Conditions: Hodgkin Disease Lymphoma, Non-hodgkin
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
This is an open label, phase I/II, dose-escalation study in the initial phase I followed by a phase II.

The primary objective of the phase I is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of TGR-1202 and carfilzomib in participants with relapsed and refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). The safety and toxicity of this combination will be evaluated throughout the entire study.

If the combination of TGR-1202 and carfilzomib is found to be feasible and an MTD is established, the phase II part of the study will be initiated.

Phase II will consist of a 2-stage design of the combination of TGR-1202 and carfilzomib for participants with R/R NHL.

Detailed description:
Dysregulated c-Myc is associated with resistance to chemotherapy and poor survival in aggressive lymphomas. Novel strategies that target this biology could markedly improve the outcome of these participants. To date no drugs that directly target Myc have been approved for cancer treatment. Recent results by Deng et al. (Blood. 2017 Jan 5. PMID: 27784673) described a highly synergistic regimen discovered in preclinical models, through combining TGR-1202, an investigational drug that inhibits PI3K delta, and carfilzomib, a drug approved by the FDA for multiple myeloma. Importantly, the combination of TGR-1202 and carfilzomib acts by potently silencing the translation of c-Myc and inducing apoptosis in many cell lines and primary lymphoma cells representing broad histological subtypes of lymphoma. These results suggest that TGR-1202 and carfilzomib may be highly effective in relapsed and refractory lymphoma where c-Myc plays a key pathological role.

Arms:
arm 1: Oral TGR-1202 will be given PO once daily on Days 1-28 and carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle.

Interventions: intervention 1: Carfilzomib intervention 2: TGR-1202
Intervention descriptions: intervention 1: Carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. This will be in combination with the oral TGR-1202 intervention 2: Oral TGR-1202 will be given PO once daily on Days 1-28 . This will be given in combination with the intravenous Carfilzomib

Protocol document:
Prot_SAP_000.pdf: 
i  
  
  
 
NCT02867618 
TITLE:     
  
Phase Ib Study of Carfilzomib and a PI3K Delta Inhibitor  
TGR-1202 in the Treatment of Patients with Relapsed or 
Refractory Lymphoma  
Principal Investigator:  
Changchun Deng, M.D., Ph.D.  
 
Assistant Professor of Medicine and Experimental Therapeutics  
 
Columbia University Medical Center  
 
  
cd2448@columbia.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
CUMC Protocol #AAAP5661  
  
 
Protocol Type / Version # / Version Date: Amendment 4/Version #1/April 25th, 2018  


ii  
  
  
TABLE OF CONTENTS  
 
SUMMARY ............................................................................................................................................................. 
1  
1. 
OBJECTIVES ................................................................................................................................................. 
14  
2. 
BACKGROUND ............................................................................................................................................. 
15  
2.1  
MALIGNANT LYMPHOMA .................................................................................................................................. 15 
2.2  TGR-1202 .................................................................................................................................................... 16  
 
2.2.1  PI3K and PI3K-delta Inhibitors ............................................................................................................... 16  
 
2.2.2  Summary of TGR-1202 Preclinical Evaluations ...................................................................................... 17  
 
2.2.3  Toxicology .............................................................................................................................................. 20  
 
2.2.4  Summary of TGR-1202 Clinical Evaluations ........................................................................................... 21  
 
2.3  
CARFILZOMIB ................................................................................................................................................. 22  
 
2.3.1  Proteasome and proteasome inhibitor .................................................................................................. 22  
2.3.2  Toxicology Studies of Carfilzomib .......................................................................................................... 23 
2.3.3  Cytochrome P450 ................................................................................................................................... 25  
 
2.3.4  Preclinical Antitumor Activity of Carfilzomib ......................................................................................... 25  
2.3.5  Phase 1 Experience with Carfilzomib as a Monotherapy ....................................................................... 26 
2.3.6  Phase 2 Experience with Carfilzomib as a monotherapy ....................................................................... 28  
 
2.3.7  Pharmacodynamics of Carfilzomib ........................................................................................................ 30  
 
2.3.8  Pharmacokinetic Profile of Carfilzomib .................................................................................................. 31  
 
2.3.9  Absorption of Carfilzomib ...................................................................................................................... 32  
 
2.3.10  
Distribution of Carfilzomib ................................................................................................................. 32  
 
2.3.11  
Metabolism of Carfilzomib ................................................................................................................ 32  
 
2.3.12  
Excretion of Carfilzomib ..................................................................................................................... 32  
 
2.4  
RATIONALE FOR THE STUDY ............................................................................................................................... 33  
3. 
PATIENT SELECTION ..................................................................................................................................... 
35  
3.1 
INCLUSION CRITERIA FOR LYMPHOMA ................................................................................................................. 35 
3.2  EXCLUSION CRITERIA ........................................................................................................................................ 36 
3.3  INCLUSION OF WOMEN AND MINORITIES............................................................................................................. 38  
4. 
REGISTRATION PROCEDURES ...................................................................................................................... 
38  
4.1 
GENERAL GUIDELINES ...................................................................................................................................... 38 
4.2  SCREENING .................................................................................................................................................... 38 
4.3  INFORMED CONSENT ....................................................................................................................................... 39  
 
4.3.1  Consent and Use of Tissue Specimens for Research ............................................................................... 40  
 
4.4  
REGISTRATION PROCESS ................................................................................................................................... 40  
5. 
TREATMENT PLAN ....................................................................................................................................... 
41  


iii  
  
5.1 
AGENT ADMINISTRATION .................................................................................................................................. 41 
5.2 DURATION OF TREATMENT ............................................................................................................................... 45 5.3 
SAMPLE SIZE .................................................................................................................................................. 46 5.4 
SAFETY .......................................................................................................................................................... 46 5.5 
EFFICACY OUTCOME ........................................................................................................................................ 46  
5.6 PHARMACOKINETIC ANALYSES ........................................................................................................................... 46 5.7 
PROPHYLACTIC MEDICINES AND SUPPORTIVE CARE ................................................................................................ 51 5.8 
 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................................................... 52 
5.9  DURATION OF THERAPY .................................................................................................................................... 53  
5.10  DURATION OF FOLLOW UP................................................................................................................................ 53 
5.11  CRITERIA FOR REMOVAL FROM STUDY ................................................................................................................. 53  
6. 
DOSING DELAYS/DOSE MODIFICATIONS ..................................................................................................... 
54  
6.1 
DOSE DELAYS ................................................................................................................................................. 54 
6.2 RESUMING ADMINISTRATION OF STUDY DRUGS .................................................................................................... 54 6.3 
 
DOSE MODIFICATIONS ..................................................................................................................................... 54  
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .......................................................................... 
54  
7.1  
SAFETY EVALUATION PROCEDURES ..................................................................................................................... 54 
7.2  COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) OF  TGR-1202 ......................................... 57 
7.3  CAEPRS OF CARFILZOMIB ................................................................................................................................ 58  
 
7.3.1  Cardiopulmonary Disorders ................................................................................................................... 64  
 
7.3.2  Acute Renal Failure ................................................................................................................................ 65  
 
7.3.3  Tumor Lysis Syndrome ........................................................................................................................... 65  
7.3.4 Infusion Reactions .................................................................................................................................. 65 
7.3.5 Thrombocytopenia ................................................................................................................................. 66  
 
7.3.6  Hepatic Toxicity ...................................................................................................................................... 66  
 
7.3.7  Thrombocytopenic Thrombotic Purpura/Hemolytic Uremic Syndrome ................................................. 66  
 
7.3.8  Posterior Reversible Encephalopathy Syndrome .................................................................................... 66  
 
7.3.9  Pulmonary Hypertension........................................................................................................................ 67  
7.4  
ADVERSE EVENT CHARACTERISTICS ..................................................................................................................... 68 
7.5  EXPEDITED ADVERSE EVENT REPORTING .............................................................................................................. 68  
 
7.5.1  Expedited Reporting Guidelines ............................................................................................................. 70  
 
7.5.2  Protocol-Specific Expedited Adverse Event Reporting Exclusions .......................................................... 70  
7.6  
PREGNANCY ON STUDY .................................................................................................................................... 71 
7.7  ROUTINE ADVERSE EVENT REPORTING ................................................................................................................ 72  
8.  PHARMACEUTICAL INFORMATION .............................................................................................................. 72  
8.1  
TGR-1202 .................................................................................................................................................... 72 
8.2  CARFILZOMIB ................................................................................................................................................. 74  
 
8.2.1  Carfilzomib Product Description ............................................................................................................ 74  
 
8.2.2  Carfilzomib Dosage Form ....................................................................................................................... 74  
 
8.2.3  Drug Supply and Storage ....................................................................................................................... 75  
 
8.3  
AGENT ACCOUNTABILITY .................................................................................................................................. 77  
9.  PHARMACOKINETIC & PHARMACODYNAMIC STUDIES ................................................................................ 77  


iv  
  
9.1  
PHARMACOKINETIC STUDIES .............................................................................................................................. 77 
9.2  PHARMACODYNAMICS STUDIES .......................................................................................................................... 78  
 
9.2.1  Biopsies .................................................................................................................................................. 78  
 
9.2.2  Handling of Specimens ........................................................................................................................... 79  
10. 
STUDY CALENDAR ................................................................................................................................... 
79  
11. 
MEASUREMENT OF EFFECT ..................................................................................................................... 
82  
 
11.1  EVALUATION OF RESPONSE ............................................................................................................................... 82  
11.1.1 Definitions ......................................................................................................................................... 83 
11.1.2 Disease Parameters ........................................................................................................................... 83  
 
11.1.3  
Methods for Evaluation of Measurable Disease in NHL .................................................................... 84  
 
11.2  RESPONSE CRITERIA ......................................................................................................................................... 84  
 
11.2.1  
Evaluation of Measurable Disease in NHL ......................................................................................... 84  
 
11.2.2  
Response Definitions ......................................................................................................................... 86  
 
11.2.3  
Evaluation of Best Response .............................................................................................................. 87  
 
11.2.4  
Objective Response Rate ................................................................................................................... 87  
12.  
DATA REPORTING / REGULATORY REQUIREMENTS ................................................................................. 87  
 
12.1  DATA REPORTING............................................................................................................................................ 87  
 
12.1.1  
Monitoring ......................................................................................................................................... 87  
 
12.1.2  
Responsibility for Data Submission .................................................................................................... 87  
12.2  DATA SAFETY MONITORING BOARD .................................................................................................................... 88 
12.3  INVESTIGATOR REPORTING RESPONSIBILITIES ........................................................................................................ 88 
12.4  STUDY AUDITING ............................................................................................................................................ 88 
12.5  PROTOCOL AMENDMENTS ................................................................................................................................ 88 
12.6  PROTOCOL DEVIATIONS .................................................................................................................................... 89  
13. 
STATISTICAL CONSIDERATIONS ............................................................................................................... 
89  
13.1 STUDY DESIGN/ PRIMARY ENDPOINTS ................................................................................................................. 89 
13.2 SAMPLE SIZE/ACCRUAL RATE ............................................................................................................................ 90 
13.3  ANALYSIS OF SECONDARY ENDPOINTS ................................................................................................................. 90  
14. 
REFERENCES ............................................................................................................................................ 
90  
  


1  
  
SUMMARY  
 
Title:  
Phase Ib Study of Carfilzomib and a PI3K Delta Inhibitor TGR-1202 in the Treatment of Patients 
with Relapsed or Refractory Lymphoma  
  
Study Design:  
This is an open label, dose-escalation phase I study followed by a phase Ib expansion 
phase.   
  
The primary objective of the phase I is to determine the maximum tolerated dose (MTD) 
and dose limiting toxicity (DLT) of the combinations of TGR-1202 and carfilzomib in 
patients with relapsed and refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin 
lymphoma (HL).  The safety and toxicity of this combination will be evaluated throughout 
the entire study.   
  
If the combination of TGR-1202 and carfilzomib is found to be feasible and an MTD is 
established, the phase Ib part of the study will be initiated.    
  
The phase Ib part of the study will be conducted in patients with peripheral T cell lymphoma 
(PTCL) and C-MYC positive (30% by IHC) diffuse large B cell lymphoma (DLBCL).   
  
Objectives:  
Phase I:  
Primary Objectives  
• 
Determine the maximum tolerated dose (MTD), maximally administered dose (MAD), 
and dose limiting toxicity (DLT) of the combination of TGR-1202 and carfilzomib.  
• 
Evaluate the safety and toxicity of the combination of TGR-1202 and carfilzomib.  
  
Secondary Objectives  
• 
Describe the maximum number of cycles received   
• 
Describe the number of dose delays and dose reductions at the MTD  


2  
  
• 
Describe the anti-tumor activity of the combination   
• 
Evaluate the objective response rate (ORR), progression free survival (PFS), and 
duration of response (DOR) of the study population.   
• 
Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (pre- and 
post-treatment) including gene expression profiling (GEP) and immunohistochemistry 
(IHC).   
• 
Establish the pharmacokinetic profile for TGR-1202 and carfilzomib when given as a 
combination in Cycle 1.   
  
Phase Ib:   
  
  
Primary Objectives  
• 
Evaluate the safety and toxicity of the combination of TGR-1202 and carfilzomib at the 
MTD dose level in patients with R/R PTCL and C-MYC positive DLBCL.  
  
  
  
Secondary Objectives  
• 
Estimate the ORR (complete + partial response) of the combination of TGR-1202 and 
carfilzomib in patients with R/R PTCL and C-MYC positive DLBCL.   
• 
Estimate the DOR and PFS of the combination in patients with R/R PTCL and CMYC 
positive DLBCL.    
  
Target Population  
  
Phase I: Patients with R/R NHL and HL.   
Phase Ib: Patients with relapsed or refractory R/R PTCL and C-MYC positive DLBCL .   
  
Inclusion Criteria   
• 
Phase I:  Patients with relapsed or refractory Hodgkin lymphoma or non-Hodgkin 
lymphoma. Patients with chronic lymphocytic leukemia (CLL) and small lymphocytic 
lymphoma (SLL) are also eligible. In addition, patients with NHL other than diffuse large  


3  
  
B cell lymphomas (DLBCL) must have received at least 2 prior therapies. Patients with 
DLBCL and HL will be eligible if there is no available standard therapy.  
• 
Phase Ib: Patients must have histologically confirmed R/R PTCL or C-MYC positive 
DLBCL (as defined by WHO criteria and IHC staining of C-MYC). The patients with PTCL 
or DLBCL will be eligible if there is no available standard therapy.  
• 
Must have received front-line chemotherapy. No upper limit for the number of prior  
therapies. Patients may have relapsed after prior autologous stem cell transplant or 
allogeneic stem cell transplant.  
• 
Evaluable Disease in the Phase I, and measurable disease for the phase Ib study as 
defined in Section 11 in the Phase Ib.  
 
  Age >18 years  
  
• 
ECOG performance status < 2   
• 
Patients must have adequate organ and marrow function as defined below:  
o absolute neutrophil count   
  
  
            >1,000/dL  
o platelets    
  
  
  
  
  
  
  
 
 
>75,000   
o total bilirubin   
  
  
  
  
  
  
  
<1.5X 
institutional limits   
Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 × ULN; aPTT, PT not to 
exceed 1.2 × ULN  
o AST(SGOT)/ALT(SGPT)   
  
  
<2.0X institutional upper limit of 
normal o Serum creatinine   
  
  
  
  
within 
normal 
institutional limits  
 
  OR  
o Measured creatinine clearance  >50 mL/min/for patients with creatinine levels above 
institutional normal.  o Left ventricular ejection fraction (LVEF)  >50% as defined by 
ECHO or MUGA.    
• 
Negative urine or serum pregnancy test for females of childbearing potential. All females 
of childbearing potential must use an effective barrier method of contraception (either an 
IUD or double barrier method using condoms or a diaphragm plus spermicide) during the 
treatment period and for at least 1 month thereafter. Male subjects should use a barrier 
method of contraception during the treatment period and for at least 3 months thereafter.      


4  
  
• 
Ability to understand and the willingness to sign a written informed consent document.  
  
Exclusion Criteria  
• 
Prior Therapy  
o Exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the 
study or those who have not recovered from adverse events due to agents 
administered more than 2 weeks earlier. o Systemic steroids that have not been 
stabilized (≥ 5 days) to the equivalent of  
≤10 mg/day prednisone prior to the start of the study drugs. o 
No other concurrent investigational agents are allowed.   
  
• 
Central nervous system metastases, including lymphomatous meningitis will be allowed 
in the phase II study, but will not be allowed in the phase I.   
• 
History of allergic reactions to TGR-1202 or carfilzomib.  
• 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.   
• 
Pregnant women   
• 
Nursing women   
• 
Active concurrent malignancy (except non-melanoma skin cancer, carcinoma in situ of the 
cervix, low risk prostate cancer). If there is a history of prior malignancy, the patient must 
be disease-free for ≥ 2 years.    
• 
Patients with a low grade lymphoma or CLL and a concurrent high grade lymphoma 
transformed from the low grade lymphoma or CLL will be eligible.   
• 
Patients known to be Human Immunodeficiency Virus (HIV)-positive   
• 
Patients with active hepatitis A, hepatitis B, or hepatitis C infection   
• 
Concomitant use of CYP3A4 inhibitors (see Appendix 2)   Significant 
cardiac 
abnormalities such as:  
o Myocardial infarction within 6 months of C1D1;  
o An ECG recorded at screening showing evidence of cardiac ischemia (ST 
depression of ≥2 mm, measured from isoelectric line to the ST segment).  If in any 
doubt, the patient should have a stress imaging study and, if abnormal, 
angiography to define whether or not CAD is present;  


5  
  
o Congestive heart failure (CHF) that meets New York Heart Association (NYHA) 
Class II to IV definitions (see Appendix 4) and/or ejection fraction <50% defined by 
ECHO and MUGA;   
• 
A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), 
Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic 
implantable cardioverter-defibrillator (AICD).  
  
Treatment Plan  
Patients will be treated with TGR-1202 and carfilzomib administered as follows: TGR-1202 from 
Days 1-21; and carfilzomib administered intravenously on Days 1, 8, and 15 of a 28-day cycle 
(Tables 1 & 2).  
In the Phase I study 3 subjects per cohort will be enrolled in each of the 2 escalating cohorts, 
using standard 3 + 3 dose-escalation design according to the modified Fibonacci rules (Tables 2 
& 3, and Figure 1).  The rules for determination of the MAD and MTD in the Fibonacci 3+3 design 
are described in Table 3.   
.  
Once the MTD is reached, the Phase Ib part of the protocol will be initiated in patients with R/R 
PTCL or C-MYC positive DLBCL (Figure 2).   
  
Duration of Treatment  
Patients will be treated until one of the following events:  
• 
Disease progression  
• 
Unacceptable adverse event(s), DLTs  
• 
Withdrawal of consent  
• 
General or specific changes in the patient's condition that render the patient   
 
unacceptable for further treatment in the judgment of the investigator  
• 
An event that in the judgment of the treating physician warrant’s discontinuation    of 
therapy.   
  


6  
  
Sample Size  
Phase I  
An estimated 9 patients (up to a maximum of 12) with R/R HL and NHL will be accrued to the 
Phase I study with 2 cohorts (Tables 2).  A minimum of 3 patients will be treated in each dose 
cohort. If no DLT is reached in cohort 3, then a total of 6 patients will be treated at that dose level.  
  
Phase Ib  
The phase Ib part of the study will accrue a total of 15 patients.   
  
Safety  
Patients will be monitored carefully for the development of adverse events as well as clinical 
and/or radiographic evidence of disease response.  Adverse events will be evaluated according 
to criteria outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 
4.0.  
  
Efficacy Outcome  
Overall response rates will be evaluated using clinical parameters, CT scan (PET scan is optional) 
and bone marrow biopsy, as outlined by the 2014 Lugano Classification[1].   
  
Pharmacokinetic Analyses  
 On day 1 of cycle 1 (Figure 3), blood samples will be obtained from patients predose (0h),  0.5, 
2.5, and 4.5h after the start of infusion of carfilzomib. PK at 6.5h is optional.  The purpose is 
to determine the plasma level of both carfilzomib and TGR-1202 (The start of infusion of 
carfilzomib is counted as 0h). The proposed time points are shown in Figure 3.  
  
  
  
  
  
  
  
  
  
  


7  
  
Table 1:  Regimen Description  
  
REGIMEN DESCRIPTION  
  
Agent  
Premedication  
Precautions  
  
Dose  
  
Route  
  
Schedule  
Cycle 
Length   
Carfilzomib  
IV hydration,  
dexamethasone   
20-56** 
mg/m2  
IV over 30 
minutes   
Days 1, 8,  
15  
28 days  
TGR-1202  
  
600-800 
mg  
Oral  
Once daily 
days 1-21  
** Doses as appropriate for assigned dose level with the following exception: on cycle 1 
day 1 of all assigned dose level carfilzomib is dosed at 20 mg/m2.  Premedication for 
carfilzomib includes hydration with 250-500 ml of normal saline, and dexamethasone 
4mg to prevent infusion reactions.  
  
  
Table 2:  Dose Escalation Scheme for the Combination of TGR-1202 and Carfilzomib  
Dose Escalation Schedule  
  
Dose Level  
Dose  
Carfilzomib (mg/m2)  
Given on days 1,8,15 of each  
28-day cycle(b)  
TGR-1202 (mg)  
Given once daily on days 1- 
21 of each 28-day cycle  
     Level -1(a)  
20*/20  
600  
     Level 1  
20*/36  
800  
     Level 2  
20*/56  
800  


8  
  
(a) In level -1, carfilzomib will be given at 20 mg/m2 on days 1, 8, 15 and 
TGR1202 on days 1-21.  
(b) For cycle 1 day 1 of each cohort, carfilzomib will be given at 20 mg/m2. If the 
treatment is tolerated, the drug will be given at the assigned dose level for all 
other treatment days involving carfilzomib.            
  
  
Table 3.  Dose Escalation & De-Escalation Decision Rules  
Number of Patients 
with DLT at a Given 
Dose Level  
Escalation Decision Rule  
0 out of 3  
Enter 3 patients at the next dose level.  
1 out of 3  
Enter at least 3 more patients at this dose level.  
• If 0 of these 3 additional patients experience DLT, 
proceed to the next dose level.  
• If 1 or more of this group experience DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose (MAD), and the dose level 
below is the MTD.    
>2  
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).    
<1 out of 6 at highest dose 
level below the maximally 
administered dose  
This is generally the recommended phase 2 dose. At least 6 
patients must be entered at the recommended phase 2 dose.  
  
 


9  
  
Figure 1.   
Drug Administration Schema  
  


10  
  
Figure 2: Study Plan Flow Chart Schema:  Phase I   
  
  
Screening  
  
  
History, Physical, Performance Status,  
Laboratory data, Biopsies, and CT scan (PET optional)  
  
 
  
CYCLE 1  
 
  
Intervention  
Oral TGR-1202 will be given PO once daily on Days 1-21 and carfilzomib given intravenously once a  
  
week for 3 consecutive weeks, on days 1, 8, 15 of the 28-day cycle.  
  
  
Evaluations  
Safety evaluations on Days 1, 8, 15  
  
Laboratory Evaluations Days 1,8,15  
Follow -up Tissue Biopsy or Fine Needle Aspiration on Day 8 to 21 (optional)  
  
 
                                                          
Future Cycles  
 
  
Intervention  
Oral TGR-1202 will be given PO once daily on Days 1-21 and carfilzomib given intravenously once a 
week for 3 consecutive weeks, on days 1,  
 8, 15 of the 28-day cycle.  
  
 
  
Tests  
Safety evaluations on Day 1  
Laboratory Evaluations Days 1, 8, 15    
CT scans at the end of Cycle 2 and 6. Then CT q3-6 months, until disease progression or initiation of new 
therapy at the discretion of the Investigator. (PET is optional).   
  
        
 
  
Discontinuation  
  Disease progression  
  Unacceptable adverse event(s), DLTs  
  Withdrawal of consent  
  General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator  


11  
  
  An event that in the judgment of the treating physician warrant’s discontinuation of therapy.  
Figure 2: Study Plan Flow Chart Schema:  Phase II   
  
  
Screening  
  
  
History, Physical, Performance Status,  
Laboratory data, Biopsies, and CT scan (PET optional)   
  
 
                                                          
Future Cycles  
 
  
Intervention  
Oral TGR-1202 will be given PO once daily on Days 1-21 and carfilzomib given intravenously once a 
week for 3 consecutive weeks, on days 1, 8, 15 on the 28  
-day cycle.  
  
 
  
Tests  
Safety evaluations on Day 1  
Laboratory Evaluations Days 1, 8, 15    
CT scans at the end of Cycle 2 and 6. Then CT q3-6 months, until disease progression or initiation of new 
therapy at the discretion of the Investigator. (PET is optional).  
  
        
 
  
  
Discontinuation  
  Disease progression  
 
   Unacceptable adverse event(s), DLTs  
  Withdrawal of consent  
  General or specific changes in the patient's condition render th  
e patient unacceptable for 
further treatment in the judgment of the investigator  
  An event that in the judgment of the treating physician warrant’s discontinuation of therapy.  
 
 
 
 
 
 
 
CYCLE 1  
Intervention  
Oral TGR - 1202 will be given PO once daily on Days  1 - 
and carfilzomib given intravenously once a  
21 
week for 3 consecutive weeks, on days 1, 8, 15 on the 28 - day cycle.  
 
Eva luations  
Safety evaluations on Days 1, 8, 15  
Laboratory Evaluations Days 1,8,15   
Follow - up Tissue Biopsy or Fine Needle Aspiration on Day 8 to 21 (optional if pat agrees)  


12  
  
Figure 3. PK Studies on Cycle 1 Day 1  
  
  
  
  
 


13  
  
TITLE:    Phase Ib Study of Carfilzomib and a PI3K Delta Inhibitor TGR-1202 in the 
Treatment of Patients with Relapsed or Refractory Lymphoma  
1. OBJECTIVES  
 
Phase I:  
Primary Objectives   
• 
Determine the maximum tolerated dose (MTD), maximally administered dose (MAD), and 
dose limiting toxicity (DLT) of the combination of TGR-1202 and carfilzomib.  
• 
Evaluate the safety and toxicity of the combination of TGR-1202 and carfilzomib.  
  
Secondary Objectives  
• 
Describe the maximum number of cycles administered   
• 
Describe the number of dose delays and dose reductions at the MTD  
• 
Describe the anti-tumor activity of the combination   
• 
Evaluate the objective response rate (ORR), progression free survival (PFS), and duration of 
response (DOR) of the study population.   
• 
Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (pre- and post- 
treatment) including gene expression profiling (GEP) and immunohistochemistry (IHC).   
• 
Establish the pharmacokinetic profile for TGR-1202 and carfilzomib when given as a 
combination in Cycle 1.  
  
Phase Ib:   
Primary Objectives  
 Evaluate the safety and toxicity of the combination of TGR-1202 and carfilzomib at the 
MTD dose level in patients with R/R PTCL and C-MYC positive DLBCL.  
  
Secondary Objectives  
• 
Estimate the ORR (complete + partial response) of the combination of TGR-1202 and 
carfilzomib in patients with R/R PTCL and C-MYC positive DLBCL.   


14  
  
• 
Estimate the DOR and PFS of the combination in patients with R/R PTCL and C- 
MYC positive DLBCL.    
  
2. BACKGROUND  
 
 
2.1  
MALIGNANT LYMPHOMA  
 
NHLs are a heterogeneous group of lymphoproliferative disorders originating in B-, T-, or natural 
killer (NK) lymphocytes.  In the United States, B-cell lymphomas represent 80% to 85% of the 
cases, with 15% to 20% being T cell lymphomas; NK lymphomas are rare[2].  In 2010, an 
estimated 65,540 new cases of NHL were diagnosed and 20,210 patients died of the disease.  
NHL is the sixth leading site of new cancer diagnoses among men and women, accounting for 
4% of new cancer cases and 4% of cancer-related deaths. As a group, the diffuse large-cell 
lymphomas (DLBCL) accounts for approximately one-third of all NHLs, and is the most common 
type of aggressive lymphoma.  While the majority of patients with DLBCL can be cured with 
presently available combination immunochemotherapy, about 1/3 of these patients with DLBCL 
will eventually succumb to the lymphoma.  Other types of aggressive lymphoma, for example, 
peripheral T cell lymphoma (PTCL), have inferior outcome to DLBCL, as the vast majority of PTCL 
develops resistance to chemotherapy and will relapse.   
  
Dysregulated Myc is associated with resistance to chemotherapy and poor survival in patients 
with aggressive lymphomas such as “double hit” lymphoma, Burkitt lymphoma, transformed 
lymphoma and diffuse large B cell lymphoma (DLBCL) [3-8]. Novel strategies that targets this 
biology could markedly improve the outcome of these patients. To date no drugs that directly 
target Myc have been approved for the treatment of any malignancy.  In fact, because Myc is 
involved in many essential functions in normal cells, direct c-Myc inhibitors could theoretically be 
associated with significant toxicity[9].  Alternatively, it may be advantageous to inhibit upstream 
cancer specific signals that converge on Myc as a therapeutic strategy to mitigate the poor risks 
associated with Myc dysregulation. Myc is known to form a positive feed-forward loop with the 
translation initiation factor eIF4F[10], which in turn is regulated by mTOR through the inhibitor 
4EBP1[11]. PI3K is one of the most important upstream activators of mTOR[12], and recently the 


15  
  
ubiquitin-proteasome pathway was also reported to be involved in the activation of mTOR[13, 14].  
Our hypothesis is that if the proteasome and PI3K pathways cooperate in the activation of mTOR, 
then combinations of drugs targeting these pathways will synergistically inhibit the mTOR-eIF4F-
Myc axis and demonstrate potent activity in the treatment of Mycdependent aggressive 
lymphoma.  
  
 
2.2  
TGR-1202  
 
 
2.2.1 PI3K AND PI3K-DELTA INHIBITORS  
 
There are four mammalian isoforms of class 1 PI3Ks: PI3K-α, β, (class 1a PI3Ks) and PI3K- (a 
class 1b PI3K).  These PI3Ks catalyze the production of phosphatidylinositol (3,4,5)trisphosphate 
(PIP3), leading to activation of the downstream effector pathways important for cellular survival, 
differentiation, and function.  PI3K-α and PI3K-β are widely expressed, and are important 
mediators of signaling from cell surface receptors.  PI3K-α is the isoform most often found mutated 
in cancers, has and is known to play a role in insulin signaling and glucose homeostasis[15, 16]. 
PI3K-β is activated in cancers where phosphatase and tensin homolog (PTEN) is deleted.  Both 
isoforms are targets of small molecule therapeutics in development for cancer.  PI3K- and P13K-
 are preferentially expressed in leukocytes, and are important in leukocyte function.  PI3K-δ is 
activated by cellular receptors (e.g., receptor tyrosine kinases) through interaction with the SH2 
domains of the PI3K regulatory subunit (p85), or through direct interaction with RAS. PI3K-γ is 
associated with G-protein coupled receptors (GPCRs), is responsible for the very rapid induction 
of PIP3 in response to GPCRs, and can be also activated by RAS downstream of other receptors.  
PIP3 produced by PI3K activates effector pathways downstream through interaction with 
pleckstrin homology (PH) domain containing enzymes (e.g., PDK-1 and AKT [PKB])[17].    
  
In hematological malignancies including various histological types of lymphoma, chronic 
lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and multiple myeloma (MM), 
overexpression and constitutive activation of PI3K-δ suggests that PI3K-δ inhibition could have 


16  
  
therapeutic benefit in these cancers[18-23].  The PI3K-δ isoform specific inhibitor CAL-101 (also 
known as GS-1101 and idelalisib) has demonstrated clinical activity in patients with hematologic 
malignancies.  In heavily pre-treated patients with refractory CLL and bulky lymphadenopathy, 
single agent CAL-101 was highly active and clinically efficacious, providing a durable clinical 
benefit[24]. Moreover, inhibition of PI3K-δ not only affected cancer cells directly, but it also 
affected the ability of the cancer cells to interact with their microenvironment.  Single agent 
treatment with CAL-101 has also been reported to be active in mantle cell lymphoma and 
refractory non-Hodgkin lymphoma, with some data suggesting that the  antitumor efficacy may be 
mediated  by pharmacological reduction of  tumor-associated chemokines and cytokines[23, 25-
29].  In refractory or relapsed indolent non-Hodgkin lymphoma (iNHL) and in CLL patients, CAL-
101 has been combined with bendamustine and rituximab demonstrating robust clinical activity 
[30, 31].  Idelalisib was approved by the FDA in 2014 for the treatment of CLL and indolent 
lymphoma, but has not demonstrated activity in aggressive lymphoma. Although idelalisib is well 
tolerated for the majority of patients, more than one third patients experienced elevated 
transaminases, 11% of patients developed pneumonitis, and grade 3 or higher diarrhea or colitis 
occurred in 13% and 4% of the patients, respectively[32].  
  
Interestingly, another PI3Kdelta inhibitor, TGR-1202, has a structure that is significantly different 
from idelalisib and is also found to have promising activity in indolent lymphoma[33].  Importantly, 
TGR-1202 is not associated with frequent transaminitis, pneumonitis, or colitis.   The established 
roles of PI3K in cancer cells and in the biology of the tumor microenvironment support the 
development of PI3K-δ inhibitors.  TGR-1202, due to its favorable toxicity profile, is an ideal 
candidate to combine with other targeting agents for the treatment of indolent and potentially 
aggressive lymphomas. For example, preliminary results by Deng et al. [34] have demonstrated 
that TGR-1202 is uniquely and potently synergistic with carfilzomib, a proteasome inhibitor 
(Section 2.4).    
  
 
2.2.2 SUMMARY OF TGR-1202 PRECLINICAL EVALUATIONS  
 
 
2.2.2.1  
IN VITRO ACTIVITY  
 


17  
  
The potency of TGR-1202 against the human and mouse δ isoform of PI3K was evaluated in a 
homogeneous time resolved fluorescence (HTRF) based enzyme assay in the presence of ATP 
at its Km value (100 μM). Selectivity over the other three isoforms, namely, α, β, and γ was also 
determined (Prasannaabc et al. 2011).  Data demonstrated the specificity of TGR-1202 towards  
PI3Kδ with >1000, 50 and 48-fold selectivity over α, β, and γ, respectively in an enzyme-based 
assay, indicating that the primary mode of action of this compound is via inhibition of the δ isoform 
(Figure 4).  
  
Figure 4.  
TGR-1202 Potency against Human and Mouse PI3K Isoforms  
PI3K isoforms  
(Human)  
IC50 (nM)  
α  
>10,000  
β  
1,116  
γ  
1,065  
δ  
22.23  
  
Proliferation of immortalized leukemic cells representative of various indications was determined 
by a MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay (Seeta et al. 
2012). Cells were incubated with TGR-1202 for different time-periods (72 -96 h) based on their 
doubling time.  Data demonstrated the ability of TGR-1202 to inhibit leukemic cell proliferation 
albeit with different potencies based on the cell type. Overall, a 50% growth inhibition for of B, T, 
and monocytic cell lines was achieved at a concentration between 0.5 -7.5 μM of TGR-1202.  
  
Subsequent to cell viability, the effect of TGR-1202 on AKT phosphorylation (Seetaa et al. 2011,  
Seetab et al. 2011, Seetac et al. 2011, Seetad et al. 2011, Seetae et al. 2011) was determined.  
AKT, a serine threonine kinase mediates the downstream effects of PI3K activity and modulates 
several cell processes including survival and growth.  Reduction of phosphorylated AKT by TGR-
1202 in representative cell lines was determined by Western blotting using a phospho-AKT 


18  
  
(Ser473) antibody, demonstrating IC50 below 1.0 micromolar for 3 of the 5 studied cell lines 
(Figure 5).  
  
Figure 5.  
Reduction of pAKT by TGR-1202 in Cell Lines by Western Blotting  
  
  
 
2.2.2.2  
IN VIVO ACTIVITY  
 
In vivo efficacy of TGR-1202 was confirmed in a subcutaneous mouse MOLT-4 xenograft model.  
Oral administration of 150 mg/kg/QD over a 25-day period resulted in a significant delay in tumor 
growth.   
FIGURE 6.  
TGR-1202 IN VIVO EFFICACY  
  
  


19  
  
 
2.2.2.3  
MECHANISM OF ACTION  
 
TGR-1202 caused a dose-dependent inhibition of endogenous pAKT expression in all the cell 
lines tested with a half-maximal reduction observed at 300 nM concentration.  Induction of 
apoptotic activity in cell lines was increased by ~50% across multiple cell lines representing NHL 
and CLL.  These data support inhibition of the PI3K-AKT pathway as a major mechanism of action 
for TGR-1202.   
  
 
2.2.3 TOXICOLOGY   
 
To assess the safety and toxicity of TGR-1202 a 28-day repeat dose study with a 14-day recovery 
period was conducted in CD-1 mice and beagle dogs. TGR-1202 was administered orally.  . No 
TGR-1202 related mortality occurred in the CD-1 mice population.  Treatment related effects 
observed included slight decrease in leukocytes (0.5x relative control) and lymphocytes (0.5x 
relative to control) observed in both males and females at 750 mg/kg/day, increases in cholesterol 
(1.2x to 2.3x relative to control) noted in males and females at 150 and 750 mg/kg/day and 
increases in AST, ALT (2.2x to 2.6x relative to control), and GGT observed in the 750 mg/kg/day 
females.  Organ weight changes in the liver (increased) and microscopic findings in the liver 
(centrilobular hypertrophy [males only], necrosis [males only], and bile duct hyperplasia and bile 
duct ectasia [females only]) were observed in mice dosed at 750 mg/kg/day RP-5264 (the free 
base of TGR-1202).     
  
After a 14-day recovery period, there was complete recovery of the organ weight changes.  There 
was complete recovery of the microscopic findings in the liver of females.  There was incomplete 
recovery of the microscopic finding in the liver of male mice (centrilobular hypertrophy).   
  
In conclusion, once daily oral administration of TGR-1202 was tolerated in mice at dose ranging 
from 50 and 150 mg/kg/day.  The microscopic findings in the liver and the increases in serum 
cholesterol, and female only ALT, AST, and GGT levels at 750 mg/kg/day were considered 
adverse.  The no-observed-adverse-effect level (NOAEL) was considered to be 150 mg/kg/day.   
  


20  
  
TGR-1202 treatment-related clinical signs were observed in dogs dosed at 655/400 and 196.5/150 
mg/kg/day.  These were most severe in the first 9 days of the study in the 3 Group 4 females, 
which showed dehydration, diarrhea, vomitus, ocular discharge, and partial palprebal closure.  
Based on the severity of these findings, these 3 animals were euthanized on Day 9 and doses 
were reduced as tabulated above.  Following reduction of the dose levels on  
Day 9, treatment-related effects at doses of 400 mg/kg/day included diarrhea; soft, mucoid, 
abnormally colored stools; vomiting; ocular discharge; and partial palpebral closure.  Isolated 
observations of thin appearance were also noted in dogs dosed at 655/400 mg/kg/day.  There 
was an apparent gain in tolerance to TGR-1202 over the course of the study, as the instances of 
vomiting and diarrhea tended to decrease with time.  
  
Test article-related decreases in body weight and food consumption, primarily limited to dogs of 
the 655/400 mg/kg/day group, were noted from the first week of the study.  No other TGR-1202 
treatment-related effects occurred on study.  The thymus in the early termination animals and 
some of the Day 30 termination animals was noted at necropsy to be small.  This observation was 
considered a secondary effect related to possible stress in the animals and not a direct effect of 
the test article.  
  
The toxicokinetics of TGR-1202 in plasma was characterized in male and female beagle dogs 
when delivered by once daily oral capsule administration of TGR-1202 at dose levels of 65.5, 
196.5, and 655 mg/kg from Day 1 to Day 8, and at dose levels of 50, 150 and 400 mg/kg from 
Day 9 to Day 28.  Peak RP-5264 (free base of TGR-1202) concentrations occurred between 0.5 
to 24 hours post-dose on Day 1, and between 1 and 10 hours post-dose on Day 28.  Due to 
sustained concentrations, the terminal elimination phase was not reached.  Exposure (mean Cmax 
and AUC[0-24]) were generally less than dose proportional between 65.5 and 655 mg/kg on Day 1 
and between 50 and 400 mg/kg on Day 28.  Exposure increased by up to 3.6-fold following 
repeated dosing for 28 days.  There were no notable differences between male and female dogs.  
  
In conclusion, once daily oral administration by capsule of TGR-1202 was well tolerated in dogs 
at levels of 50 and 150 mg/kg/day.  The gastrointestinal tract, based on clinical signs, was the 
target organ system.  Based on effects on body weight and the incidence and severity of emesis 
and diarrhea, the NOAEL was considered to be 150 mg/kg/day (114.5 mg/kg/day as free base).  
  


21  
  
Refer to the TGR-1202 Investigator’s Brochure (IB) for detailed information on toxicology studies 
conducted to date.  
 
2.2.4 SUMMARY OF TGR-1202 CLINICAL EVALUATIONS   
 
TGR-1202 is a highly specific and orally available PI3K delta inhibitor with nanomolar inhibitory 
potency. TGR-1202 is an isoflavone substituted pyrazolo pyrimidine. It is a p-Toluene sulphonic 
acid (p-TSA) salt of TGR-1202 base (TGR-1202 base is referred to as RP-5264). The specificity 
of TGR-1202 towards PI3Kδ is evidenced by >1000, 50 and 48-fold selectivity over α, β, and γ 
PI3K isoforms, respectively, in an enzyme based assay. The delta isoform of PI3K is highly 
expressed in cells of hematopoietic origin and strongly implicated in various hematologic 
malignancies, and as a result, appears to be an ideal target to treat various lymphoid malignancies 
such as CLL and NHL, among others.   
  
A multi-center (which includes the Center for Lymphoid Malignancy at Columbia University) Phase 
I dose-escalation clinical trial of TGR-1202 in patients with select hematologic malignancies is 
ongoing.  TGR-1202 was well tolerated at doses up to 1800 mg daily given in the fasting state. 
No MTD was observed[35].  Subsequently the formulation was changed to a micronized one, 
given at the fed state.  Again no MTD was observed at the cohort level of 1200mg daily[33].  The 
drug was well tolerated, without transaminitis and colitis, previously reported for idelalisib.  TGR-
1202 has demonstrated marked activity in patients with relapsed refractory CLL, with a 93% nodal 
response rate at doses ≥ 800 mg of initial formulation or any dose of micronized formulation.  
TGR-1202 appears to have promising activity in indolent lymphoma and mantle cell lymphoma.  
Although TGR-1202 has not demonstrated activity as single agent in aggressive lymphomas such 
as DLBCL, its excellent safety profile makes it an ideal candidate for rational combination with 
other drugs that targeting discrete biological signals that overlap with the PI3K pathway, for 
example, proteasome inhibitors[34], as discussed in Section 2.4.  
 
2.3  
CARFILZOMIB  
 
 
2.3.1 PROTEASOME AND PROTEASOME INHIBITOR  
 


22  
  
The proteasome is a multicatalytic proteinase complex that is responsible for degradation of a 
wide variety of protein substrates within normal and transformed cells.  Intracellular proteins 
targeted for degradation by the proteasome are first ubiquitinated via the ubiquitin conjugation 
system.  Ubiquitinated proteins are cleaved within the proteasome by one or more of three 
separate threonine protease activities: a chymotrypsin-like activity, a trypsin-like activity, and a 
caspase-like activity. The ubiquitin-proteasome pathway is the major quality-control pathway for 
newly synthesized proteins[36]. Furthermore, through targeted destruction of regulatory proteins, 
e.g. cyclins and cyclin-dependent kinase inhibitors[37], the proteasome regulates numerous 
cellular functions that are important for the proliferation and survival of cancer cells.  
Consistent with these findings, proteasome inhibitors are found to induce death and prevent 
proliferation of cancer cells[38, 39].   
  
Bortezomib is a first-in-class proteasome inhibitor approved for clinical use.  O’Connor et al. 
reported the clinical activity of bortezomib in the treatment of indolent Non-Hodgkin lymphoma 
(NHL) and mantle cell lymphoma (MCL), leading to its approval by the FDA for relapsed and 
refractory MCL[40].  Bortezomib has also demonstrated clinical activities in a number of other 
hematological malignancies as a single agent or in combinations[41].  As a single agent, however, 
bortezomib has not demonstrated promising activity in aggressive lymphoma.  Since Wilson et al. 
first reported inclusion of bortezomib with EPOCH-R[42], bortezomib has been combined with 
CHOP and other regimens[43].  These studies demonstrate the feasibility of combining 
bortezomib with chemotherapeutic agents, and in some cases produce benefit in select subtypes 
of lymphoma.  However, bortezomib is associated with significant peripheral neuropathy, a dose-
limiting toxicity (DLT) that may limit its dosage and utility as part of combination chemotherapy 
regimens. A promising strategy is to combine proteasome inhibitors and novel biologic agents to 
synergistically target oncogenic pathways.      
  
Carfilzomib (PR-171) is a tetrapeptide ketoepoxide-based inhibitor specific for the 
chymotrypsinlike active site of the 20S proteasome[44].  Carfilzomib is structurally and 
mechanistically distinct from the dipeptide boronic acid proteasome inhibitor bortezomib 
(Velcade®).  In addition, when measured against a broad panel of proteases including metallo, 
aspartyl, and serine proteases, carfilzomib demonstrated less reactivity against non-proteasomal 
proteases when compared to bortezomib.  A Phase 1 study conducted by O’Connor et al has 
demonstrated that carfilzomib is safe, and produces essentially none of the neuropathy seen with 


23  
  
bortezomib[45]. Preliminary results from by Deng et al. have demonstrated that carfilzomib is 
highly synergistic with TGR-1202, a PI3Kdelta inhibitor[34].    
  
 
2.3.2 TOXICOLOGY STUDIES OF CARFILZOMIB  
 
A chronic toxicity study in rats was preceded by a GLP-compliant, 28-day, repeat-dose study in 
which carfilzomib was administered for 2 complete cycles of once daily for 5 days followed by 9 
days of rest. In this study, the STD10 was determined to be 2 mg/kg (12 mg/m2) based upon 
mortality of 5% of the animals at this dose and > 10% at the next highest dose (24 mg/m2).  
Similar target organ toxicities were seen in the 28-day repeated toxicity study as is noted below 
in the 6-month chronic rat study. In a 6-month, GLP-compliant study, carfilzomib was administered 
to 25 animals/sex/group at doses of 6, 12, and 24 mg/m2 (1, 2, and 4 mg/kg) for 6 complete 28-
day cycles of once daily dosing for 2 days repeated weekly for 3 weeks followed by 12 days of 
rest. Toxicokinetics and PDn were assessed in satellite cohorts. Mortality of 30% of the animals 
was noted at 24 mg/m2 and in 6% of animals at 12 mg/m2. The causes of death for these animals, 
when they could be determined, were gastric hemorrhage/necrosis, cardiac failure, and renal 
tubular failure (associated with vascular thrombi). Toxicities observed in animals in the high-dose 
group sacrificed at the end of the study included thrombocytopenia, decreased RBC counts with 
a concomitant increase in reticulocytes, induction of an acute phase response (increased 
fibrinogen and circulating neutrophils and monocytes), azotemia (increased BUN) associated with 
an increased rate of chronic progressive nephropathy (common to this strain of rat), hepatocellular 
hypertrophy and periportal fatty vacuolation in the liver that was not associated with altered liver 
enzyme levels, and decreased cellularity in the thymus and spleen. In the remaining animals at 
12 mg/m2 (2 mg/kg), thrombocytopenia, increased reticulocytes, and signs of an acute phase 
response were observed. Proteasome inhibition measured in whole blood 1 hour after the first 
dose was > 90% for all dose levels in this study. The STD10 was determined to be 12 mg/m2 (2 
mg/kg) based upon rate of mortality in the high-dose group.   
  
A chronic toxicity study in monkeys was preceded by a GLP-compliant, 28-day, repeat dose study 
in which carfilzomib was administered for 2 complete cycles of once daily for 5 days followed by 
9 days of rest. In this study, the highest non-severely toxic dose (HNSTD) was determined to be 
12 mg/m2 (1 mg/kg) based upon mortality in animals at the next highest dose (24 mg/m2). Similar 


24  
  
target organ toxicities were seen in the 28-day repeated toxicity study, as is noted below in the 9-
month chronic study. In this study, carfilzomib was administered to cynomolgus monkeys (4–6 
per sex per dose) at doses of 6, 12, and 24 mg/m2 (0.5, 1, and 2 mg/kg) for 9 complete cycles, 
once daily for 2 days repeated weekly for 3 weeks followed by 12 days of rest. At 24 mg/m2, there 
was an unscheduled death of 1 male in Cycle 6 due to multiorgan toxicities, including cardiac 
inflammation, pulmonary inflammation and edema, and renal dysfunction, and an early sacrifice 
of 1 female in Cycle 5 due to declining physical condition associated with severe nonregenerative 
anemia and hypoalbuminemia. At doses of 12 and 24 mg/m2, decreases in RBCs along with 
reduced hemoglobin levels and hematocrit with increased reticulocytes were noted on Day 17 of 
each cycle (24 hours after the last dose), but recovered during the 12-day nondosing periods of 
each cycle. Also noted at these dose levels were induction of an acute phase response (increased 
fibrinogen, neutrophils, and monocytes and decreased albumin) and azotemia (increased BUN 
and serum creatinine) associated with proteinuria, hematuria, and increased kidney weight.  The 
azotemia was associated with interstitial inflammation, altered tubule size, and glomerulopathy in 
the kidney. Inflammation was also noted in the heart and interstitial regions of the lung at these 
dose levels. The HNSTD in this study was determined to be 6 mg/m2 (0.5 mg/kg) based upon 
mortality at the high dose (24 mg/m2), histomorphologic changes in the kidney, proteinuria, and 
hematuria at 12 mg/m2. Proteasome inhibition, measured in whole blood 1 hour after the first 
dose, was > 90% for all dose levels in this study.  
  
 
2.3.3 CYTOCHROME P450  
 
In an in vitro study using human liver microsomes, carfilzomib showed modest direct and 
timedependent inhibitory effect on human cytochrome P450 3A4/5 (CYP3A4/5). In vitro studies 
indicated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh human 
hepatocytes. Cytochrome P450-mediated mechanisms play a minor role in the overall metabolism 
of carfilzomib. A clinical trial of 17 patients using oral midazolam as a CYP3A probe demonstrated 
that the pharmacokinetic profile of midazolam was  unaffected by concomitant carfilzomib 
administration. Carfilzomib is not expected to inhibit CYP3A4/5 activities and/or affect the 
exposure to CYP3A4/5 substrates.  
  
 


25  
  
2.3.4 PRECLINICAL ANTITUMOR ACTIVITY OF CARFILZOMIB  
 
Incubation of tumor-derived cell lines in culture for 1 hour with carfilzomib leads to rapid inhibition 
of proteasome activity, followed by accumulation of polyubiquitinated proteins and induction of 
apoptosis[44]. This brief exposure time, which mimics in vivo exposure, induces cell death in both 
hematological and solid tumor cell lines. Hematological tumor cell lines, particularly multiple 
myeloma, are the most sensitive to such carfilzomib treatments, with IC50 values ranging from 31 
to 164 nM. Continuous (72-hour) exposure to carfilzomib is associated with more potent antitumor 
activity across a broad panel of tumor cells (IC50 values ranging from 2.4 to 20 nM). Thus, 
intensive dosing with carfilzomib was examined initially in animal efficacy and toxicity studies and 
subsequently in clinical studies. Intensive dosing strategies involved administration of a second 
dose of carfilzomib within a 24-hour period in order to delay the recovery of proteasome function 
within target cells. Sustained proteasome inhibition for 60 to 72 hours achieved with a second 
dose of carfilzomib given on Day 2 lead to significant antitumor activity in animal models that are 
resistant to bortezomib given on its clinical schedule (Day 1 and Day 4)[44].  
  
The antitumor efficacy of carfilzomib has been evaluated in immunocompromised mice implanted 
with a variety of human tumor cell lines, including HT-29, a human colorectal adenocarcinoma cell 
line[44]. A statistically significant reduction from baseline in tumor size was seen when carfilzomib 
was administered on a weekly schedule of Day 1/Day 2[44].  
  
 
2.3.5 PHASE 1 EXPERIENCE WITH CARFILZOMIB AS A MONOTHERAPY  
 
O’Connor et al. conducted the first phase I trial evaluating the safety and efficacy of carfilzomib in 
relapsed or refractory hematologic malignancies[45].   Eight dose groups of three to six patients 
received 5 consecutive days of carfilzomib intravenously at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, 
and 20 mg/m2 within 14-day cycles.  At 20 mg/m2, grade 3 febrile neutropenia and grade 4 
thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose (MTD).  
No grade 3 or 4 peripheral neuropathies were reported.  Antitumor activity was observed at doses 
equal to or higher than 11 mg/m2: one unconfirmed complete response, one partial response, and 
two minimal responses.    
  


26  
  
A separate phase I clinical trial, PX-171-002, tested carfilzomib in subjects with relapsed/refractory 
hematologic malignancies[46].  During the dose escalation portion of the trial, 37 subjects received 
carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  Subjects with multiple myeloma 
(MM), non-Hodgkin’s Lymphoma (NHL), Waldenström’s macroglobulinemia, and Hodgkin’s 
lymphoma (HL) were enrolled on the study. No DLTs were observed in the initial seven cohorts 
(doses ranged from 1.2 to 15 mg/m2) of three subjects each.  At the 20 mg/m2 dose level, one of 
eight patients experienced a Grade 3 renal failure at  
Cycle 1, Day 2 which was considered possibly related to study drug and lasted for six days.   
The patient continued on study for the remainder of Cycle 1 before having disease progression.   
At the 27 mg/m2 dose level, one of six subjects experienced a DLT during Cycle 1, consisting of 
severe hypoxia with pulmonary infiltrates following Day 2 of dosing.  In subjects where the 27 
mg/m2 dose was efficacious, a “first dose effect” was seen that included a constellation of findings 
that appeared to be the clinical sequelae of rapid tumor lysis syndrome (TLS) and/or cytokine 
release.  This syndrome was notable for fever, chills, and/or rigors occurring during the evening 
following the first day of infusion.  On the second day, three of five subjects with multiple myeloma 
experienced an increase in creatinine to Grade 2 (including the subject with the DLT).  This 
elevation was rapidly reversible and all three subjects were re-challenged with carfilzomib without 
recurrence of the events.  Interestingly, all three subjects had a rapid decline in serum and/or 
urine M-protein levels; two subjects achieved a PR and the third subject achieved a minimal 
response (MR).  There were no consistent changes in potassium, calcium, phosphorous, or uric 
acid levels although some increases in LDH and other markers of tumor lysis were noted.  
Because of the possible TLS and reversible creatinine elevations, hydration and very-low dose 
dexamethasone prophylaxis were instituted in subsequent studies and have essentially eliminated 
clinically significant TLS/creatinine elevations and the other “first-dose” effects.  Hematologic 
toxicities were primarily mild or moderate.  The thrombocytopenia reported with carfilzomib is 
cyclical and similar to that reported with bortezomib.  The cause and kinetics of the 
thrombocytopenia following treatment are different from those of standard cytotoxic agents.  In 
general, it is recommended that in order to  maximize the benefit of carfilzomib, subjects with 
thrombocytopenia should be supported as clinically indicated rather than having treatment 
reduced due to thrombocytopenia.  
  
Of the 37 evaluable patients enrolled in the dose escalation phase of PX-171-002, 20 had MM.  
Four MM patients achieved a partial response (PR), one of two at the 15 mg/m2 dose, one of six 


27  
  
at the 20 mg/m2 dose, and two of five at the 27 mg/m2 dose.  The responses have been rapid in 
onset, beginning in some subjects after 1-2 doses.  The duration of response (DOR) ranged from 
134 to 392 days. The minimal effective dose was 15 mg/m2 wherein >80% proteasome inhibition 
in peripheral blood and mononuclear cells was observed one hour after dosing.  The median 
number of prior therapies for subjects on this trial was five, and responses were seen in subjects 
who had relapsed from (including some refractory to) bortezomib and/or immunomodulatory 
agents.  Stable disease also noted in four NHL and five MM subjects, with subjects on therapy for 
up to 409 days.  Such prolonged therapy, at “full” twice-weekly doses, is not possible with 
bortezomib.  These results led to the initiation of two Phase 2 studies.  
  
An ongoing phase I study investigated weekly carfilzomib in combination with dexamethasone for 
patients with relapsed or refractory MM. Preliminary results of 18 patients have been reported in 
the abstract form[47]. The 45 and 56 mg/m2 dosing cohorts enrolled 3 patients each, and the 70 
and 88 mg/m2 dosing cohorts enrolled 6 patients each. Patients have received a median of 5.5 
cycles of treatment. At 88 mg/m2, 2 dose-limiting toxicities (DLTs) were observed: grade [Gr] 3 
dyspnea and Gr 3 vomiting. All 18 patients were evaluable for safety. The only grade 3 adverse 
event (AE) reported in more than 1 patient was increased blood creatinine (n=2). Four serious 
AEs were reported in 3 patients: Gr 3 dyspnea, Gr 3 pneumonia, Gr 3 increased blood creatinine, 
and Gr 4 hyponatremia. No peripheral neuropathy was reported. Six patients discontinued 
treatment for the following reasons: AEs of decreased renal function (n=1) and dyspnea (n=1), 
progressive disease (n=2), physician decision (n=1), and withdrawal of consent (n=1). Five 
patients required a dose reduction from 88 mg/m2 to 70 mg/m2 (1 due to an AE, 1 due to a DLT, 
and 3 per protocol due to the 2 DLTs in the 88 mg/kg2 cohort); 2 of the 5 patients had an additional 
dose reduction owing to AEs. PK analysis (n=12) from patients who received 20, 70, or 88 mg/m2 
of carfilzomib showed a dose-dependent increase in mean Cmax (703, 2640, and 3172 ng/mL, 
respectively) and AUC (283, 1045, and 1247 h·ng/mL, respectively) for carfilzomib. The mean 
terminal half-life was ~0.8 h. Fifteen patients were included in the response evaluation; 3 patients 
did not have a postbaseline assessment at the time of the data cutoff. The ORR was 67%, and 
the CBR was 87% (4 patients achieved a complete response, 1 very good PR, 5 PR, and 3 MR). 
One patient had stable disease, and 1 patient was not evaluable for response, as the patient had 
a DLT and was no longer on treatment. Median time to response for patients that achieved a ≥PR 
(n=10) was 1.6 months.   
 


28  
  
  
 
 
2.3.6 PHASE 2 EXPERIENCE WITH CARFILZOMIB AS A MONOTHERAPY  
 
Unfortunately to date, there has been very little phase 2 experience with carfilzomib in patients 
with lymphoma.  However, there is abundant data in patients with myeloma that is informative for 
the proposed study.  Two Phase 2 clinical studies have been completed with carfilzomib in MM 
patients, PX-171-003-A0 (N=46) in relapsed and refractory MM and PX-171-004 (N=39 in Part 1, 
N=120 in Part 2) in relapsed MM[48, 49].  In both studies, patients were dosed with 20 mg/m2 on 
Days 1, 2, 8, 9, 15, and 16 on a 28 day schedule.  In these studies there were four cases of 
suspected or documented TLS prior to institution of the prophylaxis guidelines.  Since these 
guidelines were implemented, no further cases of TLS have been reported including in >350 
additional patients with relapsed or refractory MM treated in ongoing Phase II studies.  In both 
studies, the most common adverse events were fatigue, anemia, thrombocytopenia (primarily 
cyclical), gastrointestinal, and dyspnea.  Almost all were Grades 1 or 2.  There were reported 
cases of increased in serum creatinine that were primarily < Grade 2 and were transient, rapidly 
reversible, and non-cumulative.  A very low rate of treatment-emergent peripheral neuropathy, 
2.2% Grade 3/4, was observed in PX-171-003-A0 despite the fact that 78% of patients had Grade 
1/2 neuropathy upon study entry.  The response rate in PX-171-003A0 was 18% PR, 7% MR and 
41% SD in these patients that entered the study with progressive disease and were refractory to 
their most recent therapy, often including bortezomib and/or an immunomodulatory drug (usually 
lenalidomide).  The median time to progression on the PX171-003-A0 study was 5.1 months with 
a DOR of 7.4 months (mean follow up of 7.6 months).  
  
A “stepped up” dosing schedule, referred to as 20/27 mg/m2 has subsequently been incorporated 
into the PX-171-003 study (referred to as PX-171-003-A1) in order to maximize the clinical benefit 
of carfilzomib[50].  Patients receive 20 mg/m2 for the first cycle and 27 mg/m2 thereafter.  The 
study completed enrollment of 266 patients.  To date, this stepped up dosing schedule has been 
well tolerated.  An independent Safety Oversight Group (SOG) evaluated the safety data from the 
40 of 250 patients to be enrolled on the 20/27 schedule and agreed that the trial should proceed 
without modification.  No cases of TLS were observed and rates of BUN and creatinine elevation 
dropped sharply, with Grade 3/4 renal impairment dropping to 2.2% in A1( from 15% in A0), most 


29  
  
likely due to hydration and very low dose dexamethasone.  The other most common adverse 
events were similar to the A0 portion of the study.  Treatment-emergent peripheral neuropathy 
remains low the study with 15% Grade 1/2 and one (0.7%) Grade 3/4 event reported to date on 
PX-171-003-A1.  In addition, anemia in the PX-171-003-A1 (higher dose) were lower than those 
reported in the PX-171-003–A0 portion of the study, possibly indicating that the higher dose of 
carfilzomib is achieving better clearing of neoplastic cells in the bone marrow allowing superior 
normal marrow reconstitution.  Rates of thrombocytopenia and neutropenia were similar in the 
two cohorts, with Grade 3 neutropenia in ~5% without any Grade 4 neutropenia to date.  
  
In PX-171-004[49], 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were 
separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m(2) for all treatment 
cycles, and Cohort 2, scheduled to receive 20 mg/m(2) for cycle 1 and then 27 mg/m(2) for all 
subsequent cycles. The primary end point was an overall response rate (>/= partial response) of 
42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response  
(overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, 
respectively. Median duration of response was 13.1 months and not reached, and median time to 
progression was 8.3 months and not reached, respectively. The most common 
treatmentemergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent 
carfilzomib elicited a low incidence of peripheral neuropathy-17.1% overall (1 grade 3; no grade 
4)-in these pretreated bortezomib-naive patients. Thus, carfilzomib can induce very high levels of 
response in patients who have not previously been treated with bortezomib and, even in 
bortezomibtreated patients, substantial anti-tumor activity is observed.  Of note, disease control 
(PR + MR + SD) was achieved in ~65% of patients with progressive MM entering the study.  
Patients on these studies have been treated for >12 cycles with good tolerability and no 
cumulative toxicity (e.g., bone marrow, severe fatigue, or neuropathy) have not been observed. 
These data formed the basis of FDA approval of carfilzomib for the treatment of relapsed and 
refractory MM, and the approved dosing schedules are 20mg/m2 for cycle 1, and 27 mg/m2 in 
subsequent cycles if tolerated.  The drug is given as an intravenous infusion over 2-10 minutes.   
  
Higher dose of carfilzomib as a monotherapy has been used in a small cohort of 47 patients with 
solid tumor or lymphoma.  In these patients carfilzomib was given intravenously over a longer 
duration, 30 minutes, at the dose  of 20 mg/m2 on Cycle 1 Days 1 and 2 only, followed by increased 
doses (36, 45, 56, 70, or 88 mg/m2) for the remainder of treatment.  No DLTs were seen in the 


30  
  
initial 20/36 mg/m2, 20/45 mg/m2, or 20/56 mg/m2 dose cohorts. Reversible DLTs were recorded 
in 2 patients in the 20/70 mg/m2 cohort: 1 patient experienced Grade 3, probably treatment-related 
proteinuria and 1 patient experienced Grade 3, possibly treatment-related renal tubular necrosis 
and Grade 4 thrombocytopenia lasting 28 days; both patients were successfully re-challenged 
and continued on treatment at reduced doses. The MTD was therefore determined to be 56 
mg/m2.  
  
 
2.3.7 PHARMACODYNAMICS OF CARFILZOMIB  
 
Proteasome subunit activities in blood and PBMC samples from Phase 1b/2 Studies PX-171005, 
PX-171-006, and PX-171-007 were measured before and after treatment with carfilzomib. 
Intravenous administration of carfilzomib over 2 to 10 minutes results in suppression of 
proteasome CT-L activity when measured in blood 1 hour after the first dose. Inhibition of 
proteasome CT-L activity was comparable in whole blood and PBMCs. On Day 1 of Cycle 1, CT-
L inhibition in PBMCs ranged from 79% to 89% at 15 mg/m2 and from 82% to 83% at 20 mg/m2. 
Inhibition of the latent membrane protein 2 (LMP2) and multicatalytic endopeptidase complex-like 
1 (MECL1) subunits of the immunoproteasome ranged from 26% to 32% and 41% to 49% at 20 
mg/m2, while little to no inhibition of the Beta1 or Beta2 was observed. On Day 1 of Cycle 2, CT-
L inhibition in PBMCs following a dose of 27 mg/m2 was 76% to 92%.  
Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each 
week of dosing, with 30-minute and bolus infusions. Near-complete recovery of proteasome 
activity was observed in PBMCs between cycles, that is, after 12 days without treatment. Upon IV 
administration of 20 mg/m2 carfilzomib over 30 minutes, the level of proteasome inhibition was 
similar to that observed in subjects receiving a 2- to 10-minute infusion.  At 20 mg/m2, inhibition 
of CT-L activity in blood and PBMC was 69.1% and 85.0%, respectively, and inhibition of LMP2 
and MECL1 in PBMC was 30.2% and 50.3%, respectively.  At the carfilzomib dose of 36 mg/m2 
inhibition of CT-L activity in blood and PBMC was 73.5% and 86.9%, respectively, and inhibition 
of LMP2 and MECL1 in PBMC was 33.6% and 54.3%, respectively. At 45 mg/m2, inhibition of 
CT-L activity in blood and PBMC was 89.3% and 94.1%, respectively, and inhibition of LMP2 and 
MECL1 in PBMC was 53.8% and 77.5%, respectively.  
  


31  
  
 
2.3.8 PHARMACOKINETIC PROFILE OF CARFILZOMIB  
 
Intensive PK sampling with single- and multiple-dose PK characterization was evaluated in 
Studies PX-171-005 and PX-171-007. Similar to the results from rodents and monkeys, 
carfilzomib demonstrated rapid clearance from plasma following IV administration to human 
subjects. Pharmacokinetic parameter calculations could not be performed for doses < 11 mg/m2, 
due to a large number (> 50%) of samples with concentration values below the limit of detection 
or high intra- and intersubject variability. At doses ≥ 15 mg/m2, systemic clearance values on 
Cycle 1 Day 1 ranged from 151 to 263 L/h, exceeding liver blood flow, and terminal t1/2 values 
were between 0.4 to 1.2 hours. The Cmax and AUC following a single IV dose of 27 mg/m2 over 
2 to 10 minutes was 4232 ng/mL and 379 ng•hr/mL, respectively. While definitive dose 
proportionality cannot be concluded due to the small number of observations available for 
analysis, a dose-dependent increase in total exposure (AUC) and Cmax was seen between 20 
and 56 mg/m2. Following repeated doses of carfilzomib at 15 and 20 mg/m2, the AUC and t1/2 
were similar on Days 1 and 15 or 16 of Cycle 1, suggesting no systemic carfilzomib accumulation.  
  
 
2.3.9 ABSORPTION OF CARFILZOMIB  
 
Carfilzomib is administered intravenously (IV) ; therefore, absorption is not applicable.  
  
 
2.3.10 DISTRIBUTION OF CARFILZOMIB  
 
The mean volume of distribution at steady state (VSS) after a 20 mg/m2 dose of carfilzomib was 
28 L in subjects with multiple myeloma. In an in vitro study, binding of carfilzomib to human plasma 
proteins averaged 97% over the concentration range of 0.4 to 4.0 micromolar and this extent of 
binding was not concentration dependent. Similarly, plasma protein binding of carfilzomib in 
multiple myeloma subjects with normal renal function and subjects with mild to severe renal 
dysfunction ranged from 97.6% to 98.3% (Study PX-171-005).  
 


32  
  
  
 
 
2.3.11 METABOLISM OF CARFILZOMIB  
 
Upon administration, carfilzomib was rapidly and extensively metabolized. The predominant 
metabolites measured in human plasma and urine, and generated in vitro by human hepatocytes, 
were peptide fragments (M14, M15) and the diol of carfilzomib (M16), suggesting that peptidase 
cleavage and epoxide hydrolysis were the principal pathways of metabolism. These metabolites 
were likely systemically formed, because a study with rat blood and tissue (kidney, heart, lung, 
and liver) homogenates demonstrated rapid formation of these metabolites. Cytochrome P450-
mediated mechanisms play a minor role in the overall metabolism of carfilzomib. Each of the 
metabolites (M14, M15, and M16) lacks an epoxyketone pharmacophore and has no known 
biologic activity. In addition, the metabolites in humans are formed in preclinical species and there 
are no unique and disproportionate metabolites in humans.  
  
 
2.3.12 EXCRETION OF CARFILZOMIB  
 
Renal and biliary elimination of unlabeled carfilzomib was evaluated in subjects with multiple 
myeloma or solid tumors in lieu of a radiolabeled mass balance study in healthy volunteers. The 
excretion profile of carfilzomib and predominant metabolites was assessed by a 24-hour collection 
of urine and fecal samples in Study PX-171-008 and urine sample collection in Study PX-171-
005. The metabolites of carfilzomib are primarily eliminated by the kidneys. Within 24 hours 
following administration of a single 27 mg/m2 IV dose of carfilzomib to subjects with multiple 
myeloma or solid tumors, approximately 30% of the administered dose of carfilzomib was excreted 
in urine as metabolites M14 (approximately 24%–31%) and M15 (approximately 2%). Urinary 
excretion of parent compound was negligible (0.3% of the total dose). These results suggest that 
carfilzomib is primarily metabolized to M14 before being excreted in urine. A small amount of 
metabolite M14 (0.2%) was recovered in feces with no detection of carfilzomib and metabolite 
(M15 and M16) in fecal samples. The relatively low recovery observed in urine and fecal samples 
could be due to the collection time limited to 24-hour and measurements not accounting for minor 


33  
  
metabolites. In addition, carfilzomib is peptidic in nature and irreversibly binds to its target; drug 
recovery would be expected to be limited by target binding in cells that are slow to turnover 
proteasomes and amino acids (leucine and phenylalanine) that may be incorporated into normal 
biosynthetic pathways.  
  
 
2.4  
RATIONALE FOR THE STUDY  
 
Dysregulated Myc is associated with resistance to chemotherapy and poor survival in patients 
with aggressive lymphomas[3-6]. Novel strategies that target this biology could markedly improve 
the outcome of these patients. To date no drugs that directly target Myc have been approved for 
cancer treatment.  In fact, since Myc is involved in many essential functions in normal cells, direct 
Myc inhibitors may theoretically be associated with significant toxicity.  Alternatively, it may be 
advantageous to inhibit upstream cancer specific signals that converge on Myc as a therapeutic 
strategy to mitigate the poor risks associated with Myc dysregulation.   
  
Myc is known to form a positive feed-forward loop with the translation initiation factor eIF4F[10], 
which in turn is regulated by mTOR through the inhibitor 4EBP1[11]. PI3K is one of the most 
important upstream activators of mTOR[12], and recently the ubiquitin-proteasome pathway was 
also reported to be involved in the activation of mTOR[13, 14].  Our hypothesis is that if the 
proteasome and PI3K cooperate in the activation of mTOR, then combinations of drugs targeting 
these pathways will synergistically inhibit the mTOR-eIF4F-Myc axis and demonstrate potent 
activity in the treatment of Myc-dependent aggressive lymphoma.  Results from our laboratory 
have demonstrated that carfilzomib and a PI3K-delta inhibitor, TGR-1202, are highly synergistic 
in models of aggressive B- and T-cell lymphoma, through downregulation of c-Myc.     
  
Preliminary results: We surveyed interactions between 2 PI3K-delta inhibitors (idelalisib/CAL101 
and TGR-1202) and 2 proteasome inhibitors (bortezomib and carfilzomib) using high throughput 
screening (HTS).  We chose these drugs based on their safety in patients.  Further, 3 of these 4 
drugs are FDA approved, idelalisib for indolent lymphoma, bortezomib for multiple myeloma (MM) 
and mantle cell lymphoma (MCL), and carfilzomib for MM. The combination TGR-1202 + 
carfilzomib caused more synergism in growth inhibition (Figure 7A) and apoptosis than the 


34  
  
combinations TGR-1202 + bortezomib, Cal-101 + carfilzomib, and Cal-101 + bortezomib in 
models of diffuse large B cell lymphoma (DLBCL). Figure 7B demonstrated both TGR-1202 + 
carfilzomib and Cal-101 + bortezomib were more effective than the single agents in the inhibition 
of AKT and Raptor. In contrast, TGR-1202 + carfilzomib was markedly more potent than Cal-101 
+ bortezomib and the single agents on the inhibition of phosphorylated 4EBP1, eIF4F subunits 
(A/E/G), and c-Myc in DLBCL. The same results were observed in T-cell acute lymphoblastic 
leukemia (T-ALL) and MCL, supporting combining PI3K and proteasome inhibitors as a 
therapeutic strategy in Myc dependent aggressive lymphoma.  The combination of TGR-1202 and 
carfilzomib is particularly synergistic, therefore promising for clinical studies.      
  
  
3. PATIENT SELECTION  
 


35  
  
 
3.1  
INCLUSION CRITERIA FOR LYMPHOMA   
 
• 
Phase I:  Patients with relapsed or refractory Hodgkin lymphoma or non-Hodgkin 
lymphoma. Patients with chronic lymphocytic leukemia (CLL) and small lymphocytic 
lymphoma (SLL) are also eligible. In addition, patients with NHL other than diffuse large B 
cell lymphomas (DLBCL) must have received at least 2 prior therapies. Patients with 
DLBCL and HL will be eligible if there is no available standard therapy.  
• 
Phase Ib: Patients must have histologically confirmed R/R PTCL or C-MYC positive 
DLBCL (as defined by WHO criteria and IHC staining of C-MYC). The patients with PTCL 
or DLBCL will be eligible if there is no available standard therapy.  
• 
Must have received front-line chemotherapy. No upper limit for the number of prior  
therapies. Patients may have relapsed after prior autologous stem cell transplant or 
allogeneic stem cell transplant.  
• 
Evaluable Disease in the Phase I, and measurable disease for the phase Ib study as 
defined in Section 11 in the Phase II.  
 
  Age >18 years  
  
• 
ECOG performance status < 2   
• 
Patients must have adequate organ and marrow function as defined below:  
o absolute neutrophil count   
  
  
            >1,000/dL  
o platelets    
  
  
  
  
  
  
  
 
 
>75,000   
o total bilirubin   
  
  
  
  
  
  
  
<1.5X 
institutional limits   
Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 × ULN; aPTT, PT not to 
exceed 1.2 × ULN  
o AST(SGOT)/ALT(SGPT)   
  
  
<2.0X institutional upper limit of 
normal o Serum creatinine   
  
  
  
  
within 
normal 
institutional limits  
 
  OR  
o Measured creatinine clearance  >50 mL/min/for patients with creatinine levels above 
institutional normal.   
o Left ventricular ejection fraction (LVEF)   >50% as defined by ECHO or MUGA.  
  


36  
  
• 
Negative urine or serum pregnancy test for females of childbearing potential. All females 
of childbearing potential must use an effective barrier method of contraception (either an 
IUD or double barrier method using condoms or a diaphragm plus spermicide) during the 
treatment period and for at least 1 month thereafter. Male subjects should use a barrier 
method of contraception during the treatment period and for at least 3 months thereafter.      
• 
Ability to understand and the willingness to sign a written informed consent document.  
  
 
3.2  
EXCLUSION CRITERIA  
 
• 
Prior Therapy  
o Exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the 
study or those who have not recovered from adverse events due to agents 
administered more than 2 weeks earlier.  
o Systemic steroids that have not been stabilized (≥ 5 days) to the equivalent of  
≤10 mg/day prednisone prior to the start of the study drugs. o 
No other concurrent investigational agents are allowed.   
  
• 
Central nervous system metastases, including lymphomatous meningitis will be allowed 
in the phase II study, but will not be allowed in the phase I.   
• 
History of allergic reactions to TGR-1202 or carfilzomib.  
• 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.   
• 
Pregnant women   
• 
Nursing women   
• 
Active concurrent malignancy (except non-melanoma skin cancer, carcinoma in situ of the 
cervix, low risk prostate cancer). If there is a history of prior malignancy, the patient must 
be disease-free for ≥ 2 years.    
• 
Patients with a low grade lymphoma or CLL and a concurrent high grade lymphoma 
transformed from the low grade lymphoma or CLL will be eligible.   
• 
Patients known to be Human Immunodeficiency Virus (HIV)-positive   
• 
Patients with active hepatitis A, hepatitis B, or hepatitis C infection   


37  
  
• 
Concomitant use of CYP3A4 inhibitors (see Appendix 2)   Significant 
cardiac 
abnormalities such as:  
o Myocardial infarction within 6 months of C1D1;   
o An ECG recorded at screening showing evidence of cardiac ischemia (ST  
depression of ≥2 mm, measured from isoelectric line to the ST segment).  If in any 
doubt, the patient should have a stress imaging study and, if abnormal, 
angiography to define whether or not CAD is present;  
o Congestive heart failure (CHF) that meets New York Heart Association (NYHA)  
Class II to IV definitions (see Appendix 4) and/or ejection fraction <50% by MUGA 
and ECHO;   
• 
A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), 
Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic 
implantable cardioverter-defibrillator (AICD).  
  
 
3.3  
INCLUSION OF WOMEN AND MINORITIES  
 
Both men and women of all races and ethnic groups are eligible for this trial.  
  
4. REGISTRATION PROCEDURES  
 
 
4.1  
GENERAL GUIDELINES  
 
Eligible patients will be enrolled on study by the study team.    
  
Following enrollment, patients should begin protocol treatment within 14 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator. If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.    
  


38  
  
 
4.2  
SCREENING  
 
All potential study patients will be screened and eligibility determined prior to enrollment.  Unless 
otherwise specified, the following procedures and evaluations will be performed as noted in the 
study calendar (Section 10) prior to the start of study drugs (cycle 1, dose 1):  
  
• 
Obtain written informed consent and privacy authorization prior to initiating any 
protocolrequired procedure that is not considered standard of care (See Section 4.3)  
• 
Review eligibility criteria  
• 
Review medical chart for past medical/surgical history  
• 
Record medications and prior treatment regimen  
• 
Record response to prior treatment regimen   Document histopathology from:  
o Original diagnosis  o Tumor biopsy in the relapsed setting  
• 
Documentation of known measurable disease parameters by the following procedures:  
o CT of neck, chest, abdomen, and pelvis (PET/CT preferred but PET is optional)  
o Skin exam if known skin involvement o Other imaging techniques documenting 
disease site other than neck, chest, abdomen, and pelvis, if applicable  
• 
Obtain a 12-lead electrocardiogram (ECG) and calculate the QTc interval.   
• 
Perform a comprehensive physical examination  
• 
Assess and record ECOG Performance Status  
• 
Local laboratory: Collect blood for hematology (CBC with differential count), chemistry (Na, K, 
Cl, HCO3, BUN, creatinine, glucose, calcium, magnesium, lactate dehydrogenase,  serum β-
human chorionic gonadotropin [β-hCG] pregnancy test for women who are not 
postmenopausal or surgically sterile [within 7 days prior to cycle 1, dose 1 and again within 
24 hours prior to first dose of the study drugs), liver function tests (total protein, albumin, AST, 
ALT, total bilirubin, direct bilirubin, and alkaline phosphatase).  
• 
Calculate creatinine clearance using the glomerular filtration rate (GFR) according to the 
Cockroft and Gault Equation, only if screening serum creatinine is > 1.5 mg/dL.   
 
4.3  
INFORMED CONSENT  
 
Study personnel must obtain documented consent from each potential patient prior to entering in 
a clinical study.  Consent must be documented on the IRB approved consent form by obtaining 


39  
  
the dated signature both of the patient and of the investigator conducting the consent discussion.  
If the patient is unable sign the consent form, then oral consent, attested to by the dated signature 
of an impartial witness (someone not involved with the conduct of the study), is the required 
alternative.  
  
If the patient is illiterate, an impartial witness should be present during the entire informed consent 
reading and discussion.  Afterward, the patient should sign and date the informed consent, if 
capable.  The impartial witness should also sign and date the informed consent along with the 
individual who read and discussed the informed consent (i.e., study staff personnel).  
  
If the patient is legally incompetent (i.e., a minor or mentally incapacitated), the written consent of 
a parent, legal guardian or legal representative must be obtained.  An impartial witness will also 
sign such consent.  
  
The information from the consent form should be translated and communicated to the subject in 
language understandable to the subject. Consent forms will be available in English and Spanish.  
When the study participant is non-English and non-Spanish speaking, the consent form must be 
read accurately in its entirety by a qualified professional translator.  The translator will provide a 
written statement indicating that the consent form has been accurately translated from the 
accompanying English version, and that the study participant consents to participation.   
The professional translator will sign the consent form as an impartial witness.  
  
A copy of the signed and dated consent form should be given to the patient before participation in 
the study.  
  
Patients may undergo study screening tests prior to giving written informed consent provided that 
these tests are considered part of standard care.  
  
The initial informed consent form and any subsequent revised written informed consent form, and 
written information will receive the IRB approval.  The patient or his/her legally acceptable 
representative will be informed in a timely manner if new information becomes available that may 
be relevant to the patient’s willingness to continue participation in the trial.  The communication of 
this information will be documented.  


40  
  
  
 
4.3.1 CONSENT AND USE OF TISSUE SPECIMENS FOR RESEARCH  
 
Patients who choose to participate in the optional biopsies will undergo a tissue biopsy 
pretreatment and a second biopsy between Day 8 and 21 of cycle 1.  The investigator or designee 
is responsible for explaining and verifying the subject’s consent before obtaining any biopsy. It will 
be explained to the patient that allowing the lymph node sample is encouraged, but optional, and 
participation in the associated clinical study is not dependent upon giving this sample.    
 
4.4  
REGISTRATION PROCESS  
 
To register a patient, the following documents should be completed by a member of the research 
staff and delivered to the study coordinator:  
• 
Eligibility Screening Worksheet   
• 
Copy of required laboratory and imaging tests  
• 
Signed patient consent forms  
• 
HIPAA authorization form  
  
The Study Coordinator will verify eligibility.  To complete the registration process, the Coordinator 
will:  
• 
Assign a patient study number  
• 
Register the patient on the study  
• 
Confirm registration with the principal investigator  
  
5. TREATMENT PLAN  
 


41  
  
 
5.1  
AGENT ADMINISTRATION  
5.1.1 Regimen Description  
Patients will be treated with TGR-1202 and carfilzomib administered as follows: TGR-1202 from 
Days 1-21; and carfilzomib administered intravenously on Days 1, 8, 15 of a 28-day cycle (Table  
 
  
REGIMEN DESCRIPTION  
 
 
  
Agent  
Premedications  
Precautions  
  
Dose  
  
Route  
  
Schedule  
Cycle 
Length   
Carfilzomib  
IV hydration,  
dexamethasone   
20-56** 
mg/m2  
IV over 30 
minutes   
Days 1, 8,  
15  
28 days  
TGR-1202  
  
600-800 
mg  
Oral  
Once daily 
on days 1- 
 
 
 
 
21  
 
** Doses as appropriate for assigned dose level with the following exception: on cycle 1 
day 1 of all assigned dose level carfilzomib is dosed at 20 mg/m2.  Premedication for 
carfilzomib includes hydration with 250-500 ml of normal saline, and dexamethasone 
4mg to prevent infusion reaction.  
  
                                               
1 ).    
  
Table 1:  Regimen Description  


42  
  
5.1.2 Dose Escalation Scheme  
In phase I, cohorts of 3 patients will be administered oral TGR-1202 and carfilzomib starting at 36 
mg/m2 for carfilzomib (note that the dose for c1d1 is 20 mg/m2).  Oral TGR-1202 will be given at 
the fixed dose of 800 mg daily.  Carfilzomib dose of 56 mg/m2 (note that the dose for c1d1 is 20 
mg/m2) representing the highest dose cohort.  The dose levels to be considered are outlined in 
the escalation schema in Table 2. The rules for dose escalation or de-escalation are outline in 
Table 3.  
Once the maximally tolerated dose (MTD) is reached the Phase Ib part of the protocol will be 
initiated in patients with R/R PTCL or C-MYC positive DLBCL (Figure 2).   
  
Table 2:  Dose Escalation Scheme for the Combination of TGR-1202 and Carfilzomib  
Dose Escalation Schedule  
  
Dose Level  
Dose  
Carfilzomib (mg/m2)  
Given on days 1,8,15 of each  
28-day cycle(b)  
TGR-1202 (mg)  
Given once daily on days 1- 
21 of each 28-day cycle  
     Level -1(a)  
20*/20  
600  
     Level 1  
20*/36  
800  
     Level 2  
20*/56  
800  
(a) In level -1, carfilzomib will be given at 20 mg/m2 on days 1, 8, 15 and 
TGR1202 on days 1-21.  
(b) For cycle 1 day 1 of each cohort, carfilzomib will be given at 20 mg/m2.  If the 
treatment is tolerated, the drug will be given at the assigned dose level for all other 
treatment days involving carfilzomib.            
  
  


43  
  
Table 3.  Dose Escalation & De-Escalation Decision Rules  
Number of Patients 
with DLT at a Given 
Dose Level  
Escalation Decision Rule  
0 out of 3  
Enter 3 patients at the next dose level.  
1 out of 3  
Enter at least 3 more patients at this dose level.  
• If 0 of these 3 additional patients experience DLT, 
proceed to the next dose level.  
• If 1 or more of this group experience DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose (MAD), and the dose level 
below is the MTD.    
>2  
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).    
<1 out of 6 at highest dose 
level below the maximally 
administered dose  
This is generally the recommended phase 2 dose. At least 6 
patients must be entered at the recommended phase 2 dose.  
  
5.1.3 REQUIRED BLOOD PARAMETERS AND OTHER INVESTIGATIONS PRIOR TO EACH 
TREATMENT  
BEFORE  
THE  START  
OF  
EACH  TREATMENT,  
PATIENTS 
 SHOULD  
BE REASSESSED AND THE FOLLOWING CRITERIA MUST BE FULFILLED:  
• 
ANC >  1000/dL.  
• 
Platelet count ≥ 50, 000/dL.  
• 
Serum creatinine concentration ≤ 2.0 × ULN or ≤ baseline, or creatinine clearance >50 ml/min.  
• 
AST (SGOT) and ALT (SGPT) ≤2.0 × ULN or ≤3.0 × ULN in presence of demonstrable liver 
metastases.  
• 
Bilirubin concentration ≤2.0 × ULN.   
• 
Recovery of any drug-related non-hematological toxicity to Grade 1 or less, unless otherwise 
indicated.  
  
5.1.4 Guidelines for Study Drug Administration  
• 
Oral TGR-1202 will be taken between the hours of 8 and 10 am daily (patient will be 
required to maintain a drug log recording side effects and time of dosage) on Days 1-21.  


44  
  
• 
Carfilzomib will be administered over 30 minutes through a peripheral or central venous 
catheter on Days 1, 8, 15 of a 28-day cycle. It will be administered within 6 hours of the 
oral dose.  Premedication for carfilzomib includes hydration with 250-500 ml of normal 
saline, and dexamethasone 4mg to prevent infusion reaction.  
• 
Administration of the study drugs will be allowed within 96 hours of the scheduled dates.  
• 
Missed doses will not be made up.   
  
5.1.5 Maximum Tolerated Dose  
The dose-escalation rules and determination of the maximum tolerated dose (MTD) are outlined 
in Tables 2 and 3.  Patients will be enrolled to receive oral TGR-1202 and carfilzomib in 
sequentially escalating doses until a maximum tolerated dose of the combination has been 
defined.  The maximum tolerated dose of oral TGR-1202 and carfilzomib will be defined as the 
dose level immediately below the dose level at which greater than or equal to 2 patients out of 6 
patients in a cohort experience a dose-limiting toxicity (DLT). Non-hematologic dose-limiting 
toxicity will be defined as any Grade 3, 4 or 5 non-hematologic toxicity, as explained further below:  
• 
Grade 3 diarrhea that in the opinion of the Investigator occurs in the setting of 
inadequate compliance with supportive care measures specified in Section 5.1.7 and 
lasts for less than 48 hours.    
• 
Grade 3 dehydration that in the opinion of the investigator, occurs in the setting of 
inadequate compliance with supportive care measures specified in Section 5.1.7 and 
lasts for less than 48 hours.  
• 
Grade 3 acidosis or alkalosis that responds to medical intervention by returning to ≤ 
Grade 2 within 48 hours.  
• 
Isolated (i.e. no other abnormalities) Grade 3 elevation of liver function tests (LFTs) 
without associated clinical symptoms, lasting for ≤ 4 days in duration.  
• 
Grade 
3 
hypocalcemia, 
hypokalemia, 
hypomagnesemia, 
hyponatremia, 
or 
hypophosphatemia that responds to medical intervention.  
• 
Grade 3 Constipation  
• 
Grade 3 Fatigue  
  
5.1.6  Dose Limiting Toxicity  
A dose limiting toxicity (DLT) is defined as any toxicity that occurs within cycle 1 and is considered 
at least “possibly related to study drug administration.”  DLT is also defined as any toxicity possibly 
related to drug, occurring up to 4 days after completion of cycle 1 that results in a delay of initiating 
cycle 2.   For patients who discontinue study drug administration after Cycle 1, DLT will be defined 
as any toxicity that occurs within 14 days of the last dose of drug on study, in cycle 1 that is 
considered at least possibly related to study drug.  
  
DLTs include:  


45  
  
a. Non-hematologic toxicity: All non-hematologic AEs of Grade 3 or greater with 
the exception of:  
i. Grade 3 nausea, vomiting controlled by supportive therapy   
ii. Any grade of alopecia.  
b. Hematologic toxicity:  
i. Grade 4 neutropenia lasting more than 4 days. ii. Grade 4 
thrombocytopenia or grade 3 thrombocytopenia with bleeding or any 
requirement for platelets transfusion. iii. Grade 3 or greater febrile 
neutropenia (temperature ≥ 38.5ºC). iv. Grade 4 anemia unexplained by 
underlying disease.  
 
5.2  
DURATION OF TREATMENT  
 
Patients will be treated until one of the following events:  
• 
Disease progression  
• 
Unacceptable adverse event(s), DLTs  
• 
Withdrawal of consent  
• 
General or specific changes in the patient's condition that render the patient unacceptable 
for further treatment in the judgment of the investigator  
• 
An event that in the judgment of the treating physician warrant’s discontinuation of therapy.   
  
 
5.3  
SAMPLE SIZE  
 
Phase I  
An estimated 9 patients (up to a maximum of 12) with R/R HL and NHL will be accrued to the 
Phase I study with 2 cohorts (Table 2).  A minimum of 3 patients will be treated at each dose 
cohort. If no DLT is reached in cohort 3, then a total of 6 patients will be treated at that dose level.  
  
Phase Ib  
The expansion phase will accrue a total of 15 patients with R/R PTCL or C-MYC positive DLBCL 
(defined by 30% positive staining on IHC).   
 
5.4  
SAFETY  
 


46  
  
Patients will be monitored carefully for the development of adverse events as well as clinical 
and/or radiographic evidence of disease response.  Adverse events will be evaluated according 
to criteria outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 
4.0.  
 
5.5  
EFFICACY OUTCOME  
 
Overall response rates will be evaluated using clinical parameters, CT scan (PET/CT scan is 
optional) and bone marrow biopsy, as outlined by the 2007 International Harmonization Project 
criteria and its update in 2014[1, 51].   
  
 
5.6  
PHARMACOKINETIC ANALYSES  
 
On day 1 of cycle 1, blood samples will be obtained from patient’s at fixed time intervals before 
and after administration of carfilzomib to determine the plasma level of both carfilzomib and TGR-
1202. This will be compared to the known pharmacokinetic data for the individual agents in order 
to identify any possible effect of the combination. The proposed time points are shown in Figure 
3.  
  
SCHEMA  
  


47  
  
Figure 1.   
Drug Administration Schema  
  
Figure 2: Study Plan Flow Chart Schema:  Phase I   
  
  
Screening  
  
  
History, Physical, Performance Status,  
Laboratory data, Biopsies, and CT scan (PET optional)  
  
 
  
CYCLE 1  
 
  
Intervention  
Oral TGR-1202 will be given PO once daily on Days 1-21 and carfilzomib given intravenously once a  
  
week for 3 consecutive weeks, on days 1, 8, 15 on the 28-day cycle.  
  
  
Evaluations  
Safety evaluations on Days 1, 8 , 15  
Laboratory Evaluations Days 1,8,15  
Follow -up Tissue Biopsy or Fine Needle Aspiration on Day 8 to 21 (optional)  
  
 


48  
  
                                                          
Future Cycles  
 
  
Intervention  
Oral TGR-1202 will be given PO once daily on Days 1-21 and carfilzomib given intravenously once a 
week for 3 con  secutive weeks, on days 1, 8, 15 on the 28-day cycle.  
  
 
  
Tests  
Safety evaluations on Day 1  
Laboratory Evaluations Days 1, 8, 15    
CT scans at the end of Cycle 2 and 6. Then CT q3-6 months, until disease progression or initiation of new 
therapy at the discretio  
n of the Investigator. (PET is optional).   
        
 
  
Discontinuation  
  Disease progression  
  Unacceptable adverse event(s), DLTs  
  Withdrawal of consent  
  General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator  
  An event that in the judgment of the treating physician warrant’s discontinuation of therapy.  
Figure 3: Study Plan Flow Chart Schema:  Phase II   
  
  
Screening  
  
  
History, Physical, Performance Status,  
Laboratory data, Biopsies, and CT scan (PET optional)   
  
 
 
 
 
 
 
 
 
CYCLE 1  
Intervention  
Oral TG R - 1202 will be given PO once daily on Days  1 - 21 and carfilzomib given intravenously once a  
week for 3 consecutive weeks,  on days 1, 8, 15  on the 28 - day cycle.  
 
Evaluations  
Safety evaluations on Days 1, 8, 15  
Laboratory Evaluations Days 1,8,15   
Follow - up Ti ssue Biopsy or Fine Needle Aspiration on Day 8 to 21 (optional)  


49  
  
                                                          
Future Cycles  
 
  
Intervention  
Oral TGR-1202 will be given PO once daily on Days 1-21 and carfilzomib given intravenously once a 
week for 3 consecutive weeks,   
on days 1, 8, 15 on the 28-day cycle.  
  
 
  
Tests  
Safety evaluations on Day 1  
Laboratory Evaluations Days 1, 8, 15    
CT scans at the end of Cycle 2 and 6. Then CT q3-6 months, until disease progression or initiation of new 
therapy at the discretion of the Investigator. (PET is optional).  
  
        
 
  
  
Discontinuation  
  Disease progression  
 
   Unacceptable adverse event(s), DLTs  
  Withdrawal of consent  
  General or specific changes in the patient's condition render the patient unacceptable for further  
treatment in the judgment of the investigator  
  An event that in the judgment of the treating physician warrant’s discontinuation of therapy.  
Figure 4. PK Studies on Cycle 1 Day 1  
  
  
 


50  
  
  
 
5.7  
PROPHYLACTIC MEDICINES AND SUPPORTIVE CARE  
 
Standard institutional guidelines for anti-emetics will be used. Supportive treatment may include 
additional anti-emetics, anti-diarrheal, anti-pyretics, anti-histamines, analgesics, antibiotics, and 
blood products.    
  
For cycle 1 of the phase 1, prophylactic G-CSF will not be administered with the following 
exception: if neutropenia is identified as a DLT at dose level 1 in cycle 1 of phase 1, then all 
subsequent patients will receive G-CSF prophylactically daily for up to 3 days in weeks 1, 2, and 
3, and up to 7 days in week 4 of the 28-day cycle. When needed, G-CSF should be given 24 
hours after the administration of carfilzomib. For patients in the phase 2, prophylactic G-CSF can 
be given at the physician’s discretion. Neulasta should only be given if there is a 14 day interval 
to the next dose.  
  
Post cycle 1, anemia may be managed with growth factors according to the ASCO guidelines: 
2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-
Based Clinical Practice Guideline http://www.jco.org/cgi/content/full/24/19/3187.  
  
Patients will be permitted to receive appropriate supportive care measures as deemed necessary 
by the treating physician including but not limited to the items outlined below:  
• 
Diarrhea: Diarrhea should be treated promptly with appropriate supportive  care, 
including loperamide.  Loperamide should not be taken prophylactically. Patients 
should be instructed to begin taking loperamide at the first sign of: 1) poorly formed or 
loose stool, 2) occurrence of more bowel movements than usual in one day or 3) 
unusually high volume of stool.    
• 
Nausea/vomiting: Carfilzomib and TGR-1202 are minimally emetigenic.  
• 
Nausea and vomiting should be treated per standard practice guidelines, with agents 
such as prochlorperazine, metoclopramide, 5-HT-3 inhibitors, or benzodiazepines. 
Patients should be strongly encouraged to maintain liberal oral fluid intake during 


51  
  
therapy.   Fatigue:  May be cumulative with increasing cycles of therapy.  Can be 
treated as indicated by the treating physician.  
• 
Anemia: TGR-1202 and carfilzomib have been associated with dose-related anemia.  
Transfusions or erythropoetin may be utilized as clinically indicated for the treatment of anemia, 
but should be clearly noted as concurrent medications.  
• 
Thrombocytopenia: Treatment with TGR-1202 and carfilzomib can cause dose- 
related thrombocytopenia. Transfusion of platelets may be used if clinically indicated. Dose 
modification for thrombocytopenia is allowed in a manner consistent with the guidelines for 
dose modification (Section [6.3]).  
• 
Neutropenia: Prophylactic use of colony-stimulating factors including G-CSF, 
pegylated G-CSF or GM-CSF should not be utilized during the first cycle of therapy. 
These factors may be utilized if clinically indicated in subsequent cycles.  
  
5.8  
GENERAL CONCOMITANT MEDICATION AND 
SUPPORTIVE CARE GUIDELINES  
 
There is no evidence of interaction TGR-1202 or carfilzomib with other concomitantly administered 
drugs through the cytochrome P450 system.  
Prohibited concurrent therapy  
 Concomitant use of other anti-cancer therapies, including radiation, thalidomide, or other 
investigational agents is not permitted while subjects are receiving protocol therapy during the 
treatment phase of the study.  
  
PROPHYLACTIC MEASURES  
Subjects should receive allopurinol and other treatment considered appropriate for tumor lysis 
prophylaxis in cycle 1 as deemed necessary by the treating physician.   
For cycle 1 of the phase 1, prophylactic G-CSF will not be administered with the following 
exception: if neutropenia is identified as a DLT at dose level 1 in cycle 1 of phase 1, then all 
subsequent patients will receive G-CSF prophylactically daily for up to 3 days in weeks 1, 2, and 
3, and up to 7 days in week 4 of the 28-day cycle. When needed, G-CSF should be given 24 
hours after the administration of carfilzomib. For patients in the phase 2, prophylactic G-CSF can 


52  
  
be given at the physician’s discretion. Neulasta should only be given if there is a 14 day interval 
to the next dose.  
  
 
5.9  
DURATION OF THERAPY  
 
Treatment may continue until one of the following criteria applies:  
• 
Disease progression  
• 
Unacceptable adverse event(s), DLTs  
• 
Withdrawal of consent  
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator  
• 
An event that in the judgment of the treating physician warrant’s discontinuation of therapy  
  
5.10 DURATION OF FOLLOW UP  
 
Patients will have an end of study visit 4 weeks (+/- 2 weeks) after their last dose of drug to 
evaluate safety. Patients will be followed every 3 to 4 months after the 4-week safety evaluation 
for one year, or until they begin a new treatment for their disease, for evaluation of delayed toxicity. 
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. Follow up visits will include toxicity assessments, review of 
concomitant medications, physical examinations, and blood work (including a CBC with 
differential and chemistries).   
  
CT scans (PET/CT optional) will not be routinely used to monitoring complete responses after 6 
months, but rather, will be used when indicated, due to concern for disease progression.  
  
  
5.11 CRITERIA FOR REMOVAL FROM STUDY  
 


53  
  
Patients will be removed from treatment when any of the criteria listed in Section 5.4 applies. The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form.  
  
Subjects/patients may withdraw at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a subject/patient may be withdrawn 
by the investigator if he/she violates the study plan or for administrative and/or other safety 
reasons. The investigator or study coordinator will notify the appropriate parties within 2 business 
days when a subject has been discontinued/ withdrawn due to an adverse event.  When a subject 
discontinues/withdraws prior to study completion, all applicable activities scheduled for the final 
study visit should be performed at the time of discontinuation. Any adverse events present at the 
time of discontinuation/withdrawal will be followed until resolution.  
6. DOSING DELAYS/DOSE MODIFICATIONS  
 
 
6.1  
DOSE DELAYS  
 
• Study drugs can be administered within 96 hours of their scheduled time.  
• Study drugs will be held for DLTs until adverse event returns to ≤ Grade 2.   
• If interruption lasts for more than 14 days, study treatment will be discontinued.  
  
 
6.2  
RESUMING ADMINISTRATION OF STUDY DRUGS  
 
For toxicities that can be treated or prevented, such as nausea, vomiting, diarrhea and 
neutropenia, treatment may be resumed at the previous dose once supportive measures have 
been instituted and toxicity recovers to Grade 2 or less.    
  
 
6.3  
DOSE MODIFICATIONS  
 


54  
  
If TGR-1202 and carfilzomib administration leads to a DLT beyond cycle 1 at a given dose level, 
dose modifications will be managed by dropping one dose level in the dose escalation scheme.  
These post Cycle 1 DLTs will not count towards the overall determination of MTD for this study.     
  
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
 
7.1  
SAFETY EVALUATION PROCEDURES  
 
Adverse Event Reporting  
An adverse event is defined as any unfavorable and unintended change in the structure, function, 
or chemistry of the body temporally associated with the use of the study drugs, whether or not 
considered related to the use of the product. Any worsening (i.e., any clinically significant adverse 
change in frequency and/or intensity) of a preexisting condition that is temporally associated with 
the use of the study drugs product, is also an adverse event.  
  
Adverse events may occur in the course of receiving study drugs or within the follow-up period 
specified by the protocol, as well as from overdose (whether accidental or intentional), from abuse, 
and from withdrawal.  
  
Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, 
version 4.0.  Toxicities will be characterized in terms including duration, intensity, and time to 
onset.  Safety endpoints will include all types of adverse events, in addition to laboratory safety 
assessments, ECOG performance scale status, ECGs, and vital signs.  
  
The investigator must assess all abnormal laboratory results for their clinical significance.  If any 
abnormal laboratory result is considered clinically significant, the investigator must provide details 
about the action taken with respect to the test drug and about the patient’s outcome.  
  
The following safety evaluations will be performed during patient screening and at defined points 
during the course of the study:  


55  
  
• 
Vital signs  
• 
Laboratory studies complete blood count (CBC), serum chemistry, urinalysis,   
  
 
coagulation studies (PT/PTT), pregnancy test, LDH  
• 
Electrocardiograms (ECG)  
• 
Physical examinations  
• 
Performance Status Evaluation using the ECOG scale  
• 
Adverse event monitoring using the NCI CTCAE v4.0  
  
Serious Adverse Event (SAE) Definition   
A serious adverse event is one that at any dose (including overdose):  
• 
Results in death  
• 
Is life-threatening1  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity2  
• 
Is a congenital anomaly or birth defect  
• 
Is an important medical event3  
• 
Pregnancy  
  
1“Life-threatening” means that the subject was at immediate risk of death at the time of the 
serious adverse event; it does not refer to a serious adverse event that hypothetically might 
have caused death if it were more severe.  
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions.  
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred.  Important medical 
events that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes listed in 
the definition above should also usually be considered serious.  Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  A new diagnosis of cancer during the course 
of a treatment should be considered as medically important.   


56  
  
  
Note: Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations; for example, important medical events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed in the definition above. Any adverse event is 
considered a serious adverse event if it is associated with clinical signs or symptoms judged by 
the investigator to have a significant clinical impact.  
Hospitalizations that do not meet these criteria are:  
• 
reasons described in the protocol, e.g., drug administration, protocol-required   
 
testing  
• 
social reason in the absence of an AE  
• 
surgery or procedure planned prior to entry into the trial  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of AEs (Section 7.2) and the characteristics of an observed AE (Section 7.3) will determine 
whether the event requires expedited (via AdEERS) in addition to routine reporting.     
  
Ongoing monitoring of the clinical safety data in this trial will be performed consistent with 
procedures outlined in the DSMC charter. This review will pay particular attention to Grade 3 or 4 
adverse events, serious adverse events (SAEs), adverse events that lead to discontinuation and 
adverse events that lead to dose reduction. Should the incidence of any particular adverse event, 
or combination of events, rise to a level of clinical concern the DSMC will be notified for possible 
review of the emergent adverse events.  
  
7.2  
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) OF  
TGR-1202  
 
The following adverse events were observed in patients treated with single agent TGR-1202 and 
were considered at least possibly related to study medication.  See the TGR-1202 investigator 
brochure for a complete list of all adverse events reported regardless of causality.  
  
  
• 
Blood and lymphatic system disorders: Neutropenia,   


57  
  
• 
Gastrointestinal disorders: Nausea, Diarrhea, Vomiting, Abdominal pain, Constipation  
• 
General disorders and administration site conditions: Fatigue  
• 
Metabolism and nutrition disorders: Decreased appetite, Hypokalemia  
• 
Nervous system disorders: Headache, Dizziness  
• 
Respiratory, thoracic, and mediastinal disorders: Cough, Dyspnea    
Skin 
and 
subcutaneous tissue disorders: Rash  
  
  
• 
Blood and lymphatic system disorders: Anemia, Leukocytosis, Thrombocytopenia  
• 
Eye Disorders: Vision blurred  
• 
Gastrointestinal disorders: Abdominal distension, Dry mouth, Dyspepsia, Eructation, 
Mouth ulceration  
• 
General disorders and administration site conditions: Asthenia, Chills, Malaise, edema 
Peripheral, Pyrexia  
• 
Hepatobiliary Disorders: Hyperbilirubinemia  
• 
Infections and infestations:  Candida infection, Lung infection, Oral candidiasis, 
Pneumonia, Urinary tract infection   
• 
Investigations: Blood creatinine increased, Blood lactate dehydrogenase increased, Blood 
phosphorus increased, Blood sodium increased, Lymphocyte count increased, Platelet 
count decreased, Weight decreased  
• 
Metabolism and nutrition disorders: Dehydration, Hyperglycemia, Hyperlipidemia, 
Hyponatremia, Hypophosphatemia  
• 
Musculoskeletal and connective tissue disorders: Arthralgia, Muscle spasms, Muscular 
weakness, Myalgia, Pain in extremity   
• 
Nervous system disorders: Dysgeusia, Somnolence, Tremor  
• 
Psychiatric Disorders: Libido decreased  
• 
Respiratory, thoracic, and mediastinal disorders: Epistaxis, Hypoxia, Respiratory failure  
• 
Skin and Subcutaneous Tissue Disorders: Alopecia, Dermatitis acneiform, Night sweats, 
Pruritus, Rash Maculo-Papular, Rash pruritic  
  
In addition to the preceding adverse events, the following adverse events occurred in patients 
administered TGR-1202 but were deemed by investigators to be unlikely related or not related to 
TGR-1202 therapy.  Due to the low number of patients evaluable for safety at this time, however, 
TG Therapeutics cannot rule out these events occurring in future studies:  


58  
  
• 
Liver Disorders: Elevated levels of certain liver enzymes  
• 
Brain and nerve related disorders: Paresthesia  
• 
Kidney disorders: Elevated blood urea nitrogen levels, Elevated phosphorus, 
Hyperuricemia  
• 
Breathing and chest related disorders: Nasal congestion, Upper respiratory tract infection  
• 
General disorders:  Arthralgia, Myalgia  
• 
Infections and Infestations: Infection  
  
 
7.3  
CAEPRS OF CARFILZOMIB  
 
Table 4 lists adverse drug reactions reported in subjects receiving carfilzomib for which there is a 
reasonable possibility of a causal relationship to carfilzomib. In addition, special warnings and 
precautions are required for the conditions described in Section 7.3.1-7.3.9.   
  
 


59  
  
Table 4.   Adverse Drug Reactions of Carfilzomib  
  


60  
  
  


61  
  
  


62  
  
  
ADR = adverse drug reaction; PRES = posterior reversible encephalopathy syndrome; PT = 
preferred term; TLS = tumor lysis syndrome; TTP/HUS = thrombotic thrombocytopenic 
purpura/hemolytic uremic syndrome.  
a 
The following ADRs were reported in the postmarketing experience: dehydration, 
peripheral neuropathy, rash, TTP/HUS, TLS including fatal outcomes, and PRES.  
b 
Not reported in the pooled clinical studies dataset. The maximum frequency for this ADR 
can be estimated per standard practice from the upper limit of 95% confidence interval for the 
point estimate, i.e., 3/1581 (or 0.19%) as zero subjects reported these events in the pooled clinical 
studies dataset.  
c 
The following clinically related terms have been grouped together and the total subject 
incidence of the grouped terms is reported: abdominal pain includes PTs of abdominal pain and 


63  
  
upper abdominal pain, cardiac failure includes PTs of cardiac failure and congestive cardiac 
failure, and respiratory tract infection includes PTs of respiratory tract infection and upper 
respiratory tract infection.  
d 
Not a specific PT. This was analyzed by grouping together systemic symptoms such as 
pyrexia, chills, and dyspnea. Adverse events of asthenia, arthralgia, chills, dyspnea, myalgia, 
pyrexia, and vomiting that were analyzed as part of this grouping are also separately called out 
as ADRs.  
  
 
7.3.1 CARDIOPULMONARY DISORDERS  
 
New or worsening cardiac failure (e.g., congestive cardiac heart failure, pulmonary edema, and 
decreased ejection fraction), myocardial ischemia, and myocardial infarction have occurred 
following administration of carfilzomib. Death due to cardiac arrest has occurred within a day of 
carfilzomib administration, and fatal outcomes have been reported with cardiac failure and 
myocardial infarction.  
  
While adequate hydration is required prior to dosing in Cycle 1, all subjects should be monitored 
for evidence of volume overload, especially subjects at risk for cardiac failure. The total volume 
of fluids may be adjusted as clinically indicated in subjects with baseline cardiac failure or who 
are at high risk for cardiac failure.  
  
Withhold carfilzomib for Grade 3 or 4 cardiac events until recovery and consider whether to restart 
carfilzomib at 1 dose level reduction based on a benefit/risk assessment.  
  
Refer to the study protocol for further instructions regarding dose modifications.  
  
The risk of cardiac failure is increased in elderly subjects (≥ 75 years).   
  
Subjects with New York Heart Association Class II-IV heart failure, recent myocardial infarction 
(within 6 months), and conduction abnormalities uncontrolled by medications were not eligible for 
the clinical trials. These subjects may be at greater risk for cardiac complications.  


64  
  
  
Dyspnea, predominantly Grade 1 and 2, has been reported in subjects enrolled in clinical trials. 
Evaluate subjects with dyspnea based on the clinical presentation and manage accordingly. 
Reduce or withhold dose as appropriate. Refer to the study protocol for further instructions 
regarding dose modifications.  
  
 
7.3.2 ACUTE RENAL FAILURE  
 
Cases of acute renal failure have been reported in subjects who received carfilzomib.  Acute renal 
failure was reported more frequently in subjects with advanced relapsed and refractory multiple 
myeloma who received carfilzomib monotherapy. This risk was increased in subjects with a 
decrease in estimated creatinine clearance, calculated using Cockcroft and Gault equation, prior 
to receiving carfilzomib. Monitor renal function with regular measurement of the serum creatinine 
and/or estimated creatinine clearance.  
  
Reduce or withhold dose as appropriate. Refer to the study protocol for further instructions 
regarding dose modifications.  
  
 
7.3.3 TUMOR LYSIS SYNDROME  
 
Cases of TLS, including fatal outcome, have been reported in subjects who received carfilzomib. 
Subjects with a high tumor burden should be considered to be at greater risk for TLS. Ensure that 
subjects are well hydrated before administration of carfilzomib in Cycle 1 and in subsequent cycles 
as needed. Uric acid-lowering drugs should be considered in subjects at high risk for TLS. Monitor 
for evidence of TLS during treatment, including regular measurement of serum electrolytes, and 
manage promptly.  Interrupt carfilzomib until TLS is resolved. Refer to the study protocol for further 
instructions regarding dose modifications.  
  
 


65  
  
7.3.4 INFUSION REACTIONS  
 
Infusion reactions, including life-threatening reactions, have been reported in subjects who 
received carfilzomib. Symptoms may include fever, chills, arthralgia, myalgia, facial flushing, facial 
edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or 
angina. These reactions can occur immediately following or up to 24 hours after administration of 
carfilzomib. Administer dexamethasone prior to carfilzomib either as premedication or as part of 
combination therapy to reduce the incidence and severity of reactions. Refer to the study protocol 
for further instructions regarding dose modifications.  
  
 
7.3.5 THROMBOCYTOPENIA  
 
Carfilzomib causes thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 
of each 28-day cycle with recovery to baseline platelet count by the start of the next cycle. Monitor 
platelet counts frequently during treatment with carfilzomib. Reduce or withhold dose as 
appropriate. Refer to the study protocol for further instructions regarding dose modifications.  
  
 
7.3.6 HEPATIC TOXICITY  
 
Cases of hepatic failure, including fatal cases, have been reported. Carfilzomib can cause 
elevations of serum transaminases.  Monitor liver enzymes regularly. Reduce or withhold dose as 
appropriate. Refer to the study protocol for further instructions regarding dose modifications.  
  
 
7.3.7 THROMBOCYTOPENIC THROMBOTIC PURPURA/HEMOLYTIC UREMIC 
SYNDROME  
 
Cases of thrombocytopenic thrombotic purpura/hemolytic uremic syndrome (TTP/HUS) including 
those with fatal outcome have been reported in subjects who received carfilzomib. Monitor for 
signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop carfilzomib and manage per 


66  
  
standard of care including plasma exchange as clinically appropriate. If the diagnosis of TTP/HUS 
is excluded, carfilzomib can be restarted. Refer to the study protocol for further instructions 
regarding dose modifications. The safety of reinitiating carfilzomib therapy in subjects previously 
experiencing TTP/HUS is not known.  
  
 
7.3.8 POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME  
 
Posterior reversible encephalopathy syndrome (PRES), formerly termed reversible posterior 
leukoencephalopathy syndrome (RPLS), is a rare neurological disorder, which can present with 
seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and 
neurological disturbances, along with hypertension.  
  
The diagnosis is confirmed by neuro-radiological imaging. If diagnosed early and treated, the 
symptoms of PRES may be reversed. Cases of PRES have been reported in subjects receiving 
carfilzomib. Discontinue carfilzomib if PRES is suspected. Refer to the study protocol for further 
instructions regarding dose modifications. The safety of reinitiating carfilzomib therapy in subjects 
previously experiencing PRES is not known.  
  
 
7.3.9 PULMONARY HYPERTENSION  
 
In Phase 2 studies, pulmonary arterial hypertension was reported in 2% of subjects treated with 
carfilzomib and was Grade 3 or greater in less than 1% of subjects. In the pooled safety data from 
studies where carfilzomib was used in combination with lenalidomide-dexamethasone and in 
monotherapy studies (with or without dexamethasone) (N = 1581), events within the narrow 
pulmonary hypertension standardized Medical Dictionary for Regulatory Activities (MedDRA) 
query were reported in 1.1% of subjects. However, the incidence of pulmonary hypertension was 
similar across treatment groups in randomized, controlled studies where carfilzomib was used in 
combination with lenalidomide-dexamethasone and also in monotherapy studies (with or without 
dexamethasone). Therefore, a causal relationship with carfilzomib has not been demonstrated 
and pulmonary hypertension is considered an important potential risk. Patients with New York 
Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, 


67  
  
and conduction abnormalities uncontrolled by medications were excluded from clinical studies 
with carfilzomib, as they may be at greater risk of cardiopulmonary complications.  
Monitor subjects for signs and symptoms of pulmonary hypertension. Evaluate with cardiac 
imaging and/or other tests as indicated. Withhold carfilzomib until resolved or returned to baseline 
and consider whether to restart carfilzomib based on a risk/benefit assessment.  
  
  
  
 
7.4  
ADVERSE EVENT CHARACTERISTICS  
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.   A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).  
  
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.2 above) for 
expedited reporting purposes only.    
• 
Attribution of the AE:  
o 
Definite – The AE is clearly related to the study treatment. o  
Probable 
– The AE is likely related to the study treatment. o  
Possible – The 
AE may be related to the study treatment. o  
Unlikely – The AE is 
doubtfully related to the study treatment.  
o 
Unrelated – The AE is clearly NOT related to the study treatment.  
  
 
7.5  
EXPEDITED ADVERSE EVENT REPORTING  
 
The Principal Investigator agrees to provide appropriate parties with copies of all serious adverse 
experiences*, within two working days.  Additionally, the Principal Investigator agrees to report 
any pregnancy occurring in association with use of an oral TGR-1202 and carfilzomib to the 
appropriate parties.   


68  
  
  
Expedited reporting by investigator to TG Therapeutics:   
Serious adverse events (SAE) are defined above.  All SAEs will be reported within 24 hours 
of the Investigator’s first knowledge of the event, even if the experience does not appear to 
be related to TGR-1202.    
  
TG Therapeutics, Inc.  
2 Gansevoort Street, 9th Floor  
New York, NY 10014  
Tel: 212-554-4484  
Fax: 212-554-4531  
  
Expedited reporting by investigator to Amgen:   
Amgen Medical Information  
800-77-AMGEN (800-772-6436)  
  
The initial SAE report must be as complete as possible, including details of the current illness and 
(serious) AE, and an assessment of the causal relationship between the event and the 
investigational product(s).  Information not available at the time of the initial report (e.g., an end 
date for the AE, laboratory values received after the report, or hospital discharge summary) must 
be documented on a follow-up form.  All follow-up information must be reported in the same 
timelines as initial information.  
  
At any time after completion of the AE reporting period (i.e., 30 days post-treatment), if an 
Investigator becomes aware of an SAE that is suspected by the Investigator to be related to one 
of the study drugs, the event must be reported to Infinity Drug Safety.   
  
Report of Adverse Events to the Institutional Review Board  
Reportable information should always be reported by the PI directly to the IRB within 5 working 
days from when the PI learns of the event or new information.     
  


69  
  
Investigator Reporting to the FDA  
The investigator is responsible for reporting any SAEs to the FDA.  Serious adverse events (SAEs) 
that are unlisted/unexpected, and at least possibly associated to the drug, and that have not 
previously been reported in the Investigators brochure, or reference safety information document 
should be reported promptly to the Food and Drug Administration (FDA) by telephone (1-800-332-
1088), fax (1-800-FDA-0178), or via MedWatch Online.  Fatal or life threatening SAEs that meet 
the criteria for reporting to the FDA must be reported to the FDA within 7 calendar days after 
awareness of the event.  All other SAEs that meet the criteria for reporting to the FDA must be 
reported to the FDA within 15 calendar days after awareness of the event.  A clear description of 
the suspected reaction should be provided along with an assessment as to whether the event is 
drug or disease related.     
  
Adverse event updates/IND safety reports  
 Both sponsor shall notify the Investigator via an IND Safety Report of the following information:  
  
• 
Any AE associated with the use of drug in this study or in other studies that is both serious 
and unexpected.  
• 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.  
  
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected AE(s) 
or significant risks to subjects.  
  
The Investigator must keep copies of all AE information, including correspondence with Amgen, 
TG Therapeutics, and the IRB/EC, on file (see Section 12 for records retention information).     
 
7.5.1 EXPEDITED REPORTING GUIDELINES  
 
Note:  All deaths on study require expedited reporting regardless of causality.  Attribution to 
treatment or other cause must be provided.  
  
Expedited AE reporting timelines defined:  


70  
  
• 
“1 business day; 5 calendar days” – The investigator must initially report the AE within 1 
business day of learning of the event followed by a complete report within 5 calendar days 
of the initial 24-hour report.  
• 
“10 calendar days” - A complete report on the AE must be submitted within 10 calendar 
days of the investigator learning of the event.   
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions.    
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported if the event occurs following treatment.  
  
 
7.5.2 PROTOCOL-SPECIFIC EXPEDITED ADVERSE EVENT REPORTING EXCLUSIONS  
 
For this protocol, certain AEs/grades are exceptions to the Expedited Reporting Guidelines and 
do not require expedited reporting.  The following AEs must be reported through the routine 
reporting mechanism (Section 7.7):  
  
  
Table 5: CTCAE AE Reporting Exclusions  
  
  
CTCAE   
Category  
  
Adverse  
Event  
  
Grade  
Hospitalization /  
Prolongation of  
Hospitalization  
  
Attribution  
Blood/Bone  
Marrow  
Neutropenia <7 days 
without fever  
4  
No  
Yes  
Blood/ Bone   
Marrow  
Thrombocytopenia  <7 
days without  bleeding  
4  
No  
Yes  


71  
  
  
 
7.6  
PREGNANCY ON STUDY  
 
No studies of carfilzomib have been conducted in pregnant women. Carfilzomib should not be 
used during pregnancy.  
  
Pregnant women and women planning to become pregnant may NOT participate in clinical trials 
with carfilzomib.  
  
Females  
Females of childbearing potential should be advised to avoid becoming pregnant while being 
treated with carfilzomib. Given that carfilzomib was clastogenic in the in vitro chromosomal 
aberration test in peripheral blood lymphocytes, as a precaution, females with childbearing 
potential and/or male partners should use effective contraception methods or abstain from sexual 
activity while treated with carfilzomib during and for 30 days following treatment. Based on its 
mechanism of action and findings in animals, carfilzomib can cause fetal harm when administered 
to a pregnant woman. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that 
were lower than in patients receiving the recommended dose. If carfilzomib is used during 
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to the fetus. Carfilzomib administered to pregnant rats and rabbits 
during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day in rats or up 
to 0.8 mg/kg/day in rabbits. Refer to the study protocol for specific information regarding length of 
time contraception should be used and acceptable contraceptive methods.  
  
Males  
The potential for carfilzomib to be transferred via semen and its effect on sperm are unknown. 
Refer to the study protocol for specific information regarding length of time contraception should 
be used and acceptable contraceptive methods for studies that require male contraception. Male 
subjects should be advised to inform the investigator or study staff immediately in the event that 
their female partner becomes pregnant during the study. Upon receipt of this information, the 
investigator should notify Amgen of the pregnancy and discuss follow-up regarding the pregnancy 
outcome with the subject.  


72  
  
  
 
7.7  
ROUTINE ADVERSE EVENT REPORTING  
 
All Adverse Events must be reported in routine study data submissions.    
  
For 30 days subsequent to study completion or withdrawal, new onset adverse events will be 
captured.  Follow up of these events will follow the same procedure as described above for AEs 
observed during the study period.  
  
8. PHARMACEUTICAL INFORMATION  
 
 
8.1  
TGR-1202  
 
Product description:    
TGR-1202 is a highly specific and orally available PI3K delta inhibitor. TGR-1202 is manufactured 
by Alembic Pharmaceuticals and supplied by TG Therapeutics, Inc. TGR-1202 is supplied in 50, 
100, and 200 mg tablets.  
  
TGR-1202 is an isoflavone substituted pyrazolo pyrimidine. It is a p-Toluene sulphonic acid (p- 
TSA) salt of RP-5264 (base of TGR-1202).  
• 
Description: Light brown to brown colored powder  
• 
Solubility: Freely soluble in dimethyl sulfoxide and soluble in methanol  


73  
  
Chemical Structure: 
  
Stability: TGR-1202 is stored at temperatures not exceeding 25°C (excursions permitted to 15°C-
25°C). Based on the results available on date a shelf life of 12 months is proposed for the drug 
product with revised primary packaging (inclusion of cotton). Further stability studies are ongoing 
and a retest period will be proposed for the drug product upon review of accumulated stability 
data.   
  
Further stability testing is in progress at the below ICH conditions as per the established  stability 
protocol and will be updated as available.    
  
  
Administration:  
TGR-1202 will be administered daily for 21 days of every 28-day cycle.  TGR-1202 is administered 
orally as a tablet formulation and will be supplied free of charge by TG Therapeutics.  TGR-1202 
will be administered as a fixed dose in 800 mg/day and should be administered using the minimal 
number of tablet necessary.    
  
 
8.2  
CARFILZOMIB  
 
 
8.2.1 CARFILZOMIB PRODUCT DESCRIPTION  
 


74  
  
Generic Name: Carfilzomib is the generic name; formerly referred to as PR-171. Chemical 
Name: (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-
2ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-
4methylpentanamide.  
Molecular Formula: C40H57N5O7 Molecular Weight: 719.9  
Chemical Structure: 
  
Pharmacologic Class: Antineoplastic agent  
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that selectively and irreversibly 
binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic 
core particle within the 26S proteasome, and displays little to no activity against other protease 
classes.  
  
 
8.2.2 CARFILZOMIB DOSAGE FORM  
 
Carfilzomib for Injection, 60 mg/vial, is supplied as a white to off white lyophilized cake or powder 
in a single-use vial. Prior to administration, the lyophilized product is aseptically reconstituted with 
29 mL Sterile Water for Injection.  
  
Reconstituted carfilzomib drug product consists of 2 mg/mL carfilzomib, 100 mg/mL 
sulfobutylether-beta-cyclodextrin, and 1.9 mg/mL citrate buffer (pH 3 to 4). Each mL of 
reconstituted drug product contains 0.3 mmol (7 mg) of sodium.  
  
8.2.3  DRUG SUPPLY AND STORAGE  
8.2.3.1  
LYOPHILIZED DRUG PRODUCT  


75  
  
Lyophilized carfilzomib for Injection vials must be kept in the labeled drug cartons and stored at 
2°C to 8°C (36°F to 46°F) in a refrigerator.  
  
Vials must be kept in cartons in order to protect from light until ready for reconstitution.  
• 
The refrigerator should be monitored daily (at a minimum) and temperature records retained 
for review.  
• 
The refrigerator should also be on a backup generator whenever possible and also alarmed 
for temperature deviations.  
  
Any temperature excursions during storage must be reported to Amgen for evaluation and 
disposition. Any product impacted by temperature excursions should be placed in quarantine 
pending completion of the Amgen evaluation and disposition. Any temperature excursion should 
be reported to Amgen using a temperature excursion form. The incident should be documented 
in the carfilzomib dispensation and accountability log. If the product must be destroyed, the vials 
should be destroyed per the site standard operating procedures. If drug destruction is unavailable 
at the site, the study monitor should be contacted for further instructions.  
  
  
 
8.2.3.2  
RECONSTITUTED DRUG PRODUCT  
 
Once a drug vial is reconstituted and inspected for particulate matters, the clear and free of 
particles solution can be stored in a refrigerator (recommended) controlled from 2°C to 8°C (36°F 
to 46°F).  
  
Reconstituted carfilzomib drug product must be used within 24 hours of reconstitution when kept 
at 2°C to 8°C (36°F to 46°F). If kept at room temperature after reconstitution, it must be used 
within 4 hours.  
  
 
8.2.3.3  
DO NOT FREEZE LYOPHILIZED OR RECONSTITUTED DRUG  
 
If reconstituted carfilzomib drug product has been frozen, the material should be discarded and a 
new solution prepared. The damaged material should be documented on the Carfilzomib 
Investigational Product Accountability Log.  


76  
  
  
Amgen should be contacted by email for any questions regarding drug storage. The country, site 
number, protocol number, and detailed question(s) should be included in the correspondence.  
  
 
8.2.3.4  
METHOD OF ADMINISTRATION  
 
Carfilzomib is administered intravenously (IV) as an infusion. Carfilzomib should not be 
administered as a bolus. Refer to the study protocol for specific information regarding length of 
time for infusion. The intravenous administration line should be flushed with normal saline or 5% 
dextrose injection immediately before and after carfilzomib administration. Do not mix carfilzomib 
with or administer as an infusion with other medicinal products.  
  
Carfilzomib is administered once each week for 3 weeks (Days 1, 8, 15), followed by a 13-day 
rest period (Days 16 to 28), except when specified by the study protocol (Figure 1 and Table 1).  
Each 28-day period is considered 1 treatment cycle.  
  
Refer to the study protocol for specific information on calculating the dose. It is recommended that 
the dose is calculated using the subject’s baseline body surface area (BSA). Subjects with a BSA 
greater than 2.2 m2 should receive a dose based upon a BSA of 2.2 m2. Dose adjustments do 
not need to be made for weight changes of less than or equal to 20%.  
  
Adequate hydration is required prior to dosing in Cycle 1, especially in subjects at high risk of 
tumor lysis syndrome (TLS) or renal toxicity. All subjects should be monitored for evidence of 
volume overload and fluid requirements should be tailored to individual subject needs. The total 
volume of fluids may be adjusted as clinically indicated in subjects with baseline cardiac failure or 
who are at high risk for cardiac failure (see Section 3.0, Special Warnings and Precautions for 
Use).  
  
Consider antiviral prophylaxis in subjects being treated with carfilzomib to decrease the risk of 
herpes zoster reactivation.  
  


77  
  
 
8.3  
AGENT ACCOUNTABILITY  
 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, 
will maintain a careful record of the inventory and disposition of all agents received from 
Appropriate parties.  
  
9. PHARMACOKINETIC & PHARMACODYNAMIC STUDIES  
 
 
9.1  
PHARMACOKINETIC STUDIES  
 
During cycle 1 day 1, blood will be collected in heparinized tubes pre- and post-treatment 
(Figure 3). After centrifuge, plasma will be stored in polypropylene screw top tube at -80ºC until 
evaluation by liquid chromatography.   
  
  
Figure 3. PK Studies on Cycle 1 Day 1  
  
  
  
  
  
  
  
  


78  
  
 
9.2  
PHARMACODYNAMICS STUDIES  
 
 
9.2.1 BIOPSIES   
 
The patient will have the option of checking off boxes within the main consent form for this study 
to indicate consent or denial for the following optional studies.    
  
A lymph node fine needle aspiration (FNA), core-needle biopsy or bone marrow biopsy will be 
performed prior to therapy and/or on between day 8 and 21 of cycle 1 after TGR-1202 and 
carfilzomib administration.  Fine needle aspirations will be performed as follows:  
  
Fine Needle Aspirations (FNA): A series of FNAs will be performed on palpable tumors in 
consenting patients as a function of drug exposure.  In general, at least 6 aspirations will be made 
using a sterile 10 cc syringe over the larger volume of the palpable tumor. Once the needle is 
placed into the tumor, the plunger will be withdrawn and pushed several times to obtain a sufficient 
sample from that location. Once withdrawn from the tumor, the syringe will be flushed clean in 1-
2 mL of RPMI. This procedure will be repeated up to 6 times in one tumor, flushing the syringe 
needle in the same 1-2 mL of RPMI. Previous experiences in mice have established that 
performing fewer than 6 aspirations on any given tumor is associated with irreproducible results. 
Once the samples are acquired, the cells will be centrifuged, and resuspended in 1 mL of RPMI.   
  
Correlations with the results of these studies will then be compared to the pharmacokinetic profile 
in order to establish the relationship with concentration, and the previous data obtained on the in 
vitro studies.  
  
Tumor Tissue Biopsies: The biopsies will be performed by a surgeon if necessary, or by 
interventional radiology.  A cytopathologist will evaluate the biopsy for tumor cells microscopically 
at the time of the biopsy.  If multiple lymph nodes are available, the safest lymph node will be 
selected. The choice of FNA versus biopsy will be made based on safety, accessibility, and 
likelihood of being pathologic.  A biopsy confirming recurrent or refractory disease is mandatory 
for participation in study.  The second FNA or biopsy is encouraged, but is not mandatory. Tissue 
will be labeled only with the protocol-specific unique identifier.  Correlative studies will be 


79  
  
performed, including staining of c-Myc, eIF4F and its upstream regulators (mTOR, 4EBP1) by 
IHC.  
  
Bone Marrow Biopsy: a bone marrow aspirate and biopsy will be performed by the study team 
when it is clinically necessary.  
  
 
9.2.2 HANDLING OF SPECIMENS  
 
All biopsies will be snap-frozen and sent to Surgical Pathology, flagged for use in the protocol.  
Paraffin 
blocks 
will 
be 
made 
to 
confirm 
histological 
diagnosis, 
and 
appropriate 
immunohistochemical staining will be performed per standard clinical practice.  Remaining tissues 
will be used for the pharmacodynamic analysis, including staining of c-Myc, eIF4F and its 
upstream regulators (mTOR, 4EBP1) by IHC.   
 
10.  
STUDY CALENDAR  
 
Baseline evaluations are to be conducted as indicated in the table below, prior to start of protocol 
therapy.  Scans must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.  Table 6 describes the study calendar in details.   


80  
  
Table 6. Study Calendar   
Cycle  
  
Cycle 1 (28-day cycle) 
(±4 days)  
Cycle 2+ 
(±4 days)  
End of 
treatmentk  
End of 
Study (4 
weeks  
after last 
dose)  
Followupl  
  
Screening  D1    
D8    
D15    
D1    
D8    
D15    
Eligibility &  
Safety  
Monitoring  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed 
Consent  
Xa  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics  
Xa  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical 
History  
Xa  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EKG  
Xa  
X  
  
  
  
  
  
  
  
  
  
  
  
X  
  
  
Urinalysis  
Xa  
Xe  
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
CT (or  
PET/CT) f  
Xa  
  
  
  
  
  
  
  
  
  
  
  
Xf  
Xf  
  
Xf  
Bone Marrow 
Biopsy  
Xh  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Lymph Node 
Biopsy  
Xh   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Concurrent 
Medications  
Xb   
Xe  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
X  
X  
Physical exam  
Xb  
Xe  
  
X  
  
X  
  
X  
  
  
  
  
  
X  
X  
X  
Vital Signs, 
weight  
Xb  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
X  
X  
Performance  
Status   
Xb  
X  
  
X  
  
X  
  
X  
  
  
  
  
  
X  
X  
X  
CBC w/  
differential  
Xb  
Xe  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
X  
X  
Chemistryc  
Xb  
Xe  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
X  
X  
Creatinine 
clearance  
Xb  
Xe  
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
Serum b-hCGd  
Xb  
X  
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
Drug  
Administration  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Oral TGR-1202  
  
                          D1-21  
                       D1-21  
  
  
  
Carfilzomib   
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
  
Toxicity  
Assessment  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
  
X  
X  
X  
Efficacy  
Measurementf  
  
  
  
  
  
  
  
  
  
  
  
  
  
Xf  
  
Xf  
Correlative 
Studies  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood for PK  
  
Xi  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood for PD  
  
Xj  
  
Xj  
  
  
  
  
  
  
  
  
  
  
  
  


81  
  
Bone Marrow 
Biopsy  
Xh  
  
  
Xg  
  
  
  
  
  
  
  
  
  
  
  
  
Lymph Node 
Biopsy  
Xh  
  
  
Xg  
  
  
  
  
  
  
  
  
  
  
  
  
  
a. 
To be done within 4 weeks of treatment start date.  
b. 
To be done within 1 week of treatment start date. CoAgs (INR, PTT, PT) at screening only.  
c. 
Chemistries include: sodium, potassium, chloride, bicarbonate, calcium, creatinine, magnesium, LDH and hepatic 
function panel.   
d. 
For patients of childbearing age.  
e. 
Not necessary if conducted within 72 hours of screening assessment.  
f. 
CT scans after cycles 2, 4, and 6, then q3-6 months, until disease progression or initiation of   new therapy 
(PET/CT is optional).   
g. 
Optional, to be done at some point between C1D8 and C1D21.   
h. 
Pre-treatment tumor and bone marrow biopsy is optional except when the procedures are needed to establish 
diagnosis.  The optional biopsies will be performed on patients who consented for these optional studies.  
i. 
PK for Carfilzomib and TGR-1202.  Blood will be drawn pre-dose, 0.5 hour, 2.5h, 4.5h after the start of 
carfilzomib (Start of carfilzomib infusion is counted as 0h). PK at 6.5h post-carfilzomib is optional.    
j. 
PD studies. Blood will be drawn on C1D1 pre-dose and between C1D8 and C1D21 at 4h post-treatment (same day 
as the optional tumor biopsy if possible).  
k. 
To be done within 4 weeks of treatment stop date.  
l. 
May be done +/- 5 days.  
  
 
11.  
MEASUREMENT OF EFFECT  
 
The primary objective of the Phase I study is to evaluate the safety and tolerability of the study 
drugs.  The measurement of toxicity is outlined in Section 7.  
  
The primary objective of the Phase II study is to evaluate clinical response.  Patients will be 
reevaluated at the end of even numbered cycles. Response will be evaluated with physical exam, 
computerized tomography (CT) and tissue biopsies as defined by the guidelines of the 
International Harmonization Project Group 2007 Revised Response Criteria. [51] Positron 
emission tomography / computerized tomography (PET/CT) will be utilized if available  
(optional).   
  
11.1 EVALUATION OF RESPONSE  
 


82  
  
For the phase I part of the study evaluable disease will be utilized as the reference for response. 
For the phase II part of the study measurable disease criteria will be utilized for response 
assessment, according to the updated Cheson Criteria/ Lugano Classification[1], details in 
Section 11.2.1.    
  
 
11.1.1 DEFINITIONS  
 
Evaluable for toxicity: Any patient receiving at least one dose of either drug will be evaluable for 
toxicity starting from Day 1 of Cycle 1.  
  
Evaluable for objective response: Evaluable patients will have received at least two full cycles of 
therapy.  
  
 
11.1.2 DISEASE PARAMETERS  
 
Measurable disease: Measurable lesions are defined as those that can be accurately measured 
in two dimension (longest diameter to be recorded) as >20 mm with conventional techniques 
(PET/CT, MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements will be recorded 
in millimeters (or decimal fractions of centimeters).  Tumor volume will be recorded as the sum of 
the product of the diameters (SPD) of the largest predominant target lesions.   
  
FDG avidity is based on comparison with background tissues.  There is no specific SUV value 
that is considered a cut-off.  
  
Non-measurable disease (evaluable disease): All other lesions (or sites of disease), including 
small lesions (<10 mm using spiral CT scan), are considered non-measurable disease.  Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), 
and cystic lesions are all non-measurable.  
  


83  
  
Target lesions: All measurable lesions up to a maximum of 6 lesions total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their SUV avidity (High SUV lesions will be 
prioritized, even if not the largest lesions) and size (lesions with the largest SPD diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or clinically).  
An SPD for all target lesions will be calculated and reported as the baseline sum SPD.  The 
baseline sum SPD will be used as reference by which to characterize the objective tumor 
response based on CT criteria.  
  
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 6 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.   
  
 
11.1.3 METHODS FOR EVALUATION OF MEASURABLE DISEASE IN NHL  
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 1 week before the beginning of the treatment.  
  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment.  
  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes).  In the case of skin lesions documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.   
  
CT, PET/CT and MRI: These techniques should be performed with cuts of 10 mm or less in slice 
thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction 


84  
  
algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and neck tumors and 
those of extremities usually require specific protocols.  
  
Ultrasound (US): Will not be used for disease assessment.  
  
11.2 RESPONSE CRITERIA  
 
 
11.2.1 EVALUATION OF MEASURABLE DISEASE IN NHL  
 
Patient response will be determined according to the updated response criteria for NHL and HL 
(Table 7)   
  


85  
  
Table 7. Revised Criteria for Response Assessment (Cheson et al., JCO 2014)  
  
  
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance 
 


86  
  
imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular 
diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the 
perpendicular diameters for multiple lesions.  
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if 
at the time of an interim scan. However, in trials involving PET where de-escalation is 
investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid 
undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal 
masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes 
should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, 
spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. 
Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal 
masses, and extranodal sites not selected as dominant or measurable or that do not meet the 
requirements for measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In 
Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be 
greater than in the mediastinum with complete metabolic response, but should be no higher than 
surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy 
or myeloid growth factors).  
†PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum 
but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; 
X, new areas of uptake unlikely to be related to lymphoma.  
  
 
11.2.2 RESPONSE DEFINITIONS  
 
Complete Response (CR):  
 Disappearance of all non-target lesions by PET/CT  
  
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits  
  
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions  
  


87  
  
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed 
at a later time by the review panel (or Principal Investigator).  
  
 
11.2.3 EVALUATION OF BEST RESPONSE  
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria.  
  
 
11.2.4 OBJECTIVE RESPONSE RATE  
 
Objective Response Rate (ORR) = CR + PR based on evaluation of best response in each patient.  
 
12.  
DATA REPORTING / REGULATORY REQUIREMENTS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).  
12.1 DATA REPORTING  
 
 
12.1.1 MONITORING  
 
The Institutional Review Board (IRB) at Columbia University Medical Center will monitor this study.  
  
 


88  
  
12.1.2 RESPONSIBILITY FOR DATA SUBMISSION  
 
The Study Coordinator is responsible for compiling data for all participants and for providing the 
data to the Principal Investigator for review.    
  
12.2 DATA SAFETY MONITORING BOARD  
 
The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center’s Data 
Safety Monitoring Board (DSMB) will oversee conduct of the study, patient safety and all interim 
analyses as specified in the data analysis plan.  Detailed guidelines regarding the structure, 
function and decision-making mechanisms for the Data Safety Monitoring Board are provided in 
the DSMB charter.  
  
12.3 INVESTIGATOR REPORTING RESPONSIBILITIES  
 
The conduct of the study will comply with all FDA safety reporting requirements.    
An IND is not needed for this study as both agents are commercially available.  
  
12.4 STUDY AUDITING  
 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and 
in the US Code of Federal Regulations.  
  
Investigators must enter study data onto CRFs or other data collection system.  The Investigator 
will permit study-related audits by the sponsors or their representatives, IRB/EC review, and 
regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the facilities where 
the study took place, to source documents, to CRFs, and to all other study documents.  
  


89  
  
12.5 PROTOCOL AMENDMENTS  
 
Any amendment to this protocol must be agreed to by the Principal Investigator and reviewed by 
the sponsors, including TG Therapeutics and Amgen.  Amendments should only be submitted to 
IRB/EC after consideration of TG Therapeutics and Amgen review.  Written verification of IRB/EC 
approval will be obtained before any amendment is implemented.    
  
12.6 PROTOCOL DEVIATIONS  
 
When an emergency occurs that requires a deviation from the protocol for a subject, a deviation 
will be made only for that subject.  A decision will be made as soon as possible to determine 
whether or not the subject (for whom the deviation from protocol was effected) is to continue in 
the study.  The subject’s medical records will completely describe the deviation from the protocol 
and state the reasons for such deviation.  In addition, the Investigator will notify the IRB/EC in 
writing of such deviation from protocol.  
  
Non-emergency minor deviations from the protocol will be permitted with approval of the Principal 
Investigator.   
  
 
13.  
STATISTICAL CONSIDERATIONS  
 
13.1 STUDY DESIGN/ PRIMARY ENDPOINTS  
 
Phase I  
This is an open label, single institution Phase I study using the 3+3 dose escalation design.  
  
The primary objective is to determine the MTD, MAD, and DLT of TGR-1202 in combination with 
carfilzomib.  The safety and toxicity of this combination will be evaluated.  
  
All patients who receive any amount of drug will be available for toxicity. Adverse events will be 
graded using the NCI CTCAE v4.0.  


90  
  
  
The dose escalation scheme will follow the guideline in Section 5.  
  
Toxicities will be described by intensity at each dose level.  
  
Phase Ib  
Phase Ib is will consist of the combination of oral TGR-1202 and carfilzomib in patients with 
relapsed and refractory PTCL and C-MYC positive DLBCL.    
  
The primary objective is to evaluate the safety and toxicity of the combination of TGR-1202 and 
carfilzomib at the MTD dose level in patients with R/R PTCL and C-MYC positive DLBCL.  
  
13.2 SAMPLE SIZE/ACCRUAL RATE  
 
Phase I  
An estimated 9 patients (up to a maximum of 12) with R/R HL and NHL will be accrued to the 
Phase I study with 3 cohorts (Tables 2 & 3).  A minimum of 3 patients will be treated at each dose 
cohort. If no DLT is reached in cohort 3, then a total of 6 patients will be treated at that dose level.  
  
We estimate accrual of an average of 1 patients per month, with a goal of completing a maximum 
of 12 accruals within 12 months.  
  
Phase Ib  
The expansion phase will accrue a total of 15 patients with PTCL or C-MYC positive DLBCL.   
  
We estimate accrual of an average of 1-2 patients per month, with a goal of completing 15 accruals 
within 10 months.  
  
13.3 ANALYSIS OF SECONDARY ENDPOINTS   
 


91  
  
Phase Ib  
Secondary Objective: To estimate ORR defined as best response by 4 cycles.   
  
Disease and patient characteristics at baseline will be summarized using descriptive statistics. 
For qualitative variables, frequency distributions and proportions will be provided; for quantitative 
variables, summary statistics (e.g., mean, median, quartiles, standard deviations, etc) and 
graphical displays (e.g., box plots).  Overall response rates will be estimated upon completion of 
the study along with exact 95% confidence intervals.   
  
 
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