Conditions: Diffuse Large B Cell Non-Hodgkin Lymphoma
Keywords: DLBCL
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This is a single institution phase I/II study using an ADAM17 inhibitor (INCB7839) with rituximab as consolidation therapy after an autologous hematopoietic cell transplant (HCT) for patients with diffuse large B cell lymphoma (DLBCL). The study consists of two phases. The dose finding phase is a modified version of a phase I trial and the extended phase is a modified version of a phase II trial.

Detailed description:
The primary goal of the dose finding phase is to determine the maximum tolerated dose (MTD) of INCB7839. Up to three dose levels will be tested (100 mg bid, 200 mg bid, and 300 mg bid). As the 300 mg bid has been proven safe in the non-transplant setting, dose escalation follows a Fast-Track Design with 1 patient enrolled per dose level unless a grade 2 or greater treatment emergent event occurs within the 1st 14 days of INCB7839. At that point, dose escalation converts to a standard 3+3 design and two additional patients are enrolled at the current dose level. If dose level 3 is completed without dose limiting toxicity (DLT) in the 1st 3 patients, an additional 3 patients will be enrolled at this level (without the staggering required by the DLT rules) prior to moving to the phase II component.

Once the phase I dose escalation is completed, an additional 12 patients will be enrolled at the MTD (or dose level 3, if no DLT) to obtain a more detailed toxicity profile as well as a preliminary estimate of progression free survival at 6 months post-transplant.

Arms:
arm 1: Rituximab will be given after day +28 re-staging and again 1 and 7 weeks later, followed by INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab Rituximab: Rituximab 375 mg/m2 IV after day +28 (as late as day 75) re-staging and again 1 and 7 weeks later INCB7839: INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab arm 2: Rituximab will be given after day +28 re-staging and again 1 and 7 weeks later, followed by INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab Rituximab: Rituximab 375 mg/m2 IV after day +28 (as late as day 75) re-staging and again 1 and 7 weeks later INCB7839: INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab arm 3: Rituximab will be given after day +28 re-staging and again 1 and 7 weeks later, followed by INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab Rituximab: Rituximab 375 mg/m2 IV after day +28 (as late as day 75) re-staging and again 1 and 7 weeks later INCB7839: INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab arm 4: Rituximab will be given after day +28 re-staging and again 1 and 7 weeks later, followed by INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab Rituximab: Rituximab 375 mg/m2 IV after day +28 (as late as day 75) re-staging and again 1 and 7 weeks later INCB7839: INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab

Interventions: intervention 1: Rituximab intervention 2: INCB7839
Intervention descriptions: intervention 1: Rituximab 375 mg/m2 IV after day +28 (as late as day 75) re-staging and again 1 and 7 weeks later intervention 2: INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab

Protocol document:
Prot_SAP_000.pdf: 
Masonic Cancer Center, University of Minnesota 
Cancer Experimental Therapeutics Initiative 
Blood and Marrow Transplantation Program 
 
 
Study of the ADAM17 Inhibitor INCB7839 Combined With Rituximab 
After Autologous Hematopoietic Cell Transplantation (HCT) For 
Patients With Diffuse Large B Cell Non-Hodgkin Lymphoma (DLBCL) 
HM2013-24 
CPRC #2013LS081 
IND 121921 
 
 
IND Sponsor/Principal Investigator: 
Veronika Bachanova, MD, PhD 
 
 
Co-Investigator: 
Jeffrey S Miller, MD 
 
 
Biostatistician: 
Qing Qao, MS 
 
 
Version Date: 
February 12, 2018 
 
 
 
 
 
 
Confidential 
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 2 of 44 
CPRC #2013LS081 
Revision History 
Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
 
11/06/2013 
original to CPRC 
 
 
12/26/2013 
in response to CPRC’s review 
 
 
01/30/2014 
• change study design from Simon’s optimal two-stage 
phase II to a phase I/II with INCB7839 dose escalation 
component – revisions throughout the protocol;  
• revise rituximab dose schedule adding 1 dose - rituximab 
is at 28 days post- transplant and then 1 and 7 weeks; 
• delay start of INCB7839 until day of 2nd rituximab dose;  
• change primary endpoint from disease free survival to 
progression free survival; 
• update and expand background; 
• edit and update inclusion/exclusion criteria; 
• clarify required DVT prophylaxis; 
• update standard of care and research “x” chart; 
• limit enrollment to 18 years and older; 
• other edits and clarifications throughout. 
n/a 
 
3/14/2014 
In response to FDA email dated 3/11/2014 
• convert from fast-track (accelerated titration design) to 
3+3 design after observing a grade 2 or greater treatment 
emergent toxicity (previously written as grade 3 or 
greater) 
• expand the definition of dose limiting toxicity to include 
selected hematologic toxicity, lower the threshold for DLT 
from grade 4 to grade 3 
• section 10.2 – document “unlikely” related adverse 
events leaving only “unrelated” adverse events not 
recorded, edit section 10.3 table for expedited reporting 
 
1 
06/04/2014 
• Study schema and section 8: convert study schedule 
from week based to day based, clarify f/u visits will 
coincide with transplant/SOC clinic visits (data obtained 
from BMT database), move PT/INR and D-dimer testing 
from SOC to research x chart 
• Section 10.2: correct definition of non-hematologic 
toxicity to match rest of protocol 
• Study schema, Sections 10.2 and 13.5: modify 
hematologic stopping rule to require persistence of 7 or 
more days 
• Section 9.1 – remove dose reference, delete 300 mg 
tablets (only 100 mg tablets are provided by 
manufacturer)    
• Other minor edits (all tracked) 
yes 
2 
04/26/2016 
• Through-out document:  mark the phase I component as 
enrollment completed March 2016 and set phase II dose 
at 300 mg bid 
• Sections 7.2.1 and 8.2:  reduce the frequency of D-dimer 
monitoring in the phase II component as abnormalities 
were not seen during phase I with a supportive care plan 
if > 3-fold increase 
• Section 7.2.3:  add a statement that dose modifications 
are allowed for individual patients and label current  - 
modifications as guidelines 
yes 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 3 of 44 
CPRC #2013LS081 
Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
• Section 8.1: standard of care – clarify screening may 
occur anytime post-transplant until day +60 
• Section 8.2:  research related – decrease d-dimer testing 
to screen, day 22 and final treatment visit; delete all 
PT/INR except baseline and final treatment visit; delete 
day 50 column (PT/INR and d-dimer deleted).add 
footnote number for day 64 and day 92 column; label day 
99 column as last day of study drug 
• Section 10: update to current IRB reporting requirements 
• Remove Linda Burns from the cover page as no longer at 
this institution 
3 
02/12/2018 
• Expand study enrollment window from through Day 60 
post-transplant to through Day 75 post-transplant 
• Add a window of ±7 days for the administration of the 3rd 
dose of rituximab 
• Remove Dr. Lazayan as Co-I from the cover page as no 
longer at this institution 
• Updates to the current protocol template 
yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IND Sponsor/Investigator Contact Information: 
Veronika Bachanova, MD, PhD 
Division of Hematology/Oncology/Transplantation 
Medicine Hematology Office 
MMC 480  
420 Delaware Street SE 
Minneapolis, MN 55455 
phone:  612-625-5469 
email:  bach0173@umn.edu 
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 4 of 44 
CPRC #2013LS081 
Table of Contents 
 
Protocol Synopsis ...................................................................................................................... 6 
Study Schema............................................................................................................................ 7 
1 
Objectives ........................................................................................................................... 8 
1.1 
Primary Objective......................................................................................................... 8 
1.2 
Secondary Objectives .................................................................................................. 8 
1.3 
Correlative Objectives .................................................................................................. 8 
2 
Background ......................................................................................................................... 8 
2.1 
Enhancing Cure Rate Of DLBCL After Autologous Hematopoietic Cell Transplant ...... 8 
2.2 
Rituximab Use After Autologous Transplantation In DLBCL ......................................... 9 
2.3 
Inhibition of ADAM17 Enhances NK Cell Function ......................................................10 
2.4 
Lymphoma-Associated Stress Ligands .......................................................................11 
3 
Summary and Rationale .....................................................................................................14 
3.1 
INCB7839 Dose Rationale ..........................................................................................14 
4 
Study Design .....................................................................................................................15 
5 
Patient Selection ................................................................................................................16 
6 
Patient Screening and Enrollment/INCB7839 Dose Level Assignment ...............................18 
6.1 
Consent and Study Screening in OnCore ...................................................................18 
6.2 
Study Enrollment ........................................................................................................18 
6.3 
INCB7839 Dose Level Assignment .............................................................................18 
6.4 
Patients Who Are Registered and Do Not Receive Study Treatment ..........................18 
7 
Treatment Plan ..................................................................................................................19 
7.1 
Rituximab ....................................................................................................................19 
7.2 
INCB7839 ...................................................................................................................19 
7.3 
Duration of INCB7839 .................................................................................................22 
7.4 
Duration of Study Participation ....................................................................................23 
8 
Schedule of Patient Activities .............................................................................................23 
8.1 
Standard of Care ........................................................................................................24 
8.2 
Research Related Procedures and Activities ..............................................................24 
9 
Study Drugs .......................................................................................................................25 
9.1 
INCB7839 ...................................................................................................................25 
9.2 
Rituximab ....................................................................................................................26 
10 
Adverse Event Reporting ................................................................................................27 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 5 of 44 
CPRC #2013LS081 
10.1 
Definitions ...................................................................................................................27 
10.2 
Adverse Event Documentation ....................................................................................29 
10.3 
Required Reporting: FDA, IRB, and MCC’s SAE Coordinator .....................................31 
11 
Study Data Collection and Monitoring .............................................................................32 
11.1 
Data Management ......................................................................................................32 
11.2 
Case Report Forms .....................................................................................................33 
11.3 
Data and Safety Monitoring Plan (DSMP) ...................................................................33 
11.4 
IND Annual Reports ....................................................................................................33 
11.5 
Monitoring ...................................................................................................................33 
11.6 
Record Retention ........................................................................................................34 
12 
Correlative Endpoints .....................................................................................................34 
13 
Statistical Considerations ...............................................................................................34 
13.1 
Rationale ....................................................................................................................34 
13.2 
Study Design ..............................................................................................................35 
13.3 
Phase II Power Calculation .........................................................................................36 
13.4 
Analysis ......................................................................................................................37 
13.5 
Early Study Stopping Rules – Phase II Component ....................................................37 
14 
Conduct of the Study ......................................................................................................37 
14.1 
Good Clinical Practice .................................................................................................37 
14.2 
Ethical Considerations ................................................................................................38 
14.3 
Informed Consent .......................................................................................................38 
15 
References .....................................................................................................................38 
Appendix I – Eligibility Checklist ................................................................................................40 
Appendix II – Performance Status Criteria ................................................................................42 
Appendix III – Phase 1-2 Study Combining INCB007839 Plus Trastuzumab In Patients With 
Previously Untreated Metastatic HER2+ Breast Cancer  ...........................................................43 
Appendix IV - INCB7839 Drug Log............................................................................................44 
 
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 6 of 44 
CPRC #2013LS081 
Protocol Synopsis 
Study of the ADAM17 Inhibitor INCB7839 Combined With Rituximab After 
Autologous Hematopoietic Cell Transplantation (HCT) For Patients With 
Diffuse Large B Cell Non-Hodgkin Lymphoma (DLBCL) 
Study 
Design: 
This is a single institution phase I/II study using an ADAM17 inhibitor (INCB7839) with 
rituximab as consolidation therapy after an autologous hematopoietic cell transplant (HCT) for 
patients with diffuse large B cell lymphoma (DLBCL). The study consists of two phases.  The 
dose finding phase is a modified version of a phase I trial and the extended phase is a 
modified version of a phase II trial. 
 
Rituximab (375 mg/m2) is given at 3 time points post-transplant - the 1st shortly after the day 28 
(but as late as day 75), with the 2nd and 3rd doses 1 and 7 weeks later. The oral ADAM 17 
inhibitor INCB7839 is taken twice daily at the assigned dose for 90 days beginning at the time 
of 2nd rituximab.    
 
The primary goal of the dose finding phase is to determine the maximum tolerated dose (MTD) 
of INCB7839. Up to three dose levels will be tested (100 mg bid, 200 mg bid, and 300 mg bid). 
As the 300 mg bid has been proven safe in the non-transplant setting, dose escalation follows 
a Fast-Track Design with 1 patient enrolled per dose level unless a grade 2 or greater 
treatment emergent event occurs within the 1st 14 days of INCB7839.  At that point, dose 
escalation converts to a standard 3+3 design and two additional patients are enrolled at the 
current dose level. If dose level 3 is completed without dose limiting toxicity (DLT) in the 1st 3 
patients, an additional 3 patients will be enrolled at this level (without the staggering required 
by the DLT rules) prior to moving to the phase II component.   
 
Once the phase I dose escalation is completed, an additional 12 patients will be enrolled at the 
MTD (or dose level 3, if no DLT) to obtain a more detailed toxicity profile as well as a 
preliminary estimate of progression free survival at 6 months post-transplant. 
 
Primary 
Objective: 
Phase I Dose Finding:  To determine the maximum tolerated dose (MTD) of INCB7839 when 
given in combination with rituximab as consolidation therapy after an autologous hematopoietic 
cell transplant (HCT) for diffuse large B cell lymphoma (DLBCL). 
Phase II Extension:  To establish a preliminary estimate of  progression free survival (PFS) at 
6 months post autologous HCT while gaining a more detailed toxicity profile of INCB7839 
when administered with rituximab as consolidation therapy  
Secondary 
Objectives: 
• To evaluate the safety and tolerability of INCB7839 in combination with rituximab  
• To determine incidence of serious adverse events  
• To evaluate 1 year disease-free survival  
• To evaluate 1 year overall survival  
• To determine time to relapse/progression 
 
Correlative 
Objectives: 
• To compare expression of CD16 and CD62L on natural killer (NK) cells and NK cells function 
after INCB7839 plus rituximab versus rituximab only and the baseline. 
• To correlate clinical response with NK frequencies, phenotype, and function  
 
Patient 
Population: 
Patients 18 years and older with DBLCL who underwent an autologous HCT and are in 
remission (CR, PR) or have stable disease at the day 28 post-transplant reassessment 
 
Enrollment: 
Phase I Dose Finding:  6 to 18 patients (Enrollment completed March 2016) 
Phase II Extension:  enroll an additional 12 patients at the phase I MTD 
 
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 7 of 44 
CPRC #2013LS081 
Study Schema 
 
 
 
 
  Start 
 
 
 
 
 
             
             Stop 
 
 
 
 
                      final rx visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study day    1             8         15 
       22 
    36 
 50 
64# 
78 
92#        105 
f/u^  
 
                         weekly clinic visits                            every 2 week clinic visits  
* also begin aspirin prophylaxis with the 1st dose of INCB7839 (unless on other anti-coag) and continue daily until 1 week after the 
last dose of INCB7839 (per section 7.2.1) 
     Rituximab 375 mg/m2 IV after day +28 re-staging and again 1 and 7 weeks later 
       Note: the 1st dose of rituximab may begin as late as day 75 post-transplant, refer to section 7 
     INCB7839 at assigned dose twice daily for 90 days – begin the morning of the 2nd dose of rituximab  
# day 64 and day 92: study coordinator to check in with patient, no clinic visit unless medically indicated 
Final treatment visit day 105 or 1 week after last dose of INCB7839 if discontinued earlier 
^F/U for disease and survival status will link to transplant related milestones and/or SOC visits with 
information obtained from BMT database 
INCB7839 Dosing Scheme 
Phase I Dose Finding:  ENROLLMENT COMPLETED MARCH 2016 – 300 mg BID for Phase II  
 
 
 
 
 
 
3+ 3 Design dose limiting toxicity (DLT) is defined as any of the following within the 1st 14 days of INCB7839: 
• any grade 3 or greater non-hematologic, non-infectious toxicity including thromboembolic 
complications 
• selected hematologic toxicity 
o grade 4 neutropenia lasting for ≥ 7 days 
o febrile neutropenia 
o grade 4 thrombocytopenia lasting for ≥ 7 days despite dosing delay 
o grade 3 thrombocytopenia associated with bleeding 
• inability to complete at least 10 days (20 doses) of twice daily INCB7839 therapy within the 1st 14 
days due to treatment related toxicity  
If dose level 3 is reached without DLT in the 1st 3 patients, an additional 3 patients (for a total of 6) will be 
enrolled without the 14 day waiting period 
Phase II Extension:  Enroll an additional 12 patients - INCB7839 at the maximum tolerated dose (MTD) 
established during phase I component or dose level 3 if no DLT 
 
Dose 
Level 
INCB7839 Dose 
(taken twice daily) 
Minimum # of 
Patients* 
1 
100 mg 
1 
2 
200 mg 
1 
3 
300 mg 
6 
Fast Track Design until 
≥grade 2 treatment emergent 
event or dose level 3 is 
reached, then convert to 3+3 
Design  
INCB7839 at assigned BID for 90 days - start with dose #2 of rituximab; 
end ~day 98, return to clinic 1 week later ~ day 105 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 8 of 44 
CPRC #2013LS081 
1 
Objectives 
1.1 
Primary Objective 
Phase I dose finding: To determine the maximum tolerated dose (MTD) of 
INCB7839 when given in combination with rituximab as consolidation 
therapy after an autologous hematopoietic cell transplant (HCT) for patients 
with diffuse large B cell lymphoma (DLBCL) 
Phase II expansion phase: To establish a preliminary estimate of 
progression free survival (PFS) at 6 months post autologous HCT while 
gaining a more detailed toxicity profile of INCB7839 when administered with 
rituximab as consolidation therapy 
1.2 
Secondary Objectives 
• To evaluate the safety and tolerability of the ADAM17 inhibitor 
INCB7839 in combination with rituximab  
• To determine incidence of serious adverse events  
• To evaluate 1 year disease-free survival 
• To evaluate 1 year overall survival  
• To determine time to relapse/progression 
1.3 
Correlative Objectives 
• To compare expression of CD16 and CD62L on natural killer (NK) cells 
and NK cell function after ADAM17 inhibitor INCB7839 plus rituximab 
versus rituximab only versus baseline   
• To correlate clinical response (relapse versus remission) with NK 
phenotype and function  
2 
Background 
2.1 
Enhancing Cure Rate Of DLBCL After Autologous Hematopoietic Cell 
Transplant 
Non-Hodgkin lymphoma (NHL) is the second most common hematologic 
malignancy. Diffuse large B cell lymphoma (DLBCL), the most common 
lymphoma subtype (30-40%), is an aggressive cancer that is rapidly fatal 
unless promptly treated. In the US, approximately 440,000 patients were 
treated for NHL in 2010 (SEER.gov). Patients with DLBCL experience 
frequent relapse and estimated 5-year survival rate is less than 50%.1, 2 
Standard treatment includes the use of high-dose chemotherapy with 
autologous 
hematopoietic 
cell 
transplantation 
for 
patients 
with 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 9 of 44 
CPRC #2013LS081 
chemosensitive recurrence. Although most patients initially achieve a 
remission, treatment fails for most patients. The relapse incidence is 
particularly high during the first 6 months after transplant3  (Figure 1).  There 
is an urgent need to develop well-tolerated and effective therapies to sustain 
remission in DLBCL. In this proposal, we hypothesize that chemoresistant 
lymphoma cells surviving post autologous 
transplantation retain sensitivity to 
cellular immune-mediated killing. This 
hypothesis is supported by clinical 
evidence that human natural killer (NK) 
and T cells can be used to treat 
cancer.4,5 NK cells (defined as CD3-
CD56+) are capable of killing virally 
infected or transformed cells without 
prior sensitization; however, autologous 
NK cells have to be activated to kill. Proposed 
trial presents the novel approach of combining 
monoclonal antibody therapy with the newly 
discovered strategy of augmenting both NK cell function and tumor homing. 
The treatment goal is to eliminate chemoresistant lymphoma cells after 
autologous transplantation. 
2.2 
Rituximab Use After Autologous Transplantation In DLBCL  
Rituximab’s key anti-cancer mechanism of action is mediated through 
FcγRIII (CD16) on NK cells; this receptor is by far the most potent NK 
activating receptor.6 Rituximab crosslinks CD16 and triggers vigorous 
production of cytokines and NK cell degranulation, leading to target cell 
killing (a process referred to as antibody-dependent cellular cytotoxicity; 
ADCC). Targeting CD20 on lymphoma cells with rituximab dramatically 
improves initial remission rates (by 10-20%), but resistance is common. The 
international CORAL study tested the impact of maintenance rituximab after 
autografting by evaluating DLBCL patients treated with rituximab or 
controls.6 The 4-year event-free survival rates were identical in the two 
groups (52% and 53%). The limitations of rituximab efficacy may be due to 
poor NK cell function post transplantation. The mechanism of rituximab 
resistance to be tested in this study presents a new therapeutic opportunity. 
We hypothesize that targeting CD16 with the ADAM17 inhibitor may 
potently improve rituximab efficacy after autologous transplantation.   
 
 
 
 
 
 
 
 
 
 
Figure 1.  Progression free survival in DLCBL after 
autologous transplant in low and high risk groups 
defined by International Prognostic Index at relapse1 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 10 of 44 
CPRC #2013LS081 
2.3 
Inhibition of ADAM17 Enhances NK Cell Function   
NK cells contain a germ line encoded set of receptors governing both their 
development and function. These receptors are either activating or 
inhibitory. Integration of downstream signaling pathways dictates how an 
NK cell will respond when interacting with its target. The most notable 
inhibitory receptors are the killer-immunoglobulin like (KIR) receptors which 
recognize the human leukocyte antigen (HLA) class I proteins (HLA-A, -B, 
and –C). The most potent NK activating receptor is FcRγ IIIA (CD16), 
present on most peripheral blood NK cells and all CD56dim NK cells. CD16 
mediates ADCC upon recognition of antibody-coated tumor cells, leading to 
target elimination through direct killing and cytokine production. Other 
activating receptors include NKG2D, which recognize “stress ligands” 
expressed on tumor cells. We recently identified a novel mechanism by 
which activated NK cells rapidly downregulate CD16.7  Loss of CD16 is an 
enzymatically regulated process limiting ADCC. Importantly, our group 
recently discovered that CD16 is clipped by a desintegrin and 
metalloproteinase-17 (ADAM17). We showed that inhibition of ADAM17 
with the small, orally available molecule INCB7839 consistently increased 
the killing of rituximab-coated lymphoma cells by preserving CD16 on NK 
cells. For the first time our data identified a novel target, ADAM17, that 
modifies the potency of monoclonal antibodies inducing ADCC. Importantly, 
the ADAM family enzymes including ADAM17 and ADAM10 are highly 
expressed in lymphoma tumor stroma.8 Additionally, others showed that 
lymphoma-associated stress ligands (ULBP3, MICA, MICB, and B7-H6) 
capable of activating NK cells are also ADAM17 targets9 
ADAM17 clips CD16 and L-selectin from NK cells and limits NK cell 
function. The anti-CD20 monoclonal antibody rituximab interacts with 
FcRIIIуa/CD16 on NK cells to induce ADCC. Upon antibody recognition, this 
activating NK cell receptor induces 
potent signals that result in cytokine 
production (IFNγ and TNFα) and cell 
cytotoxicity7,9 CD16 is rapidly down-
regulated when the NK cell is activated 
by various triggers (PMA, cytokines 
IL12+IL18, and HLA-class I negative 
cell target K562; Figure 2). This 
process, referred to as ectodomain 
clipping, is a proteolytic event that 
occurs at an extracellular site proximal 
to the plasma membrane resulting in 
Figure 2 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 11 of 44 
CPRC #2013LS081 
 
 
 
 
 
 
 
 
 
 
Figure 3 
soluble CD16 release. We were the first to report that the membrane 
metalloproteinase ADAM17 is expressed by human NK cells and clips off 
CD16 and the homing molecule L-selectin (CD62L) upon NK cell 
activation.7  
CD16 expression is decreased after treatment with rituximab in vivo. 
In a control experiment (Figure 3, top panel), we incubated CD56dim NK 
cells with rituximab (10 μg/ml) in vitro and showed that it does not block 
CD16 binding. We then tested 
peripheral blood from patients 
with DLBCL before and after 
the therapy with rituximab 
(375mg/m2 x 4 doses). At 
baseline CD56dim NK cells 
expressed 
high 
levels 
of 
CD16. After rituximab therapy, 
a large proportion of blood NK 
cells (46%) downregulated 
CD16 and became CD16 
negative (Figure 3, lower 
panel) 
demonstrating 
that 
rituximab treatment doses clip 
CD16 off NK cells in vivo. 
2.4 
Lymphoma-Associated Stress Ligands  
Others showed that ADAM family enzymes including ADAM10 and 
ADAM17 are expressed in lymphoma tumor stroma. Furthermore 
lymphoma-associated stress ligands (such as ULB, MICA, MICB and B7-
H6) are also ADAM17 protease targets.9 The significance of these findings 
is that therapeutic blockade of ADAM10 and ADAM17 seems promising for 
cancer treatment by targeting immune escape of tumors. 
2.5 
INCB7839 Is An Orally Bioavailable Small Molecule Selective 
Inhibitor Of ADAM17/ADAM10 
INCB7839 was recently developed by Incyte as an inhibitor of HER2 (also 
an ADAM17 target). The drug was tested in phase 1 studies in over 100 
patients. Results of these studies are summarized in below. 
 
 
Prior to Rituximab                      After Rituximab
Peripheral blood             In vitro control
CD56dim NK cells         CD56dim NK cells 
Rituximab in 
vitro 10μg/ml
Prior to Rituximab                      After Rituximab
Peripheral blood             In vitro control
CD56dim NK cells         CD56dim NK cells 
Rituximab in 
vitro 10μg/ml


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 12 of 44 
CPRC #2013LS081 
ADAM17 inhibitor INCB7839 plus rituximab augments NK cell 
cytokine production and cytotoxicity in vitro7 
 We recently demonstrated that pharmacological inhibition of ADAM17 
enhanced CD16-mediated NK cell function by preserving CD16 on the NK 
cell surface and thus increased the killing of rituximab-coated lymphoma 
cells.  In in-vitro assays, we purified human NK cells and incubated them 
with media alone, the B cell 
lymphoma line Raji, or Raji 
cells pre-incubated with 10 
mg/mL rituximab. Expression 
of CD16, CD62L (panel A), 
and intracellular IFNγ and 
TNFα 
(panel 
B) 
were 
measured 
after 
5 
hours 
(Figure 
4). 
Inhibition 
of 
ADAM17 
significantly 
attenuated clipping of both 
CD16 and CD62L from NK 
cells after incubation with 
rituximab-coated Raji cells (Figure A). In addition, ADAM17 inhibition 
significantly increased intracellular levels of IFN-g and TNF-a (Figure B).  
 Clinical Safety 
Phase 1 studies using INCB7839 
INCB7839 
is 
methyl 
(6S,7S)-7-[(hydroxyamino) 
carbonyl]-6-[(4-
phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2,5]octane-5-Carboxylate). 
INCB7839 is an orally bioavailable selective small molecule inhibitor of 
ADAM17/ADAM10 developed by Incyte (Wilmington, DE). It prevents 
clipping of the tumor ligands HER2 and ErbB by inhibiting the ADAM17 
protease in a dose-dependent manner. The half-life of dosing with the 
extended release tablet is 10-14 hours. Single and multiple-dose studies 
have been completed with INCB7839 in healthy volunteers. Adverse events 
were mild and self-limiting. INCB7839 (dosed 100-500mg twice a day; bid) 
was tested in an open label, dose-escalation, phase 1 study for solid 
tumors. A dose of 500mg bid was determined to be the maximum tolerated 
dose. The dose-limiting toxicity was deep venous thrombosis (DVT) with a 
total of 9 thrombotic events (in 41 patient months); however, nearly all 
patients had added thrombotic risk factors of advanced malignancy. 
However, there was not a clear relationship between the frequency of 
thrombosis and the dose administered. In patient without prophylaxis (low 
Figure 4 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 13 of 44 
CPRC #2013LS081 
dose ASA) the risk of DVT was 25%. The most recent phase 1 study 
combined INCB7839 (100-300mg bid) with the anti-HER-2 monoclonal 
antibody trastuzumab in 46 patients with previously untreated metastatic 
HER2+ breast cancer. 13 (poster in Appendix III)  The highest dose 
administered was 300mg bid, and side effects were modest. The most 
reported events (all causes) occurring in ≥ 10% of patients were: vomiting, 
pyrexia, anorexia, pain, diarrhea, dyspnea, asthenia, headache, cough, 
arthralgia, vascular events, abdominal pain, and back pain. Most were not 
serious.  The incidence of DVT was 10%, and thus, prophylactic measures 
are warranted to reduce the risk of thrombosis associated with INCB7839. 
 
CD16 plasma levels before and after therapy with INCB007839. We 
tested plasma levels of soluble CD16 in 11 patients enrolled to the 
trastuzumab+INCB7839 clinical trial by ELISA.  Soluble CD16 levels were 
significantly 
reduced 
after 
therapy 
with 
INCB7839 
(Figure 5).  
 
 
                                Figure 5: mean and standard deviation are shown.14 
2.6 
NK Cells Rapidly Develop After Autologous HCT And Express CD16  
The recovery of NK cells after 
autologous HCT is vigorous and 
prompt.  Four weeks after HCT, 
NK cells represent about 15-45% 
of lymphocytes (Figure 6) and 
are composed almost exclusively 
of 
CD56dim 
NK 
cells 
characterized 
by 
CD16 
expression. CD16 expression on 
CD56dim NK cells is 65-70% at all 
time-points after transplant, however NK function is often decreased.   
Figure 6 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 14 of 44 
CPRC #2013LS081 
2.7 
NK Cell Therapy Trial At University of Minnesota 
We have tested various strategies to enhance the cytotoxicity of NK cells to 
treat patients with lymphoma. We tested outpatient low-dose IL2 based 
immunotherapy in three clinical trials encompassing >75 patients to date.(9)  
Patients undergoing autologous HCT therapy including NHL patients were 
subsequently enrolled to a clinical trial combining daily subcutaneous IL2 
administration with infusion of autologous NK cells incubated ex vivo with 
IL-2 and combinations of IL-2 with Rituximab post autologous HCT.5,11,12  
There was significant clinical benefit of these therapies. More recently, we 
used allogeneic donor derived NK cells followed by IL-2 to treat refractory 
non-Hodgkin lymphoma patients (12) We treated 12 patients on this 
regimen and observed clinical remission in 40%, however the cost and 
complexities of production of NK cell product limited the large scale use.10  
This study builds on the established NK cell therapy program at University 
of Minnesota and explores novel platform to augment the activity of 
autologous NK cells with the use of the ADAM17 inhibitor INCB7839.   
3 
Summary and Rationale 
Our hypothesis is that the ADAM17 inhibitor INCB7839 will enhance the efficacy 
of rituximab-mediated autologous NK cell killing, resulting in a 20% improvement 
in progression free survival in DLBCL patients treated with autologous HCT.  
3.1 
INCB7839 Dose Rationale 
In this dose escalation plan, three dose levels of INCB7839 will be tested 
(100 mg bid, 200 mg bid, and 300 mg bid). The previous INCB7839 plus 
trastuzumab study showed that the 300 mg bid dose was safe; however this 
was in a non-transplant setting. Therefore this study will proceed cautiously, 
starting with a 100 mg dose but using a fast track design to minimize the 
number of patients exposed to a potentially non-therapeutic dose. With the 
fast-track design, one patient will be enrolled per dose level until a grade 2 
or greater treatment emergent toxicity is encountered. At that point, dose 
escalation will convert to a 3+3 design and three additional patients will 
enroll at the current dose level. Unless there is an interaction with the milieu 
seen in the post-transplant setting, it is expected all 3 dose levels will be 
completed without DLT and the 300 mg bid dose level will move to the 
phase II.  
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 15 of 44 
CPRC #2013LS081 
4 
Study Design 
This is a single institution phase I/II study using an ADAM17 inhibitor (INCB7839) 
with rituximab as consolidation therapy after an autologous hematopoietic cell 
transplant (HCT) for patients with DLBCL. The study consists of two phases.  The 
dose finding phase is a modified version of a phase I trial and the extended phase 
is a modified version of a phase II trial. 
The study is open to persons 18 years and older who are in a complete response, 
partial response or have stable disease at their 28 days post-transplant 
reassessment. Three doses of rituximab (375 mg/m2) will be given post-transplant. 
The first dose will be given at the day 28 post-transplant follow-up (but permitted 
through day 75), the 2nd dose 1 week later, and the 3rd dose 7 weeks after the 
1st. The oral ADAM 17 inhibitor INCB7839 at the assigned dose will be taken twice 
daily for 90 days (12 weeks). The 1st dose will be taken the morning of the 2nd 
rituximab dose after the research related labs are drawn.  
The primary goal of the dose finding phase is to determine the maximum tolerated 
dose (MTD) of INCB7839. Up to three dose levels of INCB7839 will be tested (100 
mg bid, 200 mg bid, and 300 mg bid). As the 300 mg bid has been proven safe in 
the non-transplant setting, dose escalation will follow a Fast-Track Design with 1 
patient enrolled per dose level until a grade 2 or greater treatment emergent 
adverse event occurs. A treatment emergent adverse event is any event not 
present prior to the initiation of the treatment (INCB7839) or any event already 
present that worsens in either intensity or frequency following exposure to the 
treatment. At that point, dose escalation will convert to a standard 3+3 design with 
two additional patients enrolled at the same dose level.  If dose level 3 is completed 
without dose limiting toxicity (DLT) in the 1st 3 patients, an additional 3 patients 
will be enrolled at this level (without the staggering required by the DLT rules) prior 
to moving to the phase II component. DLT is defined in section 7.2.2 of the 
protocol. 
Once the phase I dose escalation is completed, an additional 12 patients will be 
enrolled at the MTD (or dose level 300mg bid, if no DLT) to obtain a more detailed 
toxicity profile as well as a preliminary estimate of progression free survival at 6 
months post-transplant. Persons receiving less than 10 weeks of INCB7839 and/or 
fewer than 2 doses of rituximab will be replaced for the primary endpoint analysis. 
Patients will be followed for 1 year from transplant for progression free survival 
(PFS) and overall survival (OS). 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 16 of 44 
CPRC #2013LS081 
5 
Patient Selection 
Study entry is open to patients 18 years and older regardless of gender or ethnic 
background.  While there will be every effort to seek out and include women and 
minority patients, the patient population is expected to be similar to that of 
autologous HCT studies at the University Of Minnesota since this is a requirement 
for study entry.  
Inclusion Criteria 
5.1 
Patients 18 years or older who have undergone an autologous HCT for the 
treatment of DLBCL and are in a complete remission (CR), partial remission 
(PR) or have stable disease (SD) at the day 28 post-transplant 
reassessment 
5.2 
Karnofsky Score of ≥ 70% (appendix II) 
5.3 
Able to start the protocol therapy (1st dose of rituximab) between day 28-75 
post-transplant   
5.4 
Adequate organ function defined as: 
Hematologic:  platelets ≥ 50,000 x 109/L; ANC ≥ 1000 x 109/L unsupported 
by G-CSF or GM-CSF for 3 days   
Renal:  creatinine < 1.5 mg/dl or glomerular filtration rate > 50 ml/min   
Hepatic: 
 
Alanine 
transaminase 
(ALT, 
SGPT) 
and 
aspartate 
aminotransferase (SGOT, AST) < 3 x upper limit of institutional normal and 
total bilirubin < 3.0 mg/dl (if total bilirubin is ≥ 3.0 patient is eligible if direct 
bilirubin is within normal limits)  
Pulmonary:  clinically no evidence of pulmonary disease   
Cardiac:  no symptoms of uncontrolled cardiac disease 
5.5 
If post-transplant consolidation radiation therapy is given, the patient must 
be at least 14 days between last radiation treatment and 1st dose of 
rituximab  
5.6 
Able to take daily aspirin (325 mg) for the duration of INCB7839 treatment 
and 1 week after the last dose to reduce the risk of thrombosis (not 
applicable if on other anti-coagulant therapy at time of study enrollment – 
see section 5.11) 
5.7 
Females are either postmenopausal for at least 1 year, are surgically sterile 
for at least 3 months, or must agree to take appropriate precautions to avoid 
pregnancy (with at least 99% certainty) from screening through 12 months 
after the last dose of rituximab if of childbearing potential.  (Note:  Permitted 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 17 of 44 
CPRC #2013LS081 
methods that are at least 99% effective in preventing pregnancy should be 
communicated to the participants and their understanding confirmed).   
5.8 
Males must agree to take appropriate precautions to avoid fathering a child 
(with at least 99% certainty) from screening through 12 months after the last 
dose of rituximab.  (Note:  Permitted methods that are at least 99% effective 
in preventing pregnancy should be communicated to the participants and 
their understanding confirmed). 
5.9 
Voluntary written consent signed before performance of any study-related 
procedure not part of normal medical care 
Exclusions 
5.10 Pregnant or lactating – Studies to evaluate the potential for embryo toxicity 
and teratogenicity have not been performed for INCB7839.  Until additional 
information is available, women of childbearing potential should use 
appropriate precautions to avoid becoming pregnant.  Rituximab is 
Pregnancy Category C: There are no adequate and well-controlled studies 
of rituximab in pregnant women.  Females of childbearing potential must 
have a negative urine or serum pregnancy test within 14 days of study 
treatment start 
5.11 Recent venous thrombosis within 4 weeks prior to study enrollment.  
Patients at high risk for thrombotic events due to inherited risk factors (i.e. 
factor V Leiden) or DVT/PE in the past 12 months should be on secondary 
prophylaxis with anti-coagulant therapy (i.e. warfarin or low molecular 
weight heparin) prior to enrollment  
5.12 Active uncontrolled infection 
5.13 Active CNS disease 
5.14 Previous severe or life-threatening allergic reaction with rituximab or known 
allergy to the compounds found in INCB7839 
5.15 Any gastrointestinal condition causing malabsorption or obstruction (eg, 
celiac sprue, gastric bypass surgery, strictures, adhesions, history of small 
bowel resection, blind loop syndrome)  
5.16 Unwilling or unable to swallow tablets BID 
5.17 Serologic or clinical evidence of current active hepatitis B or C infection, 
defined as elevated levels of Hep B antigen or Hep C antibody (unless 
active infection is ruled out by nucleic acid tests) 
5.18 Known HIV infection 
 
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 18 of 44 
CPRC #2013LS081 
6 
Patient 
Screening 
and 
Enrollment/INCB7839 
Dose 
Level 
Assignment 
Written consent must be obtained prior to the performance of any research related 
tests or procedures. Consent is usually obtained before final eligibility is 
determined. 
Enrollment in the study and the 1st dose of rituximab may occur up to day 75 post-
transplant. 
6.1 
Consent and Study Screening in OnCore 
Any patient who has been consented is to be entered in OnCore by the 
Primary Clinical Research Coordinator (PCRC) or designee. If a patient is 
consented, but not enrolled, the patient’s record is updated in OnCore as a 
screen failure and reason for exclusion recorded.  
6.2 
Study Enrollment  
To be eligible for study enrollment, the patient must sign the treatment 
consent and meet each of the inclusion criteria and none of the exclusion 
on the eligibility checklist (Appendix I) based on the eligibility assessment 
documented in the patient’s medical record. 
The Primary Clinical Research Coordinator (PCRC) or designee will assign 
the study treatment arm and add the on-treatment date to complete 
enrollment. 
6.3 
INCB7839 Dose Level Assignment 
The PCRC or designee will assign each patient to the current dose level of 
INCB7839 no later than the day of the 2nd rituximab dose. 
In March 2016, enrollment to the phase I dose escalation component was 
completed with INCB7839 at 300 mg twice a day deemed the phase II 
dose.  
6.4 
Patients Who Are Registered and Do Not Receive Study Treatment 
If a patient is registered to the study, and is later found not able to receive 
the 1st dose of rituximab by day 75 post-transplant, for whatever reason, the 
patient will be removed from study and treated at the physician’s discretion. 
The PCRC or designee will update OnCore of the patient’s non-treatment 
status and notify the Principal Investigator. Study data will be collected until 
the time the patient is off study. The reason for removal from study will be 
clearly in OnCore. The patient will be replaced to complete enrollment. 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 19 of 44 
CPRC #2013LS081 
7 
Treatment Plan 
The first dose of rituximab will be considered study week 1 regardless of whether 
it is given at post-transplant day 28 or as late as post-transplant day 75. Routine 
post-transplant follow-up will continue as planned, independent of this study, 
although during active treatment study visits will be scheduled to coincide with 
transplant related visits (i.e. day 60, 100). Follow-up time points for disease and 
survival status will remain linked with a post-transplant visit at 6 and 12 months 
regardless of when the 1st dose of rituximab in given.  
7.1 
Rituximab 
Rituximab 375 mg/m2 IV will be administered per institutional guidelines at 
the following time points: 
• On (or shortly after) the day 28 post-transplant re-assessment, but 
no later than post-transplant day 60 
• 1 week (+/- 3 days) after the 1st dose 
• 7 weeks (+/- 7 days) after the 1st dose 
The first dose will be infused over 6 hours. Infusion should start at 50 
mg/hour and increase by 50 mg/hour every 30 minutes as tolerated to a 
maximal infusion rate at 400 mg/hour. If the infusion is well tolerated, the 
next two doses at 1 and 7 weeks may be administered at 100 mg/hour with 
100 mg/hour increments at 30 minutes intervals up to 400 mg/hour.     
Premedication: Acetaminophen 650 mg PO and diphenhydramine (e.g. 
Benadryl) 25 mg PO 30 minutes before each infusion.  
Persons receiving fewer than 2 doses of rituximab will be considered 
unevaluable and replaced. 
7.2 
INCB7839 
Patients will begin INCB7839 orally at the assigned dose bid the morning of 
the 2nd rituximab dose and after the research related blood samples are 
collected. In April 2016 the study moved to the phase II component with the 
INCB7839 dose set at 300 mg bid. Dose modifications in individual patients 
are permitted per section 7.2.3.   
The tablets are taken twice daily, morning and night, approximately 12 
hours apart for 90 days (+/- 3 days) with food.   
If the morning or evening dose is missed by more than 4 hours, the patient 
will skip that dose and take the next scheduled dose at the usual time.  
Skipped doses will not be made up. 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 20 of 44 
CPRC #2013LS081 
The patient will be provided with a daily drug log to record times of 
administration, side effects, and missed doses.  The patient will be 
instructed to bring the drug log and study drug bottles (including any 
empties) to each appointment for reconcilement.   
No pre-medications are recommended with the INCB7839 dosing, although 
side effects may be treated as needed (i.e. acetaminophen for headache, 
diphenhydramine for nausea).  
7.2.1 
Supportive Care 
In order to provide optimal patient care and to account for individual medical 
conditions, investigator discretion may be used in the prescribing of all 
supportive care drug therapy (i.e. anti-emetics, anti-pyretics).  
DVT prophylaxis (all patients):  On the same day that INCB7839 dosing 
is started, all patients will begin taking aspirin tablet (325 mg) once a day or 
on anticoagulant therapy (e.g. warfarin, low-molecular-weight heparin 
(LMWH) for the duration of INCB7839 administration and for 1 week 
afterwards as prophylactic measure to reduce the risk of thrombosis.    
In the event of “excessive DVT” defined as >20% thrombotic events in 
patients taking aspirin, all patients (current and future) will be discontinued 
from aspirin and begin anti-coagulation therapy (e.g. warfarin or LMWH at 
prophylactic dose) at the time of their next scheduled appointment.  Patients 
within 1 week of discontinuing INCB7839 may continue aspirin as planned. 
Serum D-dimer levels will be checked prior to the 1st dose of rituximab, at 
Day 22, and at the final study visit effective with the April 2016 protocol 
revision.  The frequency was decreased from the phase I monitoring 
schedule as abnormalities were not seen.  If D-dimer level increase >3-fold, 
than the patient will be considered at high risk of developing DVT/PET and 
will be switched to warfarin or LMWH for anticoagulation.  
7.2.2 
INCB7839 Dose Level Assignment  
Dose Finding Phase (COMPLETED MARCH 2016) 
INCB7839 dose level assignment will occur at the time of study registration 
based on the following Dose Level cohorts: 
 
 
 
Dose 
Level 
INCB7839 Dose 
(taken twice daily) 
Minimum # of 
Patients* 
1 
100 mg 
1 
2 
200 mg 
1 
3 
300 mg 
6 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 21 of 44 
CPRC #2013LS081 
Initially the Fast Track Design of 1 patient per dose level will be used until 
a grade 2 or greater treatment emergent adverse event is experienced. At 
that point, three additional patients will be enrolled at the same dose level 
and a standard dose escalation design will be used per section 13.2. 
Dose Limiting Toxicity is defined as any of the following within the 1st 14 
days of INCB7839 dosing: 
• any grade 3 or greater non-hematologic, non-infectious toxicity 
including thromboembolic complications 
• selected hematologic toxicity 
o grade 4 neutropenia lasting for ≥ 7 days 
o febrile neutropenia 
o grade 4 thrombocytopenia lasting for ≥ 7 days despite dosing 
delay 
o grade 3 thrombocytopenia associated with bleeding 
• inability to complete at least 20 doses of twice daily INCB7839 
therapy within the 1st 14 days due to treatment related toxicity  
Dose escalation to the next level cannot proceed until the following 
conditions are met: 
• At least 14 days has passed since the last patient within a dose level 
began INCB7839 
• The maximum tolerated dose (MTD) has not been exceeded 
If dose level 3 is reached without DLT in the 1st 3 patients, an additional 3 
patients (for a total of 6) will be enrolled without the 14 day waiting period. 
Phase II Extension (OPENED TO ENROLLMENT APRIL 2016) 
In March 2016 INCB7839 at 300 mg bid was declared the phase II dose 
level. An additional 12 patients will be enrolled at the MTD established 
during the phase I component adhering to the early stopping rules found in 
section 13.4.   
7.2.3 
INCB7839 Dose Modification/Interruptions 
Refer to section 7.2.1 for prevention and management of thromboembolic 
complications. 
With activation of the Phase II extension in April 2016, both dose 
reductions and dose interruptions are permitted in individual patients at the 
discretion of the treating physician if the 300 mg bid dose is not well 
tolerated.   


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 22 of 44 
CPRC #2013LS081 
Dose reductions will follow the phase I dose levels (i.e. 300 mg bid reduced 
200 mg bid reduced 100 mg bid).   
Dose interruptions of up to 14 days are permitted, restarting with or without 
a dose reduction.   
General Guidelines: 
Grade 1 and 2 adverse events will be treated as medically appropriate and 
the INCB7839 dose may be reduced by one phase I dose level (i.e. 300 mg 
bid may be reduced to 200 mg bid). 
INCB7839 administration should be interrupted in the event of a CTCAE v4 
grade 3 or 4 treatment related toxicity despite best medical support, until 
resolution to grade 1 or better. The patient may be restarted on INCB7839 
at 1 dose level lower (i.e. 300 mg reduced to 200 mg bid).   
Skipped doses will not be made up. 
In general a patient would be taken off treatment if any of the following 
occurs: 
• a treatment break is for more than 14 days 
• the patient is unable to tolerate INCB7839 at 100 mg bid 
• if the toxicity recurs (≥ grade 3) despite a dose reduction 
Note:  any treatment related grade 4 or 5 event may count toward the 
study’s early stopping rules per section 13.5. 
7.3 
Duration of INCB7839  
Patients will take INCB7839 twice a day beginning with the 2nd dose of 
rituximab and continuing for 90 days (+/- 3 days) unless: 
• consent is withdrawn 
• patient refuses INCB7839 or is non-compliant 
• more than 14 days pass without dosing (regardless of reason), the 
patient is unable tolerate INCB7839 at the100 mg bid level or a 
toxicity recurs (≥ grade 3) after a dose reduction  
• disease progression 
• unacceptable toxicity 
• in the treating physician’s medical judgment, continuing with 
INCB7839 is not in the best interest of the patient’s health or well-
being 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 23 of 44 
CPRC #2013LS081 
During the extension phase, patients receiving less than 10 weeks of 
INCB7839 or less than 2 doses of rituximab for reasons other than toxicity 
will be replaced. 
7.4 
Duration of Study Participation 
Active study participation will end 1 week after the last dose of INCB7839 
unless there is ongoing treatment related toxicity, which will be treated as 
medically appropriate with follow-up until toxicity resolves to grade 1 or 
better or is stable for 3 months. 
Patients will be seen at 6, 9 and 12 months post-transplant as part of the 
standard of care follow-up with information regarding disease status and 
survival recorded for this study unless one of the following occurs: 
• consent is withdrawn  
• patient is unevaluable – if a patient is not evaluable, follow only until 
the resolution or stabilization of treatment related toxicity 
8 
Schedule of Patient Activities 
For patient convenience and unnecessary clinic visits; some flexibility is permitted 
in scheduling study related visits and activities. Through the day 22 visit a window 
of ± 3 days is permitted. A window of ± 7 days is permitted for the 3rd dose of 
rituximab. After day 22, visits will coordinate with BMT anniversary visits whenever 
feasible; however a window of ± 7 days is permitted for any study visits not linked 
to a BMT anniversary visit. After the end of treatment visit, disease and survival 
status will be obtained from the BMT database. 
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 24 of 44 
CPRC #2013LS081 
8.1 
Standard of Care 
Study Time 
Point 
Screening 
(any time 
between day 
+28 and +60))  
Day 
11 
Day 
8  
2- 4 days 
after 2nd 
rituximab 
dose 
(refer to 
8.2) 
Day 
15 
Day 
22 
Day 
36 
Day 
50  
Day 
78 
End Of 
Treatment 
Visit 
Day 105 
F/U for 
Disease 
and 
Survival 
Status3 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Physical Exam 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
 
X 
 
X 
 
Review of 
transplant related
side effects 
X 
 
 
 
 
 
 
 
 
 
 
Karnofsky PS 
X 
 
 
 
X 
X 
 
 
 
X 
 
CBC/diff/plt 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Comprehensive 
Metabolic panel 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Pregnancy test 
if applicable 
X 
 
 
 
 
 
 
 
 
 
 
Disease 
Evaluation2  
X 
 
 
 
 
 
 
 
X 
 
X3 
Rituximab 
 
X 
X 
 
 
 
 
X 
 
 
 
1 – day 1 may occur anytime between day 28 and day 75 post-transplant 
2 – disease evaluations are the results of the transplant related follow-ups at approximately day +28 and day +100 
post-transplant 
3 – follow-up after the final treatment visit is linked to transplanted related milestones and/or standard of care visits – 
information for this study will be obtained from routine data collected by the BMT database 
 
8.2 
Research Related Procedures and Activities 
Study Time Point  
prior to 
1st dose 
of 
rituximab  
Day 8 
prior to 
2nd dose 
of 
rituximab  
2-4 days 
post 2nd 
dose of 
rituximab 
Day 
15 
Day 
22 
 
Day 
36 
 
Day 64 and 
Day 923 
Day 
78 
Day 
99 
(last 
dose 
of 
drug)2 
Day 
1054 
 
PT/INR 
X 
 
 
 
 
 
 
 
 
X 
D-dimer refer section 
7.2.1 
X 
 
 
 
X 
 
 
 
 
X 
Review of drug log 
(AEs)/ tablet count 
 
X 
 
 
 
X 
X3 
X 
 
X 
Monitor for stopping 
rules (phase II) 
Per section 13.5 by 4 months post-transplant 
five 10 ml heparin 
(green top) tubes, 
one 10 ml serum 
(red top) tube 
X 
X 
X 
 
X 
 
 
X 
 
X 
INCB7839 
 
begin assigned dose bid daily for 90 days (+/-3 days) 
 
1 – all blood samples go to TTL 
2- day 99 is not a scheduled clinic visit but instead the time point where the patient discontinues drug 
3- at day 64 and 92 – research nurse or designee will contact the patient; visits are not required.  
4 - or 1 week after the last dose of INCB7839 if stopped  earlier 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 25 of 44 
CPRC #2013LS081 
All samples go to the Masonic Cancer Center’s Translational Therapy Lab 
(TTL). 
 
Research sample collection is tied to the clinical care schedule of events 
and their associated window for performance. Therefore, if a clinical time 
point does not occur or is altered, the research related time point will be 
adjusted (or eliminated) as appropriate.  
 
It is recognized that with novel therapies as used in this study, the timing of 
protocol directed research samples may miss important patient specific 
events.  For this reason, up to 3 extra samples for a total of 180 ml of blood 
may be drawn at additional time points that are not specified above.   
9 
Study Drugs 
9.1 
INCB7839 
Classification:  ADAM Inhibitor 
Dosage and Administration Schedule:  For the purposes of the study, 
INCB7839 will be administered twice daily for 90 days beginning with the 
2nd dose of rituximab 
Dose Forms and Strengths:  100 mg tablets 
Availability:  For the purposes of this study INCB7839 will be provided by 
the manufacturing, Incyte Corporation packaged in HDPE bottles.  All 
bottles of Incyte investigational product contain the following language:  
“Caution:  New Drug—Limited by Federal Law to Investigational Use”.   
INCB7839 Expected Side Effects:  In healthy volunteer studies, mild 
nausea, headache, dizziness, and tinnitus have been noted which may 
possibly be due to administration of INCB7839. One patient with a history 
of hot flashes experienced a hot flash of moderate intensity. One subject 
experienced a SAE of DVT that was possibly related to drug exposure; this 
patient was subsequently found to have a deficiency of antithrombin-III. 
In studies of cancer patients, INCB7839 has generally shown to be tolerated 
at doses up to 500 mg bid.  Adverse events most frequently occurring in 
patients receiving INCB7839 include nausea or vomiting, anorexia, fatigue, 
dyspnea, constipation, pyrexia, cough, asthenia, and headache. 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 26 of 44 
CPRC #2013LS081 
Thrombotic events, primarily venous thromboses, have been observed at a 
higher than expected rate for the study population; thrombosis is defined as 
the dose-limiting toxicity. Investigators should discuss the risk with their 
patients, and maintain a high level of vigilance for signs of possible 
thromboembolism. Prophylactic anticoagulation is used as a precaution; it 
is not currently known how effective these measures are in reducing the risk 
of thromboembolism. 
Please refer to the Investigator Brochure for additional information. 
Contraindications: INCB7839 is contraindicated in subjects with clinically 
significant hypersensitivity to any component of its formulation. 
9.2 
Rituximab  
Trade name:  Rituxan  
Classification:  Monoclonal Antibody, Antineoplastic Agent 
Category:  Biological Response Modifier Agent 
Dosage and Administration Schedule:  For the purposes of the study, 
Rituximab 375 mg/m2 IV administered per institutional guidelines within 4 
weeks of the day 28 post-transplant re-assessment and again 2 and 8 
weeks later. 
Dose Forms and Strengths:  100 mg/10 mL and 500 mg/50 mL solution 
in a single-use vial    
Availability:  Available by prescription 
Warnings And Precautions:  
• 
Tumor lysis syndrome – administer prophylaxis and monitor renal 
function 
• 
PML - monitor neurologic function. Discontinue rituximab 
• 
Hepatitis B reactivation with fulminant hepatitis, sometimes fatal – 
screen high risk patients and monitor HBV carriers during and several 
months after therapy. Discontinue Rituxan if reactivation occurs. 
• 
Cardiac arrhythmias and angina can occur and can be life threatening. 
Monitor patients with these conditions closely. 
• 
Bowel obstruction and perforation - evaluate complaints of abdominal 
pain. 
• 
Do not administer live virus vaccines prior to or during Rituxan. 
• 
Monitor CBC at regular intervals for severe cytopenias 
• 
Pregnancy Category C 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 27 of 44 
CPRC #2013LS081 
10 
Adverse Event Reporting 
Toxicity and adverse events will be classified according to NCI's Common 
Terminology Criteria for Adverse Events V 4.0 (CTCAE). A copy of the CTCAE can 
be 
downloaded 
from 
the 
CTEP 
home 
page 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_
40). 
10.1 Definitions 
Note:  throughout this section the generic term “drug” refers to the 
INCB7839 and rituximab. 
The following definitions are based on the Code of Federal Regulations Title 
21 Part 312.32 (21CFR312.32(a)). 
Adverse Event:  Any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related.  
Suspected Adverse Reaction:  Any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  
Treatment-Emergent Adverse Event:  Any event not present prior to the 
initiation of the treatment or any event already present that worsens in either 
intensity or frequency following exposure to the treatment.  A treatment 
emergent AE refers to an event temporally related to the study treatment 
regardless of the causality assessment by the investigator. 
Life-Threatening Adverse Event Or Life-Threatening Suspected 
Adverse Reaction: An adverse event or suspected adverse reaction is 
considered “life-threatening” if, in the view of either the investigator or 
sponsor, its occurrence places the patient or subject at immediate risk of 
death. 
Serious Adverse Event Or Serious Suspected Adverse Reaction:  An 
adverse event or suspected adverse reaction is considered “serious” if, in 
the view of either the investigator or sponsor, it results in any of the following 
outcomes:  
• Death 
• A life-threatening adverse experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
• A congenital anomaly/birth defect.  


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 28 of 44 
CPRC #2013LS081 
• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition 
If either the IND sponsor or the investigator believes the event is life-
threatening or serious, the event must be evaluated by the sponsor for 
expedited reporting (21CRF 312.32(a)).  
Unexpected adverse event or unexpected suspected adverse 
reaction: An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the 
current application, as amended.  Thus, adverse events that occur as part 
of the disease process or underlying medical conditions are considered 
unexpected; however, they will not be reportable per section 10.3. 
Unanticipated (unexpected) problems/events as defined by the 
University Of Minnesota IRB are those that are not already described as 
potential risks in the consent form, not listed in the Investigator’s Brochure 
or not part of an underlying disease. 
Note:  The major discord between the FDA and IRB definitions is whether 
or not the underlying disease is included when considering expectedness. 
The following definitions are from the Masonic Cancer Center’s Standard 
Operating Procedure (SOP) Deviation Reporting: 
 
Major Deviation: A deviation or violation that impacts the risks and benefits 
of the research; may impact subject safety, affect the integrity of research 
data and/or affect a subject’s willingness to participate in the research. 
Deviations that place a subject at risk, but do not result in harm are 
considered to be major deviations. 
 
Minor Deviation: A deviation or violation that does not impact subject safety, 
compromise the integrity of research data and/or affect a subject’s 
willingness to participate in the research. 
Expedited (Rapid) Reporting: Certain events may require rapid 
notification to entities providing patient safety oversight (e.g. IRB, FDA) as 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 29 of 44 
CPRC #2013LS081 
detailed in section 10.3. For the IRB this is 5 business days. For studies 
under an IND, it is 7 or 15 calendar days. 
10.2 Adverse Event Documentation 
For the purposes of this study adverse event monitoring will begin with the 
1st dose of rituximab. The adverse events associated with rituximab in the 
post-transplant setting are well characterized and expected events will not 
be documented. However, any event felt at least possibly related to 
rituximab and meets the criteria for expedited reporting per section 10.3 will 
be documented. 
  
Adverse event documentation for INCB7839 will begin with the 1st dose.  
Events will be recorded onto study specific case report forms based on the 
following table: 
Relation to 
INCB7839 
Grade 1 
Grade 2 
Grade 3 
Grade 4 and 5 
Expected or 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected or 
Unexpected 
Unrelated  
Not required 
Not required 
Not required 
Not required 
Required 
Required 
Possible 
Probable 
Definite 
Unlikely 
Not required 
Required  
Required  
Required 
Required 
Required 
 
After the final treatment visit approximately 1 week after the discontinuation 
of INCB7839 formal AE documentation will end, however; the investigator 
must report upon knowledge any study treatment related event meeting the 
criteria for expedited reporting in section 10.3 or events related to the study 
stopping rules. 
During the Fast-Track Design:  any grade 2 or greater treatment emergent 
adverse event during the 1st 14 days of INCB7839 
Dose Limiting Toxicity:  The following events within the 1st 14 days of 
INCB7839 meet the definition of dose limiting toxicity during the dose 
escalation phase component and must be reported to the MCC Study 
Coordinator using the DLT Report Form: 
• 
any grade 3 or greater non-hematologic, non-infectious toxicity including 
thromboembolic complications 
• 
selected hematologic toxicity within the 1st 14 days of INCB7839 
o grade 4 neutropenia lasting for ≥ 7 days 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 30 of 44 
CPRC #2013LS081 
o febrile neutropenia 
o grade 4 thrombocytopenia lasting for ≥ 7 days despite dosing delay 
o grade 3 thrombocytopenia associated with bleeding 
• 
inability to complete at least 10 days (20 doses) of twice daily INCB7839 
therapy within the 1st 14 days due to treatment related toxicity 
 
Stopping Rule Events:  The following events count toward a study stopping 
rule during the phase II (extension) component per section 13.5 and must 
be reported to the MCC Study Coordinator using the Early Stopping Rule 
Report Form: 
• Grade 4-5 non-hematologic toxicity by 4 months post-transplant 
• Grade 4-5 hematologic toxicity lasting 7 or more days by 4 months 
post-transplant 
Events that count toward dose limiting toxicity or an early stopping rule do 
not necessarily constitute a serious adverse event requiring expedited 
reporting and should be reported as such only if they meet the criteria for 
expedited reporting to the IRB as defined in section 10.3. 
In addition, although not always an event requiring expedited reporting, 
deaths with cause will be recorded in OnCore upon knowledge in the follow-
up tab. 
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 31 of 44 
CPRC #2013LS081 
10.3 Required Reporting: FDA, IRB, and MCC’s SAE Coordinator 
 
In each IND safety report, the sponsor must identify all IND safety reports 
previously submitted to the FDA concerning a similar suspected adverse reaction 
and must analyze the significance of the suspected adverse reaction in light of the 
previous, similar reports. 
The SAE Coordinator will provide the Masonic Cancer Center’s Data and Safety 
Monitoring Council (DSMC) with the SAE in an appropriate format depending on 
the individual SAE (as reported or in a summary format). 
 
 
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
address/ 
fax 
numbers 
Copy AE to: 
U of MN 
IRB 
Unanticipated death of a locally enrolled subject(s); New or 
increased risk; Any adverse event  that require a change to 
the protocol or consent form – refer to the IRB website for 
complete details 
Within 5 
business 
days of 
event 
discovery 
Report 
Form 
irb@umn.edu 
 
SAE 
Coordinator 
mcc-
saes@umn.edu 
and copy to 
Incyte 
Corporation 
Clinical deviations per current IRB reporting requirements 
OnCore 
Deviation 
Form  
FDA 
 
Unexpected fatal or life threatening adverse reaction except 
those that can clearly be determined to be unrelated to 
INCB7839 
7 
Calendar-
Day 
MCC 
SAE 
Submit to 
CDER as an 
amendment 
to IND 
1) Serious and unexpected adverse reaction  except those 
that can clearly be determined to be unrelated to INCB7839 
or 
2)  increased occurrence of serious suspected adverse 
reactions over that listed in the protocol or investigator 
brochure or 
3) findings from other sources (other studies, animal or in 
vitro testing) 
15 
Calendar-
Day 
All other events per CRF 312.33 
At time of 
IND annual 
report 
Summary 
format 
Submit as 
part of the 
IND annual 
report 
n/a 
Note:  Events clearly determined to be unrelated to INCB7839 and felt due to the disease under treatment. the recent 
transplant or an underlying medical condition will not require expedited reporting to the FDA for the purposes of 
this study 
Masonic 
Cancer 
Center 
SAE 
Coordinator 
Events that count toward a dose limiting toxicity or stopping 
rule 
At time of 
reporting 
Event 
Form 
SAE 
Coordinator 
mcc-
saes@umn.
edu 
Not applicable 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 32 of 44 
CPRC #2013LS081 
11 
Study Data Collection and Monitoring 
11.1 Data Management 
This study will collect regulatory and clinical data using University of 
Minnesota CTSI’s instance of OnCore® (Online Enterprise Research 
Management Environment). 
 
The Oncore database resides on dedicated secure and PHI compliant 
hardware consisting of 3 physical servers: dev, DR, and production. The 
dev server is located in the University of Minnesota (UMN) datacenter 
(WBOB) and houses six database instances (test, train, sandbox, mcc 
reports, oncdm, and vendor) that are backed up locally because the data is 
refreshed from Oncore production data. The production server is located in 
the UMN datacenter (WBOB). All the data servers are managed by the 
Academic Health Center – Information Systems (AHC-IS) virtual servers 
which utilize clustered infrastructure to provide real-time failover of virtual 
servers. This real-time clustering is physically limited to the UMN data 
center. All relevant AHC IS procedures related for PHI compliant servers 
(as required by the Center of Excellence for HIPAA Data) apply to Oncore 
databases. 
 
The integrated data will be stored in PHI compliant servers managed by 
AHC IS with access given to those authorized users in the Clinical and 
Translation Science Institute Informatics team (CTSI BPIC and MCC CISS). 
The data will be integrated and extracted to researchers through the CTSI 
Informatics team and will be delivered through secure and compliant 
mechanisms (e.g. AHC IE data shelter, BOX, sftp, etc). If data de-
identification is needed, then compliant AHC IE data de-identification tools 
will be used. The informatics team will grant the IRB approved study team 
members access to data. 
 
Additional data about correlative laboratory samples generated by the 
Masonic Cancer Center Translational Therapy Laboratory (TTL) from the 
protocol-directed correlative research samples is stored in their Laboratory 
Information Management System (LIMS).The LIMS database application is 
also stored on a production server located in the UMN datacenter (WBOB) 
and is managed by the Academic Health Center 
 
Key study personnel are trained on the use of OnCore and will comply with 
protocol specific instructions embedded within the OnCore. 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 33 of 44 
CPRC #2013LS081 
11.2 Case Report Forms 
Participant data will be collected using protocol specific electronic case 
report forms (e-CRF) developed within OnCore based on its library of 
standardized forms. The e-CRF will be approved by the study’s Principal 
Investigator and the Biostatistician prior to release for use. The Primary 
Clinical Research Coordinator or designee will be responsible for 
registering the patient into OnCore at time of study entry, completing e-CRF 
based on the patient specific calendar, and updating the patient record until 
patient death or end of required study participation.   
11.3 Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring 
Plan (DSMP), which can be accessed at http://z.umn.edu/dmsp. 
For the purposes of data and safety monitoring, this study is classified as 
high risk (under a locally held IND).  Therefore the following requirements 
will be fulfilled: 
 The PI will complete and submit a quarterly Trial Progress Report to the 
Masonic Cancer Center Data and Safety Monitoring Council (DSMC) 
with the understanding the Cancer Protocol Review Committee (CPRC) 
may require more frequent reporting. 
 The PI will comply with at least twice yearly monitoring of the project by 
the Masonic Cancer Center monitoring services. 
 The PI will oversee the submission of all reportable adverse events per 
the definition of reportable in section 10.3 to the Masonic Cancer 
Center’s SAE Coordinator, the University of Minnesota IRB, and the 
FDA.  
11.4 IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the sponsor-investigator 
with assistance from the MCC Clinical Trials Office (CTO) will submit a 
progress report annually. The report will be submitted within 60 days of the 
anniversary date that the IND went into effect.    
11.5 Monitoring 
The investigator will permit study-related monitoring, audits, and 
inspections by the Masonic Cancer Center or their designee, IRB, 
government regulatory bodies, and University of Minnesota compliance 
groups. The investigator will make available all study related documents 
(e.g. source documents, regulatory documents, data collection instruments, 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 34 of 44 
CPRC #2013LS081 
study data, etc.). The investigator will ensure the capability for inspections 
of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.) will be available for trial related monitoring, audits, or regulatory 
inspections. 
11.6 Record Retention 
The investigator will retain study records including source data, copies of 
case report form, consent forms, HIPAA authorizations, and all study 
correspondence in a secured facility for at 6 years after the study file is 
closed with the IRB and FDA.   
In addition, the Clinical Trials Office (CTO) will keep a master log of all 
patients participating in the study with sufficient information to allow retrieval 
of the medical records for that patient.  
Please contact the CTO before destroying any study related records. 
12 
Correlative Endpoints 
To compared expression of CD16 and CD62L on natural killer (NK) cells and 
ADCC and IFN gamma production prior and after treatment with rituximab and 
after rituximab + INCB7839 (each patients is his/her own control). We will also 
determine the soluble CD16 and CD62L levels in vivo and soluble level of stress 
ligands MICa, MICb, UPBP3 before and after INCB7839 therapy.   
13 
Statistical Considerations 
13.1 Rationale 
We recently analyzed outcomes of 80 patients with diffuse large B cell 
lymphoma (DLBCL) who received autologous hematopoietic stem cell 
transplant at University of Minnesota between 1984 and 2002 (5). The 
median age was 47 years and most patients were in complete or partial 
remission. Post-transplant, the progression free survival at 5 years was 32% 
(95%CI 22-42%). We identified high risk group (high risk features defined 
by IPI score) and low risk group with widely different median PFS of 2 
months (high risk group) versus 8 months (low risk). Based on Kaplan –
Meyer PFS curve, we expect 65% of patients to be progression-free at 6 
months.3   
Recent prospective multicenter study comparing two different conditioning 
regimen prior to autograft for DLBCL demonstrated similar 6 months 
progression free survival of 65-70%.1,2. The most common cause of 
treatment failure is lymphoma progression/relapse.      


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 35 of 44 
CPRC #2013LS081 
13.2 Study Design 
The study is a Phase I/II trial consisting of two phases. The first phase is a 
dose escalation phase with the aim of establishing a maximum tolerated 
dose (MTD) of Adam17 inhibitor INCB7839 with rituximab as consolidation 
therapy after autologous HCT for patients with diffuse large B cell 
lymphoma. In the second phase, a larger group will be enrolled in order to 
obtain a more detailed toxicity profile of the chosen MTD from the first phase 
as well as establish a preliminary estimate of the rate progression free 
survival at 6 months. 
In the dose escalation phase, three dose levels of INCB7839 will be tested 
(100mg, 200mg, and 300mg). Since we are starting the experiment at a 
very low dose at which expected toxicity impacts are low using the standard 
dose escalation design would expose more subjects to ineffective doses 
with no expected efficacy. Therefore we decided to conduct the dose 
escalation phase following a Fast-Track Design. With the fast tract design, 
1 patient is entered per dose level until a grade 2 or greater treatment 
emergent event is experienced within the 1st 14 days of INCB7839 is 
experienced.  At that point, two additional patients will be enrolled at the 
same dose level and standard dose escalation design will be used as 
follows: 
 
 
Number of Patients 
with DLT at a Given 
Dose Level 
Escalation Decision Rule 
(see section 7.2 for dose levels) 
0 out of 3 
Enter 3 new patients at the next higher dose level 
≥ 2 out of 3 
This dose level is declared to be above the maximum tolerated dose (MTD) an 
dose escalation is stopped. Declare the next lower dose the MTD if 6 patients 
have already been treated at that dose. Enter 3 additional patients at the next 
lower dose level if only 3 patients have been treated at the dose, and if ≤ 1 out of 
6 patients has DLT then declare this dose the MTD. If ≥ 2 out of 6 patients have 
DLT then dose de-escalation continues according to the same scheme.  
1 out of 3 
Enter 3 additional patients at this dose level. 
• 
If 0 of these 3 patients (i.e. 1 out of all 6 patients) experience DLT, proceed 
to the next higher dose level. 
• 
If ≥ 1 of these 3 patients (i.e.≥ 2 out of all 6 patients) experience DLT, then 
this dose is declared to be above the MTD and dose escalation is stopped. 
Declare the next lower dose the MTD if 6 patients have already been treated 
at that dose. Enter 3 additional patients at the next lower dose level if only 3 
patients have been treated at the dose, and if ≤ 1 out of 6 patients has DLT 
then declare this dose the MTD. If ≥ 2 out of 6 patients have DLT then dose 
de-escalation continues according to the same scheme.  
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 36 of 44 
CPRC #2013LS081 
The Phase I design will continue until the MTD is declared or until the first 
dose is declared to be above MTD. After the MTD is declared, the study will 
proceed to the Phase II.  
Phase I dose limiting toxicity (DLT) is defined as any of the following with 
the 1st 14 days of INCB7839: 
• Grade 3-5 non-hematologic, non-infectious toxicity including 
thromboembolic complications  
• Select hematologic events including:   
• grade 4 neutropenia lasting for ≥ 7 days 
• febrile neutropenia 
• grade 4 thrombocytopenia lasting ≥ 7 days despite dose delay 
• grade 3 thrombocytopenia associated with bleeding  
• The inability to complete at least 10 days (20 doses) of twice daily 
INCB7839 therapy within the 1st 14 days due to treatment related 
toxicity 
If dose level 3 is reached without DLT in the 1st 3 patients, an additional 3 
patients (for a total of 6) will be enrolled without the 14 day waiting period  
Once the MTD is declared, additional 12 patients will be enrolled at the 
phase I MTD or dose level 3 if no DLT, to obtain a total of 18 patients treated 
at the designated dose.  The specific aim of this second phase is to obtain 
a more detailed toxicity of the newly established MTD and to make sure the 
preliminary estimate of 6-month progression free survival. 
13.3 Phase II Power Calculation 
If all three dose levels are tested, 3-18 patients will be enrolled in the first 
phase of the trial in order to establish the MTD. Additional 12 patients will 
be enrolled in the phase II component to obtain 18 patients treated at MTD. 
Therefore a maximum total of 15 to 30 patients will be involved in the study. 
In Phase II the designed sample size of 18 for 6 month progression free 
survival comparison will have a power of 79% to detect the difference 
between the null hypothesis 6 month progression free survival rate of 65% 
and the alternative hypothesis of progression free survival of 85% (this is 
equivalent test the null hypothesis of median disease survival time of 9.7 
months and the alternative hypothesis median disease survival time of 25.5 
months) at a 0.05 significance using two-sided test. The accrual time will be 
18 months and follow up time is 6 months.  
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 37 of 44 
CPRC #2013LS081 
13.4 Analysis 
The primary endpoint of progression free survival (PFS) and the secondary 
endpoint of overall survival (OS) will be estimated with Kaplan-Meier 
curves.15  Cumulative incidence will be used to estimate the probability of 
relapse/disease progression treating non-relapse death as a competing 
risk.16 Safety measures will be measured descriptively with frequencies and 
proportions.  
13.5 Early Study Stopping Rules – Phase II Component  
For phase II component, early stopping rules will be used to monitor the 
excess toxicity for the additional 12 patients. Stopping rules were developed 
using Pocock stopping boundaries.17 
Grade 4-5 non-hematologic toxicity by 4 months 
Stopping rules were developed for excessive Grade 4-5 non-hematologic 
toxicity.  The goal is to construct a boundary based on toxicity such that the 
probability of early stopping is at most 10% if the toxicity rate is equal to 
10% and our sample size is 12 in phase II component. Given these 
parameters, the upper stopping boundary for toxicity is 2 events out of 4 
patients, 3 out of 10, and 4 at any time. If the true toxicity rate is as high as 
40% then the chance of early stopping is 87% and the expected sample 
size is 6.0. 
Grade 4-5 hematologic toxicity lasting for ≥ 7 days by 4 months 
Stopping rules were developed for excessive Grade 4-5 hematologic 
toxicity lasting for ≥ 7 days.  The goal is to construct a boundary based on 
toxicity such that the probability of early stopping is at most 10% if the 
toxicity rate is equal to 30% and our sample size is 12 in phase II 
component. Given these parameters, the upper stopping boundary for 
toxicity is 3 events out of 3 patients, 4 out of 5, 5 out of 8, 6 out of 10, and 
7 at any time. If the true toxicity rate is as high as 60% then then chance of 
early stopping is 75% and the expected sample size is 7.7. 
14 
Conduct of the Study 
14.1 Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s). Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  
Master files should be established at the beginning of the study, maintained 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 38 of 44 
CPRC #2013LS081 
for the duration of the study and retained according to the appropriate 
regulations.   
14.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded 
in the Declaration of Helsinki. The IRB will review all appropriate study 
documentation in order to safeguard the rights, safety and well-being of the 
patients. The study will only be conducted at sites where IRB approval has 
been obtained. The protocol, consent, written information given to the 
patients, safety updates, annual progress reports, and any revisions to 
these documents will be provided to the IRB by the investigator.   
14.3 Informed Consent 
All potential study participants will be given a copy of the IRB-approved 
consent to review. The investigator or designee will explain all aspects of 
the study in lay language and answer all questions regarding the study. If 
the participant decides to participate in the study, he/she will be asked to 
sign and date the consent document. Patients who refuse to participate or 
who withdraw from the study will be treated without prejudice. 
 
15 
References 
1. Philip, T. et al. Autologous bone marrow transplantation as compared with salvage 
chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N. Engl. J. Med. 
333, 1540-1545 (1995).  
2. Vose, J. M. et al. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, 
and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous 
hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the 
BMT CTN 0401 trial. J. Clin. Oncol. 31, 1662-1668 (2013).  
3. Lerner, R. E., Thomas, W., Defor, T. E., Weisdorf, D. J. & Burns, L. J. The International 
Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse 
large-cell non-Hodgkin's lymphoma in second complete or partial remission. Biol. Blood Marrow 
Transplant. 13, 486-492 (2007).  
4. Rosenberg, S. A., Restifo, N. P., Yang, J. C., Morgan, R. A. & Dudley, M. E. Adoptive cell 
transfer: a clinical path to effective cancer immunotherapy. Nat. Rev. Cancer. 8, 299-308 (2008).  
5. Miller, J. S. et al. Successful adoptive transfer and in vivo expansion of human haploidentical 
NK cells in patients with cancer. Blood 105, 3051-3057 (2005).  
6. Gisselbrecht, C. et al. Rituximab maintenance therapy after autologous stem-cell 
transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of 
the collaborative trial in relapsed aggressive lymphoma. J. Clin. Oncol. 30, 4462-4469 (2012).  


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 39 of 44 
CPRC #2013LS081 
7. Romee, R. et al. NK cell CD16 surface expression and function is regulated by a disintegrin 
and metalloprotease-17 (ADAM17). Blood (2013).  
8. Zocchi, M. R. et al. High ERp5/ADAM10 expression in lymph node microenvironment and 
impaired NKG2D ligands recognition in Hodgkin lymphomas. Blood 119, 1479-1489 (2012).  
9. Chitadze, G. et al. Shedding of endogenous MHC class I-related chain molecules A and B from 
different human tumor entities: heterogeneous involvement of the "a disintegrin and 
metalloproteases" 10 and 17. Int. J. Cancer 133, 1557-1566 (2013).  
10. Bachanova, V. et al. Allogeneic natural killer cells for refractory lymphoma. Cancer Immunol. 
Immunother. 59, 1739-1744 (2010).  
11. Geller, M. A. et al. Intraperitoneal delivery of human natural killer cells for treatment of ovarian 
cancer in a mouse xenograft model. Cytotherapy 15, 1297-1306 (2013).  
12. Burns, L. J. et al. IL-2-based immunotherapy after autologous transplantation for lymphoma 
and breast cancer induces immune activation and cytokine release: a phase I/II trial. Bone Marrow 
Transplant. 32, 177-186 (2003).  
13. Newton, R. C. et al. Clinical benefit of INCB7839, a potent and selective ADAM inhibitor, in 
combination with trastuzumab in patients with metastatic HER2+ breast cancer. Journal of Clinical 
Oncology; ASCO Annual Meeting Proceedings 28, 3025 (2010).  
14. Wang, Y. et al. ADAM17 cleaves CD16b (FcgammaRIIIb) in human neutrophils. Biochim. 
Biophys. Acta 1833, 680-685 (2013).  
15. Kaplan EL MP. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958;53:457--481.  
16. Lin DY. Non-parametric inference for cumulative incidence functions in competing risks 
studies. Stat.Med. 1997;16:901-910. 
 
 17. Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in oncology. 
Biometrics. 2005;61:540-545. 


Appendix I – Eligibility Checklist  
Study of the ADAM17 Inhibitor INCB7839 Combined With Rituximab After Autologous 
Hematopoietic Cell Transplantation (HCT) For Patients With  
Diffuse Large B Cell Non-Hodgkin Lymphoma (DLBCL) - HM2013-24 
Eligibility Checklist – page 1 of 2 
Patient initials   
     
 
 
Patient ID
 
 
 
 
1st 2 initials of first name + 1st 2 initials of last name 
        Seq # 
 
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the patient from study entry. 
 
 
 
 
 
Yes      No 
1. 
Patients 18 years or older who have undergone an autologous hematopoietic cell transplant for the 
treatment of diffuse large B cell lymphoma with disease response (CR, PR) or stable disease at the 
day 28 post-transplant reassessment 
 
 
2. Karnofsky Score of ≥ 70%  
 
 
3. Able to start the protocol therapy (1st dose of rituximab) between day 28-75 post-transplant 
 
 
4. 
Adequate organ function defined as: 
test 
requirement 
patient value 
date  
platelets 
≥ 50,000 x 109/L 
 
/
/
 
ANC 
≥ 1000 x 109/L unsupported 
by G-CSF or GM-CSF for 3 
days 
 
/
/
 
renal function 
creatinine < 1.5 mg/dl or 
glomerular filtration rate > 
50 ml/min 
.
 
.
 
/
/
 
AST  
< 3 X UNL 
 
/
/
 
ALT 
< 3 X UNL 
 
/
/
 
total bilirubin 
< 3.0 mg/dl (if total bilirubin 
is ≥ 3.0 patient is eligible if 
direct bilirubin is WNL) 
.
 
 if direct bili is used 
/
/
 
pulmonary function 
clinically no evidence of pulmonary disease   
/
/
 
cardiac function 
no symptoms of uncontrolled cardiac disease 
/
/
 
 
 
5. If post-transplant consolidation radiation therapy is given, the patient must be at least 14 days 
between last radiation treatment and 1st dose of rituximab                   
 check if n/a 
 
 
6. Able to take daily aspirin for the duration of INCB7839 treatment and 1 week after the last dose to 
reduce the risk of thrombosis (unless of warfarin or LMWH at the time of treatment start)   
 
 
7. 
Females are either postmenopausal for at least 1 year, are surgically sterile for at least 3 months, or 
must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from 
screening through 12 months after the last dose of rituximab if of childbearing potential.   
Males must agree to take appropriate precautions to avoid fathering a child (with at least 99% 
certainty) from screening through 12 months after the last dose of rituximab.   
 
 
8. Voluntary written consent signed before performance of any study-related procedure not part of 
normal medical care 
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 41 of 44 
CPRC #2013LS081 
Study of the ADAM17 Inhibitor INCB7839 Combined With Rituximab After Autologous 
Hematopoietic Cell Transplantation (HCT) For Patients With  
Diffuse Large B Cell Non-Hodgkin Lymphoma (DLBCL) - HM2013-24 
 
Eligibility Checklist – page 2 of 2 
Patient initials   
     
 
 
Patient ID
 
 
 
 
 
EXCLUSION CRITERIA 
A "YES" response to any of the following disqualifies the patient from study entry. 
 
 
Yes      No 
9. 
 Pregnant or breast feeding - Females of childbearing potential must have a blood test or urine 
study within 14 days prior to enrollment to rule out pregnancy  
 check if n/a 
 
 
10.  
Recent venous thrombosis within 4 weeks prior to study enrollment.  Patients at high risk for 
thrombotic events due to inherited risk factors (i.e. factor V Leiden) or DVT/PE in the past 12 
months should be on secondary prophylaxis with anti-coagulant therapy (i.e. warfarin or low 
molecular weight heparin) prior to enrollment   
 check if n/a 
 
 
11.  Active uncontrolled infection 
 
 
12.  Active CNS disease 
 
 
13.  Previous severe or life-threatening allergic reaction with rituximab or known allergy to the 
compounds found in INCB7839 
 
 
14.  Any gastrointestinal condition causing malabsorption or obstruction (eg, celiac sprue, gastric 
bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome) 
 
 
15.  Unwilling or unable to swallow tablets BID 
 
 
16.  
Serologic or clinical evidence of current active hepatitis B or C infection, defined as elevated 
levels of Hep B antigen or Hep C antibody (unless active infection is ruled out by nucleic acid 
tests) 
 
 
17.  known HIV infection 
 
 
 
  
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify that this patient is eligible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of enrolling investigator 
 
 
 
 
Date 
 
 
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 42 of 44 
CPRC #2013LS081 
Appendix II – Performance Status Criteria 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
 
 


HM2013-24: INCB7839 with Rituximab after Autologous HCT for Diffuse Large B Cell NHL 
 
 
 
 
 
February 12, 2018 
Page 43 of 44 
CPRC #2013LS081 
Appendix III – Phase 1-2 Study Combining INCB007839 Plus Trastuzumab In Patients With Previously 
Untreated Metastatic HER2+ Breast Cancer 


 
Appendix IV - INCB7839 Drug Log 
Patient ID: _____________________ 
 
 
The study drug INCB7839 should be taken with food two times a day approximately 12 hours apart, every day 
until you are told to stop.  If you forget to take a dose by more than 2 hour after the scheduled time or vomit 
after you take a dose, you should skip the dose and only take the next schedule dose.  If this occurs, record a 
“0” in the time taken column and indicate the reason the dose was missed under the notes column.  One 325 
mg aspirin (if not taking other anti-coagulant therapy) is also taken each day during INCB7839 administration 
and continuing until 1 week after the last dose of INCB7839. 
Please bring this completed drug log and your study drug bottles (including any unused medication) with you to 
each appointment.  If you have any questions, please contact the study coordinator _________________ at 
________________. 
date 
morning 
(a.m.) 
time 
evening 
(p.m.) 
time 
daily aspirin or other 
anti-coagulant 
(warfarin, l low-molecular-
weight heparin) 
check box each day taken 
side effects and notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upon return of the completed log and drug reconciliation: 
Research Staff Signature:  
 
 
 
 
 
 
Date Reviewed: