 30 to 40% response rate in a future 
study will be sufficient to support further investigation, no criteria for success in this study 
are specified. 


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In addition to the tumor response rates described above, the following efficacy endpoints will be 
assessed (defined in Table 3 and reproduced below): 
• 
DOR (duration of response) – defined as the time from the first documentation of PR or 
CR to the earlier of the first documentation of disease progression or death from 
any cause. 
• 
PFS (progression-free survival) – defined as the time from the start of cerdulatinib 
treatment to the earlier of the first documentation of disease progression or death from 
any cause. 
• 
LNR (lymph node response) – defined as the proportion of patients who achieve a ≥ 50% 
decrease from baseline in the sum of the products of the greatest perpendicular diameters 
(SPD) of index lymph nodes. 
• 
TTR (time-to-treatment response) – defined as the time from the start of cerdulatinib 
treatment to the first documentation of CR or PR. 
 
11.1.4. 
Pharmacokinetic Analyses, Phase 1 and 2a 
Pharmacokinetic (PK) parameters (described in Section 9.1.1 and Section 9.1.2) will be 
calculated for each patient and summarized for patients with sufficient samples available. 
During Phase 2a, plasma samples will be taken as described in Appendix 1. 
 
11.1.5. 
Pharmacodynamic Analyses, Phase 1 and 2a 
A number of PD parameters will be measured serially as described in Section 9.2. At each 
time point, each of these parameters will be summarized by dose level. In addition, the 
parameters over time will be plotted for each patient and dose cohort. No formal statistical 
analyses are planned. 
 
11.1.6. 
Safety Analyses, Phase 1 and 2a 
The primary safety endpoint is the incidence of Grade 3 or higher clinically significant toxicity 
by dose level, and the secondary safety endpoints are as follows: 
• 
Adverse event profile (classified by NCI-CTCAE v5.0). 
• 
Clinically significant changes in vital signs, physical exams by dose level. 
• 
Changes in hematology and chemistry laboratory parameters by dose level. 
 
The incidence of Grade 3 or higher clinically significant toxicity will be summarized and listed 
by dose cohort for Phase 1. 
 
Adverse events (AEs) will be graded according to the NCI-CTCAE v4.0 (Phase 1) and 
NCI_CTCAE v5.0 (Phase 2a) and coded according to the latest MedDRA version available at 
the time of database creation. The number and percent of patients with any AE will be presented 
by System Organ Class (SOC) and preferred term for each cohort will be summarized by dose 


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cohort for Phase 1 and by Cohort for Phase 2a. An additional summary will include all patients 
who received the dose used in Phase 2a. 
 
Vital signs, laboratory parameters, and ECG intervals will be summarized and listed by time 
point for each dose cohort for Phase 1 and by Cohort for Phase 2a. No formal statistical analyses 
are planned. 
 
11.2. 
Sample Size Considerations 
11.2.1. 
Phase 1 Sample Size 
The sample size is based on clinical judgment and is typical of studies of this type. 43 patients 
were dosed with cerdulatinib.  The Phase 1 portion of the study is closed to enrollment. 
 
11.2.2. 
Phase 2a Sample Size 
Each of the 6 cohorts will consist of approximately 20 to 50 patients with relapsed or refractory 
disease. Initial enrollment into any cohort will be up to 20 patients; cohorts may be expanded to 
40 to 50 evaluable patients. A total of approximately 240 patients are planned. If fewer than 2 
responses are seen in the first 20 patients, enrollment in the cohort will be closed, as the upper 
bound (UB) of the 95% confidence interval would be approximately 25%. If 2 or more 
responses are seen, the cohort may be expanded. 
 
Patients in Cohorts 1, 3, 4, 5, and 6 will receive single-agent cerdulatinib. Patients in the 
Cohort 2 will receive cerdulatinib in combination with rituximab. The composition of each 
cohort is described in Table 6. 
 
11.3. 
Missing Data 
No imputation of missing data will be performed. Patients who do not have sufficient 
information for evaluation of response will be listed with the reason for missing response, and 
the count will be summarized. 
 
11.4. 
Multiplicity 
With multiple doses investigated in Phase 1 and multiple cohorts investigated in Phase 2a, there 
is an inflated chance of making an incorrect conclusion from this study. No adjustments will be 
made to the efficacy summaries in Phase 1 or to the safety summaries in Phase 2a to account for 
multiplicity. If 6 cohorts are assessed in Phase 2a, the difference between the observed rate and 
the underlying population rate will be biased if only the cohort with the observed rate most above 
an expected rate is considered. This will be informally considered when evaluating the data. 
 
11.5. 
Data Safety Monitoring 
There will be no formal DSMB for this trial. The composition of the Study Committee and its 
functions are specified in Section 7.6. 


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12.0 
INVESTIGATOR AND SPONSOR OBLIGATIONS 
 
12.1. 
Documentation Required for Study Initiation 
Before initiation of the study, the Investigator must provide the following documentation 
required by FDA regulations, including but not limited to, (copies of which must be maintained 
by the Investigator): 
1. FDA Form 1572. 
2. Curriculum vitae of the Investigator. 
3. A signed copy of the IRB or Ethics Committee approval notice for protocol and informed 
consent. 
4. A copy of the IRB or Ethics Committee approved informed consent. 
5. Completed financial disclosure form for the Investigator. 
 
12.2. 
Data Reporting and Case Report Forms (CRF) 
eCRFs are to be completed using a Sponsor-designated EDC system. Sites will receive training 
and have access to help text for appropriate eCRF completion. eCRFs will be submitted 
electronically to the Sponsor and should be handled in accordance with instructions from the 
Sponsor. Data entered into an eCRF will be processed in a US 21 CFR Part 11-compliant 
system. 
 
All eCRFs should be completed by designated, trained site staff. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, legibility, and timeliness of the data reported 
on the subject’s eCRF. Source documentation supporting the eCRF data should indicate the 
patient’s participation in the study and should document the dates and details of study 
procedures, AEs, and patient’s clinical status. 
 
The Investigator or designated representative should complete the eCRF as soon as possible after 
information is collected, preferably on the same day that a study patient is seen for an 
examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. eCRFs should be reviewed and 
electronically verified, signed, and dated by the Investigator or designee. 
 
12.3. 
Deviation from the Protocol 
The Investigator should not deviate from the protocol. In medical emergencies, the Investigator 
will use medical judgment and will remove the patient from immediate hazard, then notify the 
Sponsor’s MM, the Safety Monitor, and the IRB immediately regarding the type of emergency 
and course of action taken. Any action in this regard will be recorded on the appropriate CRF. 
The Sponsor will not assume any responsibility or liability for any deviation or change from 
the protocol. 


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12.4. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of Portola will 
visit the investigational study site to perform the following: 
• 
Determine the adequacy of the facilities. 
• 
Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Portola or its representatives. This will be 
documented in a Clinical Study Agreement between Portola and the Investigator. 
 
During the study, a monitor from Portola or representative will have regular contacts with the 
investigational site, for the following: 
• 
Provide information and support to the Investigator(s). 
• 
Confirm that facilities remain acceptable. 
• 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed. 
• 
Perform source data verification. This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice, and other 
records relevant to the study. This will require direct access to all original records for 
each patient (e.g., clinic charts). 
• 
Record and report any protocol deviations not previously sent to Portola. 
• 
Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to Portola and those SAEs that met criteria for reporting have been 
forwarded to the IRB. 
 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
 
12.5. 
Audits and Inspections 
Authorized representatives of Portola, a regulatory agency, an Independent Ethics Committee or 
an Institutional Review Board may visit the site to perform audits or inspections, including 
source data verification. The purpose of a Portola audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, International Council for Harmonisation (ICH) Guideline for Good Clinical 
Practice, and any applicable regulatory requirements. The Investigator should contact Portola 
immediately if contacted by a regulatory agency about an inspection. 


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12.6. 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
The Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC approval, 
and all materials approved by the IRB/IEC for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
 
12.7. 
Drug Accountability 
The Investigator must maintain accurate records of the amounts and dates study drug was 
received from Portola and dispensed to the patients. All drug supplies must be accounted for 
during the study and at the termination of the study and a written explanation provided for any 
discrepancies. All partially used or unused drug supplies will be destroyed at the site in 
accordance with site standard operating procedures approved by Portola or returned to Portola 
(or designated depot) after written authorization is obtained. The Investigator will maintain a 
record of the amount, reason and dates when unused supplies were either destroyed or returned 
to Portola.  All records will be retained as noted in Section 15.2. 
 
12.8. 
Disclosure of Data 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties other than those noted below is prohibited. Patient 
confidentiality will be further assured by utilizing patient identification code numbers to 
correspond to treatment data in the computer files. The study personnel, employees of the 
regulatory agencies, including the FDA and the study Sponsor, Portola, and its agents and 
representatives will need to review patient medical records in order to accurately record 
information for this study. If results of this study are reported in medical journals or at meetings, 
the patient’s identity will remain confidential. 


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13.0 
QUALITY CONTROL AND ASSURANCE 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
Portola may conduct a quality assurance audit. Please see Section 12.5 for more details 
regarding the audit process. 


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14.0 
ETHICS 
 
14.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
Investigator must submit written approval to Portola before he or she can enroll any 
patient/patient into the study. 
 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB or IEC must approve all advertising 
used to recruit patients for the study. The protocol must be re-approved by the IRB or IEC upon 
receipt of amendments and annually, as local regulations require. 
 
The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the investigational product. Portola 
will provide this information to the Investigator. 
 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
 
14.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH Guideline for Good Clinical Practice, 
applicable regulatory requirements and the Portola’s policy on Bioethics. 
 
14.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the patient is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study. Patients 
must also be notified that they are free to discontinue from the study at any time. The patient 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
 
The Investigator(s) must maintain the original, signed Informed Consent Form. A copy of the 
signed Informed Consent Form must be given to the patient. 


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15.0 
DATA HANDLING AND RECORD RETENTION 
 
15.1. 
Inspection of Records 
Portola will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
 
15.2. 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of 2 years 
after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Portola or the 
regulatory agency to review any documentation relating to the study, the Investigator must 
permit access to such records. 


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16.0 
PUBLICATION POLICY 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor prior to submission. 
This allows the Sponsor to protect proprietary information and to provide comments based on 
information from other studies that may not yet be available to the Investigator. 
 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual center data. In this case, a 
Coordinating Investigator will be designated by mutual agreement. 
 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors (ICMJE) authorship requirements. Any formal publication of the study 
in which contribution of Sponsor personnel exceeded that of conventional monitoring will be 
considered as a joint publication by the Investigator and the appropriate Sponsor personnel. 
 
Any inventions and resulting patents, improvements, and/or know-how originating from the use 
of data from this study will become and remain the exclusive and unburdened property of the 
Sponsor, except where agreed otherwise. 


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17.0 
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marginal-zone-lymphoma-mzl--rare-type-non-hodgkins-lymphoma.htm. 
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Wang, M.L., et al., Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell 
Lymphoma. N Engl J Med, 2013. 369(6): p. 507-16. 
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Updates. Clinical Lymphoma, Myeloma & Leukemia, 2014. 14(6): p. 431-435. 
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Treatment of B-Cell Non-Hodgkin’s Lymphoma. Pharmacy & Therapeutics, 2010. 35(3): 
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33. 
Held, G., V. Poschel, and M. Pfreundschuh, Rituximab for the treatment of diffuse large 
B-cell lymphomas. Expert Rev Anticancer Ther, 2006. 6(8): p. 1176-1186. 
34. 
RITUXAN® (rituximab) injection, [package insert]. South San Francisco, CA: 
Genentech, Inc., 2014. 
35. 
Stilgenbauer, S., R.R. Furman, and C.S. Zent, Management of Chronic Lymphocytic 
Leukemia. 2015 ASCO EDUCATIONAL BOOK, 2015: p. 164-175. 
36. 
Treon, S.P., et al., Extended rituximab therapy in Waldenstrom’s macroglobulinemia. 
Ann Oncol, 2005. 16: p. 132-138. 


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treatment of B non-Hodgkin’s lymphomas. Future Oncol, 2015. 11(9): p. 1327-1342. 
38. 
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Lymphoma: From Biology to Clinical Practice. Clin Cancer Res, 2014. 20(20): p. 5240- 
5254. 
39. 
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40. 
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lymphomas. Leukemia, 2008. 22: p. 1139-1143. 
41. 
de Leval, L. and P. Gaulard, Tricky and Terrible T-Cell Tumors: These are Thrilling 
Times for Testing: Molecular Pathology of Peripheral T-Cell Lymphomas. Hematology 
Am Soc Hematol Educ Program, 2011. 2011: p. 336-43. 
42. 
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and JAK inhibitors for clinical application. Biomarker Res, 2013. 1(1): p. Article number 
5. 
43. 
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refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol, 2015. 168: p. 811- 
819. 
44. 
O'Connor, O.A., et al., Pralatrexate in Patients With Relapsed or Refractory Peripheral 
T-Cell Lymphoma: Results From the Pivotal PROPEL Study. J Clin Oncol, 2011. 29(9): 
p. 1182-1189. 
45. 
Coiffier B., et al., Therapeutic options in relapsed or refractory peripheral T-cell 
lymphoma. Cancer Treat Rev, 2014. 40: p. 1080–1088. 
46. 
Giulia, P. and P. Corradini, Autologous Stem Cell Transplantation for T-Cell 
Lymphomas. Semin Hematol, 2014. 51: p. 59-66. 
47. 
Schmitz, N., H.-S. Wu, and B. Glass, Allogeneic Transplantation in T-Cell Lymphomas. 
Semin Hematol, 2014. 51: p. 67-72. 
48. 
DeSimone, J.A., et al., Recent advances in primary cutaneous T-cell lymphoma. Current 
Opinion Oncology, 2015. 27(2): p. 128–133. 
49. 
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Leukemia. N Engl J Med, 2014. 370(11): p. 997-1007. 
50. 
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51. 
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53. 
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Often Severe and Difficult to Treat. Acta Derm Venerol, 2010. 90: p. 12-17. 
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Choi, J., et al., Genomic landscape of cutaneous T cell lymphoma. Nature Genet, 2015. 
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Treatment Paradigms for Follicular Lymphoma. Cancer Treat Res, 2015. 165: p. 197- 
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Gopal, A.K., et al., PI3Kδ inhibition by idelalisib in patients with relapsed indolent 
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Jamroziak, K., et al., Richter syndrome in chronic lymphocytic leukemia: updates on 
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Tam, C.S., et al., Long-term results of first salvage treatment in CLL patients treated 
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Jain, P., et al., Outcomes of patients with chronic lymphocytic leukemia after 
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18.0 
APPENDICES 
The following appendices are provided: 
 
Appendix 1: 
Schedule of Assessments – Phase 2a (Exploratory) 
 
Appendix 2: 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Appendix 3: 
Strong CYP3A4 Inhibitors and Inducers and CYP3a Sensitive Substrates 
Appendix 4: 
Response Definitions for B-cell NHL and PTCL, CLL, and CTCL 
Appendix 5: 
Prognostic Factors 
Appendix 6: 
Differential of ABC vs. GCG type of DLBCL by IHC-Hans Methodology 
Appendix 7: 
Staging Systems for CLL and NHL 
Appendix 8: 
Global Health Assessment 
 
Appendix 9: 
Cockcroft-Gault Method for Evaluating Creatinine Clearance 
Appendix 10: 
Likert Scale 
Appendix 11: 
T-cell Lymphoma Classifications 


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APPENDIX 1. 
SCHEDULE OF ASSESSMENTS ─ PHASE 2A (EXPLORATORY) 
 
 
PROCEDURES 
Pre-Treatment 
Phase 2A Treatment Period 
Follow-up 
SCREENING 
CYCLE 1 
CYCLE 2 
CYCLE 3 
(and C6, C9, C12, 
C15, C18+) 
CYCLES 4 & 5 
(and C7, C8, C10, 
C11, C13, C14+) 
30 Days 
Post-last 
Treatment 
D1 
D2 
D8 
D9 
D15 
D22 
Cohort 2 Only 
D1 
D15 
D1 
D1 
D -21 
Pre-dose 
Post- 
dose 
Pre-dose Pre-dose 
Post- 
dose 
Pre-dose Pre-dose 
Post- 
dose 
Pre-dose 
Post- 
dose 
Pre-dose 
Post- 
dose 
Pre-dose 
Post- 
dose 
Pre-dose 
Post- 
dose 
Pre-dose 
Post- 
dose 
Visit Windows (Days)
Within 21 Days 
Prior to C1D1 
N/A 
N/A 
±1 
N/A 
±2 
±2 
±3 
±2 
±3 
±3 
±3 
General/Safety Assessments 
Obtain Informed Consent 
X 
Review Inclusion/Exclusion Criteria 
X 
X 
Medical History and Prognostic Factors 1 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
Vital Signs 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
Global Health Assessment 3 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 4 
X 4 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cerdulatinib Administration 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rituximab Administration (Cohort 2 Only) 6 
X 
X 
X 
X 
X 7 
X 7 
Local Disease Assessments and Laboratory Tests 
Bone Marrow Biopsy and Aspirate 8 
X 
X 
X 
CT or CT/PET 9 
X 
X 
Optional Lymph/Tumor Node Biopsy 10 
At any time throughout the study 
Optional Tumor Block/Unstained Slides 10 
X 
EBV PCR 11 
X 
HIV/HBV/HCV infection testing 12 
X 
Serum Chemistry and Hematology 13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (microscopic analysis as clinically indicated) 
X 
X 
X 
X 
X 
X 
Urine or Serum Pregnancy 14 
X 
X 
X 
X 
X 
X 
PT/PTT/INR 
X 
X 
Beta-2 Microglobulin, Lymphocyte Subsets, Immunoglobulin Levels 15 
X 16 
X 
X 
X 
X 
X 
CRP and ESR-Westergren (Sed. Rate) 
X 
X 
X 
X 
X 
Prognostic factors: cytogenetics (FISH), IgVH, Zap70, CD38 
(Cohort 4 - CLL/SLL Only) 17 
X 


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PROCEDURES 
Pre-Treatment 
Phase 2A Treatment Period 
Follow-up 
SCREENING 
CYCLE 1 
CYCLE 2 
CYCLE 3 
(and C6, C9, C12, 
C15, C18+) 
CYCLES 4 & 5 
(and C7, C8, C10, 
C11, C13, C14+) 
30 Days 
Post-last 
Treatment 
D1 
D2 
D8 
D9 
D15 
D22 
Cohort 2 Only 
D1 
D15 
D1 
D1 
D -21 
Pre-dose 
Post- 
dose 
Pre-dose Pre-dose 
Post- 
dose 
Pre-dose Pre-dose 
Post- 
dose 
Pre-dose 
Post- 
dose 
Pre-dose 
Post- 
dose 
Pre-dose 
Post- 
dose 
Pre-dose 
Post- 
dose 
Pre-dose 
Post- 
dose 
Visit Windows (Days)
Within 21 Days 
Prior to C1D1 
N/A 
N/A 
±1 
N/A 
±2 
±2 
±3 
±2 
±3 
±3 
±3 
CTCL Disease Assessment – mSWAT and Likert Scale 
(Cohort 6 - CTCL Only) 
X 
X 
X 
X 
CTCL Disease Assessment – Flow Cytometry for Sézary Cells and 
Photographs of Skin Involvement (Cohort 6 - CTCL Only) 
X 
X 
Response assessment for leukemic subtypes 
X 
X 
Skin Punch Biopsy (Cohort 6 - CTCL Only) 18 
X 
X 
Central Laboratory Tests 
Plasma PK 19 
X 
X 19 
X 19 
X 
X 19 
X 19 
X 
X 
X 
X 
Serum Cytokine Biomarker Analysis 
X 
X 
X 
X 
CLL = Chronic lymphocytic lymphoma; CT = Computed tomography; EBV = Epstein-Barr virus; ECG = Electrocardiogram; ECOG = Eastern cooperative oncology group; FISH = Florescence in situ hybridization; iNHL = indolent non-Hodgkin lymphoma; lab = Laboratory; PCR = polymerase 
chain reaction; PET = Positive-emission tomography; PK = Pharmacokinetic; PT/PTT/INR = Prothrombin time, partial thromboplastin time/international normalized ratio; SOC = Standard of care 
1. 
 
 
2. 
 
 
 
 
3. 
 
4. 
5. 
 
6. 
 
7. 
 
8. 
 
 
9. 
 
 
 
 
10. 
 
 
11. 
 
12. 
 
13. 
 
 
14. 
 
15. 
 
16. 
 
17. 
 
18. 
 
 
19. 
Medical history should include a redacted copy of the pathology report and any supporting pathology information, including the original pathology report from the diagnosis (which may include additional mutational analysis by sequencing, FISH, IHC, cytogenetics, etc.,) to be available for 
Sponsor review. 
Vital signs include temperature, respiration, blood pressure and heart rate, and should be obtained after at least 5 minutes in the sitting or semi-recumbent position. Post-dose vital signs should be obtained at 1.0 hour post-cerdulatinib administration for all patients except those in Cohort 2 for all 
onsite visits. For patients in Cohort 2 (cerdulatinib + rituximab), on visits when rituximab is administered, post-dose vital signs should be obtained at 0.5, 1.0, 2.0, 3.0, and 4.0 hours post-cerdulatinib dosing (or per standard of care), and then as clinically indicated. The collection window for 
vital signs is ± 10 minutes. 
Administer Global Health Assessment before any other protocol procedures are performed and before any protocol-related information is communicated. 
Record all medications including over the counter preparations, herbals, and vitamins taken in the 14 days prior to Cycle 1 Day 1. 
Dosing begins on Day 1 and continues daily until treatment interruption or study discontinuation. 
Rituximab dose is 375 mg/m2. Rituximab infusion should start immediately after cerdulatinib is taken. 
After Cycle 1, rituximab should be administered on Day 1 only of Cycles 4, 6, 8, and 10. 
For CLL patients only, a bone marrow biopsy and aspiration will be completed before Day 1 (within 6 weeks/42 days prior to Day 1) through the local lab and be repeated as clinically indicated. For all other patients with a history of bone marrow involvement prior to entering the study, a repeat 
biopsy should be performed to confirm a complete response or as clinically indicated. 
CT or CT/PET of chest, abdomen, pelvis, and any other areas of lymphoma may be obtained within 28 days prior to Cycle 1 Day 1; redacted copy of the report(s) to be available to the Sponsor for review. Subsequent CT or CT/PET assessments may be performed within 7 days prior to the 
scheduled visit and as clinically indicated. For CTCL patients, if baseline scan is negative for nodal/visceral/other disease, a repeat CT or CT/PET is not necessary except to confirm CR and may be done as clinically indicated. In the event of a Complete Response, confirmatory scans should be 
obtained no less than 4 weeks following determination of response. Copies of scans should be made available to Sponsor upon request. Additionally, obtain copy of molecular/mutation profile if obtained as standard of care. 
Optional: An archival tissue block or unstained slides may be submitted during Screening after eligibility has been confirmed. Tumor biopsies may also be obtained at the discretion of the treating physician as clinically indicated. For all tumor biopsies and samples, submit a formalin-fixed 
paraffin embedded tissue (FFPE) block or a minimum of 10 (preferably 20) unstained, freshly cut FFPE tissue slides from lymph node or other biopsies.  Additional information available in the Lab Manual. 
Obtain EBV PCR at screening. If EBV PCR was not obtained at screening, it should be obtained at the next visit. In addition, post-baseline EBV PCR should be obtained for any patient with an unexplained fever if there is clinical suspicion of EBV reactivation. 
Testing for HIV, HBV, and HCV will be performed if the patient does not have documentation of a negative hepatitis panel and negative HIV history within the 12-week period prior to enrollment. 
Serum chemistry includes: sodium, potassium, chloride, magnesium, CO2 (HCO3), glucose, blood urea nitrogen (BUN), creatinine, AST (SGOT), ALT (SGPT), lactate dehydrogenase, total protein, albumin, alkaline phosphatase, calcium, phosphorous, bilirubin, uric acid, amylase, and lipase. 
Hematology includes: hemoglobin, hematocrit, WBC, platelet count, complete blood count (CBC) with differential. Grade 3 or greater increases in ALT or AST require liver function testing to be repeated within 72 hours of initial test. 
Results of urine or serum pregnancy testing must be available prior to study drug administration. 
Quantitative immunoglobulins: quantitative levels of IgA, IgE, IgG, and IgM Lymphocyte subsets: quantitation of absolute numbers (or %) of CD3+, CD4+, CD8+, CD16/56+, and CD19+ by flow cytometry. 
Results obtained within 60 days prior to C1D1 may be used in lieu of the Screening assessment. 
For IgVH, results obtained within 3 months prior to C1D1 may be used. 
Skin punch biopsy is mandatory for all patients with CTCL and should be a ≥ 5 mm punch biopsy of a representative lesion. A biopsy should be obtained from 2 different areas of disease if possible (e.g., plaque and nodular lesions). Subsequent biopsies should be from the same general site if 
possible. At least 10 unstained slides or a FFPE tissue block should be submitted. 
Serial PK samples will be collected on C1D1 and C1D8 at pre-dose (i.e., within 60 minutes prior to the dose), and 1, 2, 4, 6, 8, and 24 hours post-dose (collection window is ± 10 minutes, except for the 24-hour post-dose timepoint [± 30 minutes]). The 24 hours post-dose PK samples collected 
on C1D2 and C1D9 should be collected prior to dosing in-clinic that day. If a patient is not dosed at a particular visit but is due to be dosed, a trough PK assessment should still be performed. In addition to times specified in this row, obtain a PK sample whenever a patient experiences a dose 
reduction/interruption, study drug discontinuation, and any AE that may indicate potential drug toxicity. Section 7.3.2.3 provides additional information. 


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APPENDIX 2. 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
 
Status 
1. Fully active, able to carry on all pre-disease performance without restriction. 
2. 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). 
3. Ambulatory and capable of all self-care, but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
4. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
5. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
6. Dead. 


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APPENDIX 3. 
STRONG CYP3A4 INHIBITORS AND INDUCERS AND CYP3A 
SENSITIVE SUSBSTRATES 
 
To avoid possible drug-drug interactions, strong inhibitors and inducers of CYP3A4 and CYP3A 
sensitive substrates should be avoided in patients receiving cerdulatinib (Table A3-9 and 
Table A3-10). If the Investigator feels that use of these medications is necessary, this should be 
discussed with the Medical Monitor. A dose adjustment (lowering) for CYP3A sensitive 
substrates may be considered on a case-by-case basis. 
 
Table A3-9: 
Strong CYP3A4 Inhibitors and Inducers 
 
Strong Inhibitors 
Strong Inducers 
Clarithromycin 
Barbiturates 
Telithromycin 
Efavirenz 
Ketoconazole and Posaconazole 
Nevaripine 
Itraconazole 
Pioglitazone 
Fluvoxamine 
Rifampin 
Nefazodone 
Rifabutin 
Ritonavir, Lopinavir 
Carbamazepine 
Indinavir 
Phenytoin 
Nelfinavir 
Modafinil 
Sequinavir 
St. John’s Wort 
Atazanavir 
Grapefruit/Grapefruit Juice 
 
 
Table A3-10: 
CYP3A Sensitive Substrates 
 
Generic (Trade Name) 
Albendazole (Albenza®) 
Levomilnacipran (Fetzima®) 
Alfentanil (Alfenta®) - 
drug has narrow therapeutic index 
Lopinavir and Ritonavir 
(Kaletra®) 
Aliskiren (Tekturna®) 
Lovastatin (Mevacor®) 
Almotriptan (Axert®) 
Lurasidone (Latuda®) 
Alprazolam (Xanax®) 
Maraviroc (Selzentry®) 
Aprepitant 
(Emend®) 
Medroxyprogesterone acetate 
(Depo-Provera®) 
Aripiprazole (Abilify®) 
Methadone 
Avanafil (Stendra®) 
Midazolam (Versed®) 
Brexpiprazole (Rexulti®) 
Mirtazapine (Remeron®) 
Bromocriptine (Cycloset®, Parlodel®) 
Nevirapine (Viramune®) 
Budesonide (Entocort®, Pulmicort®) 
Nisoldipine (Sular®) 
Buprenorphine (Suboxone®, Butrans®, etc.) 
Ospemifene (Osphena®) 


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Generic (Trade Name) 
Buspirone (Buspar®) 
Oxycodone (Percocet®, Oxycontin®) 
Cariprazine 
(Vraylar®) 
Paritaprevir 
(Viekira Pak™, Technivie™) - major substrate 
Clonazepam 
(Klonopin®) (probable) 
Pimozide (Orap®) - 
drug has narrow therapeutic index 
Conivaptan (Vaprisol®) 
Praziquantel (Biltricide®) 
Cyclophosphamide (Cytoxan®) 
Propafenone (Rythmol®) 
Cyclosporine 
(Neoral®, Gengraf®, Sandimmune®) - 
drug has narrow therapeutic index 
Quetiapine 
(Seroquel®) 
Daclatasvir (Daklinza™) 
Quinidine - drug has narrow therapeutic index 
Darifenacin (Enablex®) 
Roflumilast (Daliresp®) 
Darunavir (Prezista®) 
Salmeterol (Serevent®) 
Dasatinib (Sprycel®) 
Saquinavir (Invirase®) 
Diazepam (Valium®) 
Sildenafil (Viagra®) 
Dienogest (progesterone in oral contraceptives) 
Simeprevir (Olysio®) 
Dihydroergotamine (DHE-45®, Migranal®) – 
drug has narrow therapeutic index 
Simvastatin 
(Zocor®) 
Dronedarone 
(Multaq®) 
Sirolimus (Rapamune®) - 
drug has narrow therapeutic index 
Drospirenone 
(progesterone in oral contraceptives) 
Suvorexant 
(Belsomra®) 
Elbasvir 
(Zepatier®) 
Tacrolimus (Prograf®) - 
drug has narrow therapeutic index 
Eletriptan (Relpax®) 
Tadalafil (Cialis®) 
Eplerenone (Inspra®) 
Tamsulosin (Flomax®) 
Ergotamine (Cafergot®) 
Temsirolimus (Torisel®) 
Eszopiclone (Lunesta®) 
Ticagrelor (Brilinta®) 
Ethinyl Estradiol (oral contraceptives, 
Ortho Evra®, NuvaRing®) 
Tinidazole 
(Tindamax®) 
Etonogestrel 
(Implanon®, Nexplanon®, NuvaRing®) 
Tofacitinib 
(Xeljanz®) (major substrate) 
Everolimus (Afinitor®) 
Tolvaptan (Samsca®) 
Felodipine (Plendil®) 
Tipranavir (Aptivus®) 
Fentanyl (Duragesic®) - 
drug has narrow therapeutic index 
Triazolam 
(Halcion®) 
Flibanserin (Addyi®) - major substrate 
Vardenafil (Levitra®) 
Fluticasone 
(Flovent®, Arnuity Ellipta®) 
Verapamil 
(Calan®, Covera-HS®, Verelan®, etc.) 
Grazoprevir (Zepatier®) 
Vilanterol (Anoro Ellipta®) 
Guanfacine (Intuniv®) 
Vilazodone (Viibryd®) 
Hydrocodone (Norco®, Vicodin®, etc.) 
Vorapaxar (Zontivity®) 
Iloperidone (Fanapt®) 
Zolpidem (Ambien®) 
Indinavir (Crixivan®) 
Levomilnacipran (Fetzima®) 
Lapatinib (Tykerb®) 
Lopinavir and Ritonavir (Kaletra®) 


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APPENDIX 4. 
RESPONSE DEFINITIONS FOR B-CELL NHL AND PTCL, CLL, 
AND CTCL 
 
1. 
Response Criteria for NHL 
Radiographic (including PET scan) and clinical assessments will be evaluated in accordance with 
The Lugano Classification [4]. The criteria are summarized in Table A4-11. 
 
PET-CT is preferred for FDG-avid lymphomas and CT scan is preferred in other lymphomas. 
For patients staged with PET-CT, focal uptake in nodal and 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, etc. 
 
For patients staged with CT: 
• 
Selection of target (measured) lesions is as follows: 
○ Up to 6 of the largest nodes, nodal masses, and extranodal lesions selected to be 
clearly measurable in 2 diameters: 
○ A measurable node must have a longest transverse diameter of a lesion (LDi) 
> 1.5 cm. 
○ A measurable extranodal lesion (e.g., hepatic nodules) should have an LDi > 1.0 cm. 
○ Preferably, nodes should be disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas. 
○ Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and 
lungs), gastrointestinal (GI) involvement, cutaneous lesions, or those noted on 
palpation. If possible, they should: 
○ Be from disparate regions of the body. 
○ Include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved. 
• 
Selection of non-target (non-measured) lesions: 
○ Any lesions not selected as target (measured) and truly assessable lesions should be 
considered not measured. 
○ These lesions include any nodes, nodal masses, and extranodal lesions not selected as 
target (measured) or that do not meet the requirements for measurability but are still 
considered abnormal, as well as truly assessable lesions, which are any sites of 
suspected disease that would be difficult to follow quantitatively with measurement, 
(e.g., cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial effusions, 
ascites, leptomeningeal lesions/disease) and other lesions that cannot be confirmed 
and followed by imaging. 


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Table A4-11: 
Lugano Criteria [4] (Revised Criteria) for Response Assessment in NHL 
 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of the following): 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3 a with or without a residual mass on 5PS b 
It is recognized that in Waldeyer’s ring or extranodal sites with high 
physiologic uptake or with activation within spleen or marrow 
(e.g., with chemotherapy or myeloid colony-stimulating factors), 
uptake may be greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be inferred if uptake 
at sites of initial involvement is no greater than surrounding normal 
tissue even if the tissue has high physiologic uptake. 
Target nodes/nodal masses must regress to < 1.5 cm in 
LDi No extralymphatic sites of disease. 
Nonmeasured lesion 
Organ enlargement 
New lesions 
Bone marrow 
Not applicable 
Not applicable 
None 
No evidence of FDG-avid disease in marrow 
Absent 
Regress to normal 
None 
Normal by morphology; if indeterminate, IHC negative 
Partial 
Lymph nodes and extralymphatic 
sites 
Partial metabolic response 
Score 4 or 5 b with reduced uptake compared with baseline and residual 
mass(es) of any size: 
At interim, these findings suggest responding disease. 
At end of treatment, these findings indicate residual disease. 
Partial remission (all of the following): 
> 50% decrease in SPD of up to 6 target measurable nodes 
and extranodal sites. 
When a lesion is too small to measure on CT, assign 5 mm 
× 5 mm as the default value. 
When no longer visible, 0 × 0 mm. 
For a node > 5 mm × 5 mm, but smaller than normal, use 
actual measurement for calculation. 
Nonmeasured lesions 
Organ enlargement 
New lesions 
Bone marrow 
Not applicable 
Not applicable 
None 
Residual uptake higher than uptake in normal marrow but reduced 
compared with baseline (diffuse uptake compatible with reactive changes 
from chemotherapy allowed). 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. 
Absent/normal, regressed, but no increase. 
Spleen must have regressed by > 50% in length beyond 
normal. 
None 
Not applicable 


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Response and Site 
PET-CT–Based Response 
CT-Based Response 
No response or stable disease 
Target nodes/nodal masses, 
extranodal lesions 
Nonmeasured lesions 
Organ enlargement 
New lesions 
Bone marrow 
No metabolic response 
Score 4 or 5 with no significant change in FDG uptake from baseline at 
interim or end of treatment 
Not applicable 
Not applicable 
None 
No change from baseline 
Stable disease 
< 50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met 
No increase consistent with progression 
No increase consistent with progression 
None 
Not applicable 
Progressive disease 
Individual target nodes/nodal 
masses 
Extranodal lesions 
Nonmeasured lesions 
Progressive metabolic disease 
Score 4 or 5 with an increase in intensity of uptake from baseline and/or 
New FDG-avid foci consistent with lymphoma at interim or end-of- 
treatment assessment 
None 
Progressive disease requires at least 1 of the following PPD 
progression: 
An individual node/lesion must be abnormal with: LDi 
> 1.5 cm, and 
Increase by > 50% from PPD nadir and an increase in LDi 
or SDi from nadir 
0.5 cm for lesions < 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase beyond 
baseline (e.g., a 15-cm spleen must increase to > 16 cm). If 
no prior splenomegaly, must increase by at least 2 cm from 
baseline 
New or recurrent splenomegaly 
New or clear progression of preexisting nonmeasured 
lesions 


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Response and Site 
PET-CT–Based Response 
CT-Based Response 
New lesions 
New FDG-avid foci consistent with lymphoma rather than another 
etiology (e.g., infection, inflammation). If uncertain regarding etiology of 
new lesions, biopsy or interval scan may be considered. 
Regrowth of previously resolved lesions 
A new node > 15 cm in any axis 
A new extradnodal site > 1.0 cm in any axis; if < 1.0 cm in 
any axis, its presence must be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size unequivocally attributable to 
lymphoma 
New or recurrent lymphoma 
5PS = 5-point scale; CT = Computed tomography; FDG = Fluorodeoxyglucose; GI = Gastrointestinal; IHC = Immunohistochemistry; LDi = Longest 
transverse diameter of a lesion; MRI = Magnetic resonance imaging; PET = Positron emission tomography; PPD = Cross product of the LDi and 
perpendicular diameter; SDi = Shortest axis perpendicular to the LDi; SPD = Sum of the product of the perpendicular diameters for multiple lesion 
a A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid under treatment). Measured 
dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes 
should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions 
include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: 
Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, 
nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, 
including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by 
imaging. In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete 
metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or 
myeloid growth factors). 
b PET 5PS: 1, no uptake above background; 2, uptake < mediastinum; 3, uptake > mediastinum but < liver; 4, uptake moderately > liver; 5, uptake markedly 
higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 


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2. 
Response Criteria for CLL 
Radiographic and clinical assessments in accordance with the criteria established by IWCLL [2] 
will be used to determine response. CT scan is the preferred method for evaluating tumor 
response. The spleen and liver should also be assessed by physical examination. 
• 
Selection of target (measured) lesions for imaging or physical examination: 
○ Up to six of the largest nodes, nodal masses, and extranodal lesions selected to be 
clearly measurable in 2 diameters at baseline. 
○ A measurable node must have a longest transverse diameter of a lesion (LDi) 
> 1.5 cm. A measurable extranodal lesion (e.g., hepatic nodules) should have an LDi 
> 1.0 cm. 
○ Nodes should preferably be from disparate regions of the body and should include, 
where applicable, mediastinal and retroperitoneal areas. 
○ Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and 
lungs), gastrointestinal (GI) involvement, cutaneous lesions, or those noted 
on palpation. 
○ If possible, they should be from disparate regions of the body. 
○ If possible, they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved. 
• 
Selection of non-target (non-measured) lesions for imaging or physical examination: 
○ Any lesions not selected as target (measured) and truly assessable lesions should be 
considered not measured. 
○ These lesions include any nodes, nodal masses, and extranodal lesions not selected as 
target (measured) or that do not meet the requirements for measurability but are still 
considered abnormal, as well as truly assessable lesions, which are any sites of 
suspected disease that would be difficult to follow quantitatively with measurement, 
(e.g., cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial effusions, 
ascites, leptomeningeal lesions/disease) and other lesions that cannot be confirmed 
and followed by imaging. 
 
3. 
Complete Response (CR) 
To satisfy the criteria for CR, all of the following criteria must be met and must persist 
for ≥ 8 weeks: 
• 
No evidence of new disease 
• 
ALC in peripheral blood of < 4 x 109/L 
• 
Regression of all target nodal masses to normal size (i.e., ≤ 1.5 cm in the longest diameter 
for nodes that were considered large at baseline and ≤ 1.0 cm in the longest perpendicular 
diameter for nodes that were considered small at baseline) 


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• 
Normal spleen and liver size 
• 
Regression to normal of all nodal non-target disease and disappearance of all detectable 
non-nodal, non-target disease 
• 
No disease-related constitutional symptoms 
• 
Peripheral blood counts meeting all of the following criteria: 
○ ANC ≥ 1.5 x 109/L without need for exogenous growth factors (e.g., G-CSF) 
○ Platelet count ≥ 100 x 109/L without need for exogenous growth factors 
○ Hemoglobin ≥ 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (e.g., erythropoietin) 
Notes: 
• 
Morphologically negative bone marrow is defined as < 30% of nucleated cells and no 
lymphoid nodules in a bone marrow sample that is normocellular for age. 
• 
Patients who fulfill all the criteria for a CR (including bone marrow criteria) but who 
have a persistent anemia, thrombocytopenia, or neutropenia that is related to prior or 
ongoing drug toxicity (and not to CLL) will be considered as a CR with incomplete 
marrow recovery (CRi). 
 
4. 
Partial Response (PR) 
To satisfy criteria for PR, all of the following criteria must be met and must persist for 
≥ 8 weeks: 
• 
No evidence of new disease 
• 
Decrease in peripheral blood ALC by ≥ 50% from baseline 
• 
A decrease by ≥ 50% from the baseline in the SPD (sum of the products) of the target 
nodal lesions 
• 
In patients with enlargement of the spleen or liver at baseline: 
○ Normal spleen size, or a decrease by ≥ 50% from baseline in the pretreatment 
enlargement of the vertical dimension below the left costal margin (by palpation) or 
in total vertical dimension (by imaging) 
○ Normal liver size, or a decrease by ≥ 50% from baseline in the pretreatment 
enlargement of the liver total vertical dimension at the right costal margin (by 
percussion) or a qualitative decrease in liver size (by imaging) 
• 
No increase in the size of the liver or spleen 
• 
No increase in the size of non-target disease 
• 
No persistent (lasting > 4 weeks) worsening of disease-related constitutional symptoms 
• 
Peripheral blood counts meeting any of the following criteria: 


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○ ANC ≥ 1.5 x 109/L or ≥ 50% increase over baseline without need for exogenous 
growth factors (e.g., G-CSF) 
○ Platelet count ≥ 100 x 109/L or ≥ 50% increase over baseline without need for 
exogenous growth factors 
○ Hemoglobin ≥ 110 g/L (11.0 g/dL) or ≥ 50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (e.g., erythropoietin) 
 
Note: Patients who achieve a PR by IWCLL 2008 criteria [2] in all parameters 
except lymphocyte count will be considered PR with lymphocytosis. Patients 
with a PR with lymphocytosis will not be considered to have achieved a PR until 
there is a 50% reduction in ALC from baseline was achieved or ALC 
< 4 × 109/L. 
 
Note: Marrow should have at least a 50% reduction in marrow infiltrate or 
B-lymphoid nodules 
 
5. 
Stable Disease (SD) 
To satisfy the criteria for SD, the following criteria must be met: 
• 
No evidence of new disease, i.e., there is neither sufficient evidence of tumor shrinkage 
to qualify for PR nor sufficient evidence of tumor growth to qualify for definitive disease 
progression. 
 
6. 
Progressive Disease (PD) 
• 
The occurrence of any of the following events indicates definitive PD: 
Evidence of any new disease that was not present as baseline: 
• 
A new node that measures > 1.5 cm in any diameter 
• 
A new node that measures > 1.0 cm to ≥ 1.5 cm in the longest diameter and > 1.0 cm in 
the longest perpendicular diameter 
• 
New hepatomegaly or splenomegaly 
• 
New non-target disease (e.g., effusions, ascites, or other organ abnormalities related 
to CLL) 
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient 
evidence alone of PD unless histologically confirmed. Thus, a declaration of PD 
should not be made if this is the only manifestation of apparently new disease. 
 
• 
Evidence of worsening of lymph nodes, spleen or liver, or non-target disease: 
○ Increase by ≥ 50% from the nadir in the SPD of target lesions. 


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○ Increase by ≥ 50% from the nadir in the product of the perpendicular diameters for 
any individual node; progression of a single lesion requires that the lesion 
demonstrates a ≥50% in the product of its diameters and that the lesion now meets the 
definition of abnormal (a node that was considered large at baseline must now 
measure > 1.5 cm in the longest diameter and a node that was considered small at 
baseline must now measure > 1.0 cm in the longest diameter perpendicular to the long 
diameter of the lesion). 
○ Increase by ≥ 50% from the nadir in the longest diameter for any individual node if 
the node now has a longest perpendicular diameter that is >1.0 cm. 
○ In a patient with an abnormal spleen, an increase by ≥ 50% from the nadir 
enlargement of the spleen vertical dimension below the left costal margin (by 
palpation) or in total vertical dimension (by imaging). 
○ In a patient with an abnormal liver, an increase by ≥ 50% from the nadir enlargement 
of the liver total vertical dimension at the right costal margin (by percussion) or a 
unequivocal qualitative increase in liver size (by imaging). 
○ Unequivocal increase in the size of non-target disease (e.g., effusions, ascites, or 
other organ abnormalities related to CLL). 
○ Transformation to a more aggressive histology (e.g., Richter syndrome) as established 
histologically. 
 
7. 
Treatment-related Lymphocytosis 
Treatment-related lymphocytosis, for the purpose of this protocol, is defined as an elevation in 
blood lymphocyte count of ≥ 50% compared to baseline which occurs in the setting of 
unequivocal improvement in at least 1 other disease-related parameter including lymph node 
size, spleen size, hematologic parameters or disease symptoms. Patients with isolated 
lymphocytosis in the setting of reduced disease burden or improvement in hematologic 
parameters should not be considered to have progressive disease [2]. 


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Clinical Study 13-601 
Cerdulatinib 
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8. 
Response Criteria for Leukemic Forms of Peripheral T-cell Lymphoma (PTCL) (ATLL, PLL, LGL) 
A. Response Criteria for ATLL 
 
Table A4-12: 
Response Criteria for ATLL 
 
Source: NCCN 2018 [77]. 


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B. Response Criteria for PLL 
Investigators are encouraged to use the Workshop on Chronic Lymphocytic Leukemia (IWCLL) 
Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia [2] for CLL 
(Appendix 4-2). 
 
C. Response Criteria for LGL 
Response to treatment should be determined by periodic clinical assessments and blood counts 
(Table A4-13). 
 
Table A4-13: 
Response Criteria for LGL 
 
Complete Response 
The complete normalization of blood counts: 
• 
hemoglobin >12 g/dL, platelets >150×109/L, 
absolute neutrophil count >1.5×109/L, and 
lymphocytosis <4×109/L, and 
• 
a circulating LGL count of <0.5×109/L. 
Partial Response 
An improvement in blood counts: 
• 
hemoglobin >8 g/dL, platelets >50\109/L, and 
neutrophils >0.5\109/L, and 
• 
the absence of transfusion requirements. 
Treatment Failure 
Any response not meeting the above criteria within 3 
months after the beginning of the treatment. 
Source: Bareau, et al [78]. 
 
 
9. 
Response Criteria for Cutaneous T-Cell Lymphoma (CTCL) 
All relevant clinical and radiographic information required to make an assessment should be 
considered. Nodes/lesions should be selected based on criteria described by Olsen, et al [5]. 


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Table A4-14: 
Global Response Score 
 
Global Score a 
Definition 
Skin 
Nodes, Blood, Viscera 
CR 
Regression of measurable disease 
CR 
All categories have CR/NI 
PR 
Regression of measurable disease 
CR 
All categories do not have a CR/NI and 
no category has a PD 
PR 
No category has a PD and if any category 
involved at baseline, at least 1 has 
a CR or PR 
SD 
Failure to attain CR, PR, or PD 
representative of all disease 
PR 
No category has a PD and if any category 
involved at baseline, no CR or PR in any 
SD 
CR/NI, PR, SD in any category and 
no category has a PD 
PD 
Progressive disease 
PD 
PD in any category 
Relapse 
Recurrence disease in prior CR 
Relapse in any category 
CR = Complete response; NI = Noninvolved; PR = Partial response; PD = Progressive disease; SD = Stable disease 
Note: It is recommended that not only the proportion of patients who achieve a response or an unfavorable outcome 
be calculated but a life table account for the length of the interval during which each patient is under observation 
also be generated. 
 
 
Table A4-15: 
Response in Skin 
 
Response 
Definition 
CR - Complete Response 
100% of skin lesions a 
PR - Partial Response 
50 to 99% clearance of skin disease from baseline without new tumors (T3) in patients 
with T1, T2, or T4 only skin disease 
SD - Stable Disease 
< 25% increase to < 50% clearance in skin disease from baseline without new tumors 
(T3) in patients with T1, T2, or T4 only skin disease, or 
PD - Progressive Disease b 
≥ 25% increase in skin disease from baseline, or 
New tumors (T3) in patients with T1, T2, or T4 only skin disease, or 
Loss of response: in those with complete or partial response, increase of skin score 
of greater than the sum of nadir plus 50% baseline score 
Relapse 
Any disease recurrence in those with complete response 
Note: Based on modified Severity Weighted Assessment Tool score. 
a A biopsy of normal appearing skin is unnecessary to assign a complete response. However, a skin biopsy should 
be performed of a representative area of the skin if there is any question of residual disease (persistent erythema or 
pigmentary change) where otherwise a complete response would exist. If histologic features are suspicious or 
suggestive of mycosis fungoides/Sézary syndrome, the response should be considered a partial response only. 
b Whichever criterion occurs first. 


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Table A4-16: 
Response in Lymph Nodes 
 
Response 
Definition 
CR – Complete Response 
All lymph nodes a are now ≤ 1.5 cm in greatest transverse (long axis) diameter by 
method used to assess lymph nodes at baseline or biopsy negative for lymphoma; in 
addition, lymph nodes that were N3 classification and ≤ 1.5 cm in their long axis and 
> 1 cm in their short axis at baseline, must now be ≤ 1 cm in their short axis or biopsy 
negative for lymphoma 
PR - Partial Response 
Cumulative reduction ≥ 50% of the SPD of each abnormal lymph node at baseline and 
no new lymph node > 1.5 cm in the diameter of the long axis or > 1.0 cm in the 
diameter of the short axis if the long axis is 1-1.5 cm in diameter 
SD - Stable Disease 
Fails to attain the criteria for CR, PR, and PD 
PD - Progressive Disease b 
≥ 50% increase in SPD from baseline of lymph nodes, or 
Any new node > 1.5 cm in the long axis or > 1 cm in the short axis if 1-1.5 cm in the 
long axis that is proven to be N3 histologically, or 
Loss of response:  > 50% increase from nadir in SPD of lymph nodes in those with PR 
Relapse 
Any new lymph node > 1.5 cm in the long axis in those with CR proven to be N3 
histologically 
PD = Progressive disease; SPD = Sum of the maximum linear dimension (major axis) x longest perpendicular 
dimension (minor axis) 
a Peripheral and central lymph nodes. 
b Whichever criterion occurs first. 
 
 
Table A4-17: 
Response in Viscera 
 
Response 
Definition 
CR - Complete Response 
Liver or spleen or any organ considered involved at baseline should not be enlarged on 
physical exam and should be considered normal by imaging; no nodules should be 
present on imaging of liver or spleen; any post treatment mass must be determined by 
biopsy to be negative for lymphoma. 
PR - Partial Response 
≥ 50% regression in any splenic or liver nodules, or in measurable disease (SPD) in 
any organs abnormal at baseline; no increase in size of liver or spleen and no new sites 
of involvement 
SD - Stable Disease 
Fails to attain the criteria for CR, PR, and PD 
PD - Progressive Disease a 
≥ 50% increase in size (SPD) of any organs involved at baseline, or 
New organ involvement, or 
Loss of response:  > 50% increase from nadir in the size (SPD) of any previous organ 
involvement in those with PR 
Relapse 
New organ involvement in those with CR 
PD = Progressive disease; SPD = Sum of the maximum linear dimension (major axis) x longest perpendicular 
dimension (minor axis) 
a Whichever criterion occurs first. 


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Table A4-18: 
Response in Blood a 
 
Response 
Definition 
CR - Complete Response b 
B0 
PR - Partial Response c 
≥ 50% decrease in quantitative measurements of blood tumor burden from baseline in 
those with high tumor burden at baseline (B2). 
SD - Stable Disease 
Fails to attain the criteria for CR, PR, and PD. 
PD - Progressive Disease d 
B0 to B2, or 
> 50% increase from baseline and at least 5,000 neoplastic cells/µL, or 
Loss of response: B2 at baseline, > 50% increase from nadir and at least 
5,000 neoplastic cells/µL. 
Relapse 
Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR 
a As determined by absolute numbers of neoplastic cells/µL. 
b If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative 
of lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria for B0, a 
repeat bone marrow biopsy must show no residual disease or the response should be considered a PR only. 
c There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic cells that define 
B1 is not considered significant and should not affect determination of global objective response. 
d Whichever criterion occurs first. 
 
 
10. Modified Severity Weighted Assessment Tool (mSWAT) for CTCL 
D. Total Body Surface Area (TBSA) Involvement by Skin Disease 
The body is divided into 12 regions with pre-assigned %TBSA based on the burn literature. The 
extent of skin disease in each region is quantified by using the patient’s palm to measure the 
%TBSA involvement within region: patient’s palm with 4 fingers (excluding the thumb) is 1% 
of TBSA. Patient’s palm without fingers is 0.5% of TBSA. The patient’s palm with 4 fingers is 
traced on a transparency sheet at the baseline visit, using a permanent marker that will not rub off 
or smear. The transparency of the patient’s palm should be used in all mSWAT assessments 
during the course of the clinical study. The transparency will be labeled with the patient’s study 
ID number kept in the patient’s study file on site. Using the baseline visit transparency of the 
patient’s palm, the investigator will measure and record on the electronic case report form 
(example of table from eCRF is given below) the %TBSA for each lesion type within each of the 
12 regions. 
 
E. Severity Weighting Factor 
The severity weighting factors will be the following: 
1. = patch (flat erythema or erythema with mild infiltration), multiply by 1. 
2. = plaque (elevated erythema or erythema with moderate infiltration), multiply by 2. 
3. = tumor or ulceration (erythema with fissuring, ulceration or tumor), multiply by 4. 
 
Patch is defined as abnormal skin not elevated from normal skin. A plaque is defined as 
abnormal skin elevated from normal skin by < 5 mm. A plaque elevated ≥ 5 mm is a tumor. 


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F. Calculating Skin Scores 
The sum of %TBSA by lesion is derived by summing the %TBSA from all regions affected by 
the lesion. The sum of %TBSA across lesion types (patches, plaques, and tumors) within each 
region cannot exceed the %TBSA for the region. For example, the %TBSA for the head region 
is 7%. The sum of %TBSA across lesion types from head can only range from 0 to 7%. The 
skin score subtotal by lesion type are derived by multiplying the sum of %TBSA for patches 
from all regions by 1, sum of %TBS of plaques from all regions by 2, and the sum of %TBSA of 
tumors or ulcers from all regions by 4. The skin score total is derived from summing the skin 
score subtotals for patches, plaques, and tumors or ulcers. The skin score total is dimensionless 
with a scale of 0 to 400. See Table A4-19. 
 
Table A4-19: 
Calculating Skin Scores 
 
Region 
 
 
% TBSA 
for the region 
% TBSA Patch 
(or flat erythema) 
% TBSA Plaque 
(or elevated/ 
indurated 
erythema) 
% TBSA 
Tumor/Ulceration 
(or erythema 
w/fissuring, 
ulceration) 
Head 
7 
Neck 
2 
Anterior Trunk 
13 
Posterior Trunk 
13 
Buttocks 
5 
Genitalia 
1 
Upper Arms 
8 
Forearms 
6 
Hands 
5 
Thighs 
19 
Lower Leg 
14 
Feet 
7 
% BSA by Category 
100 
Severity Weighting Factor 
X 1 
X 2 
X 4 
Skin Score Subtotal 
BSA = Body surface area; TBSA = Total body surface area 


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Responses will be determined by the criteria described in Table A4-20. 
 
Progression of disease while on treatment should be confirmed by a second assessment 1 to 
4 weeks later so that patients who experience a temporary flare of disease due to skin infection 
or other intercurrent illnesses are not removed from the study prematurely. 
 
Table A4-20: 
mSWAT Response Assessment 
 
Assessment 
Description 
Status 
Completely Clear 
No evidence of disease; 100% improvement 
CR 
Marked Improvement 
Greater than or equal to 50% decrease in skin scores compared to baseline 
and improvement is maintained for 4 weeks 
PR 
Slight Improvement 
Less than 50% decrease in skin scores compared to baseline 
SD 
Worse 
≥ 25% increase in skin scores compared to baseline while the patient is 
actively taking the study drug 
or 
≥ 50% increase in the sum of the products of the greatest diameters of 
pathologically positive lymph nodes (should be documented by biopsy) 
compared to baseline while the patent is actively taking the study drug. 
PD 
CR = Complete response; PD = Progressive disease; PR = Partial response; SD = Stable disease 


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APPENDIX 5. 
PROGNOSTIC FACTORS [19] 
 
The following prognostic indices are presented: Follicular Lymphoma International Prognostic 
Index (FLIPI, Table A5-21), International Prognostic Index (Table A5-22), and Age-Adjusted 
Prognostic Index (Table A5-23), and Simplified Mantle-Cell Prognostic Index (MIPI) 
(Table A5-24). 
 
Table A5-21: 
Follicular Lymphoma International Prognostic Index -1 (FLIPI-1) 
Criteria 
 
Age 
≥ 60 years 
Ann Arbor Stage 
III-IV 
Hemoglobin Level 
< 12 g/dL 
Serum LDH Level 
> ULN 
Number of Nodal Sites 
≥ 5 
Risk Group According to FLIPI Chart 
Number of Factors 
Low 
0-1 
Intermediate 
2 
High 
≥ 3 
FLIPI-1 = Follicular Lymphoma International Prognostic Index; 
LDH = Lactic dehydrogenase; ULN = Upper limit of normal 
 
 
Table A5-22: 
International Prognostic Index (IPI) 
 
All Patients 
International Index, All Patients 
Age ≥ 60 Years 
Low 
0 or 1 
Serum LDH > Normal 
Low-intermediate 
2 
Performance Status 2-4 
High-intermediate 
3 
Stage III or IV 
High 
4 or 5 
Extranodal Involvement > 1 Site 
LDH = Lactic dehydrogenase; ULN = Upper limit of normal 
 
 
Table A5-23: 
Age-Adjusted International Prognostic Index 
 
Patients ≤ 60 Years of Age 
International Index, ≤ 60 Years of Age 
Stage III or IV 
Low 
0 
Serum LDH > normal 
Low-intermediate 
1 
Performance Status 2-4 
High-intermediate 
2 
High 
3 
LDH = Lactic dehydrogenase; ULN = Upper limit of normal 


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Table A5-24: 
Simplified Mantle-Cell Prognostic Index (MIPI) [79] 
 
Points 
Age in Years 
ECOG Status 
LDHULN 
WBC, 109/L 
0 
< 50 
0-1 
< 0.67 
< 6.700 
1 
50-59 
Not Applicable 
0.67–0.99 
6.700–9.999 
2 
60-69 
2-4 
1.000–1.49 
1.000–14.999 
3 
≥ 70 
Not Applicable 
≥ 1.5000 
≥ 1.5000 
ECOG = Eastern Cooperative Oncology Group; LDH = Lactic dehydrogenase; ULN = Upper limit of normal; 
WBC = White blood cell 
Note: For each prognostic factor, 0 to 3 points were given to each patient, and points were summed up to a 
maximum of 11. Patients with 0 to 3 points n summary were classified as low risk, patients with 4 to 5 points as 
intermediate risk, and patients with 6 to 11 points has high risk. ECOG performance status was weighted with 
2 points if patients were unable to work or bedridden (ECOG 2–4). LDH was weighted according to the ratio to 
the ULN. Thus, for a ULN of 240 U/L, the cutpoints were 180 U/L, 240 U/L, and 360 U/L, for example. 


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GCB 
APPENDIX 6. 
DIFFERENTIAL OF ABC VS. GCG TYPE OF DLBCL BY 
IHC-HANS METHODOLOGY 
 
Figure A6-5: 
Decision Tree for Immunoperoxidase Tissue Microarray (TMA) [75] 
 
 
 
CD10 
 
BCL-6 
 
 
 
 
 
DLBCL = Diffuse large B-cell lymphoma; GCB = Germinal center B-cell–like (a subclassification 
of DLBCL); non-GC = Non-germinal cell 
+ 
─ 
Non-GC 
+ 
─ 
GCB 
MUM1 
+ 
─ 
Non-GC 


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APPENDIX 7. 
STAGING SYSTEMS FOR CLL AND NHL [4, 19] 
 
The Rai and Binet staging systems for CLL are presented Table A7-25 and Table A7-26, 
respectively. The Lugano Modification of the Ann Arbor Guidelines is presented in 
Table A7-27. 
 
Table A7-25: 
Rai Staging System for Chronic Lymphocytic Lymphoma 
 
Rai Stage 
Description 
Risk Factor 
0 
Lymphocytosis and no enlargement of the lymph nodes, spleen, or liver, and 
with near normal red blood cell and platelet counts. 
Low Risk 
I 
Lymphocytosis plus enlarged lymph nodes. The spleen and liver are not 
enlarged and the red blood cell and platelet counts are near normal. 
Intermediate Risk 
II 
Lymphocytosis plus an enlarged spleen (and possibly an enlarged liver), with 
or without enlarged lymph nodes. The red blood cell and platelet counts are 
near normal. 
Intermediate Risk 
III 
Lymphocytosis plus anemia (too few red blood cells), with or without 
enlarged lymph nodes, spleen, or liver. Platelet counts are near normal. 
High Risk 
IV: Liver 
Lymphocytosis plus thrombocytopenia (too few blood platelets), with or 
without anemia, enlarged lymph nodes, spleen, or liver. 
High Risk 
 
 
Table A7-26: 
Binet Staging System for Chronic Lymphocytic Lymphoma 
 
Binet Stage 
Description 
A 
Fewer than 3 areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia. 
B 
3 or more areas of lymphoid tissue are enlarged, with no anemia or thrombocytopenia. 
C 
Anemia and/or thrombocytopenia are present. 


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Table A7-27: 
Lugano Modification of Ann Arbor Staging System (for Primary 
Nodal Lymphomas) 
 
Stage 
Involvement 
Extranodal “E” Status 
Limited 
Stage I 
One node or group of adjacent nodes 
Single extranodal lesions without nodal 
involvement 
Stage II 
2 or more nodal groups on the same side of the 
diaphragm 
Stage I or II by nodal extent with limited 
contiguous extranodal involvement 
Stage II “bulky” a 
Stage II as above with “bulky” disease 
Not applicable 
Advanced 
Stage III 
Nodes on both sides of the diaphragm 
Not applicable 
Nodes above the diaphragm with spleen 
involvement 
Stage IV 
Additional non-contiguous extralymphatic 
involvement 
Not applicable 
CT = Computed tomography; PET = Positive-emission tomography 
Notes: Extent of disease is determined by PET-CT for avid lymphomas and CT for non-avid lymphomas. Tonsils, 
Waldeyer’s ring, and spleen are considered nodal tissue. Categorization “A” or “B” has been removed from the 
Lugano Modification of Ann Arbor Staging. 
a Whether stage II bulky disease is treated a limited or advanced disease may be determined by histology and a 
number of prognostic factors. 


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APPENDIX 8. 
GLOBAL HEALTH ASSESSMENT 
 
To be completed by the patient. Patient may decline to answer. 
 
 
 
Circle the number that best represents your level of health today. 
 
0 means the worst state of health you can imagine 
10 means the best state of health you can imagine 
 
 
 
 
Worst State 
of Health 
Best State 
of Health 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
( _ ) decline to answer 


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APPENDIX 9. 
COCKCROFT-GAULT METHOD FOR EVALUATING 
CREATININE CLEARANCE [80] 
 
For serum creatinine concentration in mg/dL: 
CrCl = (140-age+) × (wt) x 0.85 (if female), or × 1.0 (if male) 
(mL/min) 72× serum creatinine (mg/dL) 
For serum creatinine concentration in μmol/L: 
CrCl = (140-age+) × (wt) × 0.85 (if female), or × 1.0 (if male) 
 
(mL/min) 0.81 × serum creatinine = (μmol/L) + age in years, weight (wt) in kilograms 
 
CrCl = Creatinine clearance; wt = Weight 


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APPENDIX 10. 
LIKERT SCALE 
 
Likert Scale for Pruritus Evaluation 
To be completed by patient. 
 
 
 
No Itch 
Worst Itch 
Imaginable 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Circle the number that best represents your level of itching. 
 
 
 
 
 
 
 
( _ ) decline to answer 


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APPENDIX 11. 
T-CELL LYMPHOMA CLASSIFICATIONS 
 
Table A11-28: 
Mature T- and NK-cell Neoplasms in the 2008 WHO Classification 
of Lymphoid Tumors [81] 
 
Leukemic or 
Disseminated 
T-cell prolymphocytic leukemia 
T-cell large granular lymphocytic leukemia 
Chronic lymphoproliferative disorders of NK cells a 
Aggressive NK-cell leukemia 
Adult T-cell lymphoma/leukemia (HTLV1-positive) 
Systemic EBV-positive T-cell lymphoproliferative disorders of childhood 
Extranodal 
Extranodal NK/T-cell lymphoma, nasal type 
Enteropathy-associated T-cell lymphoma 
Hepatosplenic T-cell lymphoma 
Cutaneous 
Mycosis fungoides 
Sézary syndrome 
Primary cutaneous CD30_ lymphoproliferative disorders 
Primary cutaneous anaplastic large cell lymphoma 
Lymphomatoid papulosis 
Subcutaneous panniculitis-like T-cell lymphoma 
Primary cutaneous gamma-delta T-cell lymphoma 
Primary cutaneous aggressive epidermotropic CD8_ cytotoxic 
T-cell lymphoma a 
Primary cutaneous small/medium CD4_ T-cell lymphoma a 
Hydroa vacciniforme-like lymphoma 
Nodal 
Angioimmunoblastic T-cell lymphoma 
Anaplastic large cell lymphoma, ALK-positive 
Anaplastic large cell lymphoma, ALK-negative 
Peripheral T-cell lymphoma, not otherwise specified 
a Provisional entity. 

SAP_001.pdf: 
PORTOLA PHARMACEUTICALS, a subsidiary of Alexion 
13-601
Statistical Analysis Plan 
Page 1 of 31 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
SAP Version: 
Final v 2.0 
Date of SAP Version 
17 November 2020 
Sponsor: 
Portola Pharmaceuticals, a subsidiary of Alexion 
270 East Grand Avenue, Suite 22 
South San Francisco, CA 94080, USA 
Study Title: 
A Phase 1/2a Open-Label, Multi-Dose, Multi-Center 
Escalation And Exploratory Study Of Cerdulatinib 
(PRT062070) In Patients With Relapsed/Refractory Chronic 
Lymphocytic Leukemia (CLL)/Small Lymphocytic 
Lymphoma (SLL) Or B-Cell Or T-Cell Non-Hodgkin 
Lymphoma (NHL) 
Drug Name: 
Cerdulatinib (PRT062070) 
Phase of Study: 
Phase 1/2a 
Protocol Number: 
13-601
Protocol Version/Date: 
Amendment 9, 14 October 2019 
NCT #NCT01994382


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SIGNATURE PAGE
AUTHOR(s):
Portola Pharmaceuticals, a subsidiary of Alexion 
20-Nov-2020 | 13:02:36 EST
Signature and Date:   
APPROVAL:
Alexion Pharmaceuticals
20-Nov-2020 | 17:34:21 EST
Signature and Date:   
Alexion Pharmaceuticals
Signature and Date:   
20-Nov-2020 | 13:48:27 EST
20-


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
BID 
Bis in die (twice a day) 
BOR 
Best overall response 
CI 
Confidence interval 
CLL 
Chronic lymphocytic leukemia 
CR 
Complete response 
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
eCRF 
Electronic case report form 
FL 
Follicular lymphoma 
IV 
Intravenously 
KM 
Kaplan-Meier 
MAD 
Maximum administered dose 
MTD 
Maximum tolerated dose 
MRD 
Minimum residual disease 
NCI CTCAE 
National Cancer Institute Common 
Terminology Criteria for Adverse Events 
NHL 
Non-Hodgkin lymphoma 
ORR 
Overall response rate 
PD 
Pharmacodynamics 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PTCL 
Peripheral T-cell lymphoma 
QD 
Quaque die (once a day) 
SD 
Stable disease 
SLL 
Small lymphocytic lymphoma 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 


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CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION 
6 
2. 
STUDY OVERVIEW 
6 
3. 
STUDY OBJECTIVES 
7 
3.1. Phase 1 Objectives (Dose Escalation) 
7 
3.1.1. Primary Objective 
7 
3.1.2. Secondary Objectives 
7 
3.2. Phase 2a Objectives (Dose Expansion/Exploratory) 
7 
3.2.1. Primary Objective 
7 
4. 
STUDY ENDPOINTS 
8 
4.1. Phase 1 Endpoints 
8 
4.1.1. Primary Endpoint 
8 
4.1.2. Secondary Endpoints 
8 
4.2. Phase 2a Endpoints 
8 
4.2.1. Primary Endpoint 
8 
4.2.2. Secondary Endpoints 
8 
4.2.3. Exploratory Endpoints 
9 
5. 
SAMPLE SIZE CONSIDERATIONS 
9 
5.1. Phase 1 Sample Size 
9 
5.2. Phase 2a Sample Size 
9 
6. 
ANALYSIS POPULATIONS 
10 
7. 
STATISTICAL METHODS 
10 
7.1 
Data Analysis General Considerations 
10 
7.1.1. Definitions and Computations 
11 
7.1.2. Handling of Missing Data 
11 


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7.2. Subject Disposition 
11 
7.3. Protocol Deviations 
12 
7.4. Demographics and other baseline characteristics 
12 
7.5. Prior systemic anti-cancer therapy 
13 
7.6. Medical History 
14 
7.7. Prior and concomitant medications 
14 
7.8. Efficacy analysis 
14 
7.8.1. Primary Efficacy Endpoint 
15 
7.8.2. 
Secondary Efficacy Endpoint 
15 
7.8.3 Subgroup Analysis 
18 
7.9. 
Safety Analysis 
18 
7.9.1 Treatment Exposure and Compliance 
18 
7.8.1. 
Adverse Events 
19 
7.8.2. 
Laboratory Values 
22 
7.8.3. 
Vital Signs 
22 
7.8.4. 
Electrocardiogram (ECG) 
22 
7.8.5. 
Physical Exam 
23 
7.9. 
Other Analyses 
23 
7.9.1. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
23 
7.9.2. 
Global Health Assessments 
23 
8. 
CHANGES IN THE PLANNED ANALYESE 
24 
9. 
REFERENCES 
25 
APPENDIX 
26 
A. 
Imputation of Missing or Partially Missing Dates 
26 
B. 
Pathology subgroup of Peripheral T-cell Lymphoma (PTCL) 
28 
C. 
Lugano Criteria for Response Assessments in NHL (Protocol Amendment 9 Table A4-11). 
29 


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1. INTRODUCTION 
 
 
This statistical analysis plan (SAP) describes the detailed plans for the analysis of safety and 
efficacy data for Study 13-601. This document is based on Protocol Amendment #9 dated 29- 
October-2019. This analysis plan does not include pharmacokinetics, pharmacodynamics, 
minimum residual disease, and exploratory biomarker analyses, which will be separate reports. 
This version of SAP (v2.0) is an amendment to the original SAP (v1.0) dated 23 July 2015 
(developed by Sarah Cannon Research Institute Development Innovations on behalf of Portola 
Pharmaceuticals, Inc) prior to Protocol Amendment #4, which initiated the change in the study 
design from a phase 1 dose escalation study to a phase 1/2a study. No formal statistical analyses 
and clinical study report (CSR) were done based on the original version of SAP (v1.0) for the 
phase 1 portion of the study. There have been 5 additional protocol amendments after Protocol 
Amendment #4, therefore, the purpose of this version of SAP (v2) is to provide a unified plan for 
analysis of both phase 1 and phase 2a portions of the study as basis for a combined clinical study 
report (CSR). 
 
 
2. STUDY OVERVIEW 
 
 
This is an open-label, Phase 1/2a, multi-dose, multi-center trial of orally administered 
cerdulatinib with 2 parts. Phase 1 is the dose-escalation portion, during which patients will 
receive single-agent cerdulatinib at their assigned dose level. The starting dose for this portion of 
the study will be 15 mg QD, administered in increasing doses until the MTD/MAD is identified. 
In the Phase 2a dose expansion portion, patients will be enrolled in one of 6 disease cohorts. Five 
cohorts will receive single-agent cerdulatinib, and 1 cohort will receive cerdulatinib plus 
rituximab administered IV during Cycle 1 on Days 1, 8, 15, and 22 and during Cycles 4, 6, 8, 
and 10 on Day 1 only. The starting dose of cerdulatinib during this portion of the study will be 
30, 25, or 20 mg BID. 


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3. STUDY OBJECTIVES 
 
 
3.1. Phase 1 Objectives (Dose Escalation) 
 
3.1.1. Primary Objective 
• To determine the maximum tolerated dose/maximum administered dose (MTD/MAD) of 
cerdulatinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), small 
lymphocytic lymphoma (SLL) or B-cell non-Hodgkin lymphoma (NHL). 
3.1.2. Secondary Objectives 
• To make a preliminary assessment of the antitumor activity of cerdulatinib in patients with 
relapsed/refractory CLL/SLL or B-cell NHL, as assessed by overall response rate (ORR), 
defined as complete response (CR)+ partial response (PR). 
• To assess the safety and tolerability of cerdulatinib. 
 
• To determine the pharmacokinetic (PK) profile of cerdulatinib. 
 
• To evaluate the pharmacodynamics (PD) of cerdulatinib. 
 
3.2. Phase 2a Objectives (Dose Expansion/Exploratory) 
 
3.2.1. Primary Objective 
• To assess the antitumor activity of cerdulatinib in patients with specific subtypes of B-cell or T- 
cell NHL, or CLL/SLL, as a single agent and in combination with rituximab for B-cell NHL. 
3.2.2. Secondary Objectives 
 
• To assess the duration of antitumor activity of cerdulatinib, amount of time to achieve tumor 
response, and magnitude of response. 
• To further evaluate the PK profile of cerdulatinib in patients with specific subtypes of B-cell or 
T-cell NHL, alone or in combination with rituximab for B-cell NHL. 
• To further evaluate the PD of cerdulatinib in patients with specific subtypes of B-cell or T-cell 
NHL, alone or in combination with rituximab for B-cell NHL. 
• To assess tumor phenotype and genotype in relation to clinical response. 
 
• To further evaluate the safety and tolerability of cerdulatinib in patients with specific subtypes 
of B-cell or T-cell NHL, or CLL/SLL. 


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4. STUDY ENDPOINTS 
 
 
4.1. Phase 1 Endpoints 
 
4.1.1. Primary Endpoint 
• The primary safety endpoint will be the incidence of Dose-limiting toxicity (DLT) by dose 
level. 
4.1.2. Secondary Endpoints 
• ORR, defined as the proportion of subjects achieve partial response (PR) or better 
 
• Clinical benefit rate, defined as the proportion of subjects achieve stable disease or better 
 
• Progression-free survival (PFS), defined as the time from the start of study treatment to the first 
documentation of disease progression as assessed by investigator or death from any cause, 
whichever occurs first. 
• Duration of response (DOR), defined as the time from the date of the earliest PR or better to the 
first documentation of disease progression or death from any cause, whichever occurs first. 
• Adverse event profile by dose level. 
 
• Clinically significant changes in vital signs, physical exams by dose level. 
 
• Changes in hematology and chemistry laboratory parameters by dose level. 
 
• PK endpoints: PK profile at each dose level and overall, including Cmax, AUC, and t½. 
 
• PD endpoints: Changes in biomarker data for a range of ex vivo assays. 
 
 
4.2. Phase 2a Endpoints 
 
4.2.1. Primary Endpoint 
• The primary efficacy endpoint is ORR 
 
4.2.2. Secondary Endpoints 
• Duration of response (DOR), progression-free survival (PFS), time to treatment response 
(TTR), and dominant mass response (target nodal and extra-nodal mass response). 


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• Clinical benefit rate 
 
• Adverse event profile 
 
• Clinically significant changes in vital signs, physical exams 
 
• Changes in hematology and chemistry laboratory parameters. 
 
• PD endpoints: Changes in biomarker data for a range of ex vivo assays. 
 
4.2.3. Exploratory Endpoints 
• Correlation in markers of inflammation with clinical response and overall health (Global Health 
Assessment). 
• Assessment of percentage of CLL/SLL patients with status of MRD- in CLL/SLL patients 
achieving a CR/CRi/PR by flow cytometry. 
 
 
5. SAMPLE SIZE CONSIDERATIONS 
 
 
5.1. Phase 1 Sample Size 
 
The sample size is based on clinical judgment and is typical of studies of this type. 43 subjects 
were enrolled in the phase 1 part of the study. 
5.2. Phase 2a Sample Size 
 
Each of the 6 cohorts will consist of approximately 20 to 50 patients with relapsed or refractory 
disease. Initial enrollment into any cohort will be up to 20 patients; cohorts may be expanded to 
40 to 50 evaluable patients. A total of approximately 240 patients are planned. If fewer than 2 
responses are seen in the first 20 patients, enrollment in the cohort will be closed, as the upper 
bound of the 95% confidence interval would be approximately 25%. If 2 or more responses are 
seen, the cohort may be expanded. 
Patients in Cohorts 1, 3, 4, 5, and 6 will receive single-agent cerdulatinib. Patients in the Cohort 
2 will receive cerdulatinib in combination with rituximab. The composition of each cohort is 
described in Table 6 of section 3.1.2 of the protocol. 


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6. ANALYSIS POPULATIONS 
 
 
The safety analysis population will consist of all patients treated with at least 1 dose of study 
medication (cerdulatinib or rituximab). The safety analysis population will be used for all safety 
analyses. Subjects disposition, demographics, baseline characteristics, and treatment exposure 
will also be analyzed based on the safety analysis population. 
The efficacy analysis population will consist of all patients who have taken at least 1 dose of 
study medication and have had at least 1 post-baseline investigator response assessment (IRA). 
The efficacy analysis population will be used for the primary and secondary efficacy endpoints 
for the follicular lymphoma (FL) patients in Cohort 1 and 2 and the peripheral T-cell lymphoma 
(PTCL) patients in Cohort 5. In addition, efficacy will also be assessed in the corresponding 
safety analysis population in Cohort 1, 2, and 5. 
 
 
7. STATISTICAL METHODS 
 
 
7.1 Data Analysis General Considerations 
 
Where applicable, descriptive statistics will be provided. For continuous variables, n, mean, 
standard deviation (SD), median, minimum, and maximum will be presented. For discrete 
variables, the frequency and percentage will be presented. For time to event variables, unless 
specified otherwise, the Kaplan-Meier (KM) estimate and corresponding two-sided 95% 
confidence intervals (CIs) will be presented for the median and quartiles and, as necessary, for 
the event-free rates at the selected time points. 
All calculations and analyses will be performed using SAS version 9.4 or higher. 
 
Unless specified otherwise, the Phase 1 portion will be summarized by the initial assigned dose 
level and the Phase 2a portion will be presented by cancer type. Summaries and analyses will be 
done for Phase 1 and Phase 2a separately. There will be no pooling of Phase 1 and Phase 2a data. 
For the subjects enrolled in Phase 1 but continued in Phase 2a, only baseline information 
(baseline demography, disease characteristics, and prior anti-cancer therapies) from Phase 1 
database will be used for corresponding Phase 2a summary tables, all other data will remain 
separate in Phase 1 and Phase 2a summary tables unless specified otherwise. 


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7.1.1. Definitions and Computations 
 
Study treatment (study drug): cerdulatinib or rituximab 
 
Study day: study day will be calculated relative to the date of the first dose of study treatment. 
Treatment duration: date of last dose of study treatment – date of first dose of study treatment +1 
Baseline: unless otherwise specified, a baseline value is defined as the last non-missing value 
collected on or before the first dose of study treatment (i.e. on/before Cycle 1 Day 1) 
 
 
7.1.2. Handling of Missing Data 
 
Missing data will not be imputed unless otherwise specified. Missing dates or partially missing 
dates will be imputed conservatively for adverse events and prior/concomitant 
medications/procedures as provided in Appendix A. 
When summarizing discrete variables, subjects with missing data are generally included in the 
denominator to calculate percentage unless otherwise specified. In general, a category of 
“Missing” will be created and the subjects with missing data will be presented. 
When summarizing continuous variables, subjects with missing data are not included in 
calculations unless otherwise specified. 
No imputation of AE grades will be performed. AEs with missing CTCAE grades will only be 
summarized in the all-grade column. If the assessment of the relationship of an AE to study 
treatment is missing, the AE is assumed to be related to the study treatment in the summary 
tables. No imputation will be done in the AE listings. 
The reason for lack of sufficient information for response evaluation for FL and PTCL subjects 
in Cohorts 1, 2, and 5 will be listed with reasons for end of treatment/study, death, and any 
subsequent anti-cancer therapy if applicable. 
 
 
7.2. Subject Disposition 
 
The following subject disposition information will be summarized: 


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• Number of subjects treated 
• Number and percentage of treated subjects who discontinued treatment 
• Primary reason for treatment discontinuation 
The number of subjects treated will be summarized by site. Due to inconsistencies in different 
versions of protocol and data entry instructions in study follow-up, the number of subjects who 
discontinued study will not be summarized. 
 
 
7.3. Protocol Deviations 
 
Protocol deviation criteria, types, and classification designations (major vs minor protocol 
deviations) are defined in the protocol deviation management plan. Protocol deviations are 
documented and reviewed throughout the study in accordance to the protocol deviation 
management plan. The list of protocol deviations and their classifications will be finalized prior 
to the database lock. Final major protocol deviations will be summarized by type and all 
protocol deviations (both major and minor) will be listed. 
 
 
7.4. Demographics and other baseline characteristics 
 
If applicable, the following demographic and baseline characteristics will be summarized for 
Phase 1 portion and Phase 2a portion, respectively. 
• Age (years) 
• Age group (<=65 vs >65 but <=75 vs >75) 
• Sex 
• Ethnicity 
• Race 
• Weight 
• ECG overall result 
• ECOG performance status 
• Hemoglobin 
• Absolute neutrophil count 
• Platelet count 
• IgG level 


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• Amylase 
• Lipase 
• Lymphocyte count 
• AST 
• ALT 
• Creatinine Clearance 
In addition, the following disease history and characteristics will be summarized for the follicular 
lymphoma (FL) patients in Cohort 1 and 2 only. 
• Time since initial diagnosis (month) 
• Time since the most recent progression (month) 
• Baseline bone marrow involvement (Yes vs No) 
• Relapsed vs refractory 
• Bulky disease (any target lesion with >=7cm in the longest diameter or at least 3 target 
lesions with >=3cm in the longest diameter: Yes vs No) 
• Prior stem cell transplant (Yes vs No) 
• Prior radiotherapy (Yes vs No) 
• Ann Arbor stage III/IV (Yes vs No) 
• Serum lactate dehydrogenase >ULN (Yes vs No) 
• Follicular Lymphoma Internal Prognosis Index (FLIPI-1 score) 
 
 
7.5. Prior systemic anti-cancer therapy 
 
For the FL patients in Phase 2a Cohort 1 and 2 and PTCL patients in Phase 2a Cohort 5 only, the 
number of prior regimens will be summarized numerically and categorically. Best overall 
response to the last regimen and time since the end of last regimen will be summarized 
descriptively. The therapies with the same regimen number are counted as one line of prior 
therapy. 
In addition, the types of prior systemic anti-cancer regimens will be internally adjudicated and 
summarized for the FL patients in Phase 2a Cohort 1 and 2 and PTCL patients in Phase 2a 
Cohort 5. 
Prior anti-cancer therapies for other subjects except FL subjects in Phase 2a Cohort 1 and 2 and 
PTCL patients in Phase 2a Cohort 5 will be listed only. 


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7.6. Medical History 
 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
(version 16.1 for Phase 1; version 21.1 for Phase 2a or higher). The number and percentage of 
subjects reporting a history of any medical condition, as recorded in the eCRF, will be 
summarized by system organ class (SOC) and preferred term (PT). 
7.7. Prior and concomitant medications 
 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
drug dictionary (version SEPTEMBER 2013 for Phase 1; version B2 Sep2018 for Phase 2a or 
higher) and further classified to the appropriate Anatomical Therapeutic Chemical (ATC) code. 
Prior medications are defined as medications that started before the first dose date. 
 
Concomitant medications are defined as medications that (1) started before the first dose of the 
study treatment and were continuing at the time of the first dose of the study treatment, or (2) 
were started on or after the first dose date of the study treatment up to 30 days after the last dose 
date. 
The number and percentage of subjects reporting prior medication and concomitant medications 
will be summarized by ATC medication class level 2 and WHO drug preferred term. 
 
 
7.8. Efficacy analysis 
 
The efficacy of the Phase 1 patients will be presented in the subject listing only. For Phase 2a 
patients, efficacy will be summarized and analyzed for the FL patients in Cohort 1 and 2 and the 
PTCL patients in Cohort 5 only. For FL subjects in Cohort 1 and 2, efficacy will be summarized 
by number of prior regimens (<=3 vs >=4). Efficacy of PTCL will be summarized by pathology 
subgroup as defined in Appendix B (AITL/TFH vs NOS vs Others). The efficacy listing will be 
provided for non-FL/non-PTCL patients in Cohort 1, 3, 4, and 6. 
All efficacy analyses will be based on the efficacy analysis population. The efficacy analyses 
will also be analyzed in the corresponding safety analysis population in Phase 2a Cohort 1, 2, 
and 5 as sensitivity analyses. 


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7.8.1. Primary Efficacy Endpoint 
 
Overall response rate (ORR) is defined as the proportion of subjects who achieve partial 
response (PR) or better as the best overall response (BOR) per Lugano criteria (Cheson, 2014, 
see appendix C) as assessed by the investigator. BOR is defined as the best response from 
treatment start to the data cutoff date (inclusive), disease progression (inclusive), or the start of 
new anti-cancer therapies (inclusive), whichever occurs first. 
ORR will be calculated by cohort, and the associated 95% exact confidence interval (CI) will be 
estimated using the Clopper-Pearson method. 
The primary endpoint of ORR may also be analyzed in additional subgroups of the efficacy 
analysis population as sensitivity analysis. 
 
 
7.8.2. Secondary Efficacy Endpoint 
 
7.8.2.1. Progression free survival 
 
Progression-free survival (PFS) is defined as the time from the start of study treatment to the first 
documentation of disease progression as assessed by investigator (see appendix C) or death from 
any cause, whichever occurs first. 
Progression-free survival = (first documentation of disease progression or death – first dose date 
of study treatment + 1) /30.4375 in months. 
PFS will be right censored for subjects who meet one of the following conditions: 1) no baseline 
disease assessments; 2) starting a new anti-cancer therapy before documented disease 
progression or death; 3) progression or death immediately after more than 6 months since the last 
disease assessment (or more than 12 months if beyond cycle 12); and alive without documented 
disease progression. The censoring convention follows the FDA guidance for Industry Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics (2018) and references within 
the guidance document. The censoring rules are summarized in Table 1. 


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Table 1. Date of Event or Censoring for PFS 
 
Scenario 
Date of PFS Event or 
Censoring 
Outcome 
Death or progression between 
the planned disease 
assessments 
Date of death or first disease 
assessment showing PD, 
whichever occurs first 
Event 
Death before the first disease 
assessment 
Date of death 
Event 
No baseline disease 
assessment 
Date of first dose of study 
treatment 
Censored 
New anti-cancer treatment 
started 
Date of last disease 
assessment prior to or on the 
date of new anti-cancer 
treatment 
Censored 
Death or progression 
immediately after missing 
more than 1 scheduled 
disease assessment [1] 
Date of the last disease 
assessment before death or 
progression 
Censored 
Alive without documented 
disease progression 
Date of last disease 
assessment 
Censored 
[1] missing >=6 months if in Cycle 1~12 or missing >=12 months if beyond Cycle 12 
 
 
The distribution of PFS, including median and the PFS rate at selected time points (e.g. 12 
months), will be estimated using the Kaplan-Meier method. The 95% CI for the median and the 
quartiles of PFS will be estimated using the Brookmeyer method (Brookmeyer 1982). The 95% 
CI for the PFS rate at the selected time points will be estimated using the Greenwood formula 
(Greenwood 1926). The duration of PFS follow-up will be estimated using the reverse Kaplan- 
Meier method (Schemper and Smith 1996). The Kaplan-Meier curve for PFS will be plotted for 
Cohort 1 and 2 FL patients, respectively. 
 
 
7.8.2.2. Duration of response 
 
For responders (PR or better), duration of response (DOR) is defined as the time from the date of 
the earliest PR or better to the first documentation of disease progression or death from any 
cause, whichever occurs first. The censoring convention and analysis method of DOR will be the 
same as those for PFS in Section 7.8.2.1. DOR will be analyzed for subjects who achieved PR or 
better (i.e. responders only). 


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DOR = (first documentation of progression or death – the date of the earliest PR or better + 1) 
/30.4375 in months. 
 
 
7.8.2.3. Time to response 
 
For responders (PR or better), time to response (TTR), defined as the time (in month) from the 
start of study treatment to the date of the earliest PR or better, will be summarized using 
descriptive statistics for a continuous variable. TTR will not be analyzed using the Kaplan-Meier 
method for time to event endpoints. 
 
 
7.8.2.4. Clinical benefit rate 
 
Clinical benefit rate (CBR) is defined as the proportion of subjects who achieve stable disease 
(SD) or better as the best overall response (BOR) per Lugano criteria (Cheson, 2014) as assessed 
by the investigator. The summary and analysis method of CBR will be the same as those for 
ORR as described in Section 7.8.1. 
 
 
7.8.2.5. Dominant mass response rate 
 
Dominant mass response rate is defined as the proportion of patients who achieve a >=50% 
decrease from baseline in the sum of products of the greatest perpendicular diameters (SPD) of 
the target nodal and extra-nodal lesions. The summary and analysis method of dominant mass 
response rate will be the same as those for ORR as described in Section 7.8.1. 
 
 
7.8.2.6. Lymphadenopathy 
 
Tumor burden in lymph nodes as measured by target nodal lesions from CT scans will be plotted 
in terms of waterfall plot SPD (sum of product of diameters). The best percentage improvement 
in target nodal lesion SPD will be plotted against subjects. New lesion will not be included in the 
waterfall plot calculation. 
Best % improvement in SPD = (lowest post-baseline SPD of target nodal lesions–baseline SPD 
of target nodal lesions)/baseline SPD of target nodal lesions X 100%. 


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7.8.3 Subgroup Analysis 
 
As appropriate (e.g. when there are sufficient number of subjects in the subgroup), the primary 
efficacy endpoint and selected secondary endpoints will be summarized in the following 
subgroups for the FL patients in Phase 2a Cohort 1 and 2 and the PTCL patients in Phase 2a 
Cohort 5: 
• Age group (<=65 vs >65) 
• Sex 
• Prior lines of systemic anti-cancer therapy (<=3 vs >=4) 
• Baseline ECOG performance score (0 vs >=1) 
• Baseline bone marrow involvement (Yes vs No) 
• Relapsed vs refractory 
• Bulky disease (any target lesion with >=7cm in LDi or at least 3 target lesions with 
>=3cm LDi: Yes vs No) 
• Follicular Lymphoma Internal Prognosis Index (FLIPI score, FL patients only) 
 
 
7.9. 
Safety Analysis 
 
All safety analyses will be performed in the safety analysis population. 
 
Safety will be primarily assessed on the basis of adverse events (AE) rates. Clinical laboratory 
data, ECG findings, physical examinations, and vital signs will also be used for determining 
safety. Descriptive statistics will be used to summarize the safety data. The Phase 1 portion will 
be summarized by the initial assigned dose level and the Phase 2a portion will be presented by 
cancer type. 
 
 
7.9.1 Treatment Exposure and Compliance 
 
Extent of exposure to study drugs will be summarized descriptively as the number of cycles 
started, duration of treatment, duration of treatment without full-day dose interruption (defined as 
full-day with 0 mg dose actually taken), cumulative total dose per subject, actual dose intensity 
and relative dose intensity. 


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The number and percentage of subjects with dose reductions, dose interruptions, dose 
interruptions >= 3 days that are not immediately followed by the end of treatment due to disease 
progression, and drug discontinuation will be tabulated, and the primary reason for dose 
modifications will be summarized. 
The actual dose intensity (mg/day) is defined as the actual cumulative dose (mg) taken based on 
the total dose per day divided by treatment duration. The relative dose intensity (RDI) is defined 
as the ratio of actual dose intensity to the planned dose intensity (i.e. the initial assigned dose 
level in mg/day) in percentage. 
Time to first occurrence of dose reduction/interruption due to an AE will be summarized 
descriptively. In addition, time to treatment failure, defined as time from start of study treatment 
to discontinuation of study treatment due to any reason, will be summarized. 
7.8.1. Adverse Events 
 
Summary tables and listings will be provided for all reported treatment emergent adverse events 
(TEAEs), defined as AEs that start on or after the first day of any study drug that is administered 
and within 30 days of the last administration of any study drug. Missing and partially missing 
AE start dates will be imputed according to the specification described in Appendix A. The 
reported AE will be coded using MedDRA (version 16.1 for Phase 1; version 21.1 or higher for 
Phase 2a). AEs severity grading scales in Phase 1 are based on the NCI CTCAE version 4.03. 
For AEs in Phase 2a, AE severity grades are mixture of grading scales of the NCI-CTCAE 
version 4.03 and the NCI CTCAE version 5. No imputation of AE grades will be performed. AE 
with missing CTCAE grade will only be summarized in the all-grade column. 
The causal relationship between the occurrence of an AE and each treatment will be assessed by 
the investigator. For summary of related AEs, causality assessment by the investigator per eCRF 
will be mapped based on Table 2. If the assessment of the relationship of an AE to study 
treatment is missing, the AE is assumed to be related to the study treatment in the table 
summary. No imputation will be done in the AE listings. 
Table 2. Causality Mapping of AEs 
 
Relationship to Study Drug per 
Investigator 
Summary of AEs 
Unrelated 
Not related 
Unlikely 
Not related 
Possible 
Related 
Probable 
Related 


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TEAEs will be summarized based on the number and percentage of subjects experiencing AEs. 
When summarizing TEAEs by MedDRA system organ class (SOC) and preferred term (PT), a 
subject reporting the same AE more than once will be counted only once when calculating the 
incidence 1) within a given SOC, and 2) within a given SOC-PT combination. Similarly, a same 
AE will be counted only once within a PT when summarizing by PT only. In both situations, the 
maximum CTCAE toxicity grade and the strongest causal relationship to the study drug for such 
events will be used. 
Tabular summaries of the following will be provided: 
 
• TEAEs by PT 
• TEAEs by SOC, PT 
• TEAEs by SOC, PT, and maximum severity grade 
• Grade 3 or higher TEAEs by PT 
• Grade 3 or higher TEAEs by SOC, PT 
• Grade 3 or higher TEAEs by SOC, PT and maximum severity grade 
• Cerdulatinib-related TEAEs by PT 
• Cerdulatinib-related TEAEs by SOC, PT 
• Cerdulatinib-related TEAEs by SOC, PT, and maximum severity grade 
• Rituximab-related TEAEs by PT (Cohort 2 only) 
• Rituximab-related TEAEs by SOC, PT (Cohort 2 only) 
• Rituximab-related TEAEs by SOC, PT, and maximum severity grade (Cohort 2 only) 
• Serious TEAEs by PT 
• Serious TEAEs by SOC, PT 
• TEAEs leading to cerdulatinib discontinuation by PT 
• TEAEs leading to cerdulatinib discontinuation by SOC, PT 
• TEAEs leading to cerdulatinib reduction by PT 
• TEAEs leading to cerdulatinib reduction by SOC, PT 
• Fatal TEAEs by PT 
• Fatal TEAEs by SOC, PT. 
TEAEs leading to rituximab dose modifications and discontinuations will be listed only. 
 
Summaries (all-grade and grade 3 or above) will be provided for cytopenia category by 
combining following preferred terms in the AE dataset: 


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• Neutropenia: neutropenia, neutrophil count decreased, febrile neutropenia 
• Thrombocytopenia: thrombocytopenia, platelet count decreased 
• Anaemia: anaemia. 
• Leukopenia: leukopenia, white blood cell count decreased 
• Lymphopenia: lymphopenia, lymphocyte count decreased 
For the following categories of TEAEs of special interest, the time to the first onset of the event 
will be analyzed (e.g. median/mean and min/max). 
• All-grade gastrointestinal disorders of special interest 
• Grade 3 or higher gastrointestinal disorders of special interest 
• All-grade infections of special interest (lower respiratory bacterial infections) 
• Grade 3 or higher infections of special interest (lower respiratory bacterial infections) 
The relationship between all-grade infections of interest and concomitant compliance use of 
antimicrobial prophylaxis will be explored. In addition, gastrointestinal disorders and infections 
of special interest may be analyzed for certain population subgroups as appropriate. 
In addition, selected safety summaries will be repeated for the subset of phase 2a subjects with 
30 mg BID as starting cerdulatinib dose. 
A summary of the number of deaths and the primary cause of death, classified by deaths within 
30 days of last dose of study drug and deaths beyond 30 days after the last dose, will be 
provided. 
7.8.1.1. Dose limiting toxicity in Phase 1 
 
The number and percentage of patients experiencing dose limiting toxicities as captured in the 
eCRF by the investigator during Phase 1 will be summarized by initial dose cohort. 
DLT is defined as any of the following toxicities, possibly or probably related to cerdulatinib, 
and clinically significant (in the judgement of the investigator) that occurs in the first 28 days 
(one cycle) of treatment. For patients to be evaluable for DLT, they must have received 80% of 
the doses in the first 28 days of Cycle 1, or been withdrawn from study therapy due to a drug- 
related toxicity. Patients who withdraw without meeting these criteria should be replaced. 
Toxicity will be graded according to the NCI-CTCAE v4.0. 
 
Hematologic 
 
• Febrile neutropenia (ANC < 1,000/μL and temperature ≥ 38.5°C). 


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• Grade 4 neutropenia for > 5 days. 
 
• Grade 4 thrombocytopenia with or without bleeding. 
 
• Grade 3 thrombocytopenia with bleeding. 
 
• Grade 4 anemia, unexplained by underlying disease. 
 
 
Non-hematologic 
 
• Grade 3 or greater nausea, vomiting, or diarrhea if persistent despite optimal antiemetic or anti- 
diarrheal therapy. 
 
 
7.8.2. Laboratory Values 
 
Summary tables will include descriptive statistics for the actual values and changes from 
baseline by scheduled time points in selected hematology, serum chemistry, and coagulation test 
results. 
The incidence of potential Hy’s law cases, identified as ALT/AST > 3 x ULN (upper limit of 
normal) and total bilirubin > 2 x ULN, will be summarized. 
All parameters will be converted to consistent units according to the International System of 
Units before summarization. 
All clinical laboratory results will be listed by subject and timing of collection. 
 
 
7.8.3. Vital Signs 
 
Summary tables for vital signs and their change from baseline will be presented for each 
scheduled time point by cohort. All vital sign data will be listed by subject and time of 
measurement. 
 
 
7.8.4. Electrocardiogram (ECG) 


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The number and percentage of subjects with ‘normal’, ‘abnormal, not clinically significant’ and 
‘abnormal, clinically significant’ ECG results will be summarized at baseline and each post- 
baseline time point. 
All ECG data will be listed by subject and time of measurement. 
 
The actual value of QTcF at each time point and change from baseline at each post-baseline time 
point will be summarized by cohort. Additionally, the number and percentage of subjects in 
each treatment group who meet any of the following criteria for QTcF will be tabulated. 
• 
Maximum value > 450 to 480 msec 
 
• 
Maximum value > 480 to 500 msec 
 
• 
Maximum value > 500 msec 
 
• 
Maximum increase from baseline > 30 to 60 msec 
 
• 
Maximum increase from baseline > 60 msec 
 
 
7.8.5. Physical Exam 
 
Physical examination results including liver and spleen assessments will be listed for all subjects. 
 
 
7.9. Other Analyses 
 
7.9.1. Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
ECOG Performance Status will be performed pre-dose on Cycle 1 Day 1, Cycle 2 Day 1, every 3 
cycles (3, 6, 9, 12+) Day 1 and 30 days post-last treatment. The number and percentage of 
subjects in each category will be summarized at each visit by cohort. All results will be listed. 
7.9.2. Global Health Assessments 
 
Global Health Assessments will be performed pre-dose on Cycle 1 Days 1, 8 and 15, Cycle 2 
Day 1, every 3 cycles (3, 6, 9, and 12+) Day 1, and 30 days post-last treatment. The Global 
Health Assessment asks patients to rate their level of health today on a scale of 0 (the worst state 


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of health you can imagine) to 10 (the best state of health you can imagine). Descriptive statistics 
for Global Health Assessments score at each visit and the change from baseline at each post- 
baseline visit will be summarized at each visit and the change from baseline at each post-baseline 
visit by cohort. All data will be listed. 
 
 
8. 
CHANGES IN THE PLANNED ANALYESE 
 
 
There are several changes in this version of SAP (v2.0) from the analyses specified in the 
protocol (amendment #9 dated 29-Oct-2019) due to data limitations as documented in the 13-601 
Study Data Handling Document. 
Most importantly, aggregated analyses of efficacy data are only limited to Phase 2a Cohort 1/2 
FL patients and Cohort 5 PTCL patients. Efficacy data of all other patients will be for listing 
purposes only. In addition, lymph node response as a secondary endpoint in phase 2a is changed 
to dominant mass response in order to include both nodal and extra-nodal target lesions as 
measure of tumor burden. 
In addition, AE severity grades in Phase 2a AE by grade analyses are mixture of the NCI 
CTCAE version 4.03 grading scales and the NCI CTCAE version 5.0 grading scales. 


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9. 
REFERENCES 
 
 
Brookmeyer, R., & Crowley, J. (1982). A Confidence Interval for the Median Survival Time. 
Biometrics, 38(1), 29-41. 
Cheson, B., et al., (2014) Recommendations for Initial Evaluation, Staging, and Response 
Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol, 
32(27): p. 3059-3067. 
Food and Drug Administration (2018). Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. 
Greenwood, M. (1926) The Natural Duration of Cancer. Public Health and Medical Subjects, 33: 
1-26. 
Schemper M, Smith TL. (1996) A note on quantifying follow-up in studies of failure time. 
Control Clin Trials. 17(4): 343-346. 


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APPENDIX 
A. Imputation of Missing or Partially Missing Dates 
 
In general, missing or partial dates will be imputed at the data level. The following rules will 
apply for the specific analysis and summary purposes mentioned below only. 
1. Prior/Concomitant Medications 
 
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant. The following rule will be applied to 
impute partial dates for medications: 
If start date of a medication is partially missing, impute as follows: 
 
• If both month and day are missing, then set to Jan 01 
• If only day is missing, then set to the 1st of the month 
If end date of a medication is partially missing, impute as follows: 
 
• If both month and day are missing, then set to Dec 31 
• If only day is missing, then set to the last day of the month 
If start/end date of a medication is completely missing, do not impute. 
 
2. Adverse Events 
 
When the start/end date of an AE is partially missing, the date will be imputed to determine 
whether the AE is treatment-emergent. When unable to determine, the AE will be considered as 
treatment emergent by default. The following rules will be applied to impute partial dates for 
AEs: 
If start date of an AE is partially missing, impute as follows: 
 
• If both month and day are missing, the imputed value will be Jan 1 or the first dosing 
date if they have the same year, whichever is later. 
• If only day is missing, the imputed day will be the first day of the month or the first 
dosing date if they have the same month and year, whichever is later. 
• If start date is completely missing, the imputed day will be the first dosing date as long 
as the AE end date is not before the first dosing date. 
If the end date of an AE is partially missing, impute as follows: 


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• If both month and day are missing, the imputed value will be Dec 31 
• If only day is missing, the imputed day will be the last day of the month 
• If end date is completely missing, do not impute 
 
 
3. Deaths 
 
In case complete death dates are not recorded, impute as follows: 
 
• If both month and day are missing, the imputed value will be Jan 1 or the last date of 
subject known to be alive+1, whichever is later. 
• If only day is missing, the imputed value will be 1st of the month or the last date of 
subject known to be alive+1, whichever is later. 
 
 
4. Subsequent Anti-cancer therapy 
 
If the start day of a subsequent anti-cancer therapy is missing, it will be assumed to be the first 
day of the month. 
5. Cancer Diagnosis 
 
If a cancer diagnosis date is partially missing, impute as follows: 
 
• If both month and day are missing, the imputed value will be Jan 1 
• If only day is missing, the imputed day will be the first day of the month 
• If end date is completely missing, do not impute 
 
 
6. Prior Therapy/Response to Prior Therapy 
 
If the day of a prior therapy or response to prior therapy date is missing, set it to 15th of the 
month. Otherwise, do not impute. 


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B. Pathology subgroup of Peripheral T-cell Lymphoma (PTCL) 
 
 
CSR TFL Column 
Pathology in EDC 
AITL/TFH 
AITCL 
PTCL Angioimmunoblastic T-Cell Lymphoma 
(AITL) 
PTCL with T-follicular helper phenotype 
NOS 
PTCL (Peripheral T-Cell Lymphoma) -NOS 
Others 
ATLL 
ATTL 
ATLL, HTLV-1 associated 
CD4+ PTCL, skin only 
CD4+ PTCL, skin-only 
Cutaneous Gamma Delta 
Cutaneous gamma-delta T-cell Lymphoma 
G/D TCL, skin and LN+ 
HTLV-1 ATLL 
Hepatosplenic T cell Lymphoma 
Hepatosplenic T-cell Lymphoma 
LGL* 
Monomorphic Epitheliotropic Intestinal T-Cell 
Lymphoma 
NK/T-cell 
PTCL Anaplastic Large Cell Lymphoma (ALCL) 
ALK Negative (-) 
Primary Cutaneous Gamma/Delta T-cell 
Lymphoma 
T-Cell Prolymphocytic Leukemia 
T-cell prolymphocytic leukemia 
aggressive epidermotropic CD8+ ** 
gamma-delta T-cell lymphoma 
hepatosplenic T Cell lymphoma 
hepatosplenic gamma-delta T cell lymphoma 
*LGL (large granular lymphocytic leukemia) was miscategorized as PTCL at study entry 
 
**CTCL with aggressive epidermotropic CD8+ was miscategorized as PTCL at study entry 


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C. Lugano Criteria for Response Assessments in NHL (Protocol Amendment 9 Table A4- 
11). 
 
 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of 
the following): 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3 a with or without a residual 
mass on 5PS b 
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic uptake or 
with activation within spleen or marrow 
(e.g., with chemotherapy or myeloid colony- 
stimulating factors), uptake may be greater than 
normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may 
be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake. 
Target nodes/nodal masses must 
regress to < 1.5 cm in LDi No 
extralymphatic sites of disease. 
Nonmeasured lesion 
Organ enlargement 
New lesions 
Bone marrow 
Not applicable 
Not applicable 
None 
No evidence of FDG-avid disease in marrow 
Absent 
Regress to normal 
None 
Normal by morphology; if 
indeterminate, IHC negative 
Partial 
Lymph nodes and 
extralymphatic sites 
Partial metabolic response 
Score 4 or 5 b with reduced uptake compared with 
baseline and residual mass(es) of any size: 
At interim, these findings suggest responding 
disease. 
At end of treatment, these findings indicate residual 
disease. 
Partial remission (all of the following): 
> 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites. 
When a lesion is too small to measure on 
CT, assign 5 mm × 5 mm as the default 
value. 
When no longer visible, 0 × 0 mm. 
For a node > 5 mm × 5 mm, but smaller 
than normal, use actual measurement for 
calculation. 
Nonmeasured lesions 
Organ enlargement 
New lesions 
Bone marrow 
Not applicable 
Not applicable 
None 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive changes 
from chemotherapy allowed). 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. 
Absent/normal, regressed, but no 
increase. 
Spleen must have regressed by > 50% in 
length beyond normal. 
None 
Not applicable 


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Response and Site 
PET-CT–Based Response 
CT-Based Response 
No response or stable 
disease 
Target nodes/nodal 
masses, extranodal 
lesions 
Nonmeasured lesions 
Organ enlargement 
New lesions 
Bone marrow 
No metabolic response 
Score 4 or 5 with no significant change in FDG 
uptake from baseline at interim or end of treatment 
Not applicable 
Not applicable 
None 
No change from baseline 
Stable disease 
< 50% decrease from baseline in SPD of 
up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
No increase consistent with progression 
No increase consistent with progression 
None 
Not applicable 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at least 1 of 
the following PPD progression: 
An individual node/lesion must be 
abnormal with: LDi > 1.5 cm, and 
Increase by > 50% from PPD nadir and 
an increase in LDi or SDi from nadir 
0.5 cm for lesions < 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 50% of 
the extent of its prior increase beyond 
baseline (e.g., a 15-cm spleen must 
increase to > 16 cm). If no prior 
splenomegaly, must increase by at least 2 
cm from baseline 
New or recurrent splenomegaly 
New or clear progression of preexisting 
nonmeasured lesions 
Individual target 
nodes/nodal masses 
Extranodal lesions 
Score 4 or 5 with an increase in intensity of uptake 
from baseline and/or 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
Nonmeasured lesions 
None 
New lesions 
New FDG-avid foci consistent with lymphoma 
rather than another etiology (e.g., infection, 
inflammation). If uncertain regarding etiology of 
new lesions, biopsy or interval scan may be 
considered. 
Regrowth of previously resolved lesions 
A new node > 15 cm in any axis 
A new extradnodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its presence 
must be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to lymphoma 
New or recurrent lymphoma 
5PS = 5-point scale; CT = Computed tomography; FDG = Fluorodeoxyglucose; GI = Gastrointestinal; IHC = 
Immunohistochemistry; LDi = Longest transverse diameter of a lesion; MRI = Magnetic resonance imaging; 
PET = Positron emission tomography; PPD = Cross product of the LDi and perpendicular diameter; SDi = 
Shortest axis perpendicular to the LDi; SPD = Sum of the product of the perpendicular diameters for multiple 
lesion 
a. A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of 
an interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid under treatment). Measured dominant lesions: Up to 
six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in 
two diameters. Nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g., liver, 
spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: 


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Any disease not selected as measured, dominant disease and truly assessable disease should be considered not 
measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or 
measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as 
truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal 
masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in 
extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with 
complete metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., with 
marrow activation as a result of chemotherapy or myeloid growth factors). 
b. PET 5PS: 1, no uptake above background; 2, uptake < mediastinum; 3, uptake > mediastinum but < liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma.