Clinical trial NCT03133221
Conditions: Non Hodgkin Lymphoma Follicular Lymphoma Indolent Lymphoma B-cell Lymphoma Transformed Lymphoma Marginal Zone Lymphoma Waldenstrom Macroglobulinemia Small Lymphocytic Lymphoma Lymphoplasmacytic Lymphoma
Keywords: NHL indolent NHL Zydelig Idelalisib B-cell NHL Non-Hodgkin Lymphoma Maintenance Transformed B-cell Non-Hodgkin's lymphoma Autologous Stem Cell Transplantation
Sponsor: University of Maryland, Baltimore
Start date: 2017-10-23; Completion date: 2024-09-29
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a pilot study to learn how safe and how effective the study drug Zydelig works, after autologous stem cell transplant as a maintenance therapy in patients with indolent or transformed indolent B-cell non-Hodgkins lymphoma (iNHL or tiNHL).

Detailed description:
This pilot study is focused on maintenance Zydelig for patients with indolent or transformed indolent B-cell non-Hodgkins lymphoma (iNHL or tiNHL) after autologous stem cell transplantation. Oral Zydelig at 150 mg (or adjusted dose) twice daily continuously on 28-day cycles. Patients will continue on Zydelig up to one year or to progression/relapse/death or unacceptable toxicity, whichever occurs first.

Arms: arm 1: Zydelig given orally at 150 mg twice daily continuously on 28-day cycles starting 30 to 120 days after autologous stem cell transplantation for patients with indolent or transformed indolent B-cell NHL, for up to 1 year maintenance duration. Dose withhold/modification is allowed according to tolerability/toxicity.
Interventions: intervention 1: Zydelig
Intervention descriptions: intervention 1: Zydelig given at 150mg continuously in 28-day cycles

Protocol documents:
Prot_SAP_000.pdf: 
August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
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TITLE: A Pilot Study of Zydelig in Patients with B-cell Malignancies as Post-Autologous Transplant 
Remission Maintenance 
 
 
Protocol Number: 
1630GCC 
 
 
IND Number: 
 
101254 
 
 
Protocol Version and Date: Protocol version 3.0, August 22nd, 2017  
 
Coordinating Center: 
Greenebaum Comprehensive Cancer Center 
University of Maryland 
Baltimore, Maryland 
 
Participating Centers: 
Virginia Commonwealth University 
Washington University, St. Louis 
 
Principal investigator(s): 
Jean Yared, M.D. 
University of Maryland, Greenebaum Comprehensive Cancer Center 
22 S. Greene St., N9E12 
Baltimore, MD 21201 
Phone: 410-328-1230 
Fax: 410-328-1975 
jyared@umm.edu 
 
Co-Principal investigators: 
 
Victor Yazbeck, M.D. 
Massey Cancer Center-GRL, Room 219 
Virginia Commonwealth University 
401 College Street 
Box 980035 
Richmond, VA 23298 
Phone: 804-628-2073  
Fax: 804-828-5941 
vyyazbeck@vcu.edu 
 
Amanda Cashen, M.D. 
Washington University School of Medicine 
660 S. Euclid Ave., Box 8007  
St. Louis, MO 63110 
Phone: 314-454-8306 
Fax: 314-454-7551 
acashen@DOM.wustl.edu 
 


August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
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Co-investigators: 
 
Aaron Rapoport, M.D. 
 
 
 
University of Maryland, Greenebaum Comprehensive Cancer Center 
 
 
 
22 S. Greene St., N9E12 
 
 
 
Baltimore, MD 21201 
 
 
 
Phone: 410-328-1230 
 
 
 
Fax: 410-328-1975 
 
 
 
arapoport@umm.edu 
 
John McCarty, M.D. 
Virginia Commonwealth University (VCU) Massey Cancer Center 
Clinical and Translational Research Laboratory 
1300 E. Marshall Street 
P.O. Box 980157 
Richmond, VA 23298-0157 
Phone: (804) 828-4596 
jmccarty@mcvh-vcu.edu  
 
Todd A. Fehniger, M.D., Ph.D. 
Washington University School of Medicine 
Campus Box 8007 
660 South Euclid Avenue 
Saint Louis, MO 63110-1010 
Office: 314- 747-1385 
Fax: 314- 362-9333 
Lab: 314- 747-1547 
tfehnige@wustl.edu 
 
 
Seung Tae Lee, M.D., Ph.D. 
University of Maryland, Greenebaum Comprehensive Cancer Center 
22 S. Greene St., S9D 
Baltimore, MD 21201 
Phone: 410-328-3689 
Fax: 410-328-6897 
seunglee@umm.edu 
 
Jennie Law, M.D. 
University of Maryland, Greenebaum Comprehensive Cancer Center 
22 S. Greene St., S9D 
Baltimore, MD 21201 
Phone: 410-328-3689 
Fax: 410-328-6897 
jennielaw@umm.edu 
 
 
 
 


August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
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Nancy Hardy, M.D. 
University of Maryland, Greenebaum Comprehensive Cancer Center 
22 S. Greene St., S9D10 
Baltimore, MD 21201 
Phone: 410-328-1230 
Fax: 410-328-1975 
Nhardy1@umm.edu 
 
Ashraf Badros, M.B., Ch. B. 
University of Maryland, Greenebaum Comprehensive Cancer Center 
22 S. Greene St., S9D10 
Baltimore, MD 21201 
Phone: 410-328-1230 
Fax: 410-328-1975 
abadros@umm.edu 
 
Mehmet Kocoglu, M.D. 
University of Maryland, Greenebaum Comprehensive Cancer Center 
22 S. Greene St., S9D10 
Baltimore, MD 21201 
Phone: 410-328-1230 
Fax: 410-328-6896 
mkocoglu@umm.edu 
 
Kathryn A. Rizzo, DO, Ph.D. 
Department of Hematopathology  
VCU Health System  
Department of Pathology  
PO BOX 980662  
Richmond, VA 23298-0662  
Phone:  804- 628-5753 
krizzo@mcvh-vcu.edu  
 
Maciej Kmieciak, Ph.D. 
VCU Massey Cancer Center 
Clinical and Translational Research Laboratory 
401 College Street 
Floor 1, Room G-111 
Richmond, VA 23298-0037 
Phone (Office): 804-628-5337  
Phone (Lab): 804-628-5335  
mkmieciak@vcu.edu 
 
 
 
 
 
Statistician: 


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Olga Goloubeva, Ph.D., M.Sc. 
Howard Hall, 111 
660 W Redwood Street 
Baltimore, Maryland 21201 
Phone: 410- 706 8502 
Fax: 410- 706 8548 
ogoloubeva@som.umaryland.edu 
 
Responsible Research Coordinator:  
Veronica Rodriguez  
Clinical Research Specialist, Lead  
University of Maryland, Greenebaum Comprehensive Cancer Center 
22 S. Greene St., Rm.  N9E12 
Baltimore, MD 21201 
Phone: 410-328-9747 
Fax: 410-328-1975 
Veronica.Rodriguez@umm.edu 
Sunita Philip 
Clinical Research Manager 
Secondary Research Coordinator 
University of Maryland, Greenebaum Comprehensive Cancer Center 
22 S. Greene St., Rm. S9A06 
Baltimore, MD 21201 
Phone: 410-328-8199 
Fax: 410-328-1180 
 
Responsible Data Manager:  
Veronica Rodriguez  
Clinical Research Specialist, Lead  
University of Maryland Greenebaum Comprehensive Cancer Center 
 
 
 
BMT Data Management Staff Member 
 
 
 
22 S. Greene St. 
 
 
 
Baltimore, Maryland 21201 
Phone: 410-328-9747 
Fax: 410-328-1975 
 
Study Coordinator/Coordinating Center Contact: 
 
 
 
 
 
Veronica Rodriguez  
Clinical Research Specialist, Lead  
University of Maryland, Greenebaum Comprehensive Cancer Center 
22 S. Greene St., Rm.  N9E12 
Baltimore, MD 21201 
Phone: 410-328-9747 
Fax: 410-328-1975 
Email: Veronica.Rodriguez@umm.edu  
 
ContentsTITLE:  1630GCC: A Pilot Study of 
Zydelig in Patients with B-cell Malignancies as Post-Autologous Transplant Remission Maintenance 
 


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SYNOPSIS 
 
1. OBJECTIVES 
1.1. Primary Objectives 
1.2. Secondary Objectives 
 
2. BACKGROUND 
2.1. Zydelig 
2.2. Study Disease - Indolent B-cell Lymphoma and Transformed B-cell Lymphoma 
2.3. Rationale 
2.4. Correlative Studies Background 
 
3. PATIENT SELECTION 
3.1. Eligibility Criteria 
3.1.1. Inclusion 
3.2 Exclusion 
3.3  Inclusion of Women and Minorities  
 
4. REGISTRATION PROCEDURES 
 
5. TREATMENT PLAN 
5.1. Zydelig Administration 
5.2. General Concomitant Medication and Supportive Care Guidelines 
5.3. Duration of Therapy  
5.4. Duration of Follow-up 
5.5. Criteria for Removal from Study 
 
6. REQUIRED DATA/STUDY CALENDAR 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
7.1. Other Non-hematologic Toxicity 
 
8. CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE 
8.1. Complete Response 
8.2. Partial Response 
8.3. Stable Disease  
8.4. Progression or Relapse 
8.5. Guidelines for Evaluation of Measurable Disease 
8.6. Particular Case of Waldenstrom Macroglobulinemia 
 
9. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
9.1. Adverse Event Definitions 
9.2. Adverse Events for Zydelig 
9.3. Adverse Event Characteristics/Evaluation 
9.4. Serious Adverse Event Reporting 
9.5. Routine Adverse Event Reporting 
9.6. Data Safety Monitoring Plan 
9.7. Secondary AML/MDS 


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10. PHARMACEUTICAL INFORMATION 
10.1. 
Zydelig 
10.2. 
Availability 
10.3. 
Storage and Stability 
10.4. 
Pharmacokinetics 
10.5. 
Toxicity 
 
11. CORRELATIVE STUDIES (See Appendix D) 
 
12. DATA REPORTING/REGULATORY CONSIDERATIONS  
 
13. CLINICAL TRIAL MONITORING 
 
14. STATISTICAL CONSIDERATIONS 
14.1. 
Study Design/Primary Endpoints 
14.2. 
Sample Size/Accrual Rate 
14.3. 
Stratification Factors 
14.4. 
Analysis of Secondary Endpoints 
 
15. REFERENCES 
 
16. APPENDIX A  
Performance Status Criteria 
 
17. APPENDIX B  
Patient Zydelig Diary 
 
18. APPENDIX C 
Inhibitors and Inducers of CYP3A 
 
19. APPENDIX D  
Correlative Studies 
19.1. 
Background and Overview 
19.2. 
Time Points 
19.3. 
Collection and Processing at Participating Sites for IHC and Immunologic Studies 
19.4. 
Collection and Processing at Participating Sites for WES Studies 
19.5. 
Sample Labeling 
19.6. 
Shipping to VCU Massey Cancer Center 
19.7. 
Shipping to Washington University 
19.8. 
Sample Processing at VCU Massey Cancer Center 
19.9. 
Sample Processing at Washington University 
19.10. 
Sample Tracking 
19.11. 
Pharmacokinetics Assessments 
19.12. 
References 
 
 
 
 
Tables 
 
Table 1  
Study Calendar 


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Table 2  
Dose Modification Schedule 
Table 3  
Dose Modification for Toxicities Due to Zydelig 
Table 4  
Categorical Response Definitions 
Table 5  
Adverse Events – Treatment-Emergent Hematological & Non-Hematological Adverse  
 
 
Events in 5% of All Subjects 
Table 6  
Serious Adverse Events Reported as Possibly, Probably, or Definitely Related to Zydelig 
Table 7  
NCI Common Terminology for Adverse Events (CTCAE) 
Table 8  
Performance Status Criteria 
Table 9  
Sample Collection Table 
 
Synopsis 
 
Concept and Rationale: 
Autologous stem cell transplantation (ASCT) represents a potential curative treatment for patients with 
relapsed and/or refractory (R/R) B-cell lymphomas, and is presently the modality that yields the best 
chance of prolonged progression-free survival in this population of patients.  
 
Unfortunately, approximately half of these patients suffer from relapsed disease and die from their 
disease within 1 to 3 years after transplantation, depending on the disease status before 
transplantation.  
Treatment of relapsed B-cell lymphomas after ASCT is challenging, and there are no standard of care or 
guidelines for this problem.  
 
Rituximab maintenance may have some limited role in follicular lymphoma post autologous 
transplantation, but most of these patients have been exposed to rituximab and meet the criteria of 
being resistant to rituximab. With the increased number of patients who are undergoing transplantation 
and with the improved non-relapse mortality, relapse after transplant has become a larger factor in 
terms of survival. Relapses occur mostly within the first 2 years after ASCT.  
 
Zydelig (Idelalisib) is the 1st marketed PI3Kδ inhibitor that has been effective against indolent B-cell 
lymphomas (iNHL) with remarkable activity in heavily treated patients, leading to an overall response 
rate (ORR) of 57%, a median progression free survival (PFS) of 11 months and a median duration of 
response of 12.4 months.1 
We propose to incorporate Zydelig into a maintenance paradigm post ASCT for patients with iNHL and 
transformed iNHL (tiNHL). The goal of this strategy is to increase the likelihood that patients are able to 
maintain a remission after ASCT at 1 and 2 years of follow-up.   
 
Mirroring the paradigm incorporating BCR/ABL TKI, lenalidomide and Sorafenib  therapies in the post-
transplant treatments of Ph+ ALL, MM, and FLT3 ITD AML respectively, we propose inhibiting the 
proliferation and survival of iNHL cells by blocking the B-cell receptor signaling (BCR) via inhibiting the 
downstream molecular target PI3Kδ with Zydelig in the post-transplant setting.  
 
 
 
Primary Objective(s): 
1. Determine the toxicity and safety of incorporating Zydelig into the post- ASCT maintenance 
setting for iNHL and tiNHL immediately after ASCT.  
 


August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
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Secondary Objective(s): 
1. Assess the efficacy of incorporating Zydelig into the post-ASCT maintenance setting for iNHL and 
tiNHL immediately after ASCT with a corresponding endpoint of 1-year PFS after the 
transplantation. 
2. 2-year Progression Free Survival (PFS). 
3. Non-relapse mortality (NRM).  
4. Overall survival (OS). 
5. Correlatives studies: 
a.  To perform pharmacodynamics studies. 
b. To understand mechanism of resistance to Zydelig. 
c. To assess the effect of Zydelig on the immune system. 
 
 
 


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Study Design: 
 
 
 
 
Number of Patients: 
We will be studying a cohort of 34 patients with iNHL or tiNHL. 
 
Main Criteria for Inclusion/Exclusion: 
Inclusion Criteria - must meet all 
1. iNHL as defined by follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic 
lymphoma/Waldenstrom disease (LPL/WM) and small lymphocytic lymphoma (SLL) or tiNHL as 
defined by large B cell transformation of any of the above entity.  
2. Patients must be eligible to undergo high dose chemotherapy (HDT) followed by ASCT as a form of 
remission consolidation.  
3. Patients without evidence of documented disease progression clinically or radiographically (stable 
disease [SD], partial remission [PR] or complete remission [CR]) who have had count recovery (ANC 
> 500 cells/mm3, non-transfused platelet count > 20,000 K/mm3) and are at least 30 days post 
ASCT, but no more than 120 days post ASCT. 
 
Exclusion Criteria: 
1. Lack of engraftment 
2. Patients with active lymphoma CNS disease 
Relapsed/ Refractory iNHL or 
tiNHL
CR, PR or SD with count recovery (ANC>500, 
Plts >50)
Transplant candidate
AutoSCT with Engraftment and count recovery
Start Oral Zydelig 150 mg Twice Daily
On Trial Continuously on 28-Day Cycles
Induction Treatment


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3. Patients with active infection defined as requiring systemic antibiotic treatment and fever within 48 
hours of screening.  
4. Patients with progressive disease, as defined in protocol section 8.4 
5. Patients who progressed while previously taking  Zydelig 
6. Patients with moderate to severe lung disease including: 
6.1. Patients requiring O2 supplementation 
6.2. Patients unable to walk 50 feet without stopping to rest 
6.3. Moderate to severe obstructive or restrictive disease of the lung 
 
7. Patients with inflammatory bowel disease 
8. Patients with active hepatic disease, liver cirrhosis, or known HBV/HCV infection  
9. Patients with de novo diffuse large B-cell lymphoma 
10. Patients with h/o PCP or CMV infections 
 
Intervention and Mode of Delivery: 
Oral Zydelig at 150 mg twice daily continuously on 28-day cycles. 
Dose delays/modifications  as below for Grade 2 or above for some hematological and non-
hematological toxicities such hepatotoxicity, diarrhea/colitis/intestinal perforation, pneumonitis, 
infections, neutropenia and thrombocytopenia, or any other grade 3 non-hematologic toxicity 
considered at least possibly related to Zydelig. 
 
Duration of Intervention and Evaluation: 
iNHL and tiNHL patients will be eligible after ASCT. 
Start of therapy would occur after engraftment, minimum at day 30 post ASCT and no later than 120 
days post-ASCT. 
Patients will continue on Zydelig up to one year or to progression/relapse/death or unacceptable 
toxicity, whichever occurs first. 
 
HDT/ASCT will occur as soon as possible based on successful mobilization, collection and infusion of 
bone marrow or peripheral blood stem cells at a minimum of 2x106 CD34+/Kg of weight. 
Myeloablative transplant preparative regimen is based on institutional standards. 
Engraftment will be defined as ANC over 500 cells/mm3 and non-transfused platelet count of 20K/mm3. 
Standard supportive care in the post-transplant setting will be given. 
 
Toxicities will be evaluated to include standard hematologic toxicities for solid tumors (i.e. count 
suppression etc.). Dose reductions will be pursued as described below for both hematologic and non-
hematologic toxicities grade 2 and above 
 
Initial dose will be 150 mg PO BID. Dose modifications for toxicities due to Zydelig will follow the 
package insert recommendations as below. For other severe or life-threatening toxicities related to 
Zydelig, withhold drug until toxicity is resolved. If resuming Zydelig after interruption for other severe or 
life-threatening toxicities, reduce the dose to 100 mg twice daily. Recurrence of other severe or life-
threatening Zydelig-related toxicity upon rechallenge should result in permanent discontinuation of 
Zydelig. Toxicity, as well as graft failure will be monitored continuously throughout the trial. 
 
Statistical Methods: 
We are studying a cohort of 34 patients with iNHL or tiNHL. A single-stage open-label design will be used 
for the study.  Please see section 14.0 Statistical Considerations for more information.  


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1. OBJECTIVES 
 
1.1. Primary Objective 
1.1.1. Determine the toxicity and safety of incorporating Zydelig into the post- ASCT 
maintenance setting for iNHL and tiNHL immediately after ASCT. Toxicity will be monitored 
continuously throughout the trial. 
 
1.2. Secondary Objectives 
1.2.1. Assess the efficacy of Zydelig into the post- ASCT maintenance setting for iNHL and tiNHL 
immediately after ASCT.  
The corresponding endpoint is to report the 1-year PFS after the transplantation. PFS is 
defined as time to progression, relapse of the disease or death. The efficacy endpoint 
would be improvement of 1-year PFS after ASCT by 20% based on an approximate 
baseline PFS of 60% for iNHL and tiNHL.1,2 The expected 1-year PFS will be around 80%. 
Survival without progression or death will be determined using the Kaplan-Meier 
estimates at 1 year post ASCT. 
1.2.2. 2-year PFS. 
2-year PFS will be determined using the Kaplan-Meier estimates at 2 years post ASCT. 
1.2.3. Non-relapse mortality (NRM). 
NRM is defined as death in the absence of competing risks, relapse or progression of 
disease. This secondary endpoint will be characterized and presented as a cumulative 
incidence at 3 months and 12 months after SCT. 
1.2.4. Overall survival (OS). 
Survival without death will be determined and presented as Kaplan-Meier estimates at 1 
and 2 years post ASCT. 
1.2.5. Correlative studies. 
See Appendix D. 
 
2. BACKGROUND 
 
2.1. Zydelig (Zydelig, GS-1101, Cal-101) 
Zydelig is is an inhibitor of PI3Kinase delta which is highly expressed in malignant lymphoid B-
cells. PI3Kδ inhibition results in apoptosis of malignant tumor cells. In addition, Zydelig inhibits 
several signaling pathways, including the B-cell receptor. Zydelig was recently approved by the 
U.S. Food and Drug Association (FDA) for the treatment of the following: 
• 
relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for 
whom rituximab alone would be considered appropriate therapy due to other co-
morbidities 
• 
relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least 
two prior systemic therapies 
• 
 relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior 
systemic therapies.1,2,3-5  
 
2.2. Study Disease – Indolent B-cell Lymphomas/Transformed B-cell Lymphomas 
Early published clinical trial of Zydelig in multiple relapsed and treated indolent B-cell 
lymphomas showed a respectable ORR of 57% (6% CR) a short median time to response of 1.9 


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months and a prolonged median duration of response of 12.5 months. Responses were seen in 
all lymphoma subtypes. The estimated median progression-free survival and overall survival 
were 11 months, and 20 months, respectively. The estimated survival rate at one year was 80%. 
This population of patients included patients who already had undergone HDT/ASCT, and these 
patients had no different responses to Zydelig compared to the other patients.4 
There are some reports in the literature showing that the PI3K/Akt/mTOR signaling pathway 
might be activated in aggressive B-cell lymphoma.6-10 Other PI3K inhibitors, such as SAR245408, 
showed some activity in 25% of aggressive B-cell lymphoma.11 
 
2.3. Rationale 
Autologous stem cell transplantation (ASCT) represents a potential curative treatment for 
patients with relapsed and/or refractory (R/R) B-cell lymphomas and is presently the modality 
that yields the best chance of prolonged survival without disease in this population of patients.  
Unfortunately, approximately half of these patients suffer from relapsed disease and die from 
their disease in 1 to 3 years after transplantation depending, on the disease status before 
transplantation.  
 
Treatment of relapsed B-cell lymphomas after ASCT is challenging, and there are no standard of 
care or guidelines for this problem.  
 
Rituximab maintenance may have some limited role in follicular lymphoma post autologous 
transplantation, but most of these patients have been exposed to rituximab and meet the 
criteria of being resistant to rituximab. With the increased number of patients who are 
undergoing transplantation and with the improved non-relapse mortality, relapse after 
transplant has become a larger factor in terms of survival. Relapses occur mostly within the first 
2 years after ASCT.  
 
Zydelig is the 1st marketed PI3Kδ inhibitor that has been effective against indolent B-cell 
lymphomas (iNHL) with remarkable activity in heavily treated patients, leading to response rate 
(ORR) of 57%, a median progression free survival (PFS) of 11 months and a median duration of 
response of 12.4 months.4 
 
We propose to incorporate Zydelig into a maintenance paradigm post ASCT for patients with 
iNHL and transformed iNHL (tiNHL). The goal of this strategy is to increase the likelihood 
patients are able to maintain a remission after ASCT at 1 and 2 years of follow-up.   
Mirroring the paradigm incorporating BCR/ABL TKI and Sorafenib targeted therapies in the post-
transplant treatments of Ph+ ALL and FLT3 ITD AML respectively, we propose inhibiting the 
proliferation and survival of iNHL cells by blocking the B-cell receptor signaling (BCR) via 
inhibiting the downstream molecular target PI3Kδ with Zydelig in the post-transplant setting. 
 
2.4. Correlative Studies Background 
Please refer to Appendix D 
 
 
3. PATIENT SELECTION 
 
3.1. Eligibility Criteria 
 


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3.1.1. Inclusion Criteria (must meet all) 
1. Histologically documented (by HPI or pathology report) iNHL as defined by follicular 
lymphoma 
(FL), 
marginal 
zone 
lymphoma 
(MZL), 
lymphoplasmacytic 
lymphoma/Waldenstrom disease (LPL/WM) and small lymphocytic lymphoma (SLL) or 
tiNHL as defined by large B cell transformation of any of the above entities including 
chronic lymphocytic leukemia (CLL) 
2. Patients must be eligible to undergo high dose chemotherapy (HDT) followed by ASCT as 
a form of remission consolidation  
3. Patients without evidence of documented disease progression clinically or 
radiographically after ASCT (stable disease (SD), partial remission (PR) or complete 
remission (CR)) who have had count recovery (ANC > 500 cells/mm3, non-transfused 
platelet count > 20,000 K/mm3) and are at least 30 days post ASCT but no more than 120 
days post ASCT 
 
3.1.2. Prior Therapy 
Patients may have received any prior therapy deemed necessary for them to be eligible to 
HDT/ASCT except for patients whom have progressed while on Zydelig. Patients who have 
responded to Zydelig previously are eligible for enrollment on the protocol. 
 
3.1.3. Age >18 
 
3.1.4. ECOG performance status <4 (see Appendix A). 
 
3.1.5. Life expectancy of greater than four months. 
 
3.1.6. Patients must have normal organ  function as defined below (after the HDT/ASCT): 
- 
total bilirubin <  2x institutional upper limit of normal 
- 
AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal 
- 
Creatinine 
< 1.5x institutional upper limit of normal OR creatinine 
clearance 
>60 mL/min/1.73 m2 for patients with creatinine levels > 1.5x 
upper limit of normal. 
 
3.1.7. Because the effects of Zydelig on the developing human fetus are unknown, women of 
child-bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry and for the duration of 
study participation.  Female subjects of childbearing potential should have a negative 
pregnancy test within 72 hours prior to receiving the first dose of Zydelig. Male subjects 
must agree to use an adequate method of contraception starting with the first dose of the 
study drug Zydelig.  Female and male participants must agree to use contraception for at 
least 30 days after the last dose of Zydelig. Women of childbearing potential is defined as 
women who continues to have menstrual periods, have not had a tubal ligation, or the 
removal of fallopian tubes, ovaries or uterus. 
 
3.1.8. Ability to understand English and the willingness to sign a written informed consent 
document. 
 
 
 


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3.2. Exclusion Criteria 
 
3.2.1 
Patients who have had chemotherapy or radiotherapy within 2 weeks of first dose of 
Zydelig. 
 
3.2.2 
Patients receiving any other investigational agents within 30 days of receiving Zydelig  
 
3.2.3 
Patients who were previously exposed to Zydelig and experienced progression of 
disease.  
 
3.2.4 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Zydelig.  
 
3.2.5 
Patients with active and/or untreated CNS lymphoma will not be eligible.   
 
3.2.6 
Patients with inflammatory bowel disease.  
3.2.7 
Uncontrolled intercurrent illness including, but not limited to ongoing or active infection 
(defined as requiring systemic antibiotic treatment and fever within 48 hours of 
screening), symptomatic congestive heart failure (patients with NYHA score of III and 
above are excluded), unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
3.2.8 
Women who are pregnant or nursing or plan to become pregnant or nurse during the 
course of the study.  
 
3.2.9 
Positive HIV status.  
 
3.2.10 Patients with lack of count recovery as defined by ANC > 500 cells/mm3, non-transfused 
platelet count > 20,000 K/mm3. 
 
3.2.11 Patients who are unable to swallow pills. 
 
3.2.12 Patients with moderate to severe lung disease  including:  
 
Patients requiring O2 supplementation 
 
Patients unable to walk 50 feet without stopping to rest 
• 
Obstructive lung disease as defined by pre-transplant FEV1 < 60% of 
predicted.  
• 
Restrictive lung disease as defined by pre-transplant FVC < 60% of 
predicted.  
 
3.2.13 Patients taking strong CYP3A4 inhibitors or inducers with Risk X (Avoid Combination) 
according to Lexicomp. Please see appendix C for more information.  
 
3.2.14 Patients with active hepatic disease, liver cirrhosis, or known HBV/HCV infection. 
 
3.2.15 Patients with de novo diffuse large B-cell lymphoma. 


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3.2.16 Patients with h/o PCP pneumonia or positive CMV viremia confirmed twice at least 1 
day apart at screening. 
 
3.3 Inclusion of Women and Minorities 
Both men and women, and members of all races and ethnic groups are eligible for this trial.   
 
4. REGISTRATION PROCEDURES 
 
All patients must sign the IRB approved informed consent. Human protection committee approval of 
this protocol and consent form is required. Patients must be registered with the Study 
Coordinator/Coordinating Center Contact,Veronica Rodriguez. The following documents are to be 
submitted for review: signed informed consent, eligibility checklist completed and signed, all 
supporting documents that demonstrate eligibility requirements have been met such as lab results, 
pathology reports, medical history/progress note of Investigator. Please fax or email these 
documents to:Veronica Rodrigiez, Fax: 410-328-1975, Veronica.Rodriguez@umm.edu. Instructions 
concerning correlative/special studies will be conveyed at the time of registration. Upon review and 
verification of eligibility, an email or fax document will be sent to the registering center to confirm 
dose assignment. 
 
5. TREATMENT PLAN 
 
5.1 Zydelig Administration 
Treatment will be orally administered on an inpatient and outpatient basis with the starting 
dose of 150 mg by mouth twice a day for continuous 28-day cycles.  Treatment will continue 
until progression, intolerance, or patient/physician discretion to stop therapy. Zydelig will be 
started with count recovery (ANC over 500 cells/mm3, non-transfused platelet count over 
20,000 K/mm3) in patients who are at least 30 days after induction and/or transplant but no 
more than 120 days post-transplant. 
 
Reported adverse events and potential risks are described in Section 9. Appropriate dose 
modifications for Zydelig are described in Section 7. No investigational or commercial agents, or 
therapies other than those described below may be administered with the intent to treat the 
patient's malignancy. 
 
Patients should swallow Zydelig tablets whole each morning and evening (i.e. every 12hours). 
Tablets may be taken with or without food. Patients should keep track of adherence to Zydelig 
therapy by using the “Patients Drug Diary” (see appendix B). This diary will be collected at the 
end of each cycle. At the time of collection, the diary will be reviewed by a staff member and the 
patient will be prompted to complete any blank entries before completion of the visit. Should a 
patient miss or vomit a dose of Zydelig within less than 6 hours of the planned dose, the patient 
should take it as soon as possible. Patients who miss or vomit a dose of Zydelig longer than 6 
hours after the planned dose should wait until the next scheduled dose to resume taking 
Zydelig. 
 
5.2 General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of Zydelig with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent 


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16 
 
use of all other drugs, over-the-counter medications, or alternative therapies.  The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes. 
 
Agents typically used in the supportive care of patients undergoing treatment for NHL should 
not be manipulated due to potential drug interactions, unless toxicity is observed.  
 
For management of skin toxicity (rash); i.e., topical emollients, topical steroids or keratolytic 
creams can be used. 
 
Avoid concurrent use of Zydelig with other drugs that may cause liver toxicity. 
 
For management of grade ≥ 2 pneumonitis, diarrhea, or hepatotoxicity, Zydelig needs to be 
held.  Systemic corticosteroids can be started at the discretion of the investigator. 
 
Recent reports showed increased risk of Pneumocystis pneumonia (PCP) and Cytomegalovirus 
infection (CMV) associated with Zydelig. Because of these known risks, Trimethoprime-
sulfamethoxazole (TMP-SMX) will be given as one double-strength tablet daily or three times 
per week, or as one single-strength tablet once daily.  For patients who cannot take TMP-SMX, 
we will offer dapsone 100 mg tablet once a day or atovaquone suspension 1500 mg once a day. 
Blood CMV PCR will be monitored once a month; no prophylaxis is required. PCP prophylaxis 
and CMV monitoring will start once the patient starts taking Zydelig and will end 1 month after 
stopping Zydelig. Patients will be taken off the study drug if they develop PCP pneumonia, if 
CMV PCR becomes detectable in the blood or they develop CMV infection. 
 
5.3 Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 1 year or 
12 cycles (28 days per cycle) after transplant or until one of the following criteria applies: 
- 
Disease Progression 
- 
Intercurrent illness that prevents further administration of treatment 
- 
Unacceptable adverse event(s) 
- 
Evidence of PCP pneumonia or CMV viremia, confirmedat 2 consecutive blood draws at 
least 1 day apart with any value >500IU/mL in plasma or evidence of documented CMV 
disease.  
- 
Patient decides to withdraw from the study 
- 
General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.4 Duration of Follow-up 
Patients will be followed for 24 months after end of study treatment or until death, whichever 
occurs first. Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  
 
5.5 Criteria for Removal from Study 
Patients will be removed from study at the time of disease progression as determined by 
protocol section 8.4.  Exclusions are made for relapse isolated to the CNS which is able to be 
managed through local therapy. 
 


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6. REQUIRED DATA/STUDY CALENDAR 
 
Pre-Study Testing Intervals 
To be completed within 16 DAYS before study treatment: 
- All blood work 
- History and physical 
 
To be completed within 28 DAYS before study treatment: 
- Any X-ray, scan of any type (e.g., CT or MRI) or ultrasound that is utilized for tumor measurement 
 
To be completed within 42 DAYS before study treatment: 
- Any X-ray, scan of any type (e.g., CT or MRI) or ultrasound that is not utilized for tumor 
measurement 
- Bone marrow biopsy and aspirate (unilateral) is required if there washistory of bone marrow 
involvement. 
 
 


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Prior to 
Treatment  
Cycle 1 
Day 1  
 
Cycle 1 
Day 8 
+ 3 days 
Cycle 1 
Day 15 
+ 3 
days 
Day 1 of Each 
Subsequent 
Cycle + 3 days I 
Cycle 2 
Day 15 
+ 3 
days   
Cycle 3 
Day 15 
+ 3 
days 
End of 
Treatment*
* 
+ 3 days 
Time of Restaging and Post-treatment 
Follow-up*, % 
 
Tests & 
Observations 
 
 
 
 
 
 
 
 
 
History & Progress 
Note 
X 
X 
 
 
X 
 
 
X 
X 
Physical 
Examination 
X 
X 
 
 
X 
 
 
X 
XJ 
Pulse, Blood 
Pressure 
X 
X 
 
 
X 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
X 
Performance Status 
X 
X 
 
 
X 
 
 
X 
X 
Drug Toxicity 
Assessment 
X 
X 
 
 
X 
 
 
X 
 
Solicited 
Abnormalities/AEs 
X 
XA 
 
 
XA 
 
 
X 
 
Laboratory Studies 
 
 
 
 
 
 
 
 
 
CBC, Diff, Platelets 
X 
X 
 
 
X 
 
 
X 
X 
Serum Creatinine, 
CrCl (est), BUN 
X 
X 
 
 
X 
 
 
X 
X 
Serum Electrolytes 
X 
X 
 
 
X 
 
 
X 
X 
AST, ALT, Alk Phos, 
Bilirubin 
X 
X 
 
X 
X^ 
X 
X 
X 
X 
Uric Acid, 
Phosphate, LDH 
X 
X 
 
 
X 
 
 
X 
X 
Blood CMV PCR 
X 
X 
 
 
X 
 
 
X 
 
Beta2-
Microglobulin 
X 
 
 
 
 
 
 
X 
 


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Table 1 
 
* Restage every 3 cycles during treatment (i.e., cycles 3, 6, 9, 12, etc.), then every 3 months for 1 year, then every 6 months for another year.   
** If off study prior to month 12 study treatment 
% Starting at cycle 15 through cycle 24: Visit window +/- 4 weeks.  Starting at cycle 27 through cycle 36: Visit window +/- 12 weeks.  
^ Monitor ALT, AST, Alk Phos and bilirubin in all patients every 2 weeks (or 15 days) for the first 3 cycles of treatment, than every 4 weeks 
during subsequent cycles. 
~ If done before the transplant, no need to repeat them. 
A. Abnormalities/adverse events should be solicited, and severity graded, on day 1 of each cycle of treatment. 
B. In women of childbearing potential (as defined in Section 3.1.7).  A negative serum or urine HCG test is required within 14 days prior to 
study. 
C. Patients with known HIV positivity are excluded. 
D. CT, PET or PET/CT done PRN to follow measurable disease. Scan to be done with or without PET depending on the patient disease status.  
Serum or Urine 
BHCG 
XB 
 
 
 
 
 
 
X 
 
Thyroid Function 
Tests (T3,T4, TSH) 
XE 
 
 
 
XE 
 
 
X 
 
Triglycerides 
XI 
 
 
 
 
 
 
X 
 
HIV~ 
XC~ 
 
 
 
 
 
 
X 
 
HBsAg~, Anti-
HBc~Ab,HepC Ab~ 
X~ 
 
 
 
 
 
 
X 
 
ECG 
X 
 
XF 
 
 
 
 
X 
 
Staging 
 
 
 
 
 
 
 
 
 
CT/MRI 
(chest/abd/pelvis) 
with Tumor 
Measurements 
X 
 
 
 
 
 
 
X 
XD 
CT Neck 
X 
 
 
 
 
 
 
X 
XD 
PET (or PET/CT) 
X 
 
 
 
 
 
 
X 
XD 
Bone Marrow Asp 
& Biopsy 
 
X 
 
 
 
 
 
 
XG 
XG 
Histologic Review 
X 
 
 
 
 
 
 
XK 
 
Correlative Samples XH 
XH 
 
 
 
 
 
XH 
XH 


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E. Thyroid function tests every 3 cycles while on treatment and at completion of protocol therapy(Prior to treatment, C3D1, C6D1, C9D1, 
C12D1). 
F. ECG on day 8 of cycle 1, and then as clinically indicated. The steady-state (day 8) ECG is a requirement of the FDA under the Alliance IND 
for Zydelig. 
G. Repeat bone marrow aspirate and biopsy to confirm CR only if involved at baseline. Also a bone marrow aspirate/biopsy will be done if 
suspicion of bone marrow involvement.  
H. See protocol 19.2 Time Points of appendix D Correlative Studies 
I. Triglycerides Day 1 of cycles 3, 6, 9, 12 and then every 3 months until month 24.  Then again at months 24, 30, & 36.  
J. Physical Exam during follow-up.  
K. Only if there is progression, as judged by the Investigator 
 
 


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7. DOSING DELAYS/DOSE MODIFICATIONS 
 
Please refer to table 2 below.   
Patients who experience a Grade 2 or 3 toxicity and recover to ≤ Grade 1 (or to pretreatment 
baseline level of toxicity) may continue treatment at the next lower dose level (i.e.,  Dose level 2 
down to dose level 1). 
 
Once the dose has been reduced, patients must remain at the reduced dose for 28 days. Dose 
escalation may occur at the discretion of the investigator and may occur every 28 days. Patients 
may have their dose de-escalated from level 2 to level 1, three times before being removed 
from treatment. 
 
Please note: 
- 
There are no dose escalations above 150 mg BID 
- 
There are no dose reductions below 100 mg BID   
 
 
Table 2 
 
Dose Modification Schedule 
 
Dose Level 
 
Dose of Zydelig 
 
Level 2 (starting dose) 
 
150 mg PO BID 
 
Level 1 
 
100 mg PO BID 
 
Table 3 
Dose Modifications for Toxicities Due to Zydelig 
Pneumonitis 
Any symptomatic pneumonitis 
Discontinue Zydelig in patients with any severity of symptomatic 
pneumonitis 
ALT/AST 
>3.0-5.0 x ULN 
>5-20 x ULN 
>20 x ULN 
 
Decrease Zydelig to 
100 mg BID and 
monitor weekly until 
<1 x ULN.  
Withhold Zydelig. 
Monitor at least 
weekly until ALT/AST 
are <1 x ULN, then may 
resume Zydelig at 100 
mg BID. 
Discontinue Zydelig 
permanently. 
Bilirubin 
>1.5-3 x ULN 
>3-10 x ULN 
>10 x ULN 


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Decrease Zydelig to 
100 mg BID. Monitor 
at least weekly until 
<1 x ULN. 
Withhold Zydelig. 
Monitor at least 
weekly until bilirubin 
is <1 x ULN, then may 
resume Zydelig at 100 
mg BID. 
Discontinue Zydelig 
permanently. 
Diarrhea* 
Moderate diarrhea 
Severe diarrhea or 
hospitalization 
Life-threatening diarrhea 
Decrease Zydelig to 
100 mg BID. Monitor 
at least weekly until 
resolved. 
Withhold Zydelig. 
Monitor at least weekly 
until resolved, then 
may resume Zydelig at 
100 mg BID. 
Discontinue Zydelig 
permanently. 
Neutropenia^ 
ANC 1.0 to <1.5 Gi/L 
ANC 0.5 to <1.0 Gi/L 
ANC <0.5 Gi/L 
Maintain Zydelig dose. 
Decrease Zydelig to 
100 mg BID. Monitor 
ANC at least weekly. 
Interrupt Zydelig. Monitor 
ANC at least weekly until 
ANC ≥0.5 Gi/L, then may 
resume Zydelig at 100 mg 
BID. 
Thrombocytopenia 
Platelets 50 to <75 Gi/L Platelets 25 to <50 Gi/L 
Platelets <25 Gi/L 
Maintain Zydelig dose. Decrease Zydelig to 100 
mg BID Monitor platelet 
counts at least weekly. 
Interrupt Zydelig. 
Monitor platelet count 
at least weekly. May 
resume Zydelig at 100 
mg BID when platelets 
≥25 Gi/L. 
Pneumocystis pneumonia 
Any symptomatic pneumonia 
Discontinue Zydelig in patients with any severity of PCP 
CMV viremia/infection 
Any CMV viremia/infection 
Discontinue Zydelig in patients with any CMV viremia/infection 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; PCP, 
pneumocystis pneumonia; CMV, cytomegalovirus; ULN, upper limit of normal 
*Moderate diarrhea: increase of 4–6 stools per day over baseline.  Severe diarrhea: increase of ≥7 stools per day 
over baseline. 
^ G-CSF might be administered at the discretion of the investigator 
 
 
 


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7.1 
Other Non-hematologic Toxicity 
For other grade 3 non-hematologic toxicity considered at least possibly related to Zydelig, 
interrupt Zydelig until toxicity improves to ≤ grade 2, and then resume Zydelig with one 
dose level reduction for all subsequent cycles.  
For other grade 4 non-hematologic toxicity, discontinue Zydelig. 
 
8. CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE  
For purposes of this study, patients should be restaged every 3 cycles during treatment (i.e., 
cycles 3, 6, 9, 12, etc.), then every 3 months for 1 year, then every 6 months for another year.  
The Revised Response Criteria for Malignant Lymphoma is adopted.13 
 
8.1 
Complete Response 
Complete response (CR) is defined as the following: 
•  Complete disappearance of all detectable clinical evidence of disease and disease-
related symptoms (if present before therapy). 
• In patients where the CT or PET/CT scan was positive before therapy, a post-treatment 
residual mass of any size is permitted as long as it is PET/CT-negative. 
•  The spleen and/or liver, if considered enlarged before therapy on the basis of a CT or 
PET/CT, should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear. However, determination of splenic involvement is not always 
reliable because a spleen considered normal in size may still contain lymphoma, whereas 
an enlarged spleen may reflect variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or other causes other than lymphoma. 
•  If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy. The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core). If the 
sample is indeterminate by morphology, it should be negative by immunohistochemistry. 
A sample that is negative by immunohistochemistry, but demonstrating a small 
population of clonal lymphocytes by flow cytometry will be considered a CR until data 
becomes available demonstrating a clear difference in patient outcome. 
 
8.2 
Partial Response 
Partial response (PR) is defined as the following: 
•  At least a 50% decrease in the sum of the product of the diameters (SPD) of up to six of 
the largest dominant nodes or nodal masses. These nodes or masses should be selected 
according to all of the following: a) they should be clearly measurable in at least two 
perpendicular dimensions; b) if possible, they should be from disparate regions of the 
body; and c) they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved. 
•  No increase should be observed in the size of other nodes, liver, or spleen. 
•  Splenic and hepatic nodules must regress by ≥ 50% in their SPD, or, for single nodules, in 
the greatest transverse diameter. 
•  With the exception of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present. 
•  Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, if positive, the cell type should be specified in the 
report (e.g., large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR by 


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24 
 
the above criteria, but who have persistent morphologic bone marrow involvement, will 
be considered partial responders. When the bone marrow was involved before therapy 
and a clinical CR was achieved, but with no bone marrow assessment after treatment, 
patients should be considered partial responders. 
•  No new sites of disease should be observed. 
•For patients if the CT or PET/CT was positive before therapy, the post-treatment PET 
should be positive in at least one previously involved site. 
 
8.3 
Stable Disease 
Stable disease (SD) is defined as when the patient fails to attain the criteria needed for a 
CR or PR, but does not fulfill those for progressive disease (see below). The CT or PET/CT 
should be positive at prior sites of disease, with no new areas of involvement on the post-
treatment CT or PET/CT. 
 
8.4 
Progression or Relapse 
Disease progression (PD) or relapse is defined as any one of the following: 
•  Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless of 
the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be 
considered abnormal if its short axis is > 1 cm. Lymph nodes ≤ 1 cm by ≤ 1 cm will not be 
considered as abnormal for relapse or progressive disease. 
•  Appearance of any new lesion > 1.5 cm in any axis during or at the end of therapy, even 
if other lesions are decreasing in size. Increased FDG uptake in a previously unaffected site 
should only be considered relapsed or progressive disease after confirmation with other 
modalities. In patients with no prior history of pulmonary lymphoma, new lung nodules 
identified by CT are mostly benign. Thus, a therapeutic decision should not be made solely 
on the basis of the CT or PET/CT without histologic confirmation. 
 
•  At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the short axis of < 1 cm 
must increase by ≥ 50% and to a size of 1.5 x 1.5 cm, or > 1.5 cm in the long axis. 
•  At least a 50% increase in the longest diameter of any single previously identified node > 
1 cm in its short axis. 
•  Lesions should be PET-positive if a typical FDG-avid lymphoma or one that was PET-
positive before therapy unless the lesion is too small to be detected with current PET 
systems (< 1.5 cm in its long axis by CT). 
 
8.5 
Guidelines for Evaluation of Measurable Disease 
Measurable extra nodal disease should be assessed in a manner similar to that for nodal 
disease. For these recommendations, the spleen is considered nodal disease. Disease that 
is not easily assessable (e.g., pleural effusions, bone lesions) will be recorded as present or 
absent only, unless, while an abnormality is still noted by imaging studies it is found to be 
histologically negative. 
 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). 
 


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Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT or PET/CT is preferable. 
 
Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to the chest, abdomen, and pelvis. Head & neck and 
extremities usually require specific protocols. 
 
Ultrasound should not be used to measure tumor lesions that are clinically not easily 
accessible when the efficacy endpoints of the study is objective response evaluation. It is a 
possible alternative to clinical measurements of superficial palpable nodes, subcutaneous 
lesions, and thyroid nodules. Ultrasound might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
 
8.6 
Particular Case of Waldenstrom Macroglobulinemia 
 
Table 4 
Categorical Response Definitions 
Response 
category 
Definition 
Complete 
response (CR) 
Absence of serum monoclonal IgM protein by 
immunofixation 
Normal serum IgM level 
Complete resolution of extramedullary disease, i.e., 
lymphadenopathy and splenomegaly if present at 
baseline 
Morphologically normal bone marrow aspirate and 
trephine biopsy 
Very good partial 
response (VGPR) 
Monoclonal IgM protein is detectable 
≥90% reduction in serum IgM level from baseline* 
Complete resolution of extramedullary disease, i.e., 
lymphadenopathy/splenomegaly if present at baseline 
No new signs or symptoms of active disease 
Partial response 
(PR) 
Monoclonal IgM protein is detectable 
≥50% but<90% reduction in serum IgM level from 
baseline* 
Reduction in extramedullary disease, i.e., 
lymphadenopathy/splenomegaly if present at baseline 
No new signs or symptoms of active disease 
Minor 
response 
(MR) 
Monoclonal IgM protein is detectable 
≥25% but<50% reduction in serum IgM level from 
baseline* 
No new signs or symptoms of active disease 


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Categorical Response Definitions 
Response 
category 
Definition 
Stable 
disease 
(SD) 
Monoclonal IgM protein is detectable 
<25% reduction and <25% increase in serum IgM level 
from baseline* 
No progression in extramedullary disease, i.e., 
lymphadenopathy/splenomegaly 
No new signs or symptoms of active disease 
Progressive 
disease (PD) 
≥25% increase in serum IgM level* from lowest nadir 
(requires confirmation) and/or 
progression in clinical features attributable the disease 
* Sequential changes in IgM levels may be determined either by M protein quantitation by 
densitometry or total serum IgM quantitation by nephelometry 
For more details, please refer to http://www.ncbi.nlm.nih.gov/pubmed/2315099714 
 
9. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
9.1 Adverse Event Definitions 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.03. A copy of the 
CTCAE version 4.03 can be downloaded from the CTEP web site. 
 
Attribution of the AE: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
 
The Definition of a Serious Adverse Event (SAE): 
 
SAE is defined as any of the following: 
• Any death that occurs while the patient is enrolled in the study or within 30 days of completing the 
study  
• Immediately life-threatening adverse event 
• Requires inpatient hospitalization 
• Prolongation of an existing hospitalization 
• Congenital anomaly/birth defect 
• Medically important event 
• Disability/incapacity (persistent or significant) 
Progression of the cancer under study is not considered an adverse event, unless it results in 
hospitalization or death.  


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9.2 Adverse Events for Zydelig  
 
The following is taken from the Investigator’s Brochure (IB) 6th Edition for Zydelig. Please 
note that this section will be replaced by the CAEPR for Zydelig when it becomes available. 
 
9.2.1 Treatment-Emergent Hematological and Non-hematological Adverse Events in ≥ 5% of All 
Subjects 
 
Table 5 
Adverse Reactions (≥ 10% of Subjects) in Patients with Indolent non-Hodgkin Lymphoma Treated with 
Zydelig 150 mg BID 
 
Zydelig Monotherapy  
N=146 (%) 
Adverse Reaction 
Any Grade 
Grade ≥3 
Gastrointestinal disorders 
diarrhea (a)  
68 (47) 
20 (14) 
nausea 
42 (29) 
2 (1) 
abdominal pain (b)  
38 (26) 
3 (2) 
vomiting 
22 (15) 
2 (1) 
General disorders and administration site conditions 
fatigue 
44 (30) 
2 (1) 
pyrexia 
41 (28) 
3 (2) 
asthenia 
17 (12) 
3 (2) 
peripheral edema 
15 (10) 
3 (2) 
Infections and infestations 
upper respiratory tract infection 
18 (12) 
0 
Respiratory, thoracic, and mediastinal disorders 
pneumonia (c)  
37 (25) 
23 (16) 
cough 
42 (29) 
1 (1) 
dyspnea 
25 (17) 
6 (4) 
Skin and subcutaneous disorders 
rash (d)  
31 (21) 
4 (3) 
night sweats 
18 (12) 
0 
Nervous system disorders 
headache 
16 (11) 
1 (1) 
Metabolism and nutrition disorders 
decreased appetite 
24 (16) 
1 (1) 


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Psychiatric disorders 
Insomnia 
17 (12) 
0 
(a) Diarrhea includes the following preferred terms: diarrhea, colitis, enterocolitis, and gastrointestinal 
inflammation. 
(b) Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, 
abdominal pain lower and abdominal discomfort. 
(c) Pneumonia includes the terms: pneumonia, pneumonitis, interstitial lung disease, lung infiltration, 
pneumonia aspiration, respiratory tract infection, atypical pneumonia, lung infection, 
pneumocystis jiroveci pneumonia, bronchopneumonia, pneumonia necrotizing, lower respiratory 
tract infection, pneumonia pneumococcal, pneumonia staphylococcal, pneumonia streptococcal, 
pneumonia cytomegaloviral, and respiratory syncytial virus infection. 
(d) Rash includes the following preferred terms: dermatitis exfoliative, rash, rash erythematous, 
rash macular, rash maculo-papular, rash pruritic, and exfoliative rash. 
 
Treatment-emergent Laboratory Abnormalities in Patients with Indolent non-Hodgkin Lymphoma 
Treated with Zydelig 150 mg BID 
 
Zydelig Monotherapy  
N=146 (%) 
Laboratory Abnormality 
Any Grade 
Grade 3 
Grade 4 
Serum chemistry  
abnormalities 
 
 
 
ALT increased 
73 (50) 
20 (14) 
7 (5) 
AST increased 
60 (41) 
12 (8) 
6 (4) 
Hematology abnormalities 
neutrophils decreased 
78 (53) 
20 (14) 
16 (11) 
hemoglobin decreased 
41 (28) 
3 (2) 
0 
platelets decreased 
38 (26) 
4 (3) 
5 (3) 
Grades were obtained per CTCAE version 4.03. 
 
 
Serious Adverse Events Reported as Possibly, Probably, or Definitely Related to Zydelig 
 
Table 6 
System Organ Class 
Adverse Event 
Blood and lymphatic system disorders 
Anemia 
Febrile neutropenia 
Neutropenia 
Red cell aplasia 
Thrombocytopenia 
Gastrointestinal disorders 
Colitis 
Diarrhea 
Ischemic colitis 
Nausea 
Esophagitis 
Stomatitis 
Vomiting 


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General disorders and administration site conditions 
Fatigue 
Fever 
Influenza-like symptoms 
Pyrexia 
Hepatobiliary disorders 
Cholecystitis 
Cholecystitis, acalculous 
Cholecystitis, acute 
Infections and infestations 
Abscess 
Brain abscess 
Cellulitis 
Cytomegalovirus infection 
Endocarditis 
Herpes zoster 
Herpes zoster, ophthalmic 
Meningitis 
Pneumonia 
Pneumonia fungal 
Pneumonia, Pneumocystis jiroveci 
Sepsis 
 Hepatotoxicity 
ALT increased 
AST increased 
Hepatic enzyme increased 
Transaminase increased 
Metabolism and nutrition disorders 
Anorexia 
Fluid retention 
Hypercalcemia 
Tumor lysis syndrome 
Renal and urinary disorders 
Renal failure 
Renal failure, acute 
Respiratory, thoracic, and mediastinal disorders 
Atelectasis 
Hypoxia 
Pneumonia, organizing 
Pneumonitis 
Pulmonary embolism 
Pulmonary fibrosis 
Skin and subcutaneous tissue disorders 
Rash 
Rash, generalized 
Rash maculopapular 
 
9.3 Adverse Event Characteristics/Evaluation 
 
 
 
An investigator who is a qualified physician will evaluate all adverse events according to 
the NCI Common Terminology for Adverse Events (CTCAE), version 4.03. Any adverse 
event which changes CTCAE grade over the course of a given episode will have each 
change of grade recorded on the adverse event case report forms/worksheets. 
 
All adverse events, regardless of CTCAE grade must also be evaluated for seriousness. 
 


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• CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will 
be utilized for AE reporting.  All appropriate treatment areas should have access to a copy 
of the CTCAE version 4.03.  A copy of the CTCAE version 4.03 can be downloaded from the 
CTEP web site  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Table 7 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
 
Grade 3 
Severe or Medically Significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life Threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of the investigational 
condition that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death 
from the event as it occurred (Note: This does not include an adverse event that, had it occurred in a 
more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to 
conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for 
continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a 
preexisting condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject exposed to the investigational condition 
regardless of time to diagnosis);or 
 
Other important medical events that may not result in death, not be life threatening, or not require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of 
time and units. 
Action 
Taken  
Did the adverse event cause the study treatment to be discontinued? 
Relationship 
to Test 
Condition  
Did the investigational condition cause the adverse event? The determination of the likelihood that the 
investigational condition caused the adverse event will be provided by an investigator who is a qualified 
physician. The investigator’s signed/dated initials on the source document or worksheet that supports the 
causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This 
initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship 
between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the investigational 
condition and the AE; the greater the correlation with the components and their respective elements (in 
number and/or intensity), the more likely the investigational condition caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the investigational condition such 
as: reliable history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time 
Did the AE follow in a reasonable temporal sequence from administration of the 


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• ‘Expectedness’:  AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes 
only. The following abnormalities/adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and for each cycle 
of treatment. 
 Fatigue 
 Skin rash 
 Diarrhea 
 Decreased neutrophils, hemoglobin and platelet count 
 Increased serum ALT and AST 
 Cough and pneumonitis 
 Fever 
 Infection  
 
9.4 Serious Adverse Event Reporting 
Investigators are responsible for monitoring the safety of patients who have entered this 
study and for alerting the UMGCCC DSM/QAC to any event that seems unusual, even if 
this event may be considered an unanticipated benefit to the patient. Any adverse event 
that meets the definition of serious  which occurs at any time during the clinical study or 
within 30 days of receiving the last dose of study medication, whether or not related to 
the study drug will be reported as follows: 
 
All  SAE’s, whether or not related to the study drug, will be reported via OnCore to the 
DSM/QAC according to the UMGCC DSM/QAC SOP. 
 
Treatment-related toxicities and other adverse events will be monitored through standard 
medical practice, in addition to scheduled follow-ups as outlined in the treatment plan. 
Adverse events should be described according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events, v. 4.03 (Table 7). 
(see http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
 
Any serious adverse event, or follow up to a serious adverse event (including death due to 
any cause other than progression of the cancer under study) that occurs to any subject 
from the time the consent is signed through end of study participationor the initiation of 
new anti-cancer therapy, whichever is earlier (whether or not related to protocol therapy) 
must be reported within 24 hours to the Coordinating Center   (Attn:  Dr. Jean Yared – FAX 
(410) 328-1975) using FDA Form 3500A (MedWatch form).  The Coordinating Center will 
then report the event to the FDA using FDA Form 3500A (MedWatch Form).   
 
Additionally, any serious adverse event considered by an investigator (who is a qualified 
physician) to be related to protocol therapy that is brought to the attention of the study 
team at any time outside of the time period specified in the previous paragraph also must 
Course 
investigational condition?  
Is the time of onset of the AE compatible with a study-induced effect (applies to trials with 
investigational medicinal product[s])? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors? 


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be reported immediately to the Coordinating Center using FDA Form 3500A (MedWatch 
Form).  
 
Any unexpected grade 4 or 5 adverse event and any death during the study period must 
be reported using FDA Form 3500A (MedWatch form) to the Coordinating Center within 
one working day (24 hours) of discovery or notification.  Please submit the adverse event 
report using FDA Form 3500A to:   
 
Veronica Rodriguez 
  
Room N9E12 
22 S. Greene Street, Baltimore, MD 21201 
Phone: 410-328-9747  
Fax: 410-328-1975  
Email: Veronica.Rodriguez@umm.edu 
 
The event should also be reported locally to the site Institutional Review Board (IRB) per 
local policy.  
 
Otherwise, unexpected serious adverse events must be reported within 15 days.  
 
If the event meets the criteria for FDA mandatory IND safety reporting (serious AND 
unexpected), the Coordinating Center will report the event to the FDA using FDA Form 
3500A (MedWatch form).  Events which are assessed as “unexpected fatal or life-
threatening” should be reported to FDA by the Coordinating Center as soon as possible, 
but no later than 7 calendar days following the  initial receipt of the information.  All other 
unexpected serious suspected adverse reactions suggesting significant risk to human 
subjects should be reported to FDA no later than 15 calendar days following the initial 
receipt of the information.   
 
A copy of all 15 Day Reports and Annual Progress Reports are to be submitted as required 
by FDA, Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. 
 
All subjects with serious adverse events must be followed up for outcome/resolution for 
at least 90 days after stopping protocol therapy. 
 
9.5 Routine Adverse Event Reporting 
An investigator who is a qualified physician will evaluate all adverse events according to 
the NCI Common Terminology for Adverse Events (CTCAE), version 4.03. Any adverse 
event which changes CTCAE grade over the course of a given episode will have each 
change of grade recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
 
9.6 Data Safety Monitoring Plan 
It is the responsibility of the Principal Investigator to oversee the safety of  study 
participants.  This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above. 


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This study will be monitored by the UMGCCC Data and Safety Monitoring and Quality 
Assurance Committee and will follow the Data Safety and Monitoring Plan as outlined in 
the Clinical Investigator Handbook of the UMGCCC Clinical Research Office. Monitoring 
will be conducted as per the plan on file with the University of Maryland IRB (also 
available in the UMGCCC Clinical Investigator Handbook. 
 
     
 
9.7 Secondary AML/MDS 
AML/MDS events are now to be reported via AdEERS (in addition to your routine AE 
reporting mechanisms).  In CTCAE v4.0, the event(s) may be reported as either: 1) 
Leukemia secondary to oncology chemotherapy, 2) Myelodysplastic syndrome, or 3) 
Treatment-related secondary malignancy. Any malignancy possibly related to cancer 
treatment (including AML/MDS) should also be reported via the routine reporting 
mechanisms outlined. 
 
 
10. PHARMACEUTICAL INFORMATION 
 
10.1 
Zydelig (GS-1101, CAL-101) () 
 
 
The substance acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks 
P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase. 
 
10.2 
Availability  
Zydelig (CAL-101) will be supplied and distributed by Gilead Sciences, Inc. Zydelig is 
supplied in bottles of 60 tablets of 100 mg and 150 mg strengths. The bottles of Zydelig 
are white high-density polyethylene with a child-resistant cap and a polyester or cotton 
coil. The tablet shape is plain-faced, modified oval. The tablets contain the inactive 
ingredients microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, 
sodium starch glycolate, and magnesium stearate. The 100 mg tablets are orange film 
coated, and the 150 mg tablets are pink film coated. Tablets should be swallowed whole. 
 
10.3 
Storage and Stability 
Zydelig tablets should be stored at a controlled room temperature of 25ºC (77ºF), with a 
range from 15ºC (59ºF) to 30ºC (86ºF). While stability of study drug tablets stored at 


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controlled room temperature has been confirmed, brief excursions to temperatures as 
low as –10°C or as high as 40°C (eg, during shipping) will not adversely affect the drug. 
Updated stability data will be provided to the sites, as appropriate.  
At the end of the study, any remaining unused Zydelig should be destroyed according to 
local institutional procedures.  
 
Preparation  
Zydelig should be dispensed in the original container.  
 
Administration  
The prescribed dose of Zydelig should be taken orally. At each dose administration, the 
tablet number corresponding to the appropriate dose of study drug is to be swallowed 
whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the tablets in 
the oral cavity, additional water should be taken as a rinse.  
Zydelig may be taken with or without food. There are no known dietary restrictions 
related to study drug use.  
 
Overdose Precautions  
In Phase 1 studies, an MTD for Zydelig was not reached when administering the drug 
continuously at dose levels of 350 mg/dose BID (700 mg per day). However, in this 
protocol, an overdose is defined as administration of more than the prescribed daily study 
drug (Zydelig) dose (ie, >300 mg in a single day).  
 
In a subject who experiences an overdose, consideration should be given as to whether 
study drug administration should be temporarily interrupted. If the overdose ingestion is 
recent and substantial, and if there are no medical contraindications, use of gastric lavage 
or induction of emesis may be considered. Observation for any symptomatic side effects 
should be instituted, and biochemical and hematological parameters should be followed 
closely (consistent with the protocol or more frequently, as needed). Appropriate 
supportive management to mitigate adverse effects should be initiated.  
 
Inadvertent Exposure and Spill Precautions  
Based on available data from nonclinical studies, Zydelig does not appear to be acutely 
toxic, genotoxic, or irritative at levels that are likely to result from inadvertent exposure to 
the contents of broken tablets. However, personnel handling the drug should use 
reasonable precautions to avoid eye contact, skin contact, inhalation, or ingestion of the 
study drug product. For further information regarding inadvertent exposure and spill 
precautions, please consult the Zydelig investigator brochure. 
 
10.4 
Pharmacokinetics 
 
Absorption 
Following oral administration of a single dose of Zydelig in the fasted state, the median 
Tmax was observed at 1.5 hours. Idelalisib exposure increased in a less than dose-
proportional manner over a dose range of 50 mg to 350 mg twice daily in the fasted state. 
Relative to fasting conditions, the administration of a single dose of Zydelig with a highfat 
meal increased idelalisib AUC 1.4-fold. Zydelig can be administered without regard to 
food. 
 


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Distribution 
Idelalisib is greater than 84% bound to human plasma proteins with no concentration 
dependence. The mean blood-to-plasma ratio was 0.7. The population apparent central 
volume of distribution at steady state is 23 L 
 
Metabolism and Elimination 
Idelalisib is metabolized to its major metabolite GS-563117 via aldehyde oxidase and 
CYP3A. GS-563117 is inactive against PI3Kδ in vitro. Idelalisib undergoes minor 
metabolism by UGT1A4. The population apparent systemic clearance at steady-state is 
14.9 L/hr. The population terminal elimination half-life of idelalisib is 8.2 hours. Following 
a single dose of 150 mg of [14C] idelalisib, 78% and 14% of the radioactivity was excreted 
in feces and urine, respectively. GS-563117 accounted for 49% of the radioactivity in the 
urine and 44% in the feces. 
 
Specific Population 
Age, Gender, Race and Weight 
Population pharmacokinetic analyses indicated that age, gender, race, and weight had no 
effect on idelalisib exposure. 
 
Patients with Renal Impairment 
A pharmacokinetic study following a single dose of 150 mg of Zydelig was performed in 
healthy subjects and subjects with severe renal impairment (CrCl 15 to 29 mL/min). 
Creatinine clearance had no effect on idelalisib exposure. No dose adjustment is needed 
for patients with CrCl ≥15 mL/min. 
 
Patients with Hepatic Impairement 
A pharmacokinetic study of Zydelig was performed in healthy subjects and subjects with 
hepatic impairment. The geometric mean AUC increased up to 1.7-fold in subjects with 
ALT or AST or bilirubin values greater than the upper limit of normal (ULN) compared to 
subjects with normal AST or ALT or bilirubin values. Limited safety and efficacy data are 
available for patients with baseline AST or ALT greater than 2.5 x ULN or bilirubin greater 
than 1.5 x ULN, as these patients were excluded from Studies 1 and 2. Patients with 
baseline hepatic impairment should be monitored for signs of Zydelig toxicity. 
 
Drug Interactions 
 
In Vitro Studies 
Idelalisib is a substrate for aldehyde oxidase, CYP3A, and UGT1A4 in vitro. Idelalisib 
inhibits CYP2C8, CYP2C19, CYP3A, and UGT1A1 and GS-563117 inhibits CYP2C8, CYP2C9, 
CYP2C19, CYP3A and UGT1A1 in vitro. Idelalisib and GS-563117 are not likely to inhibit 
CYP1A, CYP2B6, and CYP2D6. Idelalisib induces CYP2B6 and CYP3A4, but does not induce 
CYP1A2 in vitro. GS- 563117 does not induce these enzymes. Idelalisib and GS-563117 are 
substrates of P-glycoprotein (P-gp) and BCRP in vitro. Idelalisib is not a substrate of 
OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. GS- 563117 is not a substrate of OATP1B1 or 
OATP1B3. Idelalisib inhibits P-gp, OATP1B1, and OATP1B3, and GS-563117 inhibits 
OATP1B1, OATP1B3 in vitro. Idelalisib is not likely to inhibit BCRP, OCT2, OAT1, or OAT3, 
and GS-563117 is not likely to inhibit P-gp, BCRP, OCT2, OAT1, or OAT3. 
 


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Effect of Other Drugs on Idelalisib 
A single dose of 150 mg of Zydelig was administered alone and after rifampin (a strong 
CYP3A and P-gp inducer) 600 mg once daily for 8 days in healthy subjects. Rifampin 
decreased the geometric mean idelalisib AUC by 75% and the geometric mean Cmax by 
58%. Avoid coadministration of Zydelig with strong CYP3A and P-gp inducers. A single dose 
of 400 mg of Zydelig was administered alone and after ketoconazole (a strong CYP3A and 
P-gp inhibitor) 400 mg daily for 4 days in healthy subjects. Ketoconazole increased the 
geometric mean idelalisib AUC by 1.8-fold. No changes in the geometric mean Cmax were 
observed. Patients taking concomitant CYP3A inhibitors should be monitored for signs of 
Zydelig toxicity 
 
Effect of Idelalisib on Other Drugs 
A single oral dose of midazolam 5 mg was administered alone and after Zydelig 150 mg for 
15 doses in healthy subjects. The geometric mean midazolam Cmax increased by 2.4-fold 
and the geometric mean midazolam AUC increased by 5.4-fold. Avoid coadministration of 
Zydelig with CYP3A substrates, as Zydelig is a strong CYP3A inhibitor. A single dose of 10 
mg of rosuvastatin (OATP1B1 and OATP1B3 substrate) was administered alone and after 
Zydelig 150 mg for 12 doses in healthy subjects. No changes in exposure to rosuvastatin 
were observed. A single dose of 0.5 mg of digoxin (P-gp substrate) was administered alone 
and after Zydelig 150 mg for 19 doses in healthy subjects. No changes in exposure to 
digoxin were observed. 
 
10.5 
Toxicity.  
Hepatotoxicity 
Fatal and/or serious hepatotoxicity occurred in 18% of patients treated with Zydelig 
monotherapy and 11% of patients treated with Zydelig in combination trials. Elevations in 
ALT or AST greater than 5 times the upper limit of normal have occurred. These findings 
were generally observed within the first 12 weeks of treatment and were reversible with 
dose interruption. After resumption of treatment at a lower dose, 26% of patients had 
recurrence of ALT and AST elevations. Discontinue Zydelig for recurrent hepatotoxicity. 
Avoid concurrent use of Zydelig with other drugs that may cause liver toxicity. Monitor 
ALT and AST in all patients every 2 weeks for the first 3 months of treatment, every 4 
weeks for the next 3 months, then every 1 to 3 months thereafter. Monitor weekly for 
liver toxicity if the ALT or AST rises above 3 times the upper limit of normal until resolved. 
Withhold Zydelig if the ALT or AST is greater than 5 times the upper limit of normal, and 
continue to monitor AST, ALT and total bilirubin weekly until the abnormality is resolved. 
  
Severe Diarrhea or Colitis 
Severe diarrhea or colitis (Grade 3 or higher) occurred in 14% of patients treated with 
Zydelig monotherapy and 19% of patients treated with Zydelig in combination trials. 
Diarrhea can occur at any time. Avoid concurrent use of Zydelig and other drugs that 
cause diarrhea. Diarrhea due to Zydelig responds poorly to antimotility agents. Median 
time to resolution ranged between 1 week and 1 month across trials, following 
interruption of Zydelig therapy and in some instances, use of corticosteroids. 
 
Pneumonitis 
Fatal and serious pneumonitis occurred in patients treated with Zydelig. In randomized 
clinical trials of combination therapies, pneumonitis occurred in 4% of patients treated 


August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
37 
 
with Zydelig compared to 1% on the comparator arms. Time to onset of pneumonitis 
ranged from <1 to 15 months.  Patients taking Zydelig who present with pulmonary 
symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or 
a decline by more than 5% in oxygen saturation should be evaluated for pneumonitis.  If 
pneumonitis is suspected, interrupt Zydelig until the etiology of the pulmonary symptoms 
has been determined.  Patients with pneumonitis thought to be caused by Zydelig have 
been treated with discontinuation of Zydelig and administration of corticosteroids.   
 
Infections 
Fatal and/or serious infections occurred in 21% of patients treated with Zydelig 
monotherapy and 36% of patients treated with Zydelig in combination trials. The most 
common infections were pneumonia, sepsis, and febrile neutropenia. Monitor patients for 
signs and symptoms of infection and interrupt Zydelig for Grade 3 or higher infection. 
Serious or fatal Pneumocystis jirovecii pneumonia (PJP) or cytomegalovirus (CMV) 
occurred in <1% of patients treated with Zydelig. Consider prophylaxis for PJP. Interrupt 
Zydelig in patients with suspected PJP infection of any grade, and permanently 
discontinue Zydelig if PJP infection of any grade is confirmed. Interrupt Zydelig in the 
setting of positive CMV PCR or antigen test until the infection has resolved. If Zydelig is 
subsequently resumed, patients should be monitored (by PCR) for CMV reactivation at 
least monthly.  
 
Intestinal Perforation 
Fatal and serious intestinal perforation occurred in Zydelig-treated patients. At the time of 
perforation, some patients had moderate to severe diarrhea. Advise patients to promptly 
report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. 
Discontinue Zydelig permanently in patients who experience intestinal perforation 
 
Severe Cutaneous Reactions 
Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have 
occurred in patients treated with Zydelig. If SJS or TEN is suspected, interrupt Zydelig until 
the etiology of the reaction has been determined. If SJS or TEN is confirmed, permanently 
discontinue Zydelig. Other severe or life-threatening (Grade ≥3) cutaneous reactions, 
including dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, 
rash maculo- papular, rash papular, rash pruritic, exfoliative rash, and skin disorder, have 
been reported in Zydelig-treated patients. Monitor patients for the development of severe 
cutaneous reactions and discontinue Zydelig. 
 
Anaphylaxis 
Serious allergic reactions, including anaphylaxis, have been reported in patients on 
Zydelig. In patients who develop serious allergic reactions, discontinue Zydelig 
permanently and institute appropriate supportive measures. 
 
Neutropenia 
Treatment-emergent Grade 3 or 4 neutropenia occurred in 25% of patients treated with 
Zydelig monotherapy and 46% of patients treated with Zydelig in combination trials. 
Monitor blood counts closely. 
 
Embryo-fetal Toxicity 


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38 
 
Based on findings in animals, Zydelig may cause fetal harm when administered to a 
pregnant woman. Idelalisib is teratogenic in rats, at systemic exposures 12 times those 
reported in patients at the recommended dose of 150 mg twice daily. Advise females of 
reproductive potential to avoid becoming pregnant while taking Zydelig. If contraceptive 
methods are being considered, use effective contraception during treatment, and for at 
least 1 month after the last dose of Zydelig. 
 
11. CORRELATIVE STUDIES  
Please see Appendix D 
 
 
12. DATA REPORTING/REGULATORY CONSIDERATIONS  
Clinical data will be entered into the OnCore® database by performing site personnel. Information 
can be entered into Oncore® in a way that is 21CRF11.10 (electronic medical records) compliant.  
OnCore® is equipped for HIPAA-compliant internet-based entry of protocol tracking and review 
information. 
 
All study data will be collected by the research team at each and every study visit and recorded in 
the research record. This data will then be entered in to the OnCore® study database. 
 
All source documents will be obtained and retained along with any study forms, and placed into the 
patient’s research record. 
 
ADMINISTRATIVE AND REGULATORY DETAILS  
This study will be conducted in accordance with current U.S. Food and Drug Administration (FDA) 
Regulations, Good Clinical Practices (GCPs) and International Counsel on Harmonization (ICH) E6 
Guidelines. 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the trial and its results will be submitted to the 
Clinical Trials Data Bank, http://www.clinicaltrials.gov.  
Information posted will allow subjects to identify potentially appropriate trials for their disease 
conditions and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.     
 
 Institutional Review Board (IRB)  
This protocol will be submitted to the University of Maryland IRB.  Study procedures will begin once 
IRB approval is secured. All amendments, instances of reportable new information (i.e. 
unanticipated problems, data breaches, etc.) and continuing review reports will be submitted to the 
University of Maryland IRB. 
 
13. Clinical Trial Monitoring 
Data safety and verification monitoring will be conducted in accordance with the Greenebaum 
Cancer Center Sponsor-Investigator Monitoring Standard Operating Procedure (SOP), the Code of 
Federal Regulations (CFR), and FDA and International Counsel on Harmonization (ICH) E6 Guidelines. 
 
14. STATISTICAL CONSIDERATIONS 


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A true proportion of study subjects that are not removed from the study for toxicity or intolerance 
of 0.70 or higher will be considered satisfactory in this particular patient population. If the true 
proportion of severe toxicity -free patients is 50% or less, then Zydelig will not be considered a 
promising maintenance treatment post Autologous stem cell transplantation due to unacceptable 
toxicity. 
 
A single-stage open-label design will be used for the study. With 34 eligible patients on the study, 
the Type I error or probability of declaring drug desirable if the proportion of subjects removed from 
study due to toxicity or intolerability is 0.50 or higher, is 0.075.  The probability of rejecting the 
Zydelig as unacceptable due to severe toxicity compound if the proportion of subject who 
developed severe toxicity is less or equal to 30% rate is less than 20%. Hence, the study will have an 
adequate about 80% power. Addressing the safety of Zydelig, a maximum width 90% confidence 
interval for any grade 3 or higher toxicity will be about 32%, assuming that a total of 31 patients are 
enrolled. For instance, if 3 out of 31 patients (10%) develop grade 3 or higher non-hematologic 
toxicity, then a 90% confidence interval for the true toxicity rate is between 3% and 24%. For 31 
patients in this study, if the true unknown probability of a rare toxicity is 10%, the probability of 
observing 1 or more toxicities is 96%, for 5% it is 80%, and if the true toxicity rate is 3% then the 
probability of observing one or more rare toxicities is 61%.  
 
We plan to accrue 34 eligible patients to account for about 10% possible drop-out 
 
14.1 
Study Design/Primary Endpoints 
This single cohort open-label study will accrue 34 patients with iNHL or tiNHL. The 
biologically active dose of Zydelig will be 1st used at 100/150 mg PO BID. Within patient 
dose reductions are allowed for hematologic and non-hematologic toxicities above grade 
2. The proportion of patients removed from the study due to toxicity will be reported, 
along with all toxicities specified by type and grade. 
 
Early stopping guideline for toxicity: Toxicity will be monitored continuously. If it 
becomes evident that the proportion of patients being removed from the study for 
toxicity convincingly exceeds 50%, the study will be halted for a safety consultation. The 
toxicity stopping rule will hold enrollment. 
 
14.2 
Sample Size/Accrual Rate 
A sample size of 34 patients will be accrued and will be required to account for possible 
drop-out and inevaluability. The early stopping rule is defined above. Anticipated accrual 
is 1 patient per institution every 2 months. Therefore, accrual is anticipated to take from 
20 to 36 months.  
 
14.3 
Stratification Factors  
- 
Patients will be analyzed based on the indolent or aggressive type of NHL given that the 
two groups historically have different outcomes after AutoSCT. 
- 
Patients will be analyzed based on average daily dose of Zydelig through the treatment 
duration to assess for dose dependence on progression rate. 
 
14.4 
Analysis of Secondary Endpoints 
14.4.1 1-year PFS after ASCT.  


August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
40 
 
PFS is defined as the time from the date of ASCT till progression or death whatever 
comes first. PFS function will be estimated using the Kaplan-Meier approach with 90% 
Confidence Interval. 
Analysis of secondary objective(s):  
The 1-year PFS will be estimated and reported using the Kaplan-Meier curve with the 
corresponding 90% confidence interval.  
14.4.2 2-year PFS will be calculated with the same method as 1-year PFS (see 13.4.1). 
14.4.3 Cumulative incidences of NRM at 3 months and 12 months by competing risks model 
and Grey’s test. 
14.4.4  The Cox regression model will be used to assess plausible risk factors for PFS and OS. 
The correlatives findings will be incorporated into time-to-event analyses using 
appropriate statistical models. Statistical analysis will be conducted by the BSS of the 
GCC. 
14.4.5 Correlatives Studies 
Please see Appendix C 
 
15. REFERNCES 
1. Williams CD, Harrison CN, Lister TA, et al. High-dose therapy and autologous stem-cell support for 
chemosensitive transformed low-grade follicular non-hodgkin’s lymphoma: A case-matched study from 
the european bone marrow transplant registry. Journal of Clinical Oncology. 2001;19(3):727-735. 
2. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and 
survival in relapsed follicular non-hodgkin's lymphoma: Results from the randomized european CUP 
trial. J Clin Oncol. 2003;21(21):3918-3927. doi: 10.1200/JCO.2003.10.023 [doi]. 
3. U.S. food and drug administration. FDA approves zydelig for three types of blood cancers [media 
release]. 2014  http://Www.fda.gov/newsevents/newsroom/pressannouncements/ucm406387.htm  
4. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent 
lymphoma. N Engl J Med. 2014;370(11):1008-1018. http://dx.doi.org/10.1056/NEJMoa1314583. doi: 
10.1056/NEJMoa1314583. 
5. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic 
leukemia. N Engl J Med. 2014;370(11):997-1007. doi: 10.1056/NEJMoa1315226 [doi]. 
6. Pfeifer M, Lenz G. PI3K/AKT addiction in subsets of diffuse large B-cell lymphoma. Cell Cycle. 
2013;12(21):3347-3348. doi: 10.4161/cc.26575 [doi]. 
7. Sehn LH. Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell 
lymphoma. 
Hematology 
Am 
Soc 
Hematol 
Educ 
Program. 
2012;2012:402-409. 
doi: 
10.1182/asheducation-2012.1.402 [doi]. 
8. Pfeifer M, Grau M, Lenze D, et al. PTEN loss defines a PI3K/AKT pathway-dependent germinal center 
subtype of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013;110(30):12420-12425. doi: 
10.1073/pnas.1305656110 [doi]. 
9. Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for 
survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001;194(12):1861-1874. 
10. Majchrzak A, Witkowska M, Smolewski P. Inhibition of the PI3K/akt/mTOR signaling pathway in 
diffuse 
large 
B-cell 
lymphoma: 
Current 
knowledge 
and 
clinical 
significance. 
Molecules. 
2014;19(9):14304-14315. doi: 10.3390/molecules190914304 [doi]. 
11. Davids MS, Rodon J, Abrisqueta P, Egile C, Ruiz-Soto R, Awan F. Blood. 2013;122(21):4170-4170. 
12. 
Gilead 
sciences 
inc. 
ZYDELIG 
(idelalisib) 
US 
prescribing  
Information. 
2014. 
http://Www.accessdata.fda.gov/drugsatfda_docs/label/2014/206545lbl.pdf. 
accessed 31 jul 2014. .  


August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
41 
 
13. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. Journal 
of Clinical Oncology. February 10, 2007;25(5):579-586. doi: 10.1200/JCO.2006.09.2403. 
14. Owen RG, Kyle RA, Stone MJ, et al. Response assessment in waldenstrom macroglobulinaemia: 
Update from the VIth international workshop. Br J Haematol. 2013;160(2):171-176. doi: 
10.1111/bjh.12102 [doi]. 
  
 


August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
42 
 
16. Table 8  APPENDIX A Performance Status Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
4 
100% 
bedridden. 
 
Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
5 
Dead. 


August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
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17. APPENDIX B 
Patient Zydelig Diary 
 
 
PATIENT MEDICATION DIARY – Zydelig 
Today’s date ______________________________ 
Agent Zydelig 
Patient Name________________ (initials acceptable) 
Patient Study ID ______________ 
 
INSTSRUCTIONS TO THE PATIENT: 
 
1. Complete one form for each 4 week-period while you take Zydelig.  
2. You will take your dose of Zydelig twice a day.  You will take 100 mg or 150 mg tablets, depending on the 
instructions from your doctor. 
3. Record the date, the number of capsules of each size you took, and when you took them. Record doses as 
soon as you take them; do not batch entries together at a later time.  
4. If you have any comments or notice any side effects, please record them in the comments column.  If you 
make a mistake while you write, please cross it out with one line, put your initials next to it, and then write the 
corrected information next to your initials.  Example: SB 9:30 am. 
5. If you miss a dose of Zydelig, then you should take it as soon as you remember, as long as it is within 6 hours 
of the schedule.  If not, then you should skip the missed dose. 
6. Please return this form to your physician when you go for our next appointment.  
 
 
Day 
 
Date 
Time of daily dose 
# of tablets taken  
Comments 
AM 
PM 
100 mg 
150 mg 
 
1. 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
5. 
 
 
 
 
 
 
6. 
 
 
 
 
 
 
7. 
 
 
 
 
 
 
8. 
 
 
 
 
 
 
9. 
 
 
 
 
 
 
10. 
 
 
 
 
 
 
11. 
 
 
 
 
 
 
12. 
 
 
 
 
 
 
13. 
 
 
 
 
 
 


August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
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14. 
 
 
 
 
 
 
15. 
 
 
 
 
 
 
16. 
 
 
 
 
 
 
17. 
 
 
 
 
 
 
18. 
 
 
 
 
 
 
19. 
 
 
 
 
 
 
20. 
 
 
 
 
 
 
21. 
 
 
 
 
 
 
22. 
 
 
 
 
 
 
23. 
 
 
 
 
 
 
24. 
 
 
 
 
 
 
25. 
 
 
 
 
 
 
26. 
 
 
 
 
 
 
27. 
 
 
 
 
 
 
28. 
 
 
 
 
 
 
 
 
Physician’s Office Will Complete This Section: 
 
1. Date patient started this cycle: ________________________________________________ 
 
2. Date patient stopped this cycle: __________________________________________________ 
 
3. Patient’s dose cohort: ________________________________________________________________ 
 
4. Total number of capsules taken this month (each size): ______________________________________ 
 
5. Physician/Nurse/Data Manager’s Signature:_______________________________________________ 
 
 
 
 
Patient’s Signature: _____________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 


August 22nd, 2017, v 3.0, Jean Yared, M.D., Zydelig maintenance post-AutoSCT for iNHL or tiNHL 
 
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18. Appendix C. Inhibitors and Inducers of CYP3A 
 
Inhibitors and inducers of CYP3A enzymes are defined as follows. Further information can be found at 
the following website: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors 
 
indinavir  
nelfinavir 
ritonavir  
clarithromycin 
itraconazole 
ketoconazole  
nefazodone  
saquinavir  
suboxone  
telithromycin  
cobicistat  
boceprevir 
mibefradil 
telaprevir 
troleandomycin 
posaconazole 
Moderate inhibitors: 
aprepitant 
amprenavir 
amiodarone 
atazanavir 
ciprofloxacin 
cresemba 
crizotinib 
darunavir/ritonavir 
dronedarone 
erythromycin 
diltiazem 
fluconazole 
fosamprenavir 
grapefruit juice 
Seville orange juice 
verapamil 
Voriconazole a 
imatinib 
Weak inhibitors: 
cimetidine 
fluvoxamine 
All other inhibitors: 
chloramphenicol 
delavirdine 
diethyl-dithiocarbamate 
gestodene 
mifepristone 
norfloxacin 
norfluoxetine 
star fruit 
 
efavirenz 
nevirapine 
barbiturates 
glucocorticoids 
modafinil 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John’s Wort 
troglitazone 
 


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19. APPENDIX D CORRELATIVE STUDIES 
 
 
19.1 Background and Overview 
It is clear that some lymphomas become “addicted” to one or more oncogenic pathways, including the 
PI3K/Akt/mTOR axis. Patients with iNHL who are reliant on this pathway may be more responsive to 
Zydelig, which blocks PI3Kδ (1). However, there are no approved predictive biomarkers for PI3K/mTOR 
inhibitors’ activity. A recent report demonstrated that PTEN, p-AKT, and p-p70S6K correlated with 
response to trastuzumab in patients with metastatic breast cancer, lending support to the importance of 
the activation status of key proteins of the PI3K/AKT/mTOR pathway as predictive biomarkers for 
response(2).  
 
Similarly to other tyrosine kinase inhibitors, Zydelig activity is limited by de novo or acquired resistance 
(3). For example, p110α-mediated constitutive activation of PI3K has been shown to be a mechanism of 
resistance in this pathway through limiting the efficacy of p110δ-selective inhibition (4). The MEK1/2 
(mitogen-activated kinase 1/2)/ERK1/2 (extracellular signal-regulated kinase 1/2) pathway is one of the 
most frequently dysregulated signaling cascades in cancer, including in hematological malignancies (5). 
While PI3K inhibition induces compensatory activation of p-ERK, co-inhibition of the PI3K and ERK 
pathway potentiates the activity of PI3K inhibitors in several malignancies, including T-cell lymphomas 
(6-8). Given that the nature of our study lacks adequate power to definitively evaluate these biomarkers, 
our goal in this pilot study is to assess the feasibility and potential signal from several candidate 
biomarkers for response and resistance to Zydelig. 
 
As a PI3Kδ inhibitor, Zydelig has a profound effect on the immune system (9). It has been associated 
with colitis, pneumonitis, and hepatotoxicity suggestive of an autoimmune process. A recent report has 
demonstrated that inhibition of PI3Kδ in mice has a protective effect against several non-hematological 
cancers (10). The mechanism of action shown in this study was PI3Kδ-mediated inactivation of myeloid-
derived suppressor cells (MDSCs) and regulatory T cells (Treg) resulting in upregulation of CD8+ T cells. 
In addition, PI3Kδ play a role in the anti-tumor response of the natural killer (NK) cells (11, 12). Given 
these interesting results, we will determine whether regulatory T cell, CD8+ T cell, CD4+ T cell, NK cell, 
and MDSC populations change in patients enrolled in this trial, immediately prior to Zydelig, and at 3 
time points post starting Zydelig treatment (4 weeks, 12 weeks, and 6 months following the start of 
Zydelig).  
 
Whole exome sequencing (WES) has emerged as a powerful method for correlating genetic mutations 
with treatment response. Cancers are often associated with genetic alterations that result in up- or 
down-regulation of particular signaling pathways that can now be further defined through WES. Van 
Allen et al. recently performed whole exome sequencing on samples from patients with urothelial 
carcinoma that showed that somatic mutations in ERCC2, a component of the nucleotide excision repair 
pathway, correlate with response to cisplatin (13). We propose to perform a similar approach using WES 
on formalin-fixed, paraffin-embedded (FFPE) tissue sections or frozen tissue blocks from enrolled, 
consented patients and to compare DNA from tissue samples to germline DNA that will be extracted 
from either peripheral blood mononuclear cells (PBMC) or histologically normal tissue. In addition, we 
will repeat a biopsy at the time of relapse and perform WES in order to assess for the acquisition of 
additional genetic alterations that might explain the mechanism of resistance.  
 
In summary, correlative studies will be performed on samples from consenting patients to examine the 
following aims: 
 


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• 
Expression levels of p-AKT, PI3Kδ, PI3Kα, PTEN, p-p70S6K, and p-ERK pre- and post-Zydelig. 
Tumor samples (either bone marrow [BM] or lymph node [LN]) will be examined using 
immunohistochemistry (IHC).  
• 
Flow cytometric characterization of circulating MDSCs, NK cells, regulatory T cells, CD4+ T cells, 
and CD8+ T cells pre-Zydelig and at 3 time points following the start of Zydelig (post-Zydelig) at 
weeks 4 and 12, and at 6 months.  
• 
Whole exome sequencing of tumor and germline DNA pre-Zydelig and at relapse post-Zydelig.  
• Participation in the correlative studies portion of this study is highly encouraged but 
optional. 
 
19.2 Time Points 
Peripheral blood and tumor samples for WES and IHC will be collected at 2 time points: 
 
 Pre-treatment: FFPE or frozen tissue blocks samples taken from patients at time of 
transformation or relapse prior to starting Zydelig will be acquired. . Tissues obtained closer to 
starting Zydelig are highly preferred, but earlier biopsies for patients who will not have repeat 
biopsies just prior to study enrollment are acceptable. These samples will serve as a baseline 
for tracking acquired mutations or other genetic alterations associated with therapy 
resistance at relapse. The purpose of IHC and WES here is to evaluate biochemical and genetic 
markers for PI3K pathway activation and assessment of recurrent somatic mutations in 
lymphoma.   
 
 Post-Zydelig treatment: Samples taken following relapse of lymphoma after SCT and Zydelig 
treatment should be strongly encouraged for all patients, especially for those who had a 
biopsy just prior to starting Zydelig. These samples will be compared to baseline samples for 
tracking acquired alterations in signaling pathways associated with therapy resistance at 
relapse. The purpose of IHC and WES here is to identify biochemical and genetic factors that 
may contribute to “escape” from Zydelig-mediated suppression of the PI3K/Akt/mTOR axis, 
and to assess for changes in recurrent somatic mutation profiles and clonal architecture 
compared to a prior biopsy. 
 
For immunological studies, peripheral blood will be collected immediately prior to starting Zydelig 
and at the following time points after starting Zydelig: 4 weeks, 12 weeks, and 6 months.  
All samples, except for frozen specimens intended for WES, will be shipped to Maciej Kmieciak, 
PhD at VCU Massey Cancer Center (19.6.4). Frozen tumor specimens intended for WES will be 
shipped to the Fehniger Lab at Washington University (19.7).   
The Sample Collection Table 9outlines the sampling requirements for each time point and 
correlative endpoint. 
 
19.3 Collection and Processing at Participating Sites for IHC and Immunologic Studies 
Peripheral blood: 30 mL of whole blood will be drawn directly into 3 anticoagulated 10 mL blood 
collection tubes (containing sodium heparin or EDTA). Invert tubes 8-10 times to mix sample with 
anticoagulant. Samples will be labeled as specified in section 19.6.1 below and immediately 


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shipped at ambient temperature by overnight courier to VCU Massey Cancer Center (see 19.6.4 for 
shipping details). Samples must arrive at VCU Massey Cancer Center within 24 hours of blood 
draw. Coordinate with Dr. Maciej Kmieciak to ensure proper delivery on a business day.   
 
Please note that an additional tube of blood may be required for WES at certain time points (see 
19.4 below). 
 
Tumor samples will be obtained by core needle biopsy (3-5 cores) or whole LN resection at each 
time point. Institutional procedures should be followed for the procurement of the tumor samples. 
Procured BM or LN samples for IHC should be placed in formalin and held at room temperature 
until shipping (see Section 19.6.2). Please note that processing of tissue for WES samples is 
different from that described in this section.  
 
The Sample Collection Table 9 outlines the sampling requirements for each time point and 
correlative endpoint. 
 
19.4 Collection and Processing at Participating Sites for WES Studies 
For disease LN samples collected fresh, immediate snap freezing of an excisional biopsy piece or 
core biopsies is preferred. For disease bone marrow samples collected fresh, RBC lysis followed by 
centrifugation to form a cell pellet, and snap freezing is preferred. Peripheral blood samples will be 
processed as described in section 19.6, and sent immediately to VCU Massey Cancer Center for 
further processing (see 19.6.4 for shipping information). One tube of blood (10 mL) is required for 
each WES time point. Frozen specimens will be held in a freezer until shipped in batch on dry ice to 
Washington University. For FFPE tissue, tissue blocks or cores will be shipped to VCU Massey 
Cancer Center at room temperature in batch.  
 
The Sample Collection Table 9 outlines the sampling requirements for each time point and 
correlative endpoint. 
 
19.5 Sample Labeling for WES and IHC Studies 
Each collected sample should be labeled as follows: 
 Study number 
 Patient sequence identification number 
 Date of collection 
 Time of collection 
 Study time point (ie, pre-treatment or time post-treatment) 
 
19.6 Shipping to VCU Massey Cancer Center 
19.6.1 All blood samples (See Section19.6.4) for each patient must be shipped on dry ice by 
overnight courier immediately following collection. Samples must arrive within 24 hours of blood 
draw. Delivery must be coordinated with Dr. Maciej Kmieciak to ensure receipt of samples on a 
business day.   
 
19.6.2 Fixed tumor samples should not be shipped until both pre- and post-treatment samples 
have been acquired (ie, batched for each patient). The samples should be shipped in formalin at 
room temperature by overnight courier as soon as possible after the post-treatment samples have 
been procured. If post-treatment samples will not be procured, proceed with shipping of the pre-
treatment sample. 


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49 
 
 
19.6.3 FFPE tissue, tissue blocks or cores should be shipped to VCU Massey Cancer Center in batch 
at room temperature by overnight courier.  
 
19.6.4 Tumor and blood samples from all participating institutions will be shipped to the VCU 
Massey Cancer Center Clinical and Translational Research Laboratory (CTRL). The shipping date 
should be planned so that samples will arrive on a business day. Arrangements for delivery of 
samples being shipped within a 24-hour timeframe must be made in advance with the CTRL. 
Contact Dr Maciej Kmieciak in advance if any questions arise about timing of shipments. 
 
Ship to: 
Maciej Kmieciak, PhD 
VCU Massey Cancer Center 
Clinical and Translational Research Laboratory 
401 College Street 
Floor 1, Room G-111 
Richmond, VA 23298-0037 
Telephone (Office): 804-628-5337 
Telephone (Lab): 804-628-5335 
Email: mkmieciak@vcu.edu  
 
The VCU Massey Cancer Center CTRL will process and analyze all tumor samples collected for the 
correlative studies for IHC, as well as all blood samples intended for flow cytometric evaluation. VCU 
Massey Cancer Center will process blood for PBMC isolation and ship snap frozen PBMC pellets for 
sequencing to Washington University (see 19.7). Any FFPE samples intended for WES analysis will be 
shipped from VCU Massey Cancer Center to Washington University in batch. 
 
     19.7 Shipping to Washington University 
Frozen tissue samples will be shipped in batch to Washington University via Courier on dry ice. Samples 
should be labeled with the study UPN and sample information without including protected health 
information (PHI). Tracking numbers should be sent via email to addresses listed below prior to shipping, 
and all shipments should be received on a business day. Ship to: 
 
Attention: Fehniger Lab / WU-Oncology 
Southwest Tower Building, Room 634 
4940 Parkview Place 
St. Louis, MO 63110 
Phone: 314 747 1547 
Fax: 314 362 9333 
E-mail: tfehnige@wustl.edu, tchappe@dom.wustl.edu, bjewell@dom.wustl.edu 
 
   19.8 Sample Processing at VCU Massey Cancer Center 
 
17.8.1 FFPE tissue blocks and slides will be prepared, stained, and pathologically scored by Dr Kathryn 
Rizzo at VCU Massey Cancer Center. Validated antibodies for IHC staining include the following: PTEN 
(138G6) Rabbit mAb #9559 (Cell Signaling) (2), PI 3-kinase p110δ Antibody (A-8): sc-55589 (Santa Cruz) 
(15), PI3 Kinase p110α (C73F8) Rabbit mAb #4249 (Cell Signaling) (16), Phospho-Akt (Ser473) (736E11) 


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Rabbit mAb #3787 (Cell Signaling) (2), Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (D13.14.4E) XP® 
Rabbit mAb #4370 (Cell Signaling) (17), and Phospho-p70 S6 Kinase pThr389 Antibody PA1-526 (Cell 
Signaling) (2). Any FFPE samples intended for WES analysis will be shipped from VCU MCC to 
Washington University in batch. 
 
19.8.2 Blood samples will be processed immediately after arrival at VCU Massey Cancer Center for 
isolation of PBMC using Ficoll-Hypaque according to manufacturer-specified protocol and as previously 
described (14). Cells obtained for the pre- and post-treatment samples will each be divided into 2 
cryogenic tubes: tube A containing approximately 5 x 106 PBMC and tube B containing the remaining 
cells. For sequencing samples, 5 x 106 PBMC (tube A) will be pelleted, snap frozen, and shipped in batch 
to Washington University for nucleic acid isolation and sequencing. 
 
19.8.3 Flow cytometry analysis of PBMC samples will be performed by VCU Massey Cancer Center to 
assess the circulating levels of MDSCs, NK cells, regulatory T cells, CD4+ T cells, and CD8+ T cells. 
Validated antibodies for flow cytometry staining in this study include the following: anti-human CD33 PE 
(Biolegend), anti-human CD11b PE/Cy7 (Biolegend), anti-human HLA-DR Antibody APC (Biolegend), anti-
human Foxp3 PE (Bioscience), anti-human CD8a PE/Cy7 (Biolegend), anti-human CD4 FITC (Biolegend), 
anti-human CD25 APC (Biolegend), anti-human CD3 APC/Cy7 (Biolegend), anti-human CD56 PE 
(Biolegend), and Rat IgG2a K Isotype control PE (Bioscience) (18). 
 
19.9 Sample Processing at Washington University  
Genomic DNA (gDNA) will be isolated from FFPE or frozen tissue samples including diseased tissue and 
paired non-malignant tissue (QIAamp DNA mini kit, Qiagen). Quality control and mass assessments will 
be performed to ensure gDNA integrity prior to sequencing (Agilent bioanalyzer). From gDNA, Illumina 
sequencing libraries will be generated as described (19). Whole exome capture will be performed per 
manufacturer’s instruction (Nimblegen V3). Illumina sequencing will be performed as described (19). 
Somatic calls will be made using the latest version of the somatic variant bioinformatic pipeline (The 
Genome Institute at Washington University), utilizing sequencing data from paired lymphoma and non-
malignant tissue. Validation of variants may be confirmed using a custom-capture (Nimblegen), followed 
by Illumina sequencing approach (20). 
 
19.10 Sample Tracking 
Submission of all tumor samples will be logged into the appropriate fields in the database. 
 
19.11 Pharmacokinetics assessment 
Zydelig displayed in early trial linear pharmacokinetics (ie, not time dependent), a less-than dose-
proportional increase in exposure, and achieved steady state by day 8. Zydelig twice-daily administration 
resulted in higher trough concentrations, as expected, vs once-daily dosing at the corresponding dose 
level. 
 
 
 
 
 
 
 
 
 


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Table 9 
Sample Collection Table 
Sample 
Timepoints to be 
Collected 
Volume/patient 
Immediate Processing 
Instructions 
Tumor for IHC 
1. Pre-Zydelig 
treatment  
2. Post-Zydelig 
treatment 
Biopsy (3-5 cores of 
tumor or whole LN) 
Formalin at room 
temperature 
Tumor for sequencing 
1. Pre-Zydelig 
treatment  
2. Post-Zydelig 
treatment 
Fresh frozen or FFPE 
lymphoma tissue 
Snap freeze and storage 
at -20 to          -80°C 
Blood for Flow 
Cytometry 
1. Pre-Zydelig 
treatment 
2. 4 wks post-Zydelig 
treatmentA 
3. 12 wks post-Zydelig 
treatmentB 
4. 6 mo post-Zydelig 
treatmentB 
3 tubes of 30 mLC 
(10 mL per tube) 
 
Mix with anticoagulant 
and ship immediately to 
VCU Massey Cancer 
Center  
Blood for Whole Exome 
Sequencing 
1. Pre-Zydelig 
treatment  
2. Post-Zydelig 
treatmentD 
1 tube of 10 mLC 
 
Mix with anticoagulant 
and ship immediately to 
VCU Massey Cancer 
Center 
A. Plus or minus 1 week.  
B. Plus or minus 2 weeks. 
C. A total of 5x106 cells are required for the whole exome sequencing samples. Any extra cells can be 
discarded. If blood draw for flow cytometry and whole exome sequencing occurs on the same day, any 
“extra” cells from the WES collection tube may be combined in the sample for flow cytometry.  
D. Treatment will be done at End of Treatment for all patients enrolled.  
 
 
 
 
 
 
 
 


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19.12 References (Correlative Studies) 
1. 
Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kdelta 
inhibition by idelalisib in patients with relapsed indolent lymphoma. The New England journal of 
medicine. 2014;370(11):1008-18. 
2. 
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