Conditions: Multiple Myeloma
Keywords: Relapsed/Refractory Multiple Myeloma carfilzomib panobinostat
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 80
Healthy volunteers: no

Brief summary:
Relapsed/refractory Multiple Myeloma (MM) is an incurable disorder with a poor prognosis. Carfilzomib is a novel proteasome inhibitor with activity in this setting. Panobinostat is a pan-deacetylase inhibitor which has shown synergistic cytotoxicity in vitro and in vivo with proteasome inhibitors. The combination should enhance the activity of both agents against myeloma cells. In Phase I, the optimal doses of the combination of carfilzomib and panobinostat will be determined. Assuming this combination is feasible, the Phase II portion will proceed using the doses determined in Phase I.

Detailed description:
In this open-label, non-randomized Phase I/II study, a maximum of 4 planned dose levels of carfilzomib and panobinostat were evaluated to determine the maximum tolerated dose (MTD) to administer. The MTD was not reached so patients in Phase II received treatment at dose level 4 to further assess efficacy. Response to treatment was evaluated after each 4-week cycle. Those having an objective response or stable disease are continuing treatment until disease progression or unacceptable toxicity occurs.

As the MTD in the 4 planned dose levels were not reached, a parallel Phase I study was initiated to examine additional dose levels using a traditional 3+3 design. If these dose levels are tolerable, then more patients will be recruited into an expansion cohort to assess efficacy at the new dose level(s).

Arms:
arm 1: Phase I:

Carfilzomib: cycle 1 - Dose is 20 mg/m\^2 IV on day 1; 27 or 36 or 45 or 56 mg/m\^2 IV on Days 8, 9, 15, 16 cycle 2 to progression - 27 or 36 or 45 or 56 mg/m\^2 IV on days 1, 2, 8, 9, 15, 16

Panobinostat: cycle 1 and cycle 2 to progression - 20 mg or 30 mg on days 1, 3, 5, 15, 17, 19

Phase II:

Carfilzomib and Panobinostat: Dose is optimal dose determined in Phase I

Interventions: intervention 1: panobinostat intervention 2: carfilzomib
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days

Protocol document:
Prot_SAP_000.pdf: 
 
 
  
MM 27 
Phase I/II Study of the Combination of Panobinostat and Carfilzomib 
in Patients with Relapsed/Refractory Multiple Myeloma 
 
Sponsor: 
SCRI Development Innovations, LLC 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI  
asksarah@scri-innovations.com 
 
Study Chair: 
Jesus Berdeja, M.D. 
Sarah Cannon Research Institute 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI    
asksarah@scresearch.net 
 
 
Date Final:  
20 July 2011 
Amendment 1:  
27 September 2011 
Amendment 2:  
19 July 2012 
Amendment 3:  
26 March 2013 
Amendment 4:  
24 October 2013 
Amendment 5: 
03 August 2015 
 
CONFIDENTIAL 
This document is confidential and is the property of the SCRI Development Innovations, LLC (SCRI 
Innovations).  No part of this document may be transmitted, reproduced, published, or used by other 
persons without prior written authorization from the Sponsor.


 
  
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Clinical Trial Protocol Approval Page 
 
 
Phase I/II Study of the Combination of Panobinostat and Carfilzomib 
in Patients with Relapsed/Refractory Multiple Myeloma 
SCRI INNOVATIONS 
PROTOCOL NUMBER: 
 
MM 27 
TRIAL DRUG: 
 
Panobinostat 
DATE FINAL: 
20 July 2011 
Amendment Number: 
1 
Amendment Date: 
27 September 2011 
Amendment Number: 
2 
Amendment Date: 
19 July 2012 
Amendment Number: 
3 
Amendment Date: 
26 March 2013 
Amendment Number: 
4 
Amendment Date: 
24 October 2013 
Amendment Number 
5 
Amendment Date 
03 August 2015 
 
 
 
 
_____________________________ 
______________________________ 
 
_________ 
Study Chair/Coordinating Investigator 
Study Chair/Coordinating Investigator 
Date 
      
(Name Printed or Typed)  
 
Signature 
 
 
 
 
 
Jesus Berdeja, M.D 
Sarah Cannon Research Institute 
 
________________________________ 
______________________________ 
 
_________ 
Medical Monitor  
 
 
Medical Monitor Signature 
 
 
Date 
           
(Name Printed or Typed)  
 
John D. Hainsworth, MD,  
Chief Scientific Officer 
Sarah Cannon Research Institute 
 
 
 
 
________________________________ 
______________________________ 
 
_________ 
Sponsor Representative  
 
Sponsor Representative Signature 
 
Date 
         
(Name Printed or Typed)  
 
Sheetal Khedkar, Director 
SCRI Innovations 
 
 
 


 
  
Page 3 of 101 
MM 27 AMD 5/03 AUG 2015 
 
Clinical Trial Protocol Acceptance Form 
 
Phase I/II Study of the Combination of Panobinostat and Carfilzomib 
in Patients with Relapsed/Refractory Multiple Myeloma 
SCRI INNOVATIONS 
PROTOCOL NUMBER: 
 
MM 27 
TRIAL DRUG: 
 
Panobinostat 
DATE FINAL: 
20 July 2011 
Amendment Number: 
1 
Amendment Date: 
27 September 2011 
Amendment Number: 
2 
Amendment Date: 
19 July 2012 
Amendment Number: 
3 
Amendment Date: 
26 March 2013 
Amendment Number: 
4 
Amendment Date: 
24 October 2013 
Amendment Number 
5 
Amendment Date 
03 August 2015 
 
 
 
 
 
 
 
 
 
_________________________________ 
 
____________________________  
_____________ 
Principal Investigator Name 
 
 
Principal Investigator Signature 
Date 
(Name Printed or Typed) 
 
 
<Insert Site Name and ID info as applicable> 
 
 
 
 
 
 
<Insert Site Location> 


 
  
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History of Amendments for MM 27 
Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients 
with Relapsed/Refractory Multiple Myeloma 
Amd 
# 
Amd Date 
Revision(s) Made 
Refer to this Section in the 
Protocol 
1 
27 September 2011 
Exclusion criteria added, “Patient has not recovered 
from all therapy-related toxicities associated with 
prior treatments to < Grade 2 CTCAE.” 
 
Synopsis, Section 
3.2 Exclusion 
Criteria #4 
  
  
Section referring to panobinostat dose modifications 
for prolonged QTc interval has been modified to 
remove all references to centralized readings of 
ECGs by Novartis. 
All cardiac events should be treated according to 
standards and referred to a specialist if clinically 
indicated.  Treatment decisions at the sites will be 
based on QTc as determined by the automated 
machine reading (or as measured and calculated by 
trained personnel at the site).  The centralized 
readings of ECGs by eRT will use the Fridericia 
correction: QTcR.  Any final decisions concerning 
any dose modifications or patients discontinuing 
study drug permanently will be based on QTcF 
calculations assessed by eRT and evaluated via a 
discussion between the Study Chair.  If a patient 
 
Section 6.2   
 
 
References to transmit ECGs in Table 6: Criteria for 
Dose Reductions, Delays and/or Re-Institution Due to 
Drug-Related QTcF Abnormalities have been struck. 
 
Table 6 
 
 
Modifications to the Section - General Monitoring 
Principals  
#7.  All ECGs will be reviewed by the treating 
physician prior to administering the dose of 
panobinostat.  If the QTc interval is > 480 msec, the 
ECG will be sent to eRT and the SCRI Study Chair 
via SCRI ORC facsimile for review. 
#11  Two ECG paper tracings will be printed each 
time an ECG is performed.  One original will remain 
with the source documentation.  The second original 
will be stored for submission to eRT at the end of 
each treatment cycle.    
 
 
Section 6.2.1 


 
  
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History of Amendments for MM 27 (continued) 
Amd 
# 
Amd Date 
Revision(s) Made 
Refer to this Section in the 
Protocol 
1 
27 September 2011 
If any QTc interval is ≥500 msec, the patient must 
have at a minimum, hourly ECG monitoring until the 
QTc is <480 msec. In addition to the minimum hourly 
ECG monitoring, telemetry monitoring is strongly 
recommended.  ECGs must be transmitted to the 
Sponsor for prompt review. Prior to a patient with a 
QTc interval >500 msec being discharged to home, 
that patient must have at least 2 consecutive, hourly 
ECGs obtained at least 6 hours after dosing that 
demonstrate a QTc interval of ≤480 msec. 
 
Section 6.2.1 


 
  
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History of Amendments for MM 27 (continued) 
Amd 
# 
Amd Date 
Revision(s) Made 
Refer to this Section in the 
Protocol 
2 
19 July 2012 
As of December 31, 2008,2010 twenty-two 32 clinical 
studies, including clinical pharmacology, phase I 
and/or phase II, have either been completed or are 
ongoing.  A total of 789 1589 patients were enrolled 
and received at least one dose of panobinostat. 
2)  Patients must have measurable disease requiring 
systemic therapy defined as at least one of the 
following: 
 Serum M-protein ≥1 0.5 g/dl (≥10 5 g/l) 
 Urine M-protein ≥200 mg/24 hrs 
Serum free light chain assay: involved free light chain 
level ≥10 mg/dl (≥100 mg/l) provided the serum free 
light chain ratio is abnormal 
A maximum of three four dose levels will be 
evaluated. 
Cycle 2 – 12 and beyond 
Phase I Dose Level 3 Cycle 1, Carfilzomib dose is 36 
45 mg/m2  IV D8, 9 15, 16 
Phase I Dose Level 4 Cycle 1, Carfilzomib dose is 36 
45 mg/m2  IV D8, 9 15, 16 
 
CrCl changes are mostly transient, reversible, 
and non-cumulative. All patients should be well 
hydrated.  Clinically significant electrolyte 
abnormalities should be corrected prior to dosing 
with carfilzomib.  Renal function must be 
monitored closely during treatment with 
carfilzomib.  Serum chemistry values, including 
creatinine, must be obtained are strongly 
encouraged and reviewed prior to each dose of 
carfilzomib during Cycles 1 and 2.  The decision 
will be at the discretion of the treating 
physician.  Carfilzomib must be held for 
subjects with a CrCl < 15 mL/min at any time 
during study participation. 
All patients must have the following assessments 
performed before receiving their first dose of protocol 
therapy (labs may be obtained up to 72 hours prior 
to treatment): 
The physical examination, complete blood counts 
CBCs, CMP, uric acid and pregnancy test should be 
done <7 days prior to initiation of treatment.   
 
Section 1.2.1 
 
 
 
Synopsis,Section 
3.1, #2 
 
 
 
 
 
 
Synopsis, Section 
5,  
 
Section 5.1, Table 1 
 
Section 5.2, Table 2 
 
 
 
Section 6.4 
 
 
 
 
 
 
 
 
 
 
Section 7.2 
 
 
 


 
  
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Amd 
# 
Amd Date 
Revision(s) Made 
Refer to this Section in the 
Protocol 
2 
19 July 2012 
 
CBC, 3-part differential and platelets (-3 to Day 
1 window allowed)  
 
CMP (see Section 7.1.) plus magnesium and 
phosphorus (-3 to Day 1 window allowed) 
 
Uric acid (if clinically indicated) (-3 to Day 1 
window allowed) 
 
Vital signs (blood pressure, weight, pulse, 
and respiratory rate) 
 
Measurement of vital signs (blood pressure, 
pulse, and respiratory rate and weight) (Day 1 
only) 
Re-Staging – 4 Weeks(-7 to Day 1 window allowed) 
At any point in this treatment, patients suspected 
of PD will have response assessed again to 
confirm disease progression (i.e. 2 sets of 
response assessments at least 1 week apart). The 
outcomes will be reviewed by the study chair 
before the patient is removed from the study. 
MR – Minimal Response 
Minimal Response (MR) should be reported for 
patients with relapsed refractory myeloma.  When 
reported, the specific rate of MR should be 
distinguished from PR or better. 
MM 27 is a combined Phase I/II study of carfilzomib 
in combination with panobinostat in the treatment of 
relapsed/refractory multiple myeloma. 
 
Section 7.3.2, 7.3.4, 
7.3.5 
 
 
 
 
Section 7.3.3, 7.3.4  
 
 
Section 7.3.5 
 
 
Section 7.4 
 
 
 
 
 
Section 9, 
Appendix C 
 
 
 
 
Synopsis,Section 
10 
 
 


 
  
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History of Amendments for MM 27 (continued) 
 
Amd 
# 
Amd Date 
Revision(s) Made 
Refer to this Section in the 
Protocol 
3 
26 March 2013 
A maximum of four dose levels will be were 
evaluated.  Approximately 24 patients will be 
enrolled during the Phase I portion to establish the 
MTD No DLTs were seen during the Phase I 
portion. 
In the Phase II portion of this study, patients with 
relapsed/refractory multiple myeloma will receive 
treatment with the dose level 4 panobinostat and 
carfilzomib combination established during Phase I.  
Patients will be reevaluated for response to treatment 
after each cycle (4 weeks).  Patients with objective 
response or stable disease will continue treatment, 
with subsequent reevaluations every 4 weeks, until 
disease progression or unacceptable toxicity occurs. 
A parallel Phase I study will occur to evaluate a 
minimum of 3 patients and a maximum of 6 
patients following a standard dose escalation 
design at dose level 5 of the combination of 
carfilzomib and panobinostat (see Table 3).   
If dose level 5 is found to be tolerable, then 
additional patients will be recruited into an 
expansion cohort, which will be open at all sites - 
a maximum total of 36 patients (including the 
ones recruited into the parallel Phase I study) will 
be treated at this dose level.  Sites will be notified 
about the expansion cohort and patients will 
enter in the dose level confirmed in their 
enrollment confirmation from SCRI. 
Up to 54 80 eligible patients will be treated in the 
Phase I/II study.  The treatment schema for the study 
is shown in Figure 12. 
 
Section 5 
 
 
Addition of Table 3. Parallel Dose Escalation 
Study – Dose Level 5 
A parallel Phase I study will occur to evaluate a 
minimum of 3 patients and a maximum of 6 
patients following a standard dose escalation 
design at dose level 5 of the combination of 
carfilzomib and panobinostat.   
Patients will enter in the dose level confirmed in 
their enrollment confirmation from SCRI. 
 
Section 5.2 


 
  
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History of Amendments for MM 27 (continued) 
 
Amd 
# 
Amd Date 
Revision(s) Made 
Refer to this Section in the 
Protocol 
3 
26 March 2013 
If dose level 5 is found to be tolerable, then 
additional patients will be recruited at this dose 
level into an expansion cohort of 30 patients for 
Phase II for a total of 60 Phase II patients (30 
patients for dose level 4 and 30 patients for dose 
level 5).  A maximum of up to 80 total patients 
may be enrolled in this study (including patients 
from the dose escalation Phase I studies). 
 
Section 5.3 
 
 
 
Patients should receive acyclovir or similar 
(famiciclovir, valacyclovir) anti-varicella (anti-
herpes) agent prophylaxis.  In addition, patients 
should may receive antibiotic prophylaxis with 
ciprofloxacin or other fluoroquinolone (or   
imethroprim/sulfamethoxazole if fluoroquinoles 
are contradicted) if clinically indicated.   
 
Section 5.2 
 
 
Addition to Table 4 Panobinostat and Carfilzomib 
Dose Level Modifications:  
Carfilzomib IV. 15mg/m2, 20mg/m2, 27mg/m2, 
36mg/m2, 45mg/m2, 56mg/m2   
 
Section 6 
 
 
MM 27 is a Phase I/Phase II study of carfilzomib in 
combination with panobinostat in the treatment of 
relapsed/refractory multiple myeloma. The total 
number of patients expected to be accrued is up to 
5480. 
The Phase II efficacy objective is to evaluate the 
overall response in patients with relapsed/refractory 
multiple myeloma treated at the optimal dose level in 
the first 4 dose levels established during the Phase 
I portion, as well as the overall response in 
patients at dose level 5 if this dose level is found 
to be tolerable and patients are recruited into the 
expansion cohort. The response rates in the two 
dose levels will be evaluated separately. 
 
Synopsis,Section 
10.1 


 
  
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History of Amendments for MM 27 (continued) 
Amd 
# 
Amd Date 
Revision(s) Made 
Refer to this Section in the 
Protocol 
3 
26 March 2013 
Following additions made: Efficacy will be evaluated 
for patients treated at the optimal dose level from the 
first 4 dose levels during Phase I together with 
those entered in the Phase II dose expansion portion 
of the study, and at dose level 5 (if this dose level 
is found to be tolerable and patients are recruited 
into the expansion cohort). The data from the two 
dose levels will be evaluated separately, and no 
formal statistical comparisons will be made 
between the two dose levels. 
 
Section 10.4 


 
  
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History of Amendments for MM 27 (continued) 
Amd 
# 
Amd Date 
Revision(s) Made 
Refer to this Section in the 
Protocol 
4 
24 October 2013 
A parallel Phase I study will occur to evaluate a 
minimum of 3 patients and a maximum of 6 patients 
following a standard dose escalation design at 
additional dose levels of the combination of 
carfilzomib and panobinostat (see Table 3). 
If additional dose levels are found to be tolerable, 
then additional patients will be recruited into an 
expansion cohort which will be open at all sites - a 
maximum total of 36 patients (including the ones 
recruited into the parallel Phase I study) will be 
treated at this dose level. 
 
Section 5 
 
 
 
 
Dose Level 6 added as follows: 
Carfilzomib 
Cycle 1 = 20 mg/m2 IV D1,2/ 56 mg/m2  IV D 8, 9, 
15, 16 
Cycle 2 to Progression  = 56 mg/m2 IV D 1, 2, 8, 9, 
15, 16 
Panobinostat 
Cycle 1 = 20 mg D 1, 3, 5, 15, 17, 19 
Cycle 2 to progression = 20 mg D 1, 3, 5, 15, 17, 
19 
 
Table 3 
 
 
Window for Holidays and Vacations 
For holidays and vacations it is preferred to 
plan ahead and adjust D1 of treatment +/- 48 
hours of the cycle the patient plans to be gone 
for treatment so that the patient follows the 
treatment schedule per protocol.  If it is not 
possible to adjust D1, the carfilzomib infusion 
days may be adjusted +/- 48 hours after cycle 1 
for a holiday or vacation.  There is no window 
allowed during cycle 1 and for the panobinostat 
doses except for D1 with the window described 
above. 
 
Section 5.1.3 
 
 
A parallel Phase I study will occur to evaluate a 
minimum of 3 patients and a maximum of 6 patients 
following a standard dose escalation design at 
additional dose levels of the combination of 
carfilzomib and panobinostat.   
 
 
Section 5.2 
 
 
 
 
 
 


 
  
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History of Amendments for MM 27 (continued) 
Amd  
Amd Date 
Revision(s) Made 
Refer to this Section in the 
Protocol 
4 
24 October 2013 
If a dose level in the parallel Phase I study is 
found to be tolerable, then additional patients will 
be recruited at this dose level into an expansion 
cohort of 30 patients for Phase II for a total of 60 
Phase II patients (including 30 patients for dose 
level 4). and 30 patients for dose level 5)..  A 
maximum of up to 80 total patients may be enrolled 
in this study (including patients from the dose 
escalation Phase I studies).  
 
Section 5.3 
 
 
At any point in this treatment, patients suspected of 
PD will have response assessed again to confirm 
disease progression (i.e. 2 sets of response 
assessments at least 1 week apart). The outcomes 
will be reviewed by the study chair before the 
patient is removed from the study.  After the 
second set of response assessments, if disease 
progression is confirmed, the date of the first 
set of response assessments should be 
recorded as the progression date 
 
Section 7.4 
 
 
The Phase II efficacy objective is to evaluate the 
overall response in patients with relapsed/refractory 
multiple myeloma treated at the optimal dose level 
in the first 4 dose levels established during the 
Phase I portion, as well as. In addition, the overall 
response in patients at any additional dose level is 
found to be tolerable and patients are recruited into 
the expansion cohort will be evaluated. 
 
Section 10.1 
 
 
Efficacy will be evaluated for patients treated at the 
optimal dose level from the first 4 dose levels 
during Phase I together with those entered in the 
Phase II dose expansion portion of the study, and 
at any additional dose level (if this dose level is 
found to be tolerable and patients are recruited into 
the expansion cohort). 
 
Section 10.4 
 
 
 
 
SCRI and SCRI Oncology Research Consortium 
have been updated to SCRI Development 
Innovations, LLC (SCRI Innovations) as 
appropriate. 
 
Global Change 
 


 
  
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MM 27 AMD 5/03 AUG 2015 
 
History of Amendments for MM 27 (continued) 
Amd  
Amd Date 
Revision(s) Made 
Refer to this Section in the 
Protocol 
5 
03 August 2015 
Moved hydration and safety guidelines for 
carfilzomib from Section 6.4  
 
Section 5.1.2 
 
 
Deleted duplicate concomitant medication 
information 
 
Section 5.4 
 
 
Added hypertensive events to Table 8 
 
Section 6.3 
 
 
Added management guidelines for carfilzomib-
related events 
 
Section 6.4 
 
 
Amended to refer to the most current carfilzomib 
Investigator’s Brochure. 
 
Section 8.2.5  
 
 
Updated precautions and risks for carfilzomib 
 
Section 8.2.6 
 
 
Amended response criteria for Progressive Disease 
as follows: 
Increase of  ≥ 25% from the nadir in at least one of 
the following criteria: 
 
serum M-protein (absolute increase must be 
≥0.5 g/dL and absolute value must be ≥1 g/dL) 
 
Appendix C 


 
  
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SYNOPSIS 
Title of Study: 
A Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients with 
Relapsed/Refractory Multiple Myeloma 
Protocol Number: 
MM 27 
Study Phase:  I-II 
Study Centers: 
Multicentered 
Objectives: 
Primary Objectives: 
 
To establish the optimal doses of carfilzomib in and panobinostat that can be 
administered to patients with relapsed/refractory multiple myeloma. (Phase I)  
 
To evaluate the overall response in patients with relapsed/refractory multiple 
myeloma treated with the combination of panobinostat and carfilzomib.  (Phase II) 
Secondary Objectives: 
 
To evaluate time-to-progression (TTP)  
 
To evaluate progression-free-survival (PFS) 
 
To evaluate overall-survival (OS) 
 
To evaluate safety 
Study Design: 
This is an open-label, non-randomized Phase I/II study of patients with relapsed or 
refractory multiple myeloma. 
The Phase I study will determine the MTD of the combination of carfilzomib and 
panobinostat.  The Phase I portion will follow a standard dose escalation design, 
beginning with dose level 1 (see Table 2).  Patients will be assessed for dose-limiting 
toxicity (DLT) at each visit during Cycle 1 prior to receiving treatment.  Dose 
modifications will not be permitted during Cycle 1 unless a patient experiences a DLT 
(see Section 5.2.2.). Treatment cycles will be administered at 28-day intervals.  
Panobinostat will be administered orally three times weekly during weeks 1 and 3 of 
each cycle (Days 1, 3, 5, 15, 17, 19).  Carfilzomib will be administered intravenously on 
Days 1, 2, 8, 9, 15, and 16 of each cycle.  During Cycle 1, the carfilzomib dose will be 
escalated after the Day 2 dose, if well tolerated. 
A maximum of four dose levels will be evaluated.  Approximately 24 patients will be 
enrolled during the Phase I portion to establish the MTD. 
In the Phase II portion of this study, patients with relapsed/refractory multiple myeloma 
will receive treatment with the panobinostat and carfilzomib combination established 
during Phase I.  Patients will be reevaluated for response to treatment after each cycle 
(4 week).  Patients with objective response or stable disease will continue treatment, 
with subsequent reevaluations every 4 weeks, until disease progression or 
unacceptable toxicity occurs.  
Number of Patients: 
Up to 80 eligible patients will be treated in this study. 
 


 
  
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SYNOPSIS 
Drug Supply: 
Panobinostat and Carfilzomib for use in the study will be provided to the Sponsor, SCRI 
Development Innovations, LLC (SCRI Innovations).  Panobinostat will be provided to 
SCRI Innovations by Novartis Pharmaceuticals.  Carfilzomib will be provided to SCRI 
Innovations by Onyx Pharmaceuticals.  Supplies will be requested through SCRI 
Innovations.   
Study Drug(s), 
Schedule, and 
Mode of 
Administration: 
 
 
 


 
  
Page 16 of 101 
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SYNOPSIS 
Inclusion 
Criteria: 
1. 
Eligible participants must have multiple myeloma using standard criteria (Appendix B).   
2. 
Patients must have measurable disease requiring systemic therapy defined as at least 
one of the following:  
 Serum M-protein ≥0.5 g/dl (≥5 g/l) 
 Urine M-protein ≥200 mg/24 hrs 
 Serum free light chain assay: involved free light chain level ≥10 mg/dl (≥100 mg/l) 
provided the serum free light chain ratio is abnormal 
3. 
Must have progressed during or after at least one previous treatment regimen.  
Patients who have received previous high dose therapy/autologous stem cell 
transplantation are eligible. 
4. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.  (see 
Appendix A). 
5. 
Must meet the following laboratory criteria:    
 Absolute neutrophil count (ANC) ≥1000/μL; 
 Platelets ≥70,000/L;   
 AST or ALT and alkaline phosphatase (ALP) must be ≤2.5 x ULN, or ≤5 x ULN in 
patients with plasmacytomas of the liver; 
 Total bilirubin ≤1.5 x the institutional ULN; 
 Serum creatinine ≤1.5 x ULN or calculated creatinine clearance 50 ml/min;  
 Serum potassium, calcium, magnesium WNL (These may be corrected prior to 
starting therapy, to make the patient eligible.)  
6. 
Ability to swallow oral medications. 
7. 
Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction (LVEF)  
the lower limit of the institutional limits of normal. 
8. 
Male or females 18 years of age. 
9. 
Female patients must not be of child-bearing potential or must agree to use adequate 
contraceptive measures.  
10. Male patients willing to use adequate contraceptive measures. 
11. Willingness and ability to comply with the trial and follow-up procedures. 
12. Ability to understand the nature of this trial and give written informed consent. 
 
Exclusion 
Criteria: 
1. 
Currently receiving or have received systemic cancer therapy (chemotherapy, biologic 
therapy) ≤21 days of initiating study therapy.  For patients receiving small molecule 
targeted therapy, study treatment may begin >21 days after last dose or >5 half lives of 
previous treatment, whichever is shorter. Patients must have completed radiation 
therapy ≥7 days prior to starting study treatment. Patients must have recovered from or 
come to a new chronic stable baseline from all treatment-related toxicities. 
Dexamethasone or other high-dose steroid therapy must be stopped ≥7 days prior to 
starting study treatment. 
2. 
Previous treatment with HDAC, DAC, HSP90 or valproic acid for treatment of cancer.   
3. 
Requires valproic acid for any medical condition during the study ≤5 days prior to first 
panobinostat treatment.  
4. 
Patient has not recovered from all therapy-related toxicities associated with prior 
treatments to < Grade 2 CTCAE.  
 


 
  
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SYNOPSIS 
Exclusion 
Criteria: 
5. 
Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize 
carfilzomib). 
6. 
Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis 
≤14 days prior to study entry. 
7. 
Patients using medications that have a risk of prolonging the QT interval or inducing 
Torsade de Pointes if treatment cannot be discontinued or switched to a different 
medication prior to receiving study drug (see Appendix F). 
8. 
Patients with > grade 2 diarrhea. 
9. 
Patients with impaired cardiac function, including any of the following conditions: 
 
History or presence of sustained ventricular tachyarrhythmia. 
 
Any history of ventricular fibrillation or Torsade de pointes. 
 
Bradycardia defined as HR <50 bpm.  Patients with pacemakers are eligible if 
HR ≥50 bpm. 
 
Screening ECG with a QTc >450 msec. 
 
Right bundle branch block + left anterior hemiblock (bifascicular block). 
 
Patients with myocardial infarction or unstable angina ≤6 months prior to starting 
study drug. 
 
Other clinically significant heart disease (e.g. CHF NY Heart Association class III 
or IV (Appendix D), uncontrolled hypertension, history of labile hypertension, or 
history of poor compliance with an antihypertensive regimen). 
10. Infection requiring IV antibiotics. 
11. Patients with > grade 2 peripheral neuropathy. 
12. Women who are pregnant or lactating. 
13. Any concurrent medical illness that may impair the ability of the patient to tolerate study 
treatment and comply with the requirements of the study. 
14. Mental condition that would prevent patient comprehension of the nature of, and risk 
associated with, the study. 
15. Use of any non-approved or investigational agent ≤30 days prior to administration of 
the first dose of study drug.  Patients may not receive any other investigational or anti-
cancer treatments while participating in this study. 
16. Presence of other active cancers, or history of treatment for invasive cancer ≤ 5 years.  
Patients with stage I cancer who have received definitive local treatment at least 3 
years previously, and are considered unlikely to recur are eligible.  All patients with 
previously treated in situ carcinoma (i.e. non-invasive) are eligible, as are patients with 
history of non-melanoma skin cancer. 
Statistical 
Method: 
MM 27 is a Phase I/II study of carfilzomib in combination with panobinostat in the treatment 
of relapsed/refractory multiple myeloma.  The total number of patients expected to be 
accrued is 80. 
The Phase I objective is to establish the optimal dose of carfilzomib with panobinostat that 
can be administered to patients with relapsed/refractory multiple myeloma.  In this part of 
the trial, the optimal dose combination to be administered will be determined as described in 
Section 5.2. Since 3-6 patients will be treated in each cohort, the maximum number of 
patients treated in this phase will be 24. 
 


 
  
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SYNOPSIS 
Statistical 
Method: 
The Phase II efficacy objective is to evaluate the overall response in patients with 
relapsed/refractory multiple myeloma treated at the optimal dose level in the first 4 
dose levels established during the Phase I portion. In addition, the overall response in 
patients at any additional dose levels will be evaluated.  The response rates in the two 
dose levels will be evaluated separately.  When used in the treatment of patients with 
relapsed/refractory multiple myeloma, the historical carfilzomib overall response rate is 
approximately 18%.  It is hypothesized that the overall response rate for the treatment 
regimen of carfilzomib plus panobinostat is greater than that for patients treated with 
carfilzomib alone.  A sample size of 27 achieves 80% power to detect an increase in 
the overall response rate to 36% (representing a 100% relative improvement) based on 
a one-sided test of proportion at an alpha level of 0.10.  The sample size will be 
increased by 10% to account for potential non-evaluable patients and adjusted relative 
to the actual number of patients in the Phase I portion who are treated at the optimal 
dose level. 
 
SCRI DEVELOPMENT INNOVATIONS, LLC CONTACT INFORMATION: 
SCRI Innovations Phone #: 
 
1-877-MY-1-SCRI 
SCRI Innovations Email 
 
 
 
 
asksarah@scri-innovations.com 
SCRI Innovations Central Enrollment Fax #: 
 
 
(615) 699-0258 
SCRI Innovations Safety Dept. Fax #:  
 
 
(866) 807-4325 
SCRI Innovations Regulatory Fax #: 
 
 
 
(615) 297-2793 
SCRI Innovations Central Pharmacy Fax #: 
 
 
(866) 325-9364 
SCRI Innovations Central Pharmacy E-mail: 
 
 
centralpharmacy@scri-innovations.com 


 
  
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Table of Contents 
1. 
INTRODUCTION ................................................................................................... 25 
1.1. 
Background ........................................................................................... 25 
1.2. 
Panobinostat ......................................................................................... 25 
1.2.1. Overview of the Clinical Experience .......................................... 25 
1.2.2. Single Dose Panobinostat Administration and ECG Monitoring 26 
1.2.3. Phase Ib Study in Patients with MM .......................................... 27 
1.3. 
Carfilzomib ............................................................................................ 29 
1.3.1. Carfilzomib Phase 2 Single Agent Experience .......................... 29 
1.4. 
Rationale for the Study .......................................................................... 31 
2. 
STUDY OBJECTIVES ........................................................................................... 31 
2.1. 
Primary Objective .................................................................................. 31 
2.2. 
Secondary Objectives ........................................................................... 32 
3. 
PATIENT ELIGIBILITY AND WITHDRAWAL CRITERIA ...................................... 32 
3.1. 
Inclusion Criteria ................................................................................... 32 
3.2. 
Exclusion Criteria .................................................................................. 33 
3.3. 
Withdrawal Criteria ................................................................................ 34 
3.3.1. Pregnancy ................................................................................. 35 
4. 
STUDY REGISTRATION ...................................................................................... 35 
5. 
STUDY DESIGN ................................................................................................... 36 
5.1. 
Treatment Plan ...................................................................................... 38 
5.1.1. Panobinostat ............................................................................. 38 
5.1.2. Carfilzomib ................................................................................ 40 
5.1.3. Window for Holidays and Vacations .......................................... 41 
5.2. 
Phase I .................................................................................................. 41 
5.2.1. Dose Escalation Phase I ........................................................... 42 
5.2.2. Definitions of Dose-Limiting Toxicity (DLT) ............................... 44 
5.2.3. Definition of Maximum Tolerated Dose (MTD) .......................... 45 
5.3. 
Phase II ................................................................................................. 45 
5.4. 
Concomitant Medications ...................................................................... 45 
6. 
DOSE MODIFICATIONS ....................................................................................... 46 


 
  
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6.1. 
Dose Modifications for Hematologic Toxicity ......................................... 47 
6.2. 
Panobinostat Dose Modifications for Prolonged QTc Interval ............... 51 
6.2.1. General Monitoring Principles ................................................... 54 
6.3. 
Carfilzomib Dose Modifications for Non-Hematologic Toxicities ........... 55 
6.4. 
Management of Carfilzomib-Related Events ......................................... 57 
6.4.1. Cardiopulmonary Disorders ...................................................... 57 
6.4.2. Pulmonary Hypertension ........................................................... 57 
6.4.3. Acute Renal Disorder ................................................................ 58 
6.4.4. Tumor Lysis Syndrome ............................................................. 58 
6.4.5. Infusion Reactions .................................................................... 58 
6.4.6. Thrombocytopenia .................................................................... 58 
6.4.7. Hepatic Toxicity ......................................................................... 59 
6.4.8. Thrombocytopenic Thrombotic Purpura/Hemolytic Uremic 
Syndrome .............................................................................................. 59 
6.4.9. Posterior Reversible Encephalopathy Syndrome ...................... 59 
7. 
STUDY ASSESSMENTS AND EVALUATIONS .................................................... 59 
7.1. 
Comprehensive Metabolic Profile (CMP) .............................................. 59 
7.2. 
Baseline Assessment ............................................................................ 60 
7.3. 
Study Treatment Period ........................................................................ 61 
7.3.1. Cycle 1 Day 1, 2, 5, 8, 9, 15, 16 ................................................ 61 
7.3.2. Cycle 1 Day 1............................................................................ 61 
7.3.3. Cycle 1 Day 5............................................................................ 61 
7.3.4. Cycle 1 Day 8 and 15 ................................................................ 61 
7.3.5. Cycle 2 and Beyond - Day 1, 8 and 15 ..................................... 62 
7.4. 
Re-Staging – 4 Weeks (-7 to Day 1 window allowed) ........................... 62 
7.5. 
End of Study Treatment ........................................................................ 63 
7.6. 
Follow-Up .............................................................................................. 63 
7.6.1. Follow-Up for Patients who Discontinue Treatment Prior to 
Disease Progression ............................................................................. 63 
7.6.2. Follow-Up After Disease Progression ....................................... 64 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND TOXICITY 
INFORMATION ............................................................................................................. 64 


 
  
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8.1. 
Panobinostat ......................................................................................... 64 
8.1.1. Panobinostat Formulation ......................................................... 64 
8.1.2. Panobinostat  Drug Supply ....................................................... 64 
8.1.3. Storage and Stability ................................................................. 65 
8.1.4. Administration ........................................................................... 65 
8.1.5. Panobinostat Toxicities ............................................................. 65 
8.1.6. Panobinostat Precautions and Risks ........................................ 66 
8.2. 
Carfilzomib ............................................................................................ 67 
8.2.1. Carfilzomib Formulation ............................................................ 67 
8.2.2. Drug Supply of Carfilzomib ....................................................... 67 
8.2.3. Storage and Stability ................................................................. 68 
8.2.4. Administration ........................................................................... 68 
8.2.5. Carfilzomib Toxicities ................................................................ 68 
8.2.6. Carfilzomib Precautions and Risks ........................................... 68 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS......................................... 69 
10. STATISTICAL CONSIDERATIONS AND DETERMINATION OF SAMPLE SIZE . 69 
10.1. 
Determination of Sample Size ............................................................... 69 
10.2. 
Statistical Analyses ............................................................................... 70 
10.3. 
Demographic and Baseline Characteristics .......................................... 70 
10.4. 
Efficacy Analyses .................................................................................. 70 
10.4.1. Primary Efficacy Endpoint(s) ................................................... 70 
10.4.2. Secondary Efficacy Endpoint(s) .............................................. 71 
10.5. 
Safety Analyses .................................................................................... 71 
11. SAFETY REPORTING AND ANALYSES .............................................................. 71 
11.1. 
Safety Analyses .................................................................................... 71 
11.2. 
Adverse Events ..................................................................................... 71 
11.2.1. Definitions of Adverse Events ................................................. 71 
11.2.2. Recording of Adverse Events .................................................. 72 
11.2.3. Abnormal Laboratory Values and Vital Signs .......................... 72 
11.2.4. Handling of Adverse Events .................................................... 72 
11.3. 
Serious Adverse Events ........................................................................ 73 


 
  
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11.3.1. Definitions of Serious Adverse Events .................................... 73 
11.3.2. Serious Adverse Event Reporting by Investigators ................. 73 
11.3.3. Novartis Instructions for Rapid Notification of Serious Adverse 
Events  ................................................................................................ 75 
11.3.4. Safety Reporting for Studies Done Under an IND ................... 75 
11.3.5. Onyx Instructions for Reporting Serious Adverse Events ....... 75 
11.3.6. Sponsor SAE Reporting Requirements ................................... 76 
11.4. 
Recording of Adverse Events and Serious Adverse Events .................. 76 
11.4.1. Diagnosis vs. Signs and Symptoms ........................................ 76 
11.4.2. Persistent or Recurrent Adverse Events ................................. 77 
11.4.3. Abnormal Laboratory Values................................................... 77 
11.4.4. Deaths .................................................................................... 77 
11.4.5. Hospitalization, Prolonged Hospitalization, or Surgery ........... 77 
11.4.6. Pre-Existing Medical Conditions ............................................. 78 
11.4.7. Pregnancy, Abortion, Birth Defects/Congenital Anomalies ..... 78 
11.5. 
Protocol-Defined Events of Special Interest .......................................... 78 
12. ETHICAL, FINANCIAL AND REGULATORY CONSIDERATIONS ....................... 78 
12.1. 
IRB Approval ......................................................................................... 79 
12.2. 
Regulatory Approval .............................................................................. 79 
12.3. 
Insurance and Indemnity ....................................................................... 79 
12.4. 
Informed Consent .................................................................................. 79 
12.5. 
Confidentiality ........................................................................................ 80 
12.5.1. Patient Confidentiality ............................................................. 80 
12.5.2. Investigator and Staff Information ........................................... 81 
12.6. 
Financial Information ............................................................................. 81 
13. RECORD RETENTION AND DOCUMENTATION OF THE STUDY ..................... 81 
13.1. 
Amendments to the Protocol ................................................................. 81 
13.2. 
Documentation Required to Initiate the Trial ......................................... 82 
13.3. 
Trial Documentation and Storage .......................................................... 83 
13.4. 
Data Collection ...................................................................................... 84 
13.5. 
Trial Monitoring, Auditing, and Inspecting ............................................. 84 
13.6. 
Quality Assurance and Quality Control ................................................. 85 


 
  
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13.7. 
Disclosure and Publication Policy ......................................................... 85 
14. REFERENCES ...................................................................................................... 86 
15. APPENDICES ....................................................................................................... 88 
 


 
  
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List of Tables 
Table 1. 
ECG QTcF Monitoring ........................................................................... 39 
Table 2. 
Phase I Dose Levels ............................................................................. 41 
Table 3. 
Parallel Dose Escalation Study – Dose Levels 5 and 6 ......................... 42 
Table 4. 
Panobinostat and Carfilzomib Dose Level Modifications ....................... 47 
Table 5. 
Panobinostat and Carfilzomib Dose Adjustments for Hematologic 
Toxicities 
 .............................................................................................................. 47 
Table 6. 
Panobinostat Dose Adjustments for Non-Hematologic Toxicities .......... 49 
Table 7: 
Criteria for Dose Reductions, Delays and/or Re-Institution Due to Drug-
Related QTcF Abnormalities ......................................................................................... 52 
Table 8. 
Carfilzomib Dose Modifications for Non-Hematologic Toxicity .............. 56 
 
List of Figures 
Figure 1. 
CLBH589B2207 Response Rates for All Patients and Bortezomib 
Refractory 
 .............................................................................................................. 29 
Figure 2 
 Treatment Schema ............................................................................... 37 
 
 
List of Appendices 
Appendix A: 
 ECOG Performance Status Criteria ..................................................... 89 
Appendix B: 
Diagnostic Criteria and Staging for Multiple Myeloma ........................... 90 
Appendix C: 
International Myeloma Working Group Uniform Response Criteriaa ..... 92 
Appendix D: 
New York Heart Association (NYHA) .................................................... 95 
Appendix E: 
Schedule of Assessments MM 27 ......................................................... 96 
Appendix F: 
Drugs That Prolong QT Interval and/or Induce Torsades De Pointes ... 98 
Appendix G: 
Substrates, Inducers and Inhibitors of Isoenzyme CYP3A4 and CYP2D6 
Substrates 
 ............................................................................................................ 100 
 


 
  
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1. 
INTRODUCTION 
1.1. Background  
Multiple myeloma accounts for approximately 20,000 new cancer diagnoses in the US 
each year (Jemal et al. 2010).  Although myeloma patients usually benefit from initial 
therapy, sooner or later, treatment will be required for refractory or resistant disease.  
1.2. Panobinostat 
Panobinostat (LBH589) is a potent histone deacetylase (HDAC) inhibitor belonging to a 
structurally novel cinnamic hydroxamic acid class of compounds.  It is a potent class I/II 
pan-DAC inhibitor that has shown anti-tumor activity in pre-clinical models and cancer 
patients.  Deacetylases (DAC) target lysine groups on chromatin and transcription 
factors and various non-histone proteins such as p53, tubulin, HSP90 and Rb.  
Panobinostat is formulated as an oral capsule and a solution for intravenous (IV) 
injection.  Both the oral and IV formulations are currently being investigated in ongoing 
phase I and phase II studies in advanced solid tumors and hematological malignancies.   
1.2.1. Overview of the Clinical Experience  
In clinical studies, both oral and intravenous (IV) formulations of panobinostat are being 
explored for further development.  As of December 31, 2010, 32 clinical studies, 
including clinical pharmacology, phase I and/or phase II, have either been completed or 
are ongoing.  A total of 1,589 patients were enrolled and received at least one dose of 
panobinostat.  These patients constitute the safety population. 
The most common adverse events seen have been grades 1 and 2 nausea, diarrhea,   
and neutropenia.  Additional common toxicities have included fatigue and vomiting.   
With the exception of thrombocytopenia, grades 3 and 4 adverse events were 
uncommon.  The occurrence of thrombocytopenia appears to be related to the 
underlying disease (incidence is higher in patients with malignancies that involved the 
bone marrow e.g., acute myeloid leukemia, chronic myeloid leukemia, multiple 
myeloma, myelodysplastic syndrome, etc.) as well as the mode and interval of 
administration, with oral every other week schedules producing the least amount of 
toxicity. 
The most common electrocardiogram (ECG) findings adjudicated by central review 
included post-baseline increase in frequency of sinus tachycardia, T-wave changes (flat, 
biphasic, inverted), as well as depressed ST segment findings. 
The most frequently encountered laboratory abnormalities were thrombocytopenia, 
neutropenia, some degree of anemia, and fluctuations in electrolytes that might not be 
clinically relevant. 


 
  
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Thyroid function, as monitored by the measurement of TSH and free T4, did not reveal 
overt hyper- or hypothyroidism, with fluctuations in TSH values being within normal 
limits. 
1.2.2. Single Dose Panobinostat Administration and ECG Monitoring 
In the initial Phase I study utilizing the IV formulation of panobinostat administered on 
consecutive days, significant QTcF interval abnormalities were noted, with one patient 
experiencing Torsade de pointes.  With the introduction of the oral formulation and the 
three-times-weekly (TIW) administration, extensive monitoring has been conducted in 
all clinical trials of panobinostat. 
As of December 31, 2009 cardiac safety data were available for 532 patients receiving 
TIW dosing and 70 patients TIW every other week (QOW).  All of these patients 
underwent intensive pre- and post-dose ECG recording to monitor the occurrence of 
QTcF changes as well as to capture other ECG abnormalities.  There is increasing 
evidence that the most common finding is a QTcF increase of ≤60 msec (CTCAE grade 
1) from baseline in both schedules.  QTcF prolongation to >480 msec has been mostly 
observed at the highest oral dose of 60 mg given TIW.  There were no cases of Torsade 
de pointes with either schedule for oral panobinostat.  
To date, an increase from of ≤60 msec (CTCAE grade 1) was observed in 98 patients 
(16.7%) in TIW schedule.  An increase of >60 msec from baseline in 12 patients (2%) is 
less frequently reported.  QTcF prolongation translating in an absolute value above 
baseline to ≤480 msec or to ≤500 msec occurred in 61 patients (10.4%) and in 5 
patients (0.8%), respectively.  Absolute QTcF prolongation above 500 msec was 
reported in 3 patients (0.5%) treated at doses of 20 and 60 mg (2 and 1 patients, 
respectively). 
To date, an increase from baseline of ≤60 msec (CTCAE grade 1) was observed in 15 
patients out of 70 patients (21.4%) in the TIW QOW schedule.  An increase of >60 msec 
from baseline in 4 patients (5.7%) was less frequently reported.  QTcF prolongation 
translating in an absolute value above baseline to ≤480 msec or to ≤500 msec occurred 
in 9 out of 70 patients (12.9%) and in 1 out of 70 patients (1.4%), respectively.  Absolute 
QTcF prolongation above 500 msec was not observed. 
Across all doses in both schedules, the most frequent ECG findings were T-wave 
abnormalities (flat, inverted, or biphasic T-waves) and depressed ST segment.  An 
increased frequency of sinus tachycardia was also observed. 
In addition, an assessment of grade 3 or 4 cardiovascular events of clinical relevance 
(angina pectoris, cardiac failure, cardiac arrest, CHF, pericardial effusion, DVT, and 
pulmonary embolism) was conducted for both dose schedules.  The events are 
described by disease group. 
In Group 1 (N= 229) treated with 20 mg TIW, angina pectoris was reported in 4 cases 
(1.7%), cardiac failure, CHF and DVT in 2 cases (0.9%) each, cardiac arrest and 
pericardial effusion in 1 case (0.4%) each.  At 40 mg, TIW pericardial effusion and 
pulmonary embolism were reported in 2 cases (1.3%) each (N=153).  None of these 


 
  
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events were noted in the few patients (N=5) treated at the dose of 60 mg TIW.  For 
group 2 at the dose of 20 mg TIW (N=64), DVT and pulmonary embolism, cardiac 
failure and pericardial effusion were noted in 1 instance (1.6%) each.  A second event of 
cardiac failure was reported at the dose of 30 mg TIW in 8 treated patients (12.5%). 
For group 1 at 50 mg TIW QOW (N=15), cardiac failure and CHF were reported in 1 
case (6.7 %) each.  For group 2 at 45 mg TIW QOW (N-9), MI was reported in 1 case 
(11.1%).  
Given the nature of the disease under treatment, patients with such events have many 
risks factors such as underlying cardiovascular disease and concomitant medications.  
As such, it is yet to be determined whether panobinostat is causally related to these 
cardiovascular adverse events. 
1.2.3. Phase Ib Study in Patients with MM 
The primary objective of the CLBH589B2207 trial is to determine the maximum-
tolerated dose (MTD) of oral panobinostat when combined with bortezomib in patients 
with relapsed or refractory MM.  A total of 38 patients have been enrolled into five 
completed dose cohorts: (I) 10 mg panobinostat (TIW) + 1.0 mg/m2 bortezomib (IV, 
Days 1, 4, 8, 11) q 21-days, (II) 20 mg panobinostat + 1.0 mg/m2 bortezomib, (III) 20 mg 
panobinostat + 1.3 mg/m2 bortezomib and (IV) 30 mg panobinostat + 1.3 mg/m2 
bortezomib, (V) 25 mg panobinostat +1.3 mg/m2 bortezomib.  Enrollment into Cohort VI 
at 20 mg panobinostat + 1.3 mg/m2 bortezomib has enrolled 1 patient as of the 09-Oct-
03 cutoff.  In Cohorts I-V, the median number of prior therapies was two (range 1-7); 
30 patients had at least one prior auto-SCT. Out of 22 bortezomib pre-treated patients 
13 were refractory to prior bortezomib therapy (10 PD and 3 SD on bortezomib 
according to IMWG’08). Median time on study was longest in Cohort 3 at 109 days 
(range 7- 424) (Anderson et al. 2010).  
The combination of panobinostat and bortezomib was safe and tolerated in Cohorts I, II, 
III and IV.  Dose-limiting toxicities (DLT) were reported in cohorts II (one patient with 
Grade 4 afebrile neutropenia) and cohort IV (4 DLTs: 2 Grade 4 TCPs, requiring 
2 consecutive platelet transfusions), Grade 3 pneumonia and Grade 3 fatigue.  In cohort 
V, the dose of panobinostat was de-escalated to 25 mg. In this Cohort, one DLT has 
been seen to date (Grade 4 thrombocytopenia, Grade 3 asthenia, Grade 3 dizziness).  
Hematological AEs have been common, including Grade 3/4 TCP (30 in 38 patients), 
neutropenia (23) and anemia (6).  Non-hematological AEs (all grades) included diarrhea 
(23), fever (17), nausea (18), fatigue (16), and asthenia (13). A total of 2,200 ECGs 
have been analyzed: no QTcF prolongations from BL >60 msec nor absolute QTcF time 
duration >480 msec were noted. No QTcF prolongation ≥Grade 1 were seen.  
Although Grade 3/4 TCP occurred frequently it was manageable with dose 
reduction/interruption and platelet transfusion. TCP (Grade 4) was to be managed by 
platelet transfusions before study drug dose omission/reduction was allowed. 
Thrombocytopenia as the DLT in three patients in cohorts IV and V. No patients 
experienced hemorrhagic events in association with Grade 3/4 TCP. A detailed review 


 
  
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of dose reductions and interruptions as well as timing of dose modifications and platelet 
transfusions relative to time to and duration of TCP in patients enrolled in cohorts I - IV 
revealed the following findings:  
The majority of patients experienced TCP within the first 2 cycles. This resulted in dose 
reductions, interruptions and/or dose delays. The time course of TCP appeared 
predictable with the platelet count nadir in most cases occurring at the end of the 
second week, or during the 3rd, i.e. last week of the first or second treatment cycle. No 
dose relationship was seen with a similar number of Grade 3/4 TCP episodes during the 
three first cohorts. A similar number of patients receiving platelet transfusions (n=1/7, 
5/7, and 3/8 in cohorts I, II, and III), and administrations of platelet transfusion (n=15 in 
cohorts I-V). With 109 days (compared to 52 and 76 days in cohorts I and II) median 
panobinostat exposure time was longest in cohort III in spite of dose 
reductions/interruptions. Anecdotal cases have been reported in which patients were 
clinically benefiting from panobinostat, but were unable to maintain the QW dosing 
schedule even after dose reduction.  
Clinical efficacy was observed in all 5 cohorts with 26 responses (MR or better) in 38 
evaluable patients. For 22 patients, the best response was at least PR (58%) including 
2 VGPR, and immunofixation (IF) - negative CR in 4 pts. Responses were seen in the 
subset of patients refractory to prior bortezomib suggesting a strong clinical correlate of 
the preclinical synergism of the combination of panobinostat and bortezomib: 8 of 13 
bortezomib-refractory patients responded, including 6 with a PR (46%) and 2 with a MR 
(Figure 1).   One patient had received bortezomib as part of an induction regimen prior 
to autologous SCT, and experienced a VGPR (cohort I).  
According to the protocol Dex could be introduced in cycle 2 (or 3) and this was done in 
9 patients including 8 out of 18 responders (2 in cohort I, 2 in cohort II, 1 in cohort III 
and 3 in cohort IV). Five patients received Dex after first documentation of response and 
3 patients before. Eleven of 18 patients with a response did not receive Dex at all, 
including several patients refractory to bortezomib. In cohort III all 8 patients 
experienced a clinical benefit with 7 responding [immunofixation-negative CR (n=2), PR 
(n=3) including one bortezomib refractory patient, MR (n=2) including one bortezomib 
refractory patient] and one with SD. Dose modifications did not affect efficacy since the 
highest number of responders seen to date was in cohorts III, IV and V where a higher 
dose of bortezomib (1.3 mg/m2 biweekly) were used. 


 
  
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Figure 1. CLBH589B2207 Response Rates for All Patients and Bortezomib 
Refractory 
 
1.3. Carfilzomib 
Carfilzomib (PR-171) is a tetrapeptide ketoepoxide-based inhibitor specific for the 
chymotrypsin-like active site of the 20S proteasome.  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 (Demo et al. 2007 and 
Arastu-Kapur et al. 2008). 
1.3.1. Carfilzomib Phase 2 Single Agent Experience 
Two Phase 2 clinical studies are ongoing with carfilzomib in multiple myeloma (MM) 
patients, PX-171-003-A0 (N=46) in relapsed and refractory MM and PX-171-004 (N=39) 
in relapsed MM.  In both studies, patients were treated with 20 mg/m2 on Days 1, 2, 8, 
9, 15, and 16 every 28 days.  In these studies there were four cases of suspected or 
documented tumor lysis syndrome (TLS) prior to institution of the prophylaxis 
guidelines.  Since these guidelines were implemented, no further cases of TLS have 
been reported.  In both studies, the most common adverse events were fatigue, anemia, 
thrombocytopenia, gastrointestinal, and dyspnea.  There were reported cases of 
increased in serum creatinine that were primarily < Grade 2.  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 (Jagannath et al. 2009).   
Patients in the PX-171-003-A0 study had progressive myeloma   and were refractory to 
their most recent therapy, often including bortezomib and/or an immunomodulatory drug 


 
  
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(usually lenalidomide).  In this study, 18% of patients had partial responses, with 7% 
minor responses and 41% stable disease.  The median time to progression on the PX-
171-003-A0 study was 5.1 months with duration of response of 7.4 months (Jagannath 
et al. 2009).   
A “stepped up” dosing schedule, referred to as 20/27 mg/m2, has subsequently been 
incorporated into the PX-171-003 study in order to maximize the clinical benefit of 
carfilzomib.  Patients receive 20 mg/m2 for the first cycle and 27 mg/m2 thereafter.  The 
study completed enrollment of 266 patients by the end of 2009 and may form the basis 
for an accelerated approval NDA filing by the end of 2010.  To date, this dosing 
schedule has been well tolerated (Alsina et al. 2007).  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%, most likely due to hydration and very low 
dose dexamethasone.  Treatment-emergent peripheral neuropathy remains low on this 
portion of the study with 15% Grade 1/2 and one (0.7%) Grade 3/4 event reported to 
date on PX-171-003-A18.  In addition, anemia rates 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 (Jagannath et al. 2009) 
In the PX-171-004 study, a first cohort of patients received 20 mg/m2.  The subset of 
patients (N=54) that had not previously received bortezomib had an overall response 
rate (ORR) of 46% (2% CR, 9% VGPR and 35% PR), while the bortezomib treated 
patients (N=33) had an ORR of 18% (3% CR, 3% VGPR and 12% PR) (Wang et al. 
2009 and Seigel et al. 2009).  The median time to progression (TTP) was 7.6 and 5.3 
months in these two groups, respectively.   
1.3.1.1. Carfilzomib PX-171-007 Trial  
The PX-171-003-A1 study enrolled 269 patients with relapsed and refractory multiple 
myeloma by the end of 2009.  The Phase I single agent carfilzomib dose escalation 
study was ongoing as of July, 2009 with over 65 solid tumor patients starting treatment 
in the initial Phase II at the 36 mg/m2 dose.  A review of the tolerability of 36 mg/m2 
carfilzomib in these patients  indicates that this regimen was very well tolerated with 
only one DLT (fatigue) and an overall adverse event profile similar to that seen with the 
27mg/m2 carfilzomib experience with bolus dosing (see IB for details). Three patients 
completed > 12 cycles of therapy at 36 mg/m2 with no evidence of cumulative toxicity.  
There were no significant DLTs observed; the majority of discontinuations on the study 
were due to progressive disease. Because of the long-term tolerability carfilzomib, the 
Phase 1b portion of this study was reopened, and a separate arm for multiple myeloma 
was added.  


 
  
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Recently in the PX-171-007 trial, patients have been treated with carfilzomib given as a 
30-minute infusion in order to minimize Cmax-related infusion events. The PX-171-007 
trial was amended and does of 20/36 (20 mg/m2 given on Days 1 and 2 of cycle 1 only; 
followed by 36 mg/m2 for all subsequent doses), 20/45, 20/56 mg/m2 and so forth are 
being investigated.  Doses of 20/56 mg/m2 are currently being given in two separate 
cohorts of patients with advanced MM and advanced solid tumors; the lower doses 
were well tolerated.  Preliminary tolerability information at this dose level (20/56 mg/m2) 
indicated that it is reasonably well tolerated, with minimal infusion reactions.  In some 
cases at 20/56mg/m2, dexamethasone was increased from 4mg/dose to 8mg with the 
56mg/m2 doses in order to reduce fevers and hypotension.  As of March 20, 2010, 
seven patients have received 20/56mg/m2 with tolerability.  Patients with advanced, 
refractory MM being treated at 36mg/m2 and 45mg/m2  have shown very good 
tolerability (>6 months in some cases) with documented minimal and partial responses 
in these heavily pretreated patients. These data indicate that carfilzomib 30-minute 
infusion can be given at very high levels, with >95% inhibition of blood proteasome 
levels achievable and with (at least) acute tolerability.  As a result, carfilzomib is now 
administered as a 30-minute infusion if the dose is ≥36mg/m2. 
In addition to the above observations, a phase I study of carfilzomib in patients with 
relapsed and refractory multiple myeloma was reported in abstract form at the 2009 
American Society of Hematology meeting which demonstrated that carfilzomib can be 
safely administered to patients with substantial renal impairment (CrCl < 30, including 
patients on dialysis) without dose adjustment (Badros et al. 2009).   These data indicate 
that carfilzomib does not exacerbate underlying renal dysfunction, and confirm the “pre-
renal” etiology of the BUN/creatinine elevations observed with IV bolus carfilzomib. 
1.4. Rationale for the Study 
Relapsed/refractory MM is an incurable disorder with a poor prognosis.  Carfilzomib is a 
novel proteasome inhibitor with activity in this setting.  Panobinostat is a pan-
deacetylase inhibitor which has shown synergistic cytotoxicity in vitro and in vivo with 
proteasome inhibitors.  The combination should enhance the activity of both agents 
against myeloma cells.  In the Phase I part of the trial, the optimal doses of the 
combination of carfilzomib and panobinostat will be determined.  Assuming this 
combination is feasible, the Phase II portion will proceed, using the doses determined in 
Phase I.  This study will be conducted at multiple study sites by the SCRI Development 
Innovations, LLC (SCRI Innovations). 
2. 
STUDY OBJECTIVES 
2.1. Primary Objective 
 To establish the optimal doses of carfilzomib and panobinostat that can be 
administered to patients with relapsed/refractory multiple myeloma. (Phase I)  
 To evaluate the overall response in patients with relapsed/refractory multiple 
myeloma treated with the combination of panobinostat and carfilzomib (Phase II) 


 
  
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2.2. Secondary Objectives 
 To evaluate time-to-progression (TTP)  
 To evaluate progression-free-survival (PFS) 
 To evaluate overall-survival (OS) 
 To evaluate safety 
3. 
PATIENT ELIGIBILITY AND WITHDRAWAL CRITERIA 
3.1. Inclusion Criteria 
1. 
Eligible participants must have multiple myeloma using standard criteria 
(Appendix B).   
2. 
Patients must have measurable disease requiring systemic therapy defined as at 
least one of the following:  
 
 Serum M-protein ≥0.5 g/dl (≥5 g/l) 
 
 Urine M-protein ≥200 mg/24 hrs 
 
Serum free light chain assay: involved free light chain level ≥10 
mg/dl (≥100 mg/l) provided the serum free light chain ratio is 
abnormal 
3. 
Must have progressed during or after at least one previous bortezomib-containing 
treatment regimen.  Patients who have received previous high-dose 
therapy/autologous stem cell transplantation are eligible. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.  (see 
Appendix A). 
5. 
Must meet the following laboratory criteria:    
 
Absolute neutrophil count (ANC) ≥1000/μL; 
 
Platelets ≥70,000/L;   
 
AST or ALT and alkaline phosphatase (ALP) must be ≤2.5 x ULN, or 
≤5 x ULN in patients with plasmacytomas of the liver; 
 
Total bilirubin ≤1.5 x the institutional ULN; 
 
Serum creatinine ≤1.5 x ULN or calculated creatinine 
clearance 50 ml/min; 
 
Serum potassium, calcium, magnesium WNL (These may be corrected 
prior to starting therapy, to make the patient eligible.)  
6. 
Ability to swallow oral medications. 
7. 
Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction 
(LVEF)  the lower limit of the institutional limits of normal. 


 
  
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8. 
Male or females 18 years of age. 
9. 
Female patients must not be of childbearing potential or must agree to use 
adequate contraceptive measures.  
10. Male patients willing to use adequate contraceptive measures. 
11. Willingness and ability to comply with the trial and follow-up procedures. 
12. Ability to understand the nature of this trial and give written informed consent. 
3.2. Exclusion Criteria 
1. 
Currently receiving or have received systemic cancer therapy (chemotherapy, 
biologic therapy) ≤21 days of initiating study therapy.    For patients receiving small 
molecule targeted therapy, study treatment may begin >21 days after last dose or 
>5 half lives of previous treatment, whichever is shorter. Patients must have 
completed radiation therapy ≥7 days prior to starting study treatment. Patients 
must have recovered from or come to a new chronic stable baseline from all 
treatment-related toxicities.  Dexamethasone or other high-dose steroid therapy 
must be stopped ≥7 days prior to starting study treatment. 
2. 
Previous treatment with HDAC, DAC, HSP90 or valproic acid for treatment of 
cancer.   
3. 
Requires valproic acid for any medical condition during the study ≤5 days prior to 
first panobinostat treatment.  
4. 
Patient has not recovered from all therapy-related toxicities associated with prior 
treatments to < Grade 2 CTCAE. 
5. 
Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize 
carfilzomib). 
6. 
Patients with pleural effusions requiring thoracentesis or ascites requiring 
paracentesis ≤14 days prior to study entry. 
7. 
Patients using medications that have a risk of prolonging the QT interval or 
inducing Torsade de Pointes if treatment cannot be discontinued or switched to a 
different medication prior to receiving study drug (see Appendix F). 
8. 
Patients with > grade 2 diarrhea. 
9. 
Patients with impaired cardiac function, including any of the following conditions: 
 
History or presence of sustained ventricular tachyarrhythmia. 
 
Any history of ventricular fibrillation or Torsade de pointes. 
 
Bradycardia defined as HR <50 bpm.  Patients with pacemakers are 
eligible if HR ≥50 bpm. 
 
Screening ECG with a QTc >450 msec. 
 
Right bundle branch block + left anterior hemiblock (bifascicular block). 
 
Patients with myocardial infarction or unstable angina ≤6 months prior to 
starting study drug. 


 
  
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 
Other clinically significant heart disease (e.g. CHF NY Heart Association 
class III or IV (Appendix D), uncontrolled hypertension, history of labile 
hypertension, or history of poor compliance with an antihypertensive 
regimen). 
10. Infection requiring IV antibiotics. 
11. Patients with > grade 2 peripheral neuropathy or with uncontrolled pain. 
12. Women who are pregnant or lactating. 
13. Any concurrent medical illness that may impair the ability of the patient to tolerate 
study treatment and comply with the requirements of the study. 
14. Mental condition that would prevent patient comprehension of the nature of, and 
risk associated with, the study. 
15. Use of any non-approved or investigational agent ≤30 days prior to administration 
of the first dose of study drug.  Patients may not receive any other investigational 
or anti-cancer treatments while participating in this study. 
16. Presence of other active cancers, or history of treatment for invasive cancer ≤ 5 
years.  Patients with stage I cancer who have received definitive local treatment at 
least 3 years previously, and are considered unlikely to recur are eligible.  All 
patients with previously treated in situ carcinoma (i.e. non-invasive) are eligible, as 
are patients with history of non-melanoma skin cancer. 
3.3. Withdrawal Criteria 
Patients will be discontinued from study treatment for any of the following reasons: 
 
Disease progression 
 
Irreversible or intolerable toxicity or abnormal laboratory values 
thought to be related to drug toxicity 
 
Patient requests to withdraw from the trial and discontinue 
treatment 
 
Patient requests to discontinue treatment 
 
Pregnancy (see Section 3.3.1) 
 
Inability of the patient to comply with trial requirements 
 
Conditions requiring therapeutic intervention not permitted by the 
protocol 
 
Intercurrent illness (this will be at the investigator’s discretion) 
 
Non-compliance/lost to follow-up 
 
Patients who have been discontinued from trial treatment will not be replaced.  After 
withdrawal from protocol treatment, patients must be followed for AEs for 30 calendar 
days after their last dose of trial drug.  All new AEs occurring during this period must be 
reported and followed until resolution, or after 30 days (whichever comes first), unless, 
in the opinion of the investigator, these values are not likely to improve because of the 
underlying disease.  In this case, the investigators must record his or her reasoning for 


 
  
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this decision in the patients’ medical records and as a comment on the Case Report 
Form (CRF). 
All patients who have CTCAE grade 3 or 4 laboratory abnormalities at the time of 
withdrawal must be followed until the laboratory values have returned to grade 1 or 2, or 
30 days after the date of withdrawal (whichever comes first), unless it is, in the opinion 
of the investigator, not likely that these values are to improve because of the underlying 
disease.  In this case, the investigator must record his or her reasoning for making this 
decision in the patients’ medical records and as a comment on the CRF.   
3.3.1. Pregnancy 
During the course of the trial, all female patients of childbearing potential  must contact 
the treating investigator immediately if they suspect that they may be pregnant (a 
missed or late menstrual period should be reported to the treating investigator).   
If an investigator suspects that a patient may be pregnant prior to administration of trial 
drug(s), the trial drug(s) must be withheld until the result of the pregnancy test is 
confirmed.  If a pregnancy is confirmed, the patient must not receive any trial drug(s), 
and must be discontinued from the trial.   
If an investigator suspects that a patient may be pregnant after the patient has been 
receiving trial drug(s), the trial drug(s) must immediately be withheld until the result of 
the pregnancy test is confirmed.  If a pregnancy is confirmed, the trial drug(s) must be 
immediately and permanently stopped, the patient must be discontinued from the trial, 
and the investigator must notify the SCRI Innovations study chair as soon as possible.  
If a patient becomes pregnant while enrolled in the trial, a Pregnancy Form (a paper 
report form, not available within EDC system) should be completed and faxed to the 
sponsor or designee.  For more details regarding handling and reporting of pregnancies 
that occur during treatment, see Section 11.5. 
4. 
STUDY REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, 
the experimental nature of the treatment, potential benefits, alternatives, side-effects, 
risks and discomforts.  Human protection committee approvals of this protocol and 
consent form are required prior to patient enrollment.  Registration must occur prior to 
the initiation of protocol therapy.   
Eligible patients will be enrolled through SCRI Innovations.  Participating sites may call 
1-877-MY-1-SCRI for assistance, or fax a completed and signed Enrollment Form to the 
SCRI Innovations Enrollment Desk.  The SCRI Innovations fax registration number is 
(866) 699-0258 and is available, Monday through Friday, 8:30 a.m. to 4:30 p.m., Central 
Standard Time.  Patient registration will be confirmed via fax within 24 hours, or by the 
next business day.  


 
  
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5. 
STUDY DESIGN 
This is an open-label, non-randomized Phase I/II study of patients with relapsed or 
refractory multiple myeloma. 
The Phase I study will determine the MTD of the combination of carfilzomib and 
panobinostat.  The Phase I portion will follow a standard dose escalation design, 
beginning with dose level 1 (see Table 2).  Patients will be assessed for dose-limiting 
toxicity (DLT) at each visit during Cycle 1 prior to receiving treatment.  Dose 
modifications will not be permitted during Cycle 1 unless a patient experiences a DLT 
(see Section 5.2.2.).  Treatment cycles will be administered at 28-day intervals.  
Panobinostat will be administered orally three times weekly during weeks 1 and 3 of 
each cycle (Days 1, 3, 5, 15, 17, 19).  Carfilzomib will be administered intravenously on 
Days 1, 2, 8, 9, 15, and 16 of each cycle.  During Cycle 1, the carfilzomib dose will be 
escalated after the Day 2 dose, if well tolerated. 
A maximum of four dose levels were evaluated.  No DLTs were seen during the Phase I 
portion. 
In the Phase II portion of this study, patients with relapsed/refractory multiple myeloma 
will receive treatment with the dose level 4 panobinostat and carfilzomib combination.  
Patients will be reevaluated for response to treatment after each cycle (4 weeks).  
Patients with objective response or stable disease will continue treatment, with 
subsequent reevaluations every 4 weeks, until disease progression or unacceptable 
toxicity occurs.  
A parallel Phase I study will occur to evaluate a minimum of 3 patients and a maximum 
of 6 patients following a standard dose escalation design at additional dose levels  of 
the combination of carfilzomib and panobinostat (see Table 3).   
If additional dose levels  are found to be tolerable, then additional patients will be 
recruited into an expansion cohort which will be open at all sites - a maximum total of 36 
patients (including the ones recruited into the parallel Phase I study) will be treated at 
this dose level.  Sites will be notified about the expansion cohort and patients will enter 
in the dose level confirmed in their enrollment confirmation from SCRI Innovations. 
Up to 80 eligible patients will be treated in the Phase I/II study.  The treatment schema 
for the study is shown in Figure 2.    


 
  
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Figure 2 
 
Treatment Schema 
 
Relapsed/Refractory Multiple Myeloma Patient 
 
 
 
 
  
ENROLLED 
Phase I  
N = 24 
Panobinostat     PO TBD TIW Days 1, 3, 5, 15, 17 and 19      
Carfilzomib   IV TBD Days 1, 2 escalating on Days 8, 9, 15, & 16   
Dose to be determined 
Treatment cycles will be repeated every 28 days 
Once the MTD has been determined, up to 30 patients with refractory/relapsed 
multiple myeloma may enroll in the Phase II portion. 
Continue until tumor progression, or until unacceptable toxicity 
occurs.  
FOLLOW- 
UP 
Phase II 
Panobinostat PO TBD Days 1, 3, 5, 15, 17 and 19      
Carfilzomib IV TBD Days 1, 2 escalating on Days 8, 9, 15, and 16   
Treatment cycles will be repeated every 28 days 
 
Restaging:  patients will be restaged every treatment cycle (every 
4 weeks).  Patients with disease progression or unacceptable toxicity will be 
discontinued from the study. 


 
  
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5.1. Treatment Plan 
Panobinostat and carfilzomib will be administered in the Phase I and Phase II portions 
of this trial as follows: 
5.1.1. Panobinostat 
 
PO TIW during weeks 1 and 3 of each 28-day cycle (i.e. D1, 3, 5, 15, 17, 19)   
Dose levels are defined in Table 2. 
Panobinostat will be self-administered (by the patient).  Patients should be instructed to 
take their once-a-day oral dose of panobinostat at the same time of each scheduled 
treatment day.  Panobinostat should be taken with a glass of water; the entire dose 
should be taken over as short a time as possible.  Patients should swallow the capsules 
as a whole and should not chew them.  Patients must avoid grapefruit or grapefruit juice 
and Seville (sour) oranges during the entire study. 
If the patient forgets to take his/her dose, the patient may be instructed to take the dose 
up to 12 hours after the usual time.  If more than 12 hours have passed, then the dose 
should be withheld that day.  The patient should be instructed to wait until the next 
scheduled dose.  If vomiting occurs, no attempt should be made to replace the vomited 
dose.  No missed doses should be made-up.   
5.1.1.1. Panobinostat Administration – Electrolyte Monitoring and Cardiac 
Precautions 
Electrolyte Monitoring 
All patients must have an assessment of serum potassium, magnesium, and calcium 
(total corrected for albumin, or ionized calcium) ≤72 hours prior to the administration of 
oral panobinostat on Day 1 of Cycle 1 and the results must all be ≥LLN before the first 
dose of panobinostat is administered. Throughout the study serum biochemistry values 
including serum potassium, calcium, phosphorus and magnesium will be monitored 
closely. Whenever serum potassium, calcium, phosphorus and magnesium are 
assessed, if the value is <LLN, then the patient’s potassium, calcium, phosphorus or 
magnesium should be immediately supplemented following the availability of that 
laboratory result, in order to minimize the time patients have low values. Patients must 
then undergo a repeat biochemistry test to demonstrate values ≥LLN. These values 
must be ≥ LLN before the patient is re-dosed with oral panobinostat. 
Patients must be instructed to not take panobinostat if their most recent biochemistry 
values demonstrate potassium, calcium, phosphorus or magnesium <LLN. At a 
minimum, potassium, magnesium, phosphorus and calcium will be checked according 
to the protocol. More frequent testing should be done if clinically indicated (e.g. patient 


 
  
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has had prior low values; patient is taking medications that can result in lowering of their 
potassium, magnesium, phosphorus or calcium levels.  
 
ECG QTcF Monitoring 
Because of the observed QTc prolongation in several patients receiving panobinostat, 
to be eligible for this trial, the patient must have a mean QTc interval ≤450 at baseline.  
During Cycle 1 of panobinostat, ECG’s will be monitored intensively (see Table 1).  Prior 
to C1D1 and C1D5 dosing of panobinostat, all patients will have 3 12-lead ECGs, 
separated by 5-10 minutes.  Triplicate ECGs, separated by 5-10 minutes, will be 
repeated approximately 3 hours after panobinostat dosing on C1D1 and C1C5.  See 
Section 6.2.1. for additional ECG monitoring guidelines.  Refer to Table 6 for 
management of prolonged QTc interval. 
Beginning Cycle 2, patients will have a single ECG prior to the Day 1 panobinostat dose 
(assuming no QTc prolongation occurred during Cycle 1).  
 
Table 1. ECG QTcF Monitoring 
CYCLE 
DAY 
ECG(s) Time Point 
Baseline 
  
 
 Pre-Treatment 
Single ECG  to Assess Eligibility 
Cycle 1 
 
Day 1  
(day of first study drug administration) 
Pre-Dose:  3 ECGs 
(Sequential ECGs, separated by 5-10 
minutes) 
 
Post-Dose:  3 ECGs 
3 hours (± ½ hour) after dosing 
(Sequential ECGs, separated by 5-10 
minutes)  
Day 5 
Pre-Dose:  3 ECGs 
(Sequential ECGs, separated by 5-10 
minutes) 
 
Post-Dose:  3 ECGs 
3 hours (± ½ hour) after dosing 
(Sequential ECGs, separated by 5-10 
minutes)  
Cycle 2 and  
beyond 
 
 
Day 1 
    
Pre-Dose:  Single ECG 


 
  
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If the patient experiences QTcF >480 msec in cycle 1 or in any subsequent cycle, then 
repeat the monitoring schedule until they have a cycle with no QTc prolongation. 
If no significant QTcF prolongation is noted during the first 8 cycles, the QTc monitoring 
is no longer required and may be performed at the Investigator’s discretion. 
5.1.2. Carfilzomib  
Cycle 1:   
 
 
TBD mg/m2 IV Day 1, 2 then TBD mg/m2 IV Day 8, 9, 15, 16    
Cycle 2 and Beyond: 
TBD mg/m2 IV Day 1, 2, 8, 9, 15, and 16 
Carfilzomib will be administered over 30 minutes (see Section 6.4).   Dose levels to be 
tested are defined in Table 2.  
Treatment cycles will be repeated every 28 days.  Patients will be evaluated for 
response to treatment every 4 weeks (i.e. after every cycle).    Patients with stable 
disease or better may continue on study treatment until evidence of disease 
progression.   
Hydration and Fluid Monitoring 
Oral hydration - All patients must be well hydrated (i.e., volume replete).  Begin oral 
hydration equal to approximately 30 mL/kg/day (~6–8 cups of liquid per day), starting 
48 hours prior to the planned first dose of carfilzomib.  Compliance must be reviewed 
with the patient and documented by the site personnel prior to initiating treatment with 
carfilzomib; treatment is to be delayed or withheld if oral hydration is not deemed to be 
satisfactory.   
Intravenous Fluids - 250–500 mL of IV normal saline (or other appropriate IV fluid 
formulation) must be given before and after each carfilzomib dose during Cycle 1.  If 
lactate dehydrogenase (LDH) or uric acid is elevated at Cycle 2, Day 1, then the 
recommended IV hydration should be repeated for Cycle 2 and all subsequent cycles 
until progression disease at the study doctor’s discretion to monitor TLS.  The goal of 
the hydration program is to maintain robust urine output, (e.g., ≥ 2 L/day).  Patients 
should be monitored periodically during this period for evidence of fluid overload.   
In patients considered to remain at risk for tumor lysis syndrome at completion of 
Cycle 1, hydration should be continued into Cycle 2.  Patients in whom this program of 
oral and IV fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, 
cardiac, or renal impairment, will not be eligible to participate in the clinical trial. 
5.1.2.1. Carfilzomib Safety Considerations 
Based on previous Phase I and II carfilzomib studies, the following observations have 
been noted: 
 A “first dose effect” has been seen, which is notable for fever, chills, rigors, and/or 
dyspnea occurring during the evening following the first day of infusion and an 


 
  
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increase in creatinine on Day 2, which may be the clinical sequelae of rapid tumor 
lysis and/or cytokine release.    
 Should a “first dose” effect occur at any point during Cycle 1 or 2, treatment with 
high dose glucocorticoids (e.g. methylprednisolone 50–100 mg) is recommended.  In 
addition, intravenous fluids, vasopressors, oxygen, bronchodilators, and 
acetaminophen should be available for immediate use and instituted, as medically 
indicated.  
 Dexamethasone 4 mg PO/IV will be administered prior to all carfilzomib doses 
during the first cycle and prior to all carfilzomib doses during the first dose-escalation 
(for example from 20 mg/m2 to 27 mg/m2) cycle.  If treatment-related fever, rigors, 
chills, and/or dyspnea are observed post any dose of carfilzomib after 
dexamethasone has been discontinued, dexamethasone (4 mg PO/IV) should be re-
started and administered prior to subsequent doses.  
 Patients should receive acyclovir or similar (famiciclovir, valacyclovir) anti-varicella 
(anti-herpes) agent prophylaxis.  In addition, patients may receive antibiotic 
prophylaxis with ciprofloxacin or other fluoroquinolone (or 
timethroprim/sulfamethoxazole if fluoroquinoles are contradicted) if clinically 
indicated.    
 CrCl changes are mostly transient, reversible, and non-cumulative. All patients 
should be well hydrated.  Clinically significant electrolyte abnormalities should be 
corrected prior to dosing with carfilzomib.  Renal function must be monitored closely 
during treatment with carfilzomib.  Serum chemistry values, including creatinine, are 
strongly encouraged prior to each dose of carfilzomib during Cycles 1 and 2.  The 
decision will be at the discretion of the treating physician.  Carfilzomib must be held 
for subjects with a CrCl < 15 mL/min at any time during study participation. 
5.1.3. Window for Holidays and Vacations 
For holidays and vacations it is preferred to plan ahead and adjust D1 of treatment +/- 
48 hours of the cycle the patient plans to be gone for treatment, so that the patient 
follows the treatment schedule per protocol.  If it is not possible to adjust D1, the 
carfilzomib infusion days may be adjusted +/- 48 hours after cycle 1 for a holiday or 
vacation.  There is no window allowed during cycle 1 and for the panobinostat doses 
except for D1 with the window described above. 
5.2. Phase I 
The Phase I doses to be tested are defined in Table 2.  
 Table 2. 
Phase I Dose Levels  
28-Day Cycles 
Cycle 1   
Cycle 2 to Progression   
Dose Level  -1 


 
  
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Carfilzomib 
 15 mg/m2 IV D1, 2  /20 mg/m2 IV D8, 9, 15, 16 
  20 mg/m2 IV D 1, 2, 8, 9, 15, 16 
Panobinostat 
  20 mg D 1, 3, 5, 15, 17, 19 
  20 mg D 1, 3, 5, 15, 17, 19 
Dose Level  1 
Carfilzomib 
20 mg/m2 IV D1, 2  / 27 mg/m2 IV D8, 9, 15, 16 
27 mg/m2 IV D 1, 2, 8, 9, 15, 16 
Panobinostat 
20 mg D 1, 3, 5, 15, 17, 19 
20 mg D 1, 3, 5, 15, 17, 19 
Dose Level  2 
Carfilzomib 
20 mg/m2 IV D1, 2 / 36 mg/m2 IV D8 ,9, 15, 16 
36 mg/m2 IV D 1, 2, 8, 9, 15, 16 
Panobinostat 
20 mg D 1, 3, 5, 15, 17, 19 
20 mg D 1, 3 ,5, 15, 17, 19 
Dose Level  3 
Carfilzomib 
20 mg/m2 IV D 1, 2 / 45 mg/m2 IV D8, 9, 15, 16 
  45 mg/m2 IV D 1 ,2, 8 ,9, 15, 16 
Panobinostat 
 20 mg D 1, 3, 5, 15, 17, 19 
  20 mg D 1, 3, 5, 15, 17, 19 
Dose Level   4 
Carfilzomib 
20 mg/m2 IV D 1, 2 / 45 mg/m2 IV D8, 9, 15, 16 
 45 mg/m2 IV D 1 ,2, 8 ,9, 15, 16 
Panobinostat 
30 mg D 1, 3, 5, 15, 17, 19 
 30 mg D 1, 3, 5, 15, 17, 19 
 
Table 3. 
Parallel Dose Escalation Study – Dose Levels 5 and 6 
28-Day Cycles 
Cycle 1   
Cycle 2 to Progression   
Dose Level   5 
Carfilzomib 
20 mg/m2 IV D 1, 2 / 56 mg/m2 IV D 8, 9, 15, 16 
 56 mg/m2 IV D 1 ,2, 8 ,9, 15, 16 
Panobinostat 
30 mg D 1, 3, 5, 15, 17, 19 
 30 mg D 1, 3, 5, 15, 17, 19 
Dose Level   6 
Carfilzomib 
20 mg/m2 IV D 1, 2 / 56 mg/m2 IV D 8, 9, 15, 16 
 56 mg/m2 IV D 1 ,2, 8 ,9, 15, 16 
Panobinostat 
20 mg D 1, 3, 5, 15, 17, 19 
 20 mg D 1, 3, 5, 15, 17, 19 
A parallel Phase I study will occur to evaluate a minimum of 3 patients and a maximum 
of 6 patients following a standard dose escalation design at additional dose levels of the 
combination of carfilzomib and panobinostat.   
Patients will enter in the dose level confirmed in their enrollment confirmation from SCRI 
Innovations. 
5.2.1. Dose Escalation Phase I   
The study will follow a standard dose-escalation design (see Table 2).  For each cohort, 
the decision whether to dose-escalate will be made once all subjects have been 


 
  
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enrolled into the cohort and have received one full cycle (28 days) of study drug 
treatment.  The following dose-escalation rules will be used: 
 Initially, 3 subjects will be entered into a dose level. 
 If 2 or more of the initial subjects experience dose-limiting toxicity 
(DLT) (see Section 5.2.2), then the MTD (see Section 5.2.3) has been 
exceeded. 
 If none of the 3 subjects initially enrolled into this dose level cohort 
experiences DLT, then subsequent subjects will be enrolled in the next 
higher dose level. 
 If 1 of the initial subjects experiences DLT, then 3 additional subjects 
(to a total of 6 subjects) will be enrolled in the dose level. 
 If it is found that 1 of the 6 subjects in the dose level encounters DLT, 
then subsequent subjects will be enrolled into the next higher dose 
level cohort. 
 If it is found that 2 or more of the 6 subjects in a dose level encounter 
DLT, then the MTD has been exceeded.  If ≥2 of 6 patients have DLT 
on the first dose level tested (Dose Level 1, Table 2), dose level -1 will 
be evaluated.  If dose level -1 is too toxic (≥2 of 6 patients with DLT), 
the study will continue only after discussion by the study chair and the 
sponsors. 
No intra-patient dose escalation is permitted. 
 
When the MTD has been exceeded: 
When the MTD has been exceeded, the next lower dose previously studied will be 
evaluated for the MTD criteria.  If only 3 subjects have been treated at this dose level, 
3 additional subjects will be entered into this dose level until 6 subjects total have been 
treated. 
 Once 6 subjects have been enrolled and evaluated at this dose level, if 
there was ≤1 DLT, this dose level will be declared the MTD. 
 If >1 DLT occurred, then the MTD has been exceeded, and the next 
lower dose level will be similarly evaluated. 
 Dose level -1 will only be tested if dose level 1 exceeds MTD.  
 


 
  
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5.2.2. Definitions of Dose-Limiting Toxicity (DLT) 
For the purpose of determining the MTD (see Section 5.2.3), DLT is defined as 
any of the following that are determined to be related to study treatment during 
Cycle 1:    
 Grade 4 neutropenia (absolute neutrophil count [ANC] <500/µL) for 
>7 days. 
 Febrile neutropenia (ANC <1000/ µL with fever >101°F [38.5°C]). 
 Grade 3 thrombocytopenia with ≥ Grade 2 bleeding. 
 Grade 4 thrombocytopenia (platelets <25,000/µL) > 7 days (patients 
may receive platelet support/transfusion). 
 ≥ Grade 2 neuropathy with uncontrolled pain 
 ≥ Grade 3 non-hematologic drug-related toxicity (excluding alopecia) 
despite optimal supportive care lasting >72 hours or requiring a dose 
reduction in the first cycle. 
 Patients who are unable to receive 75% of the required doses of both 
agents secondary to toxicity. 
 
Adverse events will be graded using the National Cancer Institute (NCI) Common 
Toxicity Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). 
Dose modifications are not permitted during Cycle 1 in any cohort unless the subject 
experiences a DLT.  Subjects in dose level -1 (see Table 2) who develop a DLT during 
Cycle 1 will be discontinued from the study.  Subjects in dose level 1 or higher who 
experience a DLT during Cycle 1 will have treatment held.  The DLT will be counted 
toward the assessment of the MTD for the given cohort; however, the subject may 
continue on therapy if the toxicity resolves and dose modifications can be implemented 
according to the dose modification guidelines in Section 6.0. 
Patients who withdraw from the study before receiving 75% of their scheduled 
Cycle 1 doses due a non-drug related AE (i.e., tumor progression) will be considered 
inevaluable and will be replaced.    
Patients without clinical evidence of progressive disease at the end of the first cycle of 
study therapy will continue treatment.  Patients will be reevaluated for response after 
completing 2 cycles (8 weeks) of treatment.  Patients with objective response or stable 
disease according the International Myeloma Working Group Uniform Response Criteria 
(see Appendix C) will continue treatment, with reevaluations until disease progression 
occurs, unacceptable toxicity develops, or the subject chooses to discontinue study 
treatment.  


 
  
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5.2.3. Definition of Maximum Tolerated Dose (MTD) 
The MTD of carfilzomib and panobinostat when given as a combination therapy will be 
defined as the highest dose level at which ≤1 of 6 subjects experiences dose-limiting 
toxicity (DLT). 
When the MTD has been determined: 
When the MTD has been determined, the trial will continue to enroll patients with 
relapsed/refractory multiple myeloma at the established MTD established during the 
Phase I portion.   
5.3. Phase II 
If a dose level in the parallel Phase I study is found to be tolerable, then additional 
patients will be recruited  into an expansion cohort of 30 patients for Phase II for a total 
of 60 Phase II patients (including 30 patients for dose level 4)..  A maximum of up to 80 
total patients may be enrolled in this study (including patients from the dose escalation 
Phase I studies).  
5.4. Concomitant Medications 
Patients must be instructed not to take any additional medications (including over-the-
counter products) during the trial without prior consultation with the study physician.  All 
medications taken within 30 days of screening should be noted. If concomitant therapy 
must be added or changed, the reason and name of the drug/therapy should be 
recorded. 
In general, the use of any concomitant medication/therapies deemed necessary for the 
care of the patient are allowed, including drugs given prophylactically (e.g. antiemetics) 
with the following exceptions: 
 Any medications which may cause QTc prolongation or induce Torsades 
de Pointes should not be used (see Appendix F).  Dolasetron is 
contraindicated while on treatment with Panobinostat. 
 Any medications that have the potential to alter serum electrolytes 
(e.g. diuretics) should be monitored very closely for electrolyte 
abnormalities as these can contribute to the risk of QTc prolongation and 
vent. 
 No other investigational therapy should be given to patients. 
 Allopurinol (in subjects at risk for TLS due to high tumor burden) is optional 
and will be prescribed at the study physician’s discretion.  These  patients 
may receive allopurinol 300 mg PO BID (Cycle 1 Day -2, Day -1), 
continuing for 2 days after Cycle 1 Day 1 (total of 4 days), then reduce 
dose to 300 mg PO QD, continuing through Day 17 of Cycle 1.  Allopurinol 
dose should be adjusted according to the package insert.    


 
  
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 No anticancer agents other than the study medications administered as 
part of this study protocol should be given to patients. If such agents are 
required for a patient then the patient must first be withdrawn from the 
study. 
 Leukocyte growth factors (e.g. G-CSF and GM-CSF) are not to be 
administered prophylactically but may be prescribed by the study physician 
for severe neutropenia if this is thought to be appropriate.  
 Medications known to be substrates of the isoenzyme CYP2D6 should be 
avoided if possible, as panobinostat can inhibit isoenzyme CYP2D6 at low 
micromolar ranges (see Appendix G).  
 Medications, food, and herbal preparations known to be strong inducers or 
inhibitors of CYP34A should be avoided if possible (see Appendix G). 
6. 
DOSE MODIFICATIONS 
The criteria for interruption and resumption of treatment due to toxicity are outlined in 
the following tables. Dose re-escalation will not be allowed in any patient.  All toxicities 
will be graded utilizing the NCI CTCAE v4.0.  If toxicity occurs, the toxicity will be 
graded, and appropriate supportive care treatment will be administered to decrease the 
signs and symptoms thereof.  If one drug is held, treatment may continue with the other 
study drug as appropriate.  If study medication is held for over 3 weeks due to toxicity, 
that study medication will be discontinued.  Treatment medications will be adjusted with 
a one level dose-reduction.  The dose level criteria in Table 3 should be used to adjust 
the panobinostat or carfilzomib dose in the event of toxicity. If patients who are on the 
lowest allowable dose have a toxicity requiring dose reduction, the offending agent 
should be discontinued.  Either or both drugs may be adjusted according to the dose 
modification tables below. 


 
  
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Table 4. Panobinostat and Carfilzomib Dose Level Modifications 
 
Panobinostat PO 
 
Carfilzomib IV 
15 mg 
20 mg 
30 mg 
 
15 mg/m2 
20 mg/m2 
27 mg/m2 
36 mg/m2 
45 mg/m2 
56 mg/m2 
6.1. Dose Modifications for Hematologic Toxicity  
Panobinostat and carfilzomib have been associated with hematologic toxicity.  Blood 
counts will be measured on Days 1, 8, and 15 of each cycle, and dose modifications will 
be based on these blood counts.  Dose reductions, when necessary, are outlined in 
Table 5.  If toxicity occurs when the patient is already on the lowest acceptable dose, 
the drug should be discontinued. 
Table 5. Panobinostat and Carfilzomib Dose Adjustments for Hematologic 
Toxicities 
AE Term and 
Description 
Dose Modification 
 
Panobinostat 
Carfilzomib 
 THROMBOCYTOPENIA 
Grade 1 or  2 
Maintain dosing; monitor as clinically 
indicated. 
Maintain dosing; monitor as clinically 
indicated. 
Grade 3  
(25 - 50 x 109/L) 
 
1. Interrupt study treatment until toxicity 
reduced to ≤ grade 2a.   
2. Restart treatment with a 1 level dose-
reduction (Table 3). 
1. Interrupt study treatment until toxicity 
reduced to ≤ grade 2a.   
2. If improves in ≤ 7 days, maintain 
same dose, if > 7 days reduce dose 1 
level. 
Grade 4 (<25 x 109/L) 
1. 
Interrupt study treatment until toxicity 
reduced to ≤ grade 2a.   
2. 
Restart treatment with a 1 level dose-
reduction. 
1. Interrupt study treatment until toxicity 
reduced to ≤ grade 2a.  
2. Restart treatment with a 1 level dose-
reduction. 
Recurrent Grade 3/4 
Event After Initial Dose 
Reduction 
1. 
Interrupt study treatment until toxicity 
reduced to ≤ grade 2a.   
2. 
Restart treatment with a second 1 
level dose-reduction. 
1. Interrupt study treatment until toxicity 
reduced to ≤ grade 2a.  
2. Restart treatment with a second 1 
level dose-reduction. 
Recurrent Grade 3/4 
Event After 2 Dose 
Reductions   
Discontinue 
Discontinue 


 
  
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Table 5. 
Panobinostat and Carfilzomib Dose Adjustments for Hematologic 
Toxicities (continuation) 
 
AE Term and 
Description 
Dose Modification 
 
Panobinostat 
Carfilzomib 
NEUTROPENIA 
Grade 1 or  2 
 
Maintain dosing; monitor as clinically 
indicated. 
Maintain dosing; monitor as clinically 
indicated. 
Grade 3  
(0.5 x 109/L ≤ ANC 
1.0 x 109/L) 
1. Interrupt study treatment until 
toxicity reduced to ≤ grade 2a.   
2. Restart treatment with a 1 level 
dose-reduction (Table 3). 
1. Interrupt study treatment until 
toxicity reduced to ≤ grade 2a.   
2. If improves in ≤ 7 days, maintain 
same dose, if >7 days reduce 
dose 1 level. 
Grade 4   
(ANC <0.5 x 109/L) 
1. Interrupt study treatment until 
toxicity reduced to ≤ grade 2a.   
2. Restart treatment with a 1 level 
dose-reduction. 
1. Interrupt study treatment until 
toxicity reduced to ≤ grade 2a.   
2. Restart treatment with a 1 level 
dose-reduction. 
Recurrent Grade 3/4 
Event After Initial Dose 
Reduction 
1. Interrupt study treatment until 
toxicity reduced to ≤ grade 2a.   
2. Restart treatment with a 1 level 
dose-reduction. 
1. Interrupt study treatment until 
toxicity reduced to ≤ grade 2a.   
2. Restart treatment with a 1 level 
dose-reduction. 
Recurrent Grade 3/4 
Event After 2 Dose 
Reductions   
Discontinue 
Interrupt until toxicity ≤ grade 2a and  
restart treatment with a 1 level dose-
reduction if possible, or discontinue. 
FEBRILE NEUTROPENIA 
Grade 3   ANC 1.0 x 
109/L, fever ≥38.5°C 
 
1. Interrupt study treatment until 
ANC recovery to ≤ grade 2a (ANC 
≥ 1.0 x 109/L) and resolution of 
fever <38.5°C.  
2. Restart treatment with a 1 level 
dose-reduction. 
1.  Interrupt study treatment until 
ANC recovery to ≤ grade 2a 
(ANC ≥ 1.0 x 109/L) and 
resolution of fever <38.5°C.  
2. Restart treatment with a 1 level 
dose-reduction. 
Grade 4    ANC 1.0 x 
109/L, fever ≥38.5°C and 
life-threatening 
consequences 
 Discontinue 
1.  Interrupt study treatment until 
ANC recovery to ≤ grade 2a 
(ANC ≥ 1.0 x 109/L) and 
resolution of fever <38.5°C and 
any complications.  
2. Restart treatment with a 1 level 
dose-reduction. 
a Repeat labs weekly until recovery. 
 
The criteria for adjusting the dose of panobinostat in the event of non-hematologic 
toxicities are detailed in Table 6. 
  


 
  
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Table 6. Panobinostat Dose Adjustments for Non-Hematologic Toxicities 
AE Term and Description 
Panobinostat Dose Modification 
RENAL  
Serum Creatinine 
Serum creatinine  2 x ULN 
Maintain dosing. 
Serum creatinine 2-3 X ULN 
 
1. Interrupt panobinostat until toxicity resolved to ≤ 1.5 X ULN. 
2. Restart treatment with a 1 level dose-reduction (Table 3). 
Serum creatinine (>3 X ULN) 
Grade  3 or 4 
Discontinue panobinostat 
Recurrent Event After Initial 
Dose Reduction 
1. Interrupt panobinostat until toxicity ≤ 1.5 X ULN. 
2. Restart treatment with a second 1 level dose-reduction.  
Recurrent Event After 2 
Dose Reductions   
Discontinue panobinostat 
 
HEPATIC 
Total Bilirubin 
Total bilirubin  2 x ULN 
Maintain dosing. 
Total bilirubin 2-3 X ULN 
 
1. Interrupt panobinostat until toxicity resolved to ≤ 1.5 X ULN. 
2. Restart treatment with a 1 level dose-reduction (Table 3). 
Total bilirubin (>3 X ULN) 
Grade  3 or 4 
Discontinue panobinostat 
Recurrent Event After Initial 
Dose Reduction 
1. Interrupt panobinostat until toxicity ≤ 1.5 X ULN. 
2. Restart treatment with a second 1 level dose-reduction.  
Recurrent Event After 2 
Dose Reductions   
Discontinue panobinostat 
 
AST/SGOT, ALT/SGPT 
AST/SGOT, ALT/SGPT 
≤5 x ULN (Grade 1 or  2) 
Maintain dosing. 
AST/SGOT, ALT/SGPT  
>5 - 10 x ULN 
 
1. Interrupt panobinostat until toxicity resolved to ≤ grade 1 (or 
baseline). 
2. Restart treatment with a 1 level dose-reduction (Table 3). 
Total bilirubin (>3 X ULN) 
Grade  3 or 4 
Discontinue panobinostat 
Recurrent Event After Initial 
Dose Reduction 
1. Interrupt panobinostat until toxicity resolved to ≤ grade 1 (or 
baseline). 
2. Restart treatment with a second 1 level dose-reduction.  
Recurrent Event After 2 
Dose Reductions   
Discontinue panobinostat 
 


 
  
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Table 6. Panobinostat Dose Adjustments for Non-Hematologic Toxicites 
(continuation) 
AE Term and Description 
Panobinostat Dose Modification 
GASTROINTESTINAL 
Diarrhea1 
Grade 1 
Maintain dosing. 
Grade 2 or Grade 32 
(Despite anti-diarrheal therapy) 
 
1. Interrupt panobinostat until toxicity resolved to ≤ grade 1.  
2. Restart treatment with a 1 level dose-reduction (Table 3). 
Grade 4 
Discontinue panobinostat 
Recurrent Event After Initial 
Dose Reduction 
1. Interrupt panobinostat until toxicity resolved to ≤ grade 1. 
2. Restart treatment with a second 1 level dose-reduction.  
Recurrent Event After 2 
Dose Reductions   
Discontinue panobinostat 
 
Vomiting 
 Grade 1 
Maintain dosing. 
Grade 2 or Grade 32 
(Despite anti-nausea therapy) 
 
1. Interrupt panobinostat until toxicity resolved to ≤ grade 1.   
2. Restart treatment with a 1 level dose-reduction (Table 3). 
 Grade 4 
Discontinue panobinostat 
Recurrent Event After Initial 
Dose Reduction 
1. Interrupt panobinostat until toxicity resolved to ≤ grade 1.    
2. Restart treatment with a second 1 level dose-reduction.  
Recurrent Event After 2 
Dose Reductions   
Discontinue panobinostat 
 
Fatigue 
Grade 4 
1. Interrupt panobinostat until toxicity resolved to ≤ grade 2 or baseline. 
2. If resolved in 7 days after interruption of panobinostat, then restart 
panobinostat at an unchanged dose level.   
3. If resolved in more than 7 days after interruption of panobinostat, 
then restart panobinostat with a 1 level dose-reduction. 
Other Non-Hematologic Toxicity 
Grade 3 
 
1. Interrupt panobinostat until toxicity resolved to ≤ grade 1 or baseline.   
2. Restart treatment with a 1 level dose-reduction (Table 3). 
Grade 4 
Discontinue panobinostat 
 
Recurrent Event After Initial 
Dose Reduction 
1. Interrupt panobinostat until toxicity resolved to ≤ grade 1.   
2. Restart treatment with a second 1 level dose-reduction. 
Recurrent Event After 2 
Dose Reductions   
Discontinue panobinostat 
 


 
  
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Table 6. Panobinostat Dose Adjustments for Non-Hematologic Toxicites 
(continuation) 
Each patient is allowed a maximum of 2 dose reductions (Table 3). No patient will receive less than 15 
mg three times weekly. If toxicity recurs at this dose level, panobinostat will be discontinued. 
Patients with grade 4 adverse event should be discontinued from further treatment with study drug.   
* Common Terminology Criteria for Adverse Events (CTCAE Version 4.0) 
1 Patients should be instructed to contact their physician at the onset of diarrhea.  Each patient should be 
instructed to have loperamide readily available and to begin treatment for diarrhea at the first episode of 
poorly formed or loose stools or the earliest onset of bowel movements more frequent than normally 
expected for the patient.  Loperamide 4 mg should be taken at the first loose stool or more frequent than 
usual bowel movements, followed by 2 mg as needed, no more frequently than every 4 hours not to 
exceed a total of 16 mg in 24 hours.  Patients with diarrhea grade 2 despite this loperamide regimen 
should interrupt treatment with panobinostat as described in the table.  If the above regimen is 
inadequate then additional evaluation and treatment should be pursued as medically indicated.   
Premedication with loperamide is not recommended. 
The use of drugs with laxative properties should be avoided because of the potential for exacerbation of 
diarrhea. Patients should be advised to contact their physician to discuss any laxative use.  Patients 
should be instructed to contact their physician at the onset of diarrhea. 
If severe diarrhea (grade 3 and 4) happens, patient should be admitted into the hospital. Replace IV 
fluids and electrolytes as appropriate. Treatment should follow institutional standard of care or local 
guidelines. 
2If patient has two grade 3 diarrhea events or vomiting episodes with or without prophylaxis medications, 
the patient may be discontinued from study drug rather than attempting dose reductions at the discretion 
of the investigator. 
 
6.2. Panobinostat Dose Modifications for Prolonged QTc Interval 
All cardiac events should be treated according to institutional standards and referred to 
a specialist if clinically indicated.  Treatment decisions at the sites will be based on QTc 
as determined by the automated machine reading (or as measured and calculated by 
trained personnel at the site). If a patient cannot be dosed due to prolonged QTcF for 
more than 7 days since last dose, patient should be discontinued from study.


 
  
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Table 7: Criteria for Dose Reductions, Delays and/or Re-Institution Due to Drug-
Related QTcF Abnormalities  
 
ECG TIME POINT  
ABNORMALITY 
DOSE MODIFICATION GUIDELINE 
Dose modifications are based on local readings of the average QTcF of triplicate ECGs. 
Cycle 1 Dose Modification Criteria: 
Cycle 1 PRE-DOSE  
Days 1 and 5 
Triplicate ECGs 
Day 1: 
Average QTcF:  
>450 msec 
 
 
 
 
 
Day 5: 
Average QTcF: 
≥480 msec to 
<500 msec 
Or  
>60 msec increase 
from baseline 
average 
 
 
Check and correct the patient’s serum potassium, 
magnesium, calcium, phosphorus immediately, as 
well as evaluate concomitant medications. 
If abnormality noted on Cycle 1 Day 1: 
Repeat 3 pre-dose ECGs. 
If the 3 pre-ECGs:  
Do not meet criteria again, discontinue patient from 
study.  
Do meet criteria for dosing; administer panobinostat. 
If abnormality noted on Cycle 1 Day 5: 
Delay dose at least 3 days and repeat 3 pre-dose 
ECGs. 
If the repeat 3 pre-dose ECGs: 
Do not meet pre-dose ECG criteria again, discontinue 
panobinostat. 
Do meet pre-dose ECG criteria for dosing and QTc 
prolongation determined to be related to panobinostat, 
resume panobinostat treatment with a 1-level dose 
reduction.   If however, it was determined that the QTc 
prolongation was secondary to electrolyte 
abnormalities or concomitant medications, continue at 
the same dose level.  Repeat ECGs – pre-dose (x3), 
3-hours post-dose (x3), on the next scheduled dosing 
day. 
Average QTcF: 
≥500 msec 
Check and correct the patient’s serum potassium, 
magnesium, calcium and phosphorus immediately. 
Discontinue patient from panobinostat. 
If however, it was determined that the QTc 
prolongation was secondary to electrolyte 
abnormalities or concomitant medications: 
Omit dose. On the next scheduled dosing day 
continue at the same dose level. Repeat ECGs - pre-
dose (x3), 3-hours post-dose (x3), on the next 
scheduled dosing day. 


 
  
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Table 7. Criteria for Dose Reductions, Delays, Re-Institution Due to Drug 
Related QTcF Abnormalities (continuation) 
6.2.1. General Monitoring Principles 
ECG TIME POINT  
ABNORMALITY 
DOSE MODIFICATION GUIDELINE 
Dose modifications are based on local readings of the average QTcF of triplicate ECGs. 
Cycle 1 Dose Modification Criteria:   
Cycle 1 POST-DOSE    
Days 1 and 5 
Triplicate ECGs  
Average QTcF: 
≥480 msec to 
<500 msec 
Or  
>60 msec increase 
from baseline 
average 
 
Check and correct the patient’s serum potassium, 
magnesium, calcium, phosphorus immediately, as 
well as evaluate concomitant medications. 
Monitor ECG hourly or by telemetry until at least 2 
consecutive hourly ECGs performed at least 6 hours 
post dose are <480. 
Next scheduled dosing day: repeat 3 pre-dose ECGs. 
If these 3 pre-dose ECGs: 
Do not meet pre-dose ECG criteria for dosing 
(average QTcF ≥480 msec), discontinue patient from 
study. 
Do meet pre-dose ECG criteria for dosing (average 
QTcF <480 msec) and QTc prolongation determined 
to be related to panobinostat, resume panobinostat 
treatment with a 1-level dose reduction.  If however, it 
was determined that the QTc prolongation was 
secondary to electrolyte abnormalities or concomitant 
medications, continue at the same dose level. Repeat 
ECGs - pre-dose (x3), 3-hours post-dose (x3) on the 
next scheduled dosing day. 
 
Average QTcF: 
 ≥ 500 msec 
Check and correct the patient’s serum potassium, 
magnesium, calcium and phosphorus immediately. 
Discontinue patient from panobinostat. 
If however, it was determined that the QTc 
prolongation was secondary to electrolyte 
abnormalities or concomitant medications: omit dose. 
On the next scheduled dosing day continue at the 
same dose level. Repeat ECGs - pre-dose (x3), 3-
hours post-dose (x3), on the next scheduled dosing 
day. 


 
  
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6.2.1. General Monitoring Principles 
The following cardiac monitoring guidelines are required for this study: 
1. Patients in screening will have a baseline ECG performed to determine eligibility. 
2. Enrolled patients will have ECGs collected as defined in Table 1.   
3. On treatment days when ECGs are to be obtained, the patient will take their 
medication in the clinic.  Prior to the first dose of panobinostat (Cycle 1, Day 1), the 
QTcF interval from each of the 3 ECGs  must be ≤450 msec and the average of the 
pretreatment QTc intervals must be ≤450 msec before the patient is dosed.  This 
real-time assessment will be based on the QTc intervals as determined at the clinical 
center.  
4. If the patient does not meet the QTc criteria for dosing,  the patient’s serum 
potassium, magnesium, calcium and phosphorus must be measured immediately, 
and the patient must receive supplements to correct any low values. 
5. If the patient experiences a QTcF >480 msec in Cycle 1 or in any subsequent cycle, 
the  Cycle 1 ECG monitoring schedule will be repeated until they have a treatment 
cycle with no QT prolongation. 
6. At any time, if any ECGs (baseline or post-dose) demonstrate a QTc value 
≥ 480 msec the Investigator must notify the Sponsor immediately.  In addition, the 
patient’s serum potassium, magnesium, calcium and phosphorus must be measured 
immediately, and the patient must receive supplements to correct any low values.   
7. All ECGs will be reviewed by the treating physician prior to administering the dose of 
panobinostat.    
8. In general, panobinostat dose reductions or discontinuations will occur in the 
following circumstances: 
 Repeat dosing delays due to prolonged QTc intervals 
 QTc ≥ 480 msec but < 500 msec (in absence of electrolyte abnormalities). 
 Any QTc ≥ 500 msec (discontinuation). 
For patients requiring a dose reduction, 3 pre-dose ECG’s will be done on the first 
day of the new lower dose, and 3-hours post-dose (x 3).    
If however, it was determined that the QTc prolongation was secondary to electrolyte 
abnormalities or concomitant medications, panobinostat may be continue at the 
same dose level.   ECGs will be repeated - pre-dose (x3), 3-hours post-dose (x3), on 
the next scheduled dosing day. 
9. Any QTc ≥ 500 msec will lead to discontinuation of the panobinostat. 
10. All other cardiac events should be treated as per the local standard of care and 
referred to a specialist by the investigator (if clinically indicated). 


 
  
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11. If no significant QTcF prolongation is noted during the first 8 cycles, the QT 
monitoring is no longer required and may be performed at the Investigator’s 
discretion. 
Any patient who has an ECG with a QTc  500 msec must be monitored very 
closely. Check and correct the patient’s serum potassium, magnesium, calcium, and 
phosphorus immediately.   
If any QTc interval is ≥500 msec, the patient must have at a minimum, hourly ECG 
monitoring until the QTc is <480 msec. In addition to the minimum hourly ECG 
monitoring, telemetry monitoring is strongly recommended. Prior to a patient with a QTc 
interval >500 msec being discharged to home, that patient must have at least 2 
consecutive, hourly ECGs obtained at least 6 hours after dosing that demonstrate a 
QTc interval of ≤480 msec. 
If any patient has a QTc interval ≥500 msec, the Investigator must notify the Sponsor 
immediately. The patient must not receive any further doses of panobinostat and must 
be discontinued from the study. 
6.3. Carfilzomib Dose Modifications for Non-Hematologic Toxicities 
Treatment with carfilzomib and panobinostat should be held for ≥ grade 3 events until 
resolved to ≤ grade 1 or return to baseline.  If the adverse event was not treatment-
related, or was attributable to panobinostat, subsequent treatment with carfilzomib may 
be resumed at full dose after resolution to ≤ grade 1 or return to baseline. 
If the event was carfilzomib-related, subsequent treatment with carfilzomib will resume 
at one level dose reduction (see Table 3).  If toxicity continues or recurs, a 2nd 
carfilzomib dose reduction is permitted unless the patient is already receiving the lowest 
dose level shown in Table 3.  If toxicity continues, the patient should be discontinued 
from treatment. 
If there is no resolution of carfilzomib-related toxicity after 2 weeks of withholding 
carfilzomib (up to 3 weeks for infection treatment), carfilzomib will be discontinued. 
Specific carfilzomib-associated non-hematologic toxicities are addressed in Table 7. 


 
  
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Table 8. Carfilzomib Dose Modifications for Non-Hematologic Toxicity 
Event  
Action to be Taken 
Allergic reaction/hypersensitivity 
Grade 2 – 3  
Grade 4 
Hold until ≤ Grade 1, reinstitute at full dose.  
Discontinue 
Tumor lysis syndrome  
(≥ 3 of following: ≥ 50% increase in creatinine, 
uric acid, or phosphate; ≥ 30% increase in 
potassium; ≥ 20% decrease in calcium; or 
≥ 2-fold increase in LDH 
 
Hold carfilzomib until all abnormalities in serum 
chemistries have resolved.  Reinstitute at full doses. 
Infection  
Grade 3 or 4 
Hold carfilzomib (no more than 3 weeks) until systemic 
treatment for infection complete.  If no neutropenia, 
restart at full dose.  If neutropenic, follow neutropenic 
instructions (Table 4). 
Herpes zoster or simplex of any grade 
Hold carfilzomib until lesions are dry. Reinstitute at full 
dose. 
Neuropathy 
Grade 2 treatment emergent neuropathy with 
pain or Grade 3 neuropathy 
 
Grade 4 neuropathy 
 
Continue to dose.  If neuropathy persists for more than 
two weeks hold carfilzomib until resolved to ≤ Grade 2 
without pain. Then restart at 1 dose decrement 
Discontinue carfilzomib 
Renal Dysfunction 
 
CrCl ≤ 30 mL/min 
 
 
 
Hold until CrCl > 30 mL/minute; restart at 1 dose 
decrement 
Congestive heart failure 
Any subject with symptomatic congestive heart failure, 
whether or not drug related, must have the dose held 
until resolution or return to baseline, after which 
treatment may continue at a reduced dose, or the 
subject may be withdrawn from the study.  If no 
resolution after 2 weeks, the subject will be withdrawn 
from the study. 
Hypertension 
All patients should be evaluated for hypertension and 
treated as needed.  If hypertension cannot be 
controlled, reduce carfilzomib. 
 


 
  
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Table 8 Carfilzomib Dose Modifications for Non-Hematologic Toxicity 
Event  
Action to be Taken 
Hypertensive crisis, 
or Pulmonary hypertension, 
or Pulmonary toxicity 
Stop carfilzomib until resolved or returned to baseline. 
Consider whether to restart carfilzomib based on a 
benefit/risk assessment. 
Other non-hematologic toxicity assessed as 
carfilzomib-related > Grade 3 
Hold dose until toxicity resolves to ≤ Grade 1 or 
baseline.  Restart at 1 dose decrement. 
 
6.4. Management of Carfilzomib-Related Events 
6.4.1.  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. 
6.4.2. 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.  


 
  
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Patients with New York Heart Association Class III and IV heart failure, myocardial 
infarction in the preceding 6 months, 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. 
6.4.3. Acute Renal Disorder 
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. 
6.4.4. 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. 
6.4.5. 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, and 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. 
6.4.6. 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. 


 
  
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6.4.7. 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. 
6.4.8. 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 standard of care including plasma 
exchange as clinically appropriate.  If the diagnosis of TTP/HUS is excluded, carfilzomib 
can be restarted.  The safety of reinitiating carfilzomib therapy in subjects previously 
experiencing TTP/HUS is not known.  
6.4.9. 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.  The 
safety of reinitiating carfilzomib therapy in subjects previously experiencing PRES is not 
known. 
7. 
STUDY ASSESSMENTS AND EVALUATIONS 
All patients should visit the study center on the days specified within this protocol.  The 
Schedule of Assessments for this trial is shown in Appendix E.    
7.1. Comprehensive Metabolic Profile (CMP) 
The following laboratory tests should be performed for each patient for assessment of 
CMP:   
 
glucose 
 
blood urea nitrogen (BUN) 
 
creatinine 
 
sodium 
 
potassium 
 
chloride 
 
calcium 


 
  
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 
carbon dioxide (CO2) 
 
alkaline phosphatase 
 
AST (SGOT) 
 
ALT (SGPT) 
 
total bilirubin 
 
total protein 
 
albumin 
plus 
 
magnesium 
 
phosphorus 
7.2. Baseline Assessment  
All patients must have the following assessments performed before receiving their first 
dose of protocol therapy (labs may be obtained up to 72 hours prior to treatment): 
 
Obtain Signed Consent Form 
 
Medical history 
 
Physical examination, including measurement of vital signs (blood 
pressure, height, pulse, and respiratory rate) and weight [BSA].  Height 
will be obtained only at baseline. 
 
ECOG PS (Appendix A) 
 
Complete blood count (CBC )3-part differential and platelets 
 
CMP  (see Section 7.1.) plus magnesium and phosphorus  
 
Uric acid 
 
LDH  
 
PT/PTT/INR  
 
Chest X-ray (repeat if/when clinically indicated) 
 
12- lead ECG 
 
MUGA or ECHO with calculated left ventricular ejection fraction (LVEF) 
(repeat if/when clinically indicated) 
 
Serum or urine pregnancy test (for women of childbearing potential) 
 
Bone marrow biopsy/aspiration (including flow cytometry, cytogenetics 
and FISH for the following chromosomal abnormalities: 1q amplification, 
1p del, t(4;14), t(11;14), t(14,16) or 17p del  
 
Skeletal survey  
 
Serum free light chain 
 
Serum immunoglobulin G, A, M 
 
Serum ß-2 microglobulin 
 
SPEP and immunofixation 
 
UPEP and immunofixation requiring a 24-hour urine sample collection 
 
Record concomitant medications 


 
  
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The baseline assessments described in Appendix E will be collected prior to the 
initiation of treatment.  The physical examination, ECOG PS, CBC, CMP, uric acid and 
pregnancy test should be done <7 days prior to initiation of treatment.  All other 
assessments should be performed ≤4 weeks prior to initiation of treatment. 
7.3. Study Treatment Period 
7.3.1. Cycle 1 Day 1, 2, 5, 8, 9, 15, 16 
 
Vital signs (blood pressure, weight, pulse, and respiratory rate) at each 
treatment visit. 
 
Adverse event evaluation 
7.3.2. Cycle 1 Day 1 
 
Physical examination, including measurement of vital signs (blood 
pressure, pulse, and respiratory rate) and weight.  
 
ECOG PS (Appendix A) 
 
12- lead ECGs - three ECGs will be obtained 5-10 minutes apart before 
the patient takes panobinostat and repeated three hours later (x 3) 5-10 
minutes apart. 
 
CBC, 3-part differential and platelets (-3 to Day 1 window allowed) 
 
CMP (see Section 7.1.) plus magnesium and phosphorus (-3 to Day 1 
window allowed) 
 
Uric acid (-3 to Day 1 window allowed) 
 
LDH 
 
PT/PTT/INR (if medically indicated or if patient is receiving warfarin or 
other anti-coagulant)  
 
Adverse event evaluation 
 
Record concomitant medications 
7.3.3. Cycle 1 Day 5 
 
12- lead ECGs – three will be obtained 5-10 minutes apart before the 
patient takes panobinostat and repeated three hours later (x 3) 5-10 
minutes apart. 
 
Vital signs (blood pressure, weight, pulse, and respiratory rate) 
7.3.4. Cycle 1 Day 8 and 15 
 
Medical history (Day 15 only) 
 
Physical examination (Day 15 only)  
 
ECOG PS (Appendix A) 


 
  
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 
Vital signs (blood pressure, weight, pulse, and respiratory rate) 
 
CBC, 3-part differential and platelets (-3 to Day 1 window allowed)  
 
CMP (see Section 7.1.) plus magnesium and phosphorus (-3 to Day 1 
window allowed) 
 
Uric acid  (-3 to Day 1 window allowed) 
 
LDH 
 
PT/PTT/INR (if medically indicated or if patient is receiving warfarin or 
other anti-coagulant)  
 
Adverse events assessment  
 
Record concomitant medication  
7.3.5. Cycle 2 and Beyond - Day 1, 8 and 15 
 
Medical history (Day 1 only)  
 
Physical examination (Day 1 only)   
 
Measurement of vital signs (blood pressure, pulse, and respiratory rate 
and weight)  
 
ECOG PS (Day 1 only) (Appendix A) 
 
CBC, 3-part differential and platelets (-3 to Day 1 window allowed) 
 
CMP (see Section 7.1.) plus magnesium and phosphorus (Day 1 only) 
(-3 to Day 1 window allowed) 
 
Uric acid (if clinically indicated) (-3 to Day 1 window allowed) 
 
LDH (if clinically indicated) 
 
PT/PTT/INR (Day 1 only; if medically indicated or if patient is receiving 
warfarin or other anti-coagulant)  
 
12- lead ECG (Day 1 only if no previous problems with QTc 
prolongation) 
 
Adverse event evaluation 
 
Record concomitant medications 
7.4. Re-Staging – 4 Weeks (-7 to Day 1 window allowed) 
 
Bone marrow biopsy/aspiration (including cytogenetics and FISH 
for the following chromosomal abnormalities: 1q amplification, 
1p del, t(4;14), t(11;14), t(14,16) or 17p del)  (REQUIRED ONLY 
TO DOCUMENT A CR) 
 
Serum free light chain 
 
Serum immunoglobulin G, A, M 
 
SPEP and immunofixation 
 
UPEP and immunofixation requiring a 24-hour urine sample collection   
At any point in this treatment, patients suspected of PD will have response assessed 
again to confirm disease progression (i.e. 2 sets of response assessments at least 1 


 
  
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week apart). The outcomes will be reviewed by the study chair before the patient is 
removed from the study.  After the second set of response assessments, if disease 
progression is confirmed, the date of the first set of response assessments should be 
recorded as the progression date.   
7.5. End of Study Treatment 
The following assessments will be performed for each patient within 30 days after 
treatment ends according to protocol guidelines.    
 
Physical examination, including measurement of vital signs 
 
Update Medical history 
 
ECOG Performance Status 
 
CBC, 3-part differential and platelets  
 
CMP (see Section 7.1.) plus magnesium and phosphorus 
 
Uric acid (if clinically indicated) 
 
LDH (if clinically indicated) 
 
12-lead ECG 
 
Serum free light chain 
 
Serum immunoglobulin G, A, M 
 
SPEP and immunofixation 
 
UPEP and immunofixation requiring a 24-hour urine sample collection   
 
Adverse event assessment 
 
Concomitant medication review 
 
Patients who discontinue treatment prior to disease progression will have the study 
assessments performed as described in Appendix E.   
If treatment is discontinued because of toxicity or any other reason(s) at a treatment 
visit and no study treatment is administered, that visit may fulfill the End of Treatment 
Visit. 
After withdrawal from or completion of protocol treatment, patients must be followed for 
adverse events for 30 calendar days after the last dose of study drug. 
7.6. Follow-Up 
7.6.1. Follow-Up for Patients who Discontinue Treatment Prior to Disease 
Progression 
Patients who discontinue study treatment prior to the occurrence of disease progression 
will be followed every 3 months from date of last dose of study drug during years 1 and 
2, every 6 months during years 3-5, and annually thereafter for toxicity, disease 
progression, and survival.  Appropriate disease assessments will be performed every 
3 months during years 1 and 2 after study discontinuation, and every 6 months during 


 
  
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years 3, 4, and 5.  After disease progression is documented, patients will be followed 
every 3 months as specified in Section 7.5.2.  Assessments at these visits will be 
performed as described in Appendix E. 
7.6.2. Follow-Up After Disease Progression 
After disease progression is documented, patients will be followed every 3 months.  
Assessments during this time will be performed as described in Appendix E. 
7.6.2.1. Pregnancy test 
All females of childbearing potential should complete a serum or urine pregnancy test 
within 7 days prior to the administration of trial drug on day 1 of cycle 1.  
Postmenopausal women must have been amenorrheic for ≥ 12 months in order to be 
considered “of non-childbearing potential”.  
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND TOXICITY 
INFORMATION  
8.1. Panobinostat 
8.1.1. Panobinostat Formulation 
Panobinostat (also known as LBH589) will be provided by Novartis. Oral panobinostat 
will be supplied as 5-mg, 15-mg, or 20-mg pink/opaque-colored, hard gelatin capsules. 
8.1.2. Panobinostat  Drug Supply 
Panobinostat for use in this study will be supplied to the Sponsor, SCRI Development 
Innovations, LLC (SCRI Innovations), by Novartis.  Study sites will obtain panobinostat 
from Sponsor designee(s) at SCRI Innovations per instructions provided to participating 
study sites.   
Accountability for the drug at all study sites is the responsibility of the principal 
investigator at each study site.  The investigator will ensure that the drug is used only in 
accordance with this protocol.  Drug accountability records indicating the drug’s delivery 
date to the site (if applicable), inventory at the site (if applicable), use by each patient, 
and return to SCRI Innovations or disposal of the drug (if applicable and if approved by 
SCRI Innovations) will be maintained by the clinical site.  Accountability records will 
include dates, quantities, lot numbers, expiration dates (if applicable), and patient 
numbers.  Once panobinostat is shipped to a site, it may not be shipped or shared with 
another site or patient. 
All material containing panobinostat will be treated and disposed of as hazardous waste 
in accordance with governing regulations. 


 
  
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8.1.3. Storage and Stability 
The storage conditions for study drug will be described on the medication label. 
8.1.4. Administration 
Oral panobinostat capsules should be administered as follows:  
 Patients should be instructed to take their three times a week oral dose of 
panobinostat at the same time on each dosing day (e.g. day 1, 3, and 5).  Doses 
should be separated by a minimum of 30 hours.    
 
Dose may be taken with or without food.  
o In the event that the patient does not take the daily dose at the specified 
routine time, unrelated to toxicity (for example, the patient forgets), but the 
dose can be taken within 12 hours of the specified time, then s/he may 
take the daily dose at that time.  If more than 12 hours have passed, that 
day’s dose should be withheld, and the patient should wait to take 
panobinostat until the next scheduled treatment day.  The patient should 
then continue treatment with the original dosing schedule.  This should be 
clearly documented on the Dosage Administration Record CRF by a 
member of the research team. 
o Each dose of panobinostat should be taken with a glass (approximately 
240 mL) of water.  Patients should be instructed to swallow the capsules 
whole and not chew them.  
o If vomiting occurs during the course of treatment, then no re-dosing of the 
patient is allowed before the next scheduled dose.  
o Patients must avoid grapefruits, grapefruit juice, Seville (sour) oranges 
and Seville orange juice during the entire study period. 
Note:  Food influence on panobinostat PK was evaluated in patients with advanced 
cancer who received 20 mg panobinostat twice a week and were randomized to receive 
1 of 6 treatment sequences where PK was evaluated weekly under fasting, high fat, and 
normal breakfast conditions CLBH589B2111.  The overall exposure and inter-patient 
variability (CV 59%) in 34 patients remained unchanged with or without food, whereas 
Cmax was transiently reduced (<45%) by food (i.e., both normal and high fat breakfast). 
 Since the overall extent of absorption was not altered by food, food is unlikely to 
significantly impact panobinostat systemic exposure in cancer patients.  
8.1.5. Panobinostat Toxicities 
Most frequently reported adverse events (occurred in at least 30% of patients): 
1. Fatigue and weakness 
2. Decreased appetite, anorexia or altered taste 
3. Diarrhea which can lead to dehydration, loose stools, abdominal cramping  
4. Nausea and vomiting  


 
  
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5. Thrombocytopenia 
6. Leukopenia 
7. Anemia 
Additional side effects that have been observed in ongoing clinical trials: 
1. Weight loss 
2. QTc prolongation, atrial fibrillation 
3. Changes in thyroid function 
4. Changes in blood electrolytes and glucose 
5. Increase in creatinine levels  
6. Other side effects reported include:  back, extremity, muscle, joint and bone pain, 
headache, coughing, breathing problems including shortness of breath, anxiety, 
depression, dizziness, constipation, fever, abdominal pain, swelling in the legs or 
eye, itchiness, peripheral ischemia, chest pain, loss of feeling or tingling in the 
arms and legs, inflammation of nose, throat and lining of the mouth. 
8.1.6. Panobinostat Precautions and Risks 
Patients must avoid grapefruit or grapefruit juice and Seville (sour) oranges or juice 
during the entire study. 
Medications known to be substrates of the isoenzyme CYP2D6 should be avoided if 
possible, since panobinostat can inhibit isoenzyme CYP2D6 at low micromolar ranges. 
Drugs that can inhibit/induce CYP3A4/5  
Drugs that can inhibit CYP3A4/5  
Panobinostat is metabolized in vitro by CYP3A4/5. A clinical drug-drug interaction 
study with ketoconazole and panobinostat has recently been completed.  The less 
than 2-fold increase in panobinostat AUC upon co-administration with 
ketoconazole suggests that CYP3A contribution to the total clearance of 
panobinostat is low.  The observed interaction is not considered clinically relevant, 
as panobinostat doses at least 2-fold greater than 20 mg (40 and 60 mg) have 
been safely administered in patients.  CYP3A4 inhibitors should have no major 
impact on the exposure of panobinostat and may be co-administered when 
medically necessary.  
Drugs that are potent CYP3A4/5 inducers  
As it is with other medications that are metabolized by CYP3A4, clinical judgment 
is to be exercised when potent CYP3A4 inducers are concomitantly taken with 
panobinostat.  


 
  
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Serum Electrolytes  
Any patients who are taking medications that have the potential to alter serum 
electrolytes (e.g. diuretics) should be monitored closely for electrolyte abnormalities as 
these can contribute to the risk of QTc prolongation and ventricular arrhythmias. 
Anti-Coagulant Therapy 
Panobinostat therapy is commonly associated with mild to moderate degree 
thrombocytopenia, which may increase the risk of bleeding with concomitant sodium 
warfarin (Coumadin).  It is recommended that patients who require anticoagulation 
therapy while on panobinostat therapy use low molecular weight heparin (LMWH).  
However, if the use of LMWH is not feasible, patients on sodium warfarin may continue 
such therapy while on panobinostat but for such patients, PT/INR should be closely 
monitored and maintained within a therapeutic range.  The dose of sodium warfarin may 
be adjusted as needed while on panobinostat. If the patient’s platelets drop below 
50,000 consideration should be given to suspending treatment with anticoagulation. 
8.2. Carfilzomib 
8.2.1. Carfilzomib Formulation 
Carfilzomib for injection will be provided as a lyophilized powder which, when 
reconstituted, contains 2 mg/mL isotonic solution of carfilzomib free base in 10 mM 
sodium citrate buffer (pH 3.5) containing 10% (w/v) sulfobutylether--cyclodextrin 
(SBE--CD, Captisol®).   
8.2.2. Drug Supply of Carfilzomib 
Carfilzomib for use in this study will be supplied to the Sponsor, SCRI Innovations by 
Onyx.  Study sites will obtain carfilzomib from Sponsor designee(s) at SCRI Innovations 
per instructions provided to participating study sites.   
Accountability for the drug at all study sites is the responsibility of the principal 
investigator at each study site.  The investigator will ensure that the drug is used only in 
accordance with this protocol.  Drug accountability records indicating the drug’s delivery 
date to the site (if applicable), inventory at the site (if applicable), use by each patient, 
and return to SCRI Innovations or disposal of the drug (if applicable and if approved by 
SCRI Innovations) will be maintained by the clinical site.  Accountability records will 
include dates, quantities, lot numbers, expiration dates (if applicable), and patient 
numbers.  Once carfilzomib is shipped to a site, it may not be shipped or shared with 
another site or patient. 
All material containing carfilzomib will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 


 
  
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8.2.3. Storage and Stability 
Lyophilized carfilzomib for injection must be stored at 2–8ºC, in a securely locked area 
to which access is limited to appropriate study personnel. 
8.2.4. Administration   
Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use 
vials. The lyophilized product is reconstituted with water for injection to a final 
carfilzomib concentration of 2.0 mg/mL prior to administration.  The dose will be 
calculated using the subject’s actual BSA at baseline.  Subjects with a BSA > 2.2 m2 will 
receive a dose based upon a 2.2 m2 BSA.   
At least 48 hours before Cycle 1 Day 1, oral hydration should be given as follows:  
30 mL/kg/day (approximately 6 to 8 cups of liquid per day) continuing up to the time of 
treatment.  Subject compliance must be assessed before initiating treatment, which is to 
be delayed if oral hydration is not adequate.  In subjects considered at risk for TLS, oral 
hydration should be continued in Cycle 2 and beyond as required by the subject’s 
medical condition and at the Investigator’s discretion.  
IV hydration will be given immediately prior to carfilzomib during Cycle 1.  This will 
consist of 250 to 500 mL normal saline or other appropriate IV fluid.  If lactate 
dehydrogenase (LDH) or uric acid is elevated (and/or in subjects considered still at risk 
for TLS) at Cycle 2 Day 1, then the recommended IV hydration should be given 
additionally before each dose in Cycle 2.  The goal of the hydration program is to 
maintain robust urine output (e.g., ≥ 2 L/day).  Subjects should be monitored periodically 
during this period for evidence of fluid overload.  
If the subject has a dedicated line for carfilzomib administration, the line must be flushed 
with a minimum of 20 mL of normal saline prior to and after drug administration.     
Carfilzomib will be given as an IV infusion over approximately 10 minutes.  For doses > 
27 mg/m2, carfilzomib should be infused over 30 minutes.  The dose will be 
administered at a facility capable of managing hypersensitivity reactions.  Subjects will 
remain at the clinic under observation for at least 1 hour following each dose of 
carfilzomib in Cycle 1 and following the dose on Cycle 2 Day 1.  During these 
observation times, post dose IV hydration (between 250 mL and 500 mL normal saline 
or other appropriate IV fluid formulation) will be given.  Subjects should be monitored 
periodically during this period for evidence of fluid overload. 
8.2.5. Carfilzomib Toxicities 
Most frequently reported adverse events are reported in the current carfilzomib 
Investigator’s Brouchure (IB). 
8.2.6. Carfilzomib Precautions and Risks 
The precautions and risks that are related to carfilzomib are pulmonary hypertension, 
cardiopulmonary disorders, acute renal failure, tumor lysis syndrome, infusion reactions, 


 
  
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thrombocytopenia, hepatic toxicity, thrombocytopenic thrombotic purpura/hemolytic 
uremic syndrome (TTP/HUS), and posterior reversible encephalopathy syndrome 
(PRES).  Management of carfilzomib-related toxicities is addressed in Section 6.3 and 
6.4 and in the current carfilzomib IB. 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
Response to treatment and disease progression will be evaluated using the 
International Myeloma Working group Uniform Response Criteria: Disease Progression 
and Relapse (see Appendix C). 
 
CR 
 
Complete Response 
sCR subcategory: stringent complete response 
VGPR  
Very good partial response 
PR 
 
Partial response 
SD 
 
Stable disease 
PD 
 
Progressive disease 
 
All response categories (CR, sCR, VGPR, PR, PD) require two consecutive 
assessments made at any time before the institution of any new therapy, as well as no 
known evidence of progressive or new bone lesions if radiographic studies were 
performed. Radiographic studies are not required to satisfy these response 
requirements. Bone marrow assessments are not required to be confirmed by repeat 
testing. 
Complete Response should be confirmed with a bone marrow biopsy for morphology 
and a bone marrow aspiration for flow cytometry, FISH and cytogenetics performed 
locally.  Additional confirmatory studies include SPEP, UPEP, immunofixation of blood 
and urine and serum free light chains (see Appendix E).  
MR 
 
Minimal Response 
Minimal Response (MR) should be reported for patients with relapsed refractory 
myeloma.  When reported, the specific rate of MR should be distinguished from PR or 
better. 
10. 
STATISTICAL CONSIDERATIONS AND DETERMINATION OF SAMPLE SIZE  
10.1. Determination of Sample Size 
MM 27 is a Phase I/Phase II study of carfilzomib in combination with panobinostat in the 
treatment of relapsed/refractory multiple myeloma. The total number of patients 
expected to be accrued is up to 80. 


 
  
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The Phase I efficacy objective is to establish the optimal dose of carfilzomib with 
panobinostat that can be administered to patients with relapsed/refractory multiple 
myeloma. In this part of the trial, the optimal dose combination to be administered will 
be determined as described in Section 5.2.  Since 3-6 patients will be treated in each 
cohort, the maximum number of patients treated in this phase will be 24. 
The Phase II efficacy objective is to evaluate the overall response in patients with 
relapsed/refractory multiple myeloma treated at the optimal dose level in the first 4 dose 
levels established during the Phase I portion. In addition, the overall response in 
patients at any additional dose levels  will be evaluated. The response rates in the two 
dose levels will be evaluated separately. When used in the treatment of patients with 
relapsed/refractory multiple myeloma, the historical carfilzomib overall response rate is 
approximately 18%.  It is hypothesized that the overall response rate for the treatment 
regimen of carfilzomib plus panobinostat is greater than that for patients treated with 
carfilzomib alone.  A sample size of 27 achieves 80% power to detect an increase in the 
overall response rate to 36% (representing a 100% relative improvement) based on a 
one-sided test of proportion at an alpha level of 0.10.  The sample size will be increased 
by 10% to account for potential non-evaluable patients and adjusted relative to the 
actual number of patients in the Phase I portion who are treated at the optimal dose 
level. 
10.2. Statistical Analyses 
10.3. Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using descriptive 
statistics for continuous variables, and frequencies and percentages for categorical 
variables. 
10.4. Efficacy Analyses 
Efficacy will be evaluated for patients treated at the optimal dose level from the first 4 
dose levels during Phase I together with those entered in the Phase II dose expansion 
portion of the study, and at any additional dose levels (if found to be tolerable and 
patients are recruited into the expansion cohort). The data from the two dose levels will 
be evaluated separately, and no formal statistical comparisons will be made between 
the two dose levels.  
The efficacy endpoints are overall response rate (primary endpoint), time-to-
progression, progression-free survival, and overall survival. 
10.4.1. Primary Efficacy Endpoint(s) 
The overall response rate (CR, VGPR, or PR) will be presented along with 95% 
confidence intervals calculated using both asymptotic normal approximation and exact 
binomial methods. 


 
  
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10.4.2. Secondary Efficacy Endpoint(s) 
Time-to-progression (TTP), progression-free survival (PFS) and overall survival (OS) 
will be analyzed using Kaplan-Meier methods. Time-to-progression will be measured 
from the date of first protocol treatment until the date of tumor progression is 
documented (event), or date of last adequate tumor assessment (censored).  
Progression-free survival will be measured from the date of first protocol treatment until 
the date of tumor progression is documented or death occurs (event), or date of last 
adequate tumor assessment (censored). Overall survival will be measured as the 
interval from first study treatment until date of death (event), or date last known alive 
(censored). Median progression-free survival and median overall survival will be 
reported using the respective point estimate and 95% confidence intervals. 
10.5. Safety Analyses 
Safety will be evaluated for patients entered in the Phase I and Phase II portions of the 
study. The primary safety endpoint is tolerability of combination panobinostat and 
carfilzomib. 
The analyses of safety will be based on the frequency of adverse events and their 
severity for patients in each cohort who received at least one dose of study treatment.  
Worst toxicity grades per patient will be tabulated for select adverse events and 
laboratory measurements by using NCI CTCAE criteria v4.0. 
11. 
SAFETY REPORTING AND ANALYSES 
11.1. Safety Analyses 
Safety assessments will consist of monitoring and recording protocol-defined adverse 
events (AEs) and serious adverse events (SAEs); measurement of protocol specified 
hematology, clinical chemistry, and urinalysis variables; measurement of protocol-
specified vital signs; and other protocol-specified tests that are deemed critical to the 
safety evaluation of the trial drug. 
11.2. Adverse Events 
The PI is responsible for recognizing and reporting adverse events to the Sponsor.  If 
not delegated it is the Sponsor’s responsibility to report relevant SAEs to the applicable 
local, national, or international regulatory body. 
11.2.1. Definitions of Adverse Events 
An adverse event is the development of an undesirable medical condition, or the 
deterioration of a pre-existing medical condition following or during exposure to a 
medicinal product, whether or not considered causally related to the product.   


 
  
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An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver), or the abnormal results of an investigation 
(e.g., laboratory findings).   
11.2.2. Recording of Adverse Events 
All adverse events of any patient during the course of the trial will be reported in the 
case report form, and the investigator will give his or her opinion as to the relationship of 
the adverse event to trial drug treatment (i.e., whether the event is related or unrelated 
to trial drug administration).  If the adverse event is serious, it should be reported 
immediately to the sponsor or designee.  Other untoward events occurring in the 
framework of a clinical trial are also to be recorded as AEs (i.e., AEs that occur prior to 
assignment of trial treatment that are related to a protocol-mandated intervention, 
including invasive procedures such as biopsies, medication washout, or no treatment 
run-in). 
All AEs regardless of seriousness or relationship to trial drug(s), spanning from the start 
of trial treatment, until 30 calendar days after discontinuation   of protocol-specific 
treatment as defined by the protocol for that patient, are to be recorded on the 
corresponding   case report form (CRF).  
11.2.3. Abnormal Laboratory Values and Vital Signs 
The reporting of abnormalities of vital signs as adverse events should be avoided.  
Abnormalities of vital signs should not be reported unless any criterion for an SAE is 
fulfilled, the vital signs abnormalities cause the patient to discontinue trial treatment, or 
the investigator insists that the abnormality should be reported as an AE.  Any grade 
3 or 4 laboratory abnormalities or any clinically significant grade 1 or 2 hematology or 
biochemistry laboratory value(s) should be recorded as an AE.  If an abnormal 
laboratory value or vital sign is associated with clinical signs and/or symptoms, the sign 
or symptom should be reported as an AE, and the associated laboratory value or vital 
sign should be considered additional information that must be collected on the relevant 
CRF. 
11.2.4. Handling of Adverse Events 
All adverse events resulting in discontinuation from the trial should be followed until 
resolution or stabilization.  Patients must be followed for AEs for 30 calendar days after 
discontinuation   of protocol-specific treatment (e.g., chemotherapy, radiation, oral 
medications, targeted therapy, and surgery).  All new AEs occurring during this period 
must be reported and followed until resolution unless, in the opinion of the investigator, 
these values are not likely to improve because of the underlying disease.  In this case, 
the investigators must record his or her reasoning for this decision in the patient’s 
medical record and as a comment on the CRF.  After 30 days, only AEs, SAEs, or 
deaths assessed by the investigator as treatment related are to be reported. 


 
  
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11.3. Serious Adverse Events 
11.3.1. Definitions of Serious Adverse Events 
The definitions of serious adverse events (SAEs) are given below.  The principal 
investigator is responsible for ensuring that all staff involved in the trial are familiar with 
the content of this section. 
An SAE or reaction is defined as any untoward medical occurrence that: results in 
death, is immediately life-threatening, requires at least a 24-hour in-patient 
hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect. 
The definition of SAE also includes any important medical event.  Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as 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 previous 
definition.  These should also usually be considered serious.  Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse.  Death due to disease progression will be recorded on 
the CRF and as an SAE up to 30 days post the last dose of trial drug. 
Treatment within or admission to the following facilities is not considered to meet the 
criteria of “in-patient hospitalization” (although if any other SAE criteria are met, the 
event must still be treated as an SAE and immediately reported): 
 Emergency Department or Emergency Room 
 Outpatient or same-day surgery units 
 Observation or short-stay unit 
 Rehabilitation facility 
 Hospice or skilled nursing facility 
 Nursing homes, Custodial care or Respite care facility 
Hospitalization during the trial for a pre-planned surgical or medical procedure (one 
which was planned prior to entry in the trial), does not require reporting as a serious 
adverse event to the Sponsor. 
11.3.2. Serious Adverse Event Reporting by Investigators 
It is important to distinguish between “serious” and “severe” adverse events, as the 
terms are not synonymous.  Severity is a measure of intensity; however, an AE of 
severe intensity need not necessarily be considered serious.  For example, nausea 
which persists for several hours may be considered severe nausea, but may not be 
considered an SAE.  On the other hand, a stroke which results in only a limited degree 
of disability may be considered only a mild stroke, but would be considered an SAE.  


 
  
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Severity and seriousness should be independently assessed when recording AEs and 
SAEs on the CRF. 
Adverse events classified by the treating investigator as serious require expeditious 
handling and reporting to the sponsor in order to comply with regulatory requirements.  
Serious adverse events may occur at any time from the start of trial treatment through 
the 30-day follow-up period after the last trial treatment.  The sponsor must be notified 
of all SAEs, regardless of causality, within one business day of the first knowledge of 
the event by the treating physician or research personnel.   
To report a SAE, the appropriate CRF pages should be completed with the necessary 
information.  The CRF pages required for SAE reporting include: 
 Adverse Event and Safety Complementary pages 
 Trial drug dosing 
 Concomitant Medications 
 Demographics  
 Medical History 
 
 
All SAEs and medically confirmed deaths (regardless of causality assessment) 
occurring on trial treatment or within 30 days of last trial treatment must be reported to 
the sponsor as SAEs within the CRF and followed until resolution (with autopsy report if 
applicable). 
Deaths occurring 30 days after last trial treatment that are deemed ‘possibly’ or 
‘probably’ related to trial drug must be reported as SAEs within the CRF (with an 
autopsy report if available). 
Deaths occurring 30 after last trial treatment and not attributed to trial treatment 
(e.g., disease progression) need not be reported as SAEs, but simply captured on the 
appropriate CRF. 
The investigator must review and sign off on the SAE data within the CRF.   The SAE 
will be reported to the sponsor or designee as outlined in the Safety Monitoring Plan.   
Follow-up information for SAEs and information on non-serious AEs that become 
serious should also be reported to the sponsor or designee as soon as it is available; 
these reports should be submitted using the CRF.   The detailed SAE reporting process 
will be provided to the sites in the Safety Monitoring Plan.  
Investigators must report SAEs and follow-up information to their responsible 
Institutional Review Board (IRBs)/Ethics Committee according to the policies of the 
responsible IRB/IEC. 
Contact details for SCRI Innovations Sponsor Safety department are as follows: 
Phone:  615-329-7941 
Fax:  866-807-4325 
 


 
  
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11.3.3. Novartis Instructions for Rapid Notification of Serious Adverse Events 
The Sponsor has the obligation to report all SAEs to Novartis Pharmaceuticals Clinical 
Safety and Epidemiology Department (CS&E), and to report SAEs to the FDA and IRB 
as applicable.  All events reported to the FDA are to be filed utilizing Form FDA 3500A 
(MedWatch Form), or other approved form. 
All events must be reported by fax to Novartis Pharmaceuticals CS&E Department 
within 24 hours of learning of its occurrence.  This includes serious, related, unlabeled 
(unexpected) adverse experiences.  All deaths during treatment or within 30 days 
following completion of active protocol therapy must be reported within 1 business day 
of learning of its occurrence.  Reports should be faxed to:  
Novartis Pharmaceuticals  
Clinical Safety and Epidemiology Dept. 
Fax #:  888-299-4565 
 
Any SAE occurring until 4 weeks after the patient has stopped study participation must 
be reported.  This includes the period in which the study protocol interferes with the 
standard medical treatment given to a patient (e.g., treatment withdrawal during 
washout period, change in treatment to a fixed dose of concomitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need 
only be reported if a relationship to the Novartis study drug (or therapy) is suspected.  
11.3.4. Safety Reporting for Studies Done Under an IND 
All written IND Safety Reports submitted to the FDA by the Sponsor must also be faxed 
to:  
Novartis Pharmaceuticals  
Clinical Safety and Epidemiology Dept. 
Fax #:  888-299-4565 
Onyx Drug Safety and Pharmacovigilance  
Onyx Fax:   
(800) 783-7954 
 
11.3.5. Onyx Instructions for Reporting Serious Adverse Events 
All relevant SAEs will be reported to the competent authority, other applicable regulatory 
authorities, and participating investigators, in accordance with ICH guidelines, FDA 
regulations, and/or local regulatory requirements by the Sponsor. 
All SAEs will be submitted to Onyx within 24 hours of learning of the events.    


 
  
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Onyx Drug Safety and Pharmacovigilance  
Contact Information: 
 
Onyx Fax:   
(800) 783-7954 
SAE hotline:  
(510)-597-6501 
E-mail:  
adverse.events@onyx-pharm.com 
 
11.3.6. Sponsor SAE Reporting Requirements 
The sponsor is responsible for reporting relevant SAEs to the competent authority, other 
applicable regulatory authorities, and participating investigators, in accordance with ICH 
guidelines, FDA regulations, and/or local regulatory requirements. 
The Sponsor is responsible for reporting unexpected fatal or life-threatening events 
associated with the use of the trial drugs to the regulatory agencies and competent 
authorities via telephone or fax within 7 calendar days after being notified of the event.  
The sponsor will report all related but unexpected SAEs including non-death/non-life-
threatening related but unexpected SAEs associated with the use of the trial 
medications to the appropriate competent authorities (according to local guidelines), 
investigators, and central IRBs/IECs (except in the United States where investigators 
are responsible for reporting to their IRBs per local requirements) by a written safety 
report within 15 calendar days of notification. 
11.4. Recording of Adverse Events and Serious Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs or 
SAEs on the SAE Report Forms and AE CRF.  Avoid colloquialisms and abbreviations. 
All AEs, including those that meet SAE reporting criteria, should be recorded on the AE 
CRF; AEs that meet the definition of an SAE should additionally be reported following 
the procedures noted in Section 11.3.2. 
11.4.1. Diagnosis vs. Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in 
the opinion of the Coordinating Investigator or designated physician, the AEs constitute 
components of a recognized condition, disease, or syndrome.  In the latter case, the 
condition, disease, or syndrome should be named rather than each individual sign or 
symptom.  If a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual 
event should be recorded as an AE or SAE as appropriate on the relevant form(s) (SAE 
Report Form and/or AE CRF).  If a diagnosis is subsequently established, it should be 
reported as follow-up information is available.  If a diagnosis is determined subsequent 
to the reporting of the constellation of symptoms, the signs/symptoms should be 
updated to reflect the diagnosis. 


 
  
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11.4.2. Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points.  Such events should only be recorded once on the SAE Report 
Form and/or the AE CRF.  If a persistent AE becomes more severe or lessens in 
severity, it should be recorded on a separate SAE Report Form and/or AE CRF.   
A recurrent AE is one that occurs and resolves between patient evaluation time points, 
and subsequently recurs.  All recurrent AEs should be recorded on an SAE Report 
Form and/or AE CRF. 
11.4.3. Abnormal Laboratory Values 
Any grade 3 or 4 laboratory abnormalities or any clinically significant grade 1 or 2 
hematology or biochemistry laboratory value(s) should be recorded as an AE.  If an 
abnormal laboratory value or vital sign is associated with clinical signs and/or 
symptoms, the sign or symptom should be reported as an AE, and the associated 
laboratory value or vital sign should be considered additional information that must be 
collected on the relevant CRF.  If the laboratory abnormality is a sign of a disease or 
syndrome, only the diagnosis needs to be recorded on the SAE Report Form or AE 
CRF. 
11.4.4. Deaths 
For this protocol, progression-free survival is the primary efficacy endpoint; time to 
treatment-failure, overall survival, and response rate are secondary endpoints.  Deaths 
that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of disease will be recorded on the “Trial 
Discontinuation”  CRF and reported as SAEs for up to 30 days post the last dose of trial 
drug.  All other on-trial deaths, regardless of attribution, will be recorded on an SAE 
Report Form and expeditiously reported to the Sponsor. 
When recording a serious adverse event with an outcome of death, the event or 
condition that caused or contributed to the fatal outcome should be recorded as the 
single medical concept on the Adverse Event page of the CRF.  If the cause of death is 
unknown and cannot be ascertained at the time of reporting, record “Death NOS” on the 
CRF Adverse Event page.  During post-trial survival follow-up, deaths attributed to 
progression of disease will be recorded only on the “After Progressive Disease Follow-
Up” CRF. 
11.4.5. Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolonged hospitalization should 
be documented and reported as an SAE unless specifically instructed otherwise in this 
protocol.  There are some hospitalization scenarios that do not require reporting as an 
SAE when there is no occurrence of an AE (refer to Section 11.3.1).   


 
  
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11.4.6. Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the trial.  Such 
conditions should be recorded on the General Medical History CRF.  A pre-existing 
medical condition should be recorded as an AE or SAE only if the frequency, severity, 
or character of the condition worsens during the trial.  When recording such events on 
an SAE Report Form and/or AE CRF, it is important to convey the concept that the pre-
existing condition has changed by including applicable descriptors. 
11.4.7. Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
Pregnancy, abortion, birth defects, and congenital anomalies are events of special 
interest.  Please refer to Section 11.5 for specific instructions. 
11.5. Protocol-Defined Events of Special Interest 
The following are events of special interest, and will need to be reported expeditiously 
(see Section 11.2.1): 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies: 
If a patient becomes pregnant while enrolled in the trial, a Pregnancy Form (a paper 
report form, not available within EDC system) should be completed and faxed to the 
sponsor.  The sponsor should be notified expeditiously, irrespective of whether or not it 
meets the criteria for expedited reporting.  Abortions (spontaneous, accidental, or 
therapeutic) must also be reported to the Sponsor. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE 
reporting.  A Pregnancy Form should also have been previously completed, and will 
need to be updated to reflect the outcome of the pregnancy. 
Trial Drug Overdose 
Symptomatic and non-symptomatic overdose must be reported in the CRF.  Any 
accidental or intentional overdose with the trial treatment that is symptomatic, even if 
not fulfilling a seriousness criterion, is to be reported to the sponsor immediately (within 
one working day) using the corresponding screens in the CRF, and following the same 
process described for SAEs (see Section 11.3). 
12. 
ETHICAL, FINANCIAL AND REGULATORY CONSIDERATIONS  
This trial will be conducted according to the standards of Good Clinical Practice outlined 
in the ICH E6 Tripartite Guideline and CFR Title 21 part 312, applicable government 
regulations, institutional research policies and procedures and any other local applicable 
regulatory requirement(s).  


 
  
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12.1. IRB Approval 
The trial protocol, investigators, informed consent form, IB, available safety information, 
patient documents (e.g., trial diary), patient recruitment procedures (e.g., 
advertisements), information about payments (i.e., PI payments) and compensation 
available to the patients and documentation evidencing the PI’s qualifications should be 
submitted to the IRB for ethical review and approval if required by local regulations, 
prior to the trial start.   
The Sponsor will follow all necessary regulations to ensure appropriate, initial, and 
ongoing, IRB trial review. The Sponsor must submit and, where necessary, obtain 
approval from the IRB for all subsequent protocol amendments and changes to the 
informed consent document.  Investigators will be advised by the sponsor or designee 
whether an amendment is considered substantial or non-substantial and whether it 
requires submission for approval or notification only to an IRB.  
12.2. Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, 
and approval of the appropriate regulatory bodies obtained, prior to trial initiation. If 
required, the Sponsor will also ensure that the implementation of substantial 
amendment to the protocol and other relevant trial documents happen only after 
approval by the relevant regulatory authorities. 
Safety updates for panobinostat (Novartis) and carfilzomib (Onyx) will be prepared by 
the pharmaceutical company or its representative as required, for submission to the 
relevant regulatory authority. 
12.3. Insurance and Indemnity 
Details of insurance and/or indemnity will be contained within the written agreement 
between the PI or site and the Sponsor.  
12.4. Informed Consent 
Informed consent is a process by which a subject voluntarily confirms his or her 
willingness to participate in a particular trial, after having been informed of all aspects of 
the trial that are relevant to the subject's decision to participate.  Informed consent is 
documented by means of a written, signed and dated informed consent form. 
The informed consent form will be submitted for approval to the IRB that is responsible 
for review and approval of the trial.  Each consent form must include all of the relevant 
elements currently required by the FDA, as well as local county authority or state 
regulations. 
Before recruitment and enrollment into the trial, each prospective candidate will be 
given a full explanation of the trial.  Once the essential information has been provided to 
the prospective candidate, and the investigator is sure that the individual candidate 


 
  
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understands the implications of participating in this trial, the candidate will be asked to 
give consent to participate in the trial by signing an informed consent form.  A notation 
that written informed consent has been obtained will be made in the patient’s medical 
record.  A copy of the informed consent form, to include the patient’s signature, will be 
provided by the investigator to the patient.   
If an amendment to the protocol substantially alters the trial design or the potential risks 
to the patients, the patient’s consent to continue participation in the trial should be 
obtained. 
12.5. Confidentiality 
12.5.1. Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with Health 
Insurance Portability and Accountability Act of 1996 (HIPPA) require that, in order to 
participate in the trial, a patient must sign an authorization from the trial that he or she 
has been informed of following:  
 What protected health information (PHI) will be collected from patients in 
this trial; 
 Who will have access to that information and why; 
 Who will use or disclose that information;  
 That health information may be further disclosed by the recipients of the 
information, and that if the information is disclosed the information may no 
longer be protected by federal or state privacy laws;  
 The information collected about the research trial will be kept separate 
from the patient’s medical records, but the patient will be able to obtain the 
research records after the conclusion of the trial; 
 Whether the authorization contains an expiration date; and 
 The rights of a research patient to revoke his or her authorization.  
 
In the event that a patient revokes authorization to collect or use his or her PHI, the 
investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of patient authorization.  For patients that have revoked authorization to 
collect or use PHI, attempts should be made to obtain permission to collect at least vital 
status (i.e., that the patient is alive) at the end of their scheduled trial period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a 
requirement that the investigator and institution permit authorised representatives of 
Sponsor, the regulatory authorities and the IRB direct access to review the patient’s 
original medical records at the site for verification of trial-related procedures and data.  
Measures to protect confidentiality include: only a unique trial number and initials will 
identify patients on the CRF or other documents submitted to the Sponsor.  This 
information, together with the patient’s date of birth, will be used in the database for 
patient identification. Patient names or addresses will not be entered in the CRF or 


 
  
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database. No material bearing a patient’s name will be kept on file by Sponsor.  Patients 
will be informed of their rights within the ICF. 
12.5.2. Investigator and Staff Information 
Personal data of the investigators and sub-investigators may be included in the 
SCRI Innovations database, and shall be treated in compliance with all applicable laws 
and regulations.  When archiving or processing personal data pertaining to the 
investigator or sub-investigator, SCRI Innovations shall take all appropriate measures to 
safeguard and prevent access to this data by any unauthorized party. 
12.6. Financial Information 
SCRI Innovations is sponsoring this study.  The pharmaceutical company Novartis will 
provide funding to SCRI Innovations for this study, and will also provide the study drug 
panobinostat for all study participants.  Onyx Pharmaceuticals provide funding to SCRI 
Innovations for this study, and will provide carfilzomib for all study patients.  The 
physicians participating in this study will receive compensation from the SCRI Oncology 
Research Consortium. 
13. 
RECORD RETENTION AND DOCUMENTATION OF THE STUDY 
13.1. Amendments to the Protocol 
Amendments to the protocol shall be planned, documented and signature authorized 
prior to implementation.   
If an amendment to the protocol is required, the amendment will be originated and 
documented by the Sponsor.  All amendments require review and approval of Novartis, 
Onyx, and the Principal Investigator supporting the trial.  The written amendment must 
be reviewed and approved by the Sponsor, and submitted to the IRB at the 
investigator’s facility for the board’s approval. 
Amendments specifically involving change to trial design, risk to patient, increase to 
dosing or exposure, subject number increase, addition or removal of new tests or 
procedures, shall be reviewed and approved by the IRB at the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by 
SCRI Innovations as applicable, after IRB approval and specifically when an increase to 
dosing or patient exposure and/or subject number has been proposed; or, when the 
addition or removal of an Investigator is necessitated. 
Items requiring a protocol amendment with IRB and/or FDA approval include, but are 
not limited to, the following: 
 
Change to trial design  
 
Risk to patient 
 
Increase to dose or patient exposure to drug  


 
  
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 
Subject number increase  
 
Addition or removal of tests and / or procedures  
 
Addition/removal of a new Investigator  
 
It should be further noted that, if an amendment to the protocol substantially alters the 
trial design or the potential risks to the patients, their consent to continue participation in 
the trial should be obtained. 
13.2. Documentation Required to Initiate the Trial 
Before the study may begin, certain documentation required by FDA regulations must 
be provided by the Investigator.  The required documentation should be submitted to: 
SCRI Development Innovations, LLC 
Regulatory Affairs 
3322 West End Avenue, Suite 900 
Nashville, Tennessee  37203 
1-877-MY-1-SCRI 
Fax #:  (615) 297-2793 
 
Documents at a minimum required to begin a trial in the US include, but are not limited 
to, the following: 
 
A signature-authorized protocol and contract; 
 
A copy of the official IRB approval of the trial and the IRB members list; 
 
Current Curricula Vita for the principal investigator and any associate 
investigator(s) who will be involved in the trial; 
 
Indication of appropriate accreditation for any laboratories to be used in 
the trial and a copy of the normal ranges for tests to be performed by 
that laboratory; 
 
Original Form FDA 1572 (Statement of Investigator), appropriately 
completed and signed; 
 
A copy of the IRB-approved consent form containing permission for audit 
by representatives of the Sponsor, SCRI Innovations, Novartis, Onyx, 
the IRB, and the FDA;  
 
Financial disclosure forms for all investigators listed on Form FDA 1572; 
 
GCP Certificate for trial training; 
 
Site qualification reports, where applicable; 
 
Verification of Principal Investigator acceptability from local and/or 
national debarment list(s)  


 
  
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13.3. Trial Documentation and Storage 
The PI must maintain a list of appropriately qualified persons to whom he/she has 
delegated trial duties and should ensure that all persons assisting in the conduct of the 
trial are informed of their obligations. All persons authorised to make entries and/or 
corrections on the CRFs are to be included on this document. All entries in the patient’s 
CRF are to be supported by source documentation where appropriate. 
Source documents are the original documents, data, records and certified copies of 
original records of clinical findings, observations and activities from which the patient’s 
CRF data are obtained. These can include, but are not limited to, hospital records, 
clinical and office charts, laboratory, medico-technical department and pharmacy 
records, diaries, microfiches, ECG traces, copies or transcriptions certified after 
verification as being accurate and complete, photographic negatives, microfilm or 
magnetic media, X-rays, and correspondence. 
The PI and trial staff are responsible for maintaining a comprehensive and centralised 
filing system (Site Trial File/SSF or ISF) of all trial-related (essential) documentation, 
suitable for inspection at any time by representatives from the Sponsor and/or 
applicable regulatory authorities.  The ISF/SSF must consist of those documents that 
individually or collectively permit evaluation of the conduct of the trial and the quality of 
the data produced.  The ISF/SSF should contain as a minimum all relevant documents 
and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, 
including key documents such as the IB and any amendments, protocol and any 
amendments, PIs, signed ICFs, copies of completed CRFs, IRB approval documents, 
Financial Disclosure forms, patient identification lists, enrollment logs, delegation of 
authority log, staff qualification documents, laboratory normal ranges, records relating to 
the trial drug including accountability records.  Drug accountability records should, at a 
minimum, contain information regarding receipt, shipment, and disposition.  Each form 
of drug accountability record, at a minimum, should contain PI name, date drug 
shipped/received, date, quantity and batch/code, or lot number for identity of each 
shipment.  In addition, all original source documents supporting entries in the CRF must 
be maintained and be readily available. 
The Sponsor shall maintain adequate investigational product records and financial 
interest records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after 
the last marketing application has been approved by FDA; or, in the event that the 
marketing application has not been approved by FDA, for no less than 2 years after the 
last shipment / delivery of the drug for investigational use is discontinued and FDA has 
been notified of the discontinuation. 
The IRB shall maintain adequate documentation / records of IRB activities as per 
21CFR Part 56.115 for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories and 
any other trial-related records as per 21 CFR Part 312.62 for no less than 2 years after 


 
  
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the last marketing application has been approved by FDA; or, in the event that the 
marketing application has not been approved by FDA, for no less than 2 years after the 
last shipment / delivery of the drug for investigational use is discontinued and FDA has 
been notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or 
its representative, the investigator additionally agrees to keep records, including the 
identity of all participating patients (sufficient information to link records e.g., CRFs and 
medical records), all original, signed informed consent forms, and copies of all CRFs, 
SAE Reporting forms, source documents, detailed records of treatment disposition, and 
related essential regulatory documents.  The documents listed above must be retained 
by the investigator for as long as needed to comply with national and international 
regulations (generally 2 years after discontinuing clinical development or after the last 
marketing approval).  The Sponsor will notify the investigator(s)/institutions(s) when the 
trial-related records are no longer required.   
If the investigator relocates, retires, or for any reason withdraws from the trial, both the 
sponsor and its representative should be prospectively notified.  The trial records must 
be transferred to an acceptable designee, such as another investigator, another 
institution, or to sponsor.  The investigator must obtain the sponsor written permission 
before disposing of any records, even if retention requirements have been met.  All trial 
files will be maintained by the Sponsor <or its representative> throughout the trial, and 
will be transferred to the Sponsor at the conclusion of the trial. 
13.4. Data Collection 
The trial CRF is the primary data collection instrument for the trial. CRFs will be 
completed using the English language and should be kept current to enable the monitor 
to review the patients’ status throughout the course of the trial. 
In order to maintain confidentiality, only trial number, patient number, initials and date of 
birth will identify the patient in the CRF.  If the patient’s name appears on any other 
document (e.g. laboratory report), it must be obliterated on the copy of the document to 
be supplied to SCRI Innovations and replaced instead with the patient number and 
patient’s initials.  The investigator will maintain a personal patient identification list 
(patient numbers with corresponding patient identifiers) to enable records to be 
identified and verified as authentic. Patient data/information will be kept confidential, 
and will be managed according to applicable local, state, and federal regulations.  
13.5. Trial Monitoring, Auditing, and Inspecting 
The investigator will permit trial-related monitoring, quality audits, and inspections by the 
sponsor, government regulatory authorities, the Sponsor or its representative(s) of all 
trial-related documents (e.g., source documents, regulatory documents, data collection 
instruments, case report forms).  The investigator will ensure the capability for 
inspections of applicable trial-related facilities.  The investigator will ensure that the trial 


 
  
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monitor or any other compliance or QA reviewer is given access to all trial-related 
documents and trial-related facilities.   
Participation as an investigator in this trial implies the acceptance of potential inspection 
by government regulatory authorities, the sponsor or its representative(s).  
At the Sponsor’s discretion Source Document Verification (SDV) may be performed on 
all data items or a percentage thereof.  
13.6. Quality Assurance and Quality Control 
Each trial site shall be required to have Standard Operating Procedures (SOP’s) to 
define and ensure quality assurance/control processes for trial conduct, data generation 
& collection, recording of data/documentation and reporting according to the protocol, 
GCP and any applicable local, national or international regulations. 
13.7. Disclosure and Publication Policy 
All information provided regarding the trial, as well as all information 
collected/documented during the course of the trial, will be regarded as confidential.  
The Sponsor reserves the right to release literature publications based on the results of 
the trial.  Results from the trial will be published/presented as per the Sponsor’s 
publication strategy. 
The financial disclosure information will be provided to the Sponsor prior to trial 
participation from all PIs and Sub-Investigators who are involved in the trial and named 
on the FDA 1572 form. 
 
  


 
  
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14. 
REFERENCES 
Anderson K. Panorama 2: A phase 2 study of panobinostat (LBH589) in combination 
with bortezomib and dexamethasone in patients with relapsed and bortezomib-
refractory multiple myeloma 2010 ASCO Abstract Presentation 
Alsina M, Trudel S, Vallone M, Molineaux C, Kunkel L and Goy A. Phase 1 Single Agent 
Antitumor Activity of Twice Weekly Consecutive Day Dosing of the Proteasome 
Inhibitor Carfilzomib (PR-171) in Hematologic Malignancies. Blood (ASH Annual 
Meeting Abstracts), 2007; 110: 411. 
Arastu-Kapur S, Shenk K, Parlati F and Bennett M. Non-Proteasomal Targets of 
Proteasome Inhibitors Bortezomib and Carfilzomib. Blood (ASH Annual Meeting 
Abstracts), Nov 2008; 112: 2657. 
Badros AZ, Vij R, Martin T, Zonder JA, Woo T, Wang, Lee S, Wong A, and Niesvizky R. 
Phase I Study of Carfilzomib in Patients (Pts) with Relapsed and Refractory 
Multiple Myeloma (MM) and Varying Degrees of Renal Insufficiency. Blood (ASH 
Annual Meeting Abstracts), Nov 2009; 114: 3877. 
 Demo SD, Kirk CJ, Aujay MA, et al. Anti-tumor activity of PR-171, a novel irreversible 
inhibitor of the proteasome. Cancer Res.  2007; 67(13):6383-91. 
Jagannath S, Vij R, Stewart K, Somlo G, Jakubowiak A, Trudel S, Schwartz R, Siegel D, 
Kunkel L, The Multiple Myeloma Research Consortium (MMRC). Final results of 
PX-171-003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib 
(CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). J 
Clin Oncol. 2009 27:15s (suppl; abstr 8504). 
Kelly W, O’Conner O, Richon VM, et al (2003) Phase I clinical trial of an oral histone 
deacetylase inhibitor: Suberoylanilide hydroxamic acid (SAHA) [abstract]. Proc 
AACR-NCI-EORTC. Abstract C174. 
Siegel D, Wang L, Orlowski RZ, Kaufman JL, Stewart AK, Kukreti V, Alsina M, 
Jakubowiak AJ, Jagannath D, McDonagh KT, Belch A, Bahlis NJ, Shustik C, Le 
MH, Kunkel L, Bennett MK, Kauffman M, Vij R, and the Multiple Myeloma 
Research Consortium (MMRC) PX-171-004, an ongoing open-label, phase II 
study of single-agent carfilzomib (CFZ) in patients with relapsed or refractory 
myeloma (MM); updated results from the bortezomib-treated cohort. Blood (ASH 
Annual Meeting Abstracts), Nov 2009; 114: 303 


 
  
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Wang L, Siegel D, Kaufman JL, Stewart AK, Jakubowiak AJ, Alsina M, Kukreti V, Bahlis 
NJ, McDonagh KT, Belch A, Sebag M, Gabrail N, Le MH, Bennett MK, Kunkel L, 
Kauffman M, Orlowski RZ, Vij R, and The multiple myeloma research consortium 
(MMRC).  Updated results of bortezomib-naïve patients in PX-171-004, an 
ongoing open-label, phase II study of single-agent carfilzomib (CFZ) in patients 
with relapsed or Refractory myeloma (MM). Blood (ASH Annual Meeting 
Abstracts), Nov 2009; 114: 302. 


 
  
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15. 
APPENDICES 


 
  
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Appendix 1:  
ECOG Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry on all 
pre-disease performance without restriction. 
 
100 
Normal, no complaints, no 
evidence of disease. 
 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary 
nature (e.g., light housework, office work). 
 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work. 
2 
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 
50% of waking hours. 
 
60 
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs. 
 
50 
Requires considerable 
assistance and frequent 
medical care. 
3 
In bed >50% of the time.  Capable of only limited 
self-care, confined to bed or chair more than 
50% of waking hours. 
 
40 
Disabled, requires special 
care and assistance 
 
30 
Severely disabled, 
hospitalization indicated.  
Death no imminent. 
4 
100% bedridden.  Completely disabled.  Cannot 
carry on any self-care.  Totally confined to bed 
or chair. 
 
20 
Very sick, hospitalization 
indicated.  Death not 
imminent. 
 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead 
0 
Dead 
 


 
  
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 Appendix 2: 
Diagnostic Criteria and Staging for Multiple Myeloma 
 
International Myeloma Working Group Criteria for Diagnosis 
The following criteria must be met except as noted: 
 
clonal bone marrow plasma cells ≥10% 
 
presence of serum and/or urinary monoclonal protein (except in 
patients with non-secretory multiple myeloma*) and  
 
evidence of end-organ damage, which can be attributed to the 
underlying plasma cell proliferative disorder, specifically: 
o hypercalcemia: serum calcium ≥11.5 mg/dL 
o renal insufficiency: serum creatinine >2 mg/dL  
o anemia: normochromic, normocytic with a hemoglobin value 
of >2 g/dL below the lower limit of normal or, a hemoglobin 
value of <10 g/dL 
o bone lesions: lytic lesions, severe osteopenia or pathologic 
fractures  
*More than 10% clonal plasma cells are required for the diagnosis of nonsecretory 
myeloma 
Dimopoulos., et al., Consensus recommendations for standard investigative workup:  report of the 
International Myeloma Workshop Consensus Panel 3. 2011 Blood J 117: 4701-4705 
 
A. 
Durie and Salmon Staging System 
Stage I 
All of the following: 
 Hemoglobin >10 g/dL 
 Serum calcium <12 mg/dL 
 Normal bone structure or solitary plasmacytoma on radiographs 
 Low M component  
 
IgG <5 g/dL 
 
IgA <3 g/dL 
 
Urine light chains <4 g/24 hours 
 
Stage II 
Fitting neither Stage I nor Stage III 
 


 
  
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Stage III 
One or more of the following: 
 Hemoglobin < 8.5 g/dL 
 Serum calcium >12 mg/dL 
 Advanced lytic bone lesions 
 Hyper M component 
 
IgG > 7 g/dL 
 
IgA > 5 g/dL 
 
Urinary light-chain excretion > 12 g/24 hour 
Subclassification  
A:  serum creatinine < 2.0 mg/dL 
B:  serum creatinine equal to or > 2.0 mg/dL 
 
B.  International Staging System (ISS) for Myeloma 
 
 
Stage I 
 
Serum ß2-microglobulin < 3.5 mg/L  
 
 
Serum albumin ≥ 3.5 g/dL 
Stage II  
Fitting neither Stage I nor III* 
Stage III  
Serum ß2-microglobulin ≥ 5.5 mg/L  
 
*There are two categories for stage II:  serum ß2-microglobulin < 3.5 mg/L  
but serum albumin < 3.5 g/dL; or  serum ß2-microglobulin ≥ 3.5 mg/L and < 5.5 mg/L 
irrespective of the serum albumin level. 
Greipp P., et al., International staging system for multiple myeloma. 2005. JCO 23:3412-3420  


 
  
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Appendix 3: International Myeloma Working Group Uniform Response Criteriaa  
Response Category 
Definition  
sCR 
Stringent Complete 
Response  
CR criteria as defined below AND 
 
Normal free light chain (FLC) ratio  
AND 
 
Absence of clonal PCs by immunochistochemistry or 2-to 
4-color flow cytometry 
CR 
Complete Response  
 
Negative immunofixation on the serum and urine  
AND 
 
Disappearance of any soft tissue plasmacytoma(s) 
AND 
 
< 5% plasma cells in bone marrowb. 
 
In case the only measurable disease in a patient with CR at 
baseline is the serum FLC level, a normal FLC ratio of 0.26 
to 1.65 is required additionally to qualify for CR. 
VGPR 
Very Good Partial 
Response  
 
Serum and  urine M-protein detectable by immunofixation 
but not  by electrophoresis (PEP) or  ≥90% reduction from 
baseline serum) AND  urine M-protein level <100 mg/  24h 
AND 
 
In case of presence of soft tissue plasmacytoma(s) at 
baseline, disappearance of any soft tissue plasmacytomas 
In case the only measurable disease in a patient with VGPR 
at baseline is the serum FLC level (i.e. no measurable 
disease in serum and urine PEP), a decrease of > 90% in the 
difference between involved and uninvolved FLC levels from 
baseline is required. 
PR 
Partial Response  
 ≥50% reduction from baseline in serum M-protein   
AND 
 ≥ 90% reduction from baseline in 24h urinary M-protein OR  
urine M-protein <200 mg/24h    
 
If serum and urine M-protein are non-measureable at 
baseline, a > 50% reduction form baseline in the difference 
between involved and uninvolved FLC levels is required in 
place of the M-protein criteria. 
If serum and urine M-protein are non-measurable, and serum 
free light assay is also non-measurable, >50% reduction from 
baseline in percent plasma cells in bone marrow is required 
instead of M-protein measurement, provided baseline plasma 
cells in bone marrow was > 30%.  
AND 
In case of presence of soft tissue plasmacytoma(s) at 
baseline, a reduction in the SPD by >50% is required. 


 
  
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Appendix C: International Myeloma Working Group Uniform Response Criteria: 
Complete Response and Other Response Categories (continuation) 
SD  
Not meeting criteria for sCR, CR, VGPR, PR or PD 
PDc  
Progressive Disease  
  
Increase of  ≥ 25% from the nadir in at least one of the 
following criteria: 
 
serum M-protein (absolute increase must be ≥0.5 g/dL) 
 
urine M-protein (absolute increase must be ≥200 mg/24h) 
 
only in patients with non-measurable serum and urine M-
protein levels: difference in involved and uninvolved FLC 
levels (absolute increase must be >10 mg/dL) 
 
only in patients with non-measurable serum and urine M-
protein levels and non-measurable disease by FLC levels, 
bone marrow plasma cell percentage (absolute % must be 
≥10%) 
OR 
 
definite development of new lytic bone lesions or increase 
from baseline in size of lytic bone lesion(s) 
OR 
 
development of new soft tissue plasmacytoma(s) or definite 
increase from nadir in existing soft tissue plasmacytomas 
OR 
 
development of hypercalcemia (corrected serum calcium 
>11.5 mg/dL) for patients without hypercalcemia at 
baseline. In case of preexisting hypercalcemia at baseline, 
PD will only be assessed due to the hypercalcemia criterion 
in case the corrected serum calcium level was ≤11.5 mg/dL 
post-baseline and increased thereafter beyond 11.5 mg/dL. 
Patients with relapsed refractory myeloma (adopted from the European Group for Blood and 
Marrow Transplantation [EBMT] criteria) 
MR 
Minimal Response 
 
 
≥25% but ≤49% reduction of serum M protein and reduction 
in 24-hour urine M-protein by 50-89% 
AND 
 
If present at baseline, 25-49% reduction in the size of sort 
tissue plasmacytomas is also required 
 
No increase in size or number of lytic bone lesions 
(development of compression fracture does not exclude 
response 
aAll response categories require two consecutive assessments made at any time before the institution of any new therapy; all 
categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic 
studies are not required to satisfy these response requirements. 
bConfirmation with repeat bone marrow biopsy not needed. 
cAt any point in this treatment, patients suspected of PD will have response assessed again to confirm disease progression (i.e. 2 
sets of response assessments at least 1 week apart). The outcomes will be reviewed by the study chair before the patient is 
removed from the study 
 
Rajkumar et al. Consensus recommendations for the uniform reporting of clinical trials:  report of the 
International Myeloma Workshop Consensus Panel 1.  Blood J 2011 117: 4691-4695 
 
Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients 
with multiple myeloma treated by high dose therapy and haemopoietic stem cell transplantation: 


 
  
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Myeloma Subcommittee of the EBMT, European Group for Blood and Marrow Transplant. Br J 
Haematol. 1998;102(5):1115-1123.


 
  
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Appendix 4: New York Heart Association (NYHA) 
 
 
Class 
Description 
I 
Patients with cardiac disease but without resulting limitations of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity.  
They are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity.  
They are comfortable at rest.  Less than ordinary physical activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on physical activity 
without discomfort.  Symptoms of cardiac insufficiency or of the anginal 
syndrome may be present event at rest.  If any physical activity is undertaken, 
discomfort is increased. 
This table is an excerpt from the Oxford Textbook of Medicine, 2nd ed. Oxford; New York: Oxford University Press, 1987, p. 222 


 
  
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Appendix 5: Schedule of Assessments MM 27 
 
Procedures 
Pre-
Treatment 
Cycle 1 
Cycle = 28 days 
 
Cycle 2 and beyond 
 
Restage 
Every 
Cycle 
(4 weeks) 
 
End of 
Study 
Treatment
O 
Follow-up 
BaselineA 
DayI,J 
DayI,J 
Off Study 
Prior to 
ProgressionP 
After 
Disease 
Progression
Q 
1 
2 
5 
8 
9 
15 
16 
1 
8 
15 
TESTS & OBSERVATIONS 
 
 
Medical history  
X 
 
 
 
 
 
X 
 
XD 
 
 
 
X 
X 
 
Physical examination  
X 
X 
 
 
  
 
X 
 
XD 
 
 
 
X 
X 
 
Vital signs, height, 
weight B  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
ECOG Performance 
Status 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
12-lead ECG  
X 
XG 
 
XG 
 
 
 
 
XH 
 
 
 
X 
X 
 
Chest x-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA or ECHO  
 XK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Concomitant medication 
review 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LABORATORY TESTS 
 
CBC, 3-part differential    
& platelets 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
  
X 
X 
 
CMPC plus magnesium & 
phosphorus 
X 
X 
 
 
X 
 
X 
 
X 
  
  
  
X 
X 
 
Uric acid  & LDHC 
X 
X 
 
 
X 
 
X 
 
XS 
 
 
 
XS 
 
 
PT/INRF 
X 
XF 
 
 
XF 
 
XF 
 
XF 
  
  
  
 
 
 
Serum or Urine β-HCGE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DISEASE ASSESSMENTST 
 
Bone Marrow 
Aspiration/BiopsyL 
X 
  
 
 
 
 
 
 
 
 
 
  XL 
 
 
 
Skeletal SurveyN 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum free light chain 
X 
 
 
 
 
 
 
 
 
 
 
   XM 
  XM 
 XM 
 
Serum immunoglobulin 
G, A, M 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Serum -2 microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPEP & immunofixation 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
UPEP & immunofixation 
XR 
 
 
 
 
 
 
 
 
 
 
  XR 
  XR 
 XR 
 


 
  
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Appendix E: 
Schedule of Assessments for MM 27 Phase I Portion (continued) 
A    The physical examination, ECOG PS, CBC, CMP, PT/INR, urinalysis, and pregnancy test should be done <7 days prior to initiation of treatment. However, if 
these initial examinations are obtained ≤72 hours of Cycle Day1 they do not have to be repeated.   
B 
Vital signs are defined as height, blood pressure, pulse, respirations, weight.   Only at the baseline visit, height will be recorded.   
C 
CMP includes the following laboratory tests:  glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, alkaline phosphatase, AST, ALT, total 
bilirubin, total protein, and albumin plus magnesium and phosphorus.  Uric acid and LDH will also be collected during Cycle 1.  Cycle 2 and beyond (and end 
of study) Uric acid and LDH will be obtained if clinically indicated.  Labs may be obtained ≤72 hours of any or all assessments. 
D 
Update of the medical history and physical examination should be obtained on D1 (+/- 72 hrs) of each   cycle after Cycle 1 until progression.   
E 
A serum pregnancy test will be performed only for women of childbearing potential (see Section 3.3.1). 
F     Evaluation should be performed at screening visit and repeated at investigator’s discretion, if medically indicated.  If patient is receiving warfarin or other anti-coagulant therapy, 
coagulation parameters should be monitored as indicated.    
G 
On Cycle 1 Day 1, and Cycle 1 Day 5, three ECGs will be obtained 5-10 minutes apart before the patient takes panobinostat, and will be repeated (x 3, 5-10 
minutes apart) approximately 3 hours after the panobinostat dose is taken orally.    
H 
If no problems with QTc prolongation occur during Cycle 1, a single pre-dose ECG on Day 1 of each subsequent cycle is required. 
I 
Oral hydration – (6-8 cups of liquid per day) starting 48 hours prior to the 1st dose of carfilzomib ( i.e. Day -2 and Day -1, Cycle 1), and prior to all carfilzomib 
doses during Cycle 1. In patients considered at risk for TLS, oral hydration should be continued in Cycle 2 and beyond as required by the patient’s medical 
condition and at the study doctor’s discretion. 
J 
IV hydration – 250-500 mL of NS (or other IV formulation) before and after each carfilzomib dose during Cycle 1 (Days 1, 2, 8, 9, 15 and 16).  If LDH or uric 
acid is elevated at Cycle 2, Day 1, the recommended hydration should be repeated for Cycle 2. 
K     MUGA or ECHO must demonstrate LVEF> the lower limits of the institutional normal.  
L  
Bone marrow should be sent for flow cytometry, cytogenetics and FISH for 1q amplification, 1p del, t(4;14), t(11;14), t(14;16) and 17p del).  Repeat if clinically 
indicated or only to document a CR.   
M    Repeat if abnormal at baseline.   
N   Skeletal survey need only be repeated if clinically indicated (i.e. bone pain). 
O    After patients are discontinued from the study, they will visit the study center ≤30 days from the date of last dose of study drug for end-of treatment-
assessments. 
P     Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 3 months during years 1 and 2, every 6 months 
during years 3-5, and annually thereafter for toxicity, disease progression, and survival.   
Q      After disease progression is documented, patients will be followed every 3 months for survival assessment. 
R     UPEP requires the collection of a 24-hour urine sample. 
S     Evaluation should be performed at screening visit and C1 as indicated to monitor for TLS. If LDH and uric acid were normal during Cycle 1, repeat at study 
doctor’s discretion, if clinically appropriate from C2 to progression (e.g. patients considered still at risk for TLS). 
T     Restaging must be done ≤ 7 days Day 1 of each cycle. 
 


 
  
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Appendix 6: Drugs That Prolong QT Interval and/or Induce Torsades De Pointes 
Patients who are receiving treatment with any of the medications in the table below, and cannot either 
discontinue form this treatment or switch to a different medication prior to study enrollment, will be 
excluded from this study.  Patients may not begin study treatment while receiving any of the 
medications identified below.  If a patient must receive these drugs, the patient should be removed 
from study.  Enrolling patients should be off study treatment at least 72 hours prior to taking the first 
dose of a medication listed below.   This is not a comprehensive list.  A complete list may be found 
and updated at the following web address: qtdrugs.org/medical-pros/drug-lists/drug-lists.htm. 
 
Antiarrhythmics  
Amiodarone (Cordarone® ) (Pacerone® ) 
Disopyramide (Norpace®) 
Dofetilide (Tikosyn®) 
Ibutilide (Corvert®) 
Procainamide (Pronestyl®) (Procan®) 
Quinidine (Quinaglute®) (Cardioquin®) 
Sotalol (Betapace®) 
 
Antibiotics 
Clarithromycin (Biaxin®) 
Erythromycin (Erythrocin®) (E.E.S. ®) 
Gatifloxacin 
Moxifloxacin 
Sparfloxacin (Zagam®) 
Antipsychotics 
Chlorpromazine (Thorazine®) 
Haloperidol (Haldol®) 
Mesoridazine (Serentil®) 
Pimozide (Orap®) 
Risperidone 
Thioridazine (Mellaril®) 
Ziprasidone 


 
  
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Appendix F:  Drugs That Prolong QT Interval and/or Induce Torsades De Pointes 
(continuation) 
Antidepressants 
Amitriptyline 
Desipramine 
Doxepin  
Imipramine 
Maprotiline 
Venlafaxine 
Antifungals (azoles)* 
Ketoconazole 
Itraconazole 
Antimalarials 
Chloroquine (Arelan®) 
Halofantrine (Halfan®) 
Antiemetics 
Dolasetron 
Domperidone (Motilium®) 
Droperidol (Inapsine®) 
Ondansetron 
Tropisetron  
Miscellaneous  
Arsenic trioxide (Trisenox®) 
Bepridil (Vascor®) 
Methadone (Methadose®) 
Pentamidine (NebuPent®) 
Cisapride (Propulsid®) 
Tacrolimus 
 


 
  
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Appendix 7:  Substrates, Inducers and Inhibitors of Isoenzyme CYP3A4 and CYP2D6 
Substrates 
CYP3A4 SUBSTRATES (Competitive Inhibition) 
CYP3A4 INHIBITORS 
CYP3A4 INDUCERS 
Antibiotics: 
 
clarithromycina 
 
erythromycin  
 
telithromycina 
 
Anti-Arrhythmics: 
 
quinidine 
 
Benzodiazepines: 
 
alprazolam 
 
diazepam 
 
midazolam 
 
triazolam 
 
Immune Modulators: 
 
cyclosporine 
 
tacrolimus (FK506) 
 
HIV Protease Inhibitors: 
 
indinavira 
 
ritonavira 
 
saquinavira 
 
Prokinetic: 
 
cisapride 
 
Antihistamines: 
 
astemizole 
 
chlorpheniramine 
 
Calcium Channel Blockers: 
 
amlodipine 
 
diltiazem 
 
felodipine 
 
nifedipine 
 
nisoldipine 
 
nitrendipine 
 
verapamil 
 
HMG CoA Reductase 
Inhibitors:  
 
atorvastatin 
 
cerivastatin 
 
lovastatin 
 
simvastatin 
 
Miscellaneous: 
aprepitant 
buspirone 
haloperidol 
methadone 
pimozide  
quinine 
sildenafil 
tamoxifen 
trazodone 
vincristine 
Inhibitors: 
Amiodarone 
Cimetidine 
Clarithromycin 
Delaviridine 
Diltiazem 
Erythromycin 
Fluvoxaminea 
Grapefruit juice 
Seville orange 
Indinavir 
Itraconazolea 
Ketoconazolea 
Voriconazolea 
Posaconazolea 
Mibefradil 
Nefazodonea 
Nelfinavira 
Troleandomycin 
Verapamil 
Inducers: 
Carbamazepine 
Phenobarbital 
Phenytoina 
Rifabutina 
Rifampina 
St John’s wort 
Troglitazone 
 
Others: 
barbiturates 
glucocorticoids 
modafinil 
pioglitazone 
 
 
From:  Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms, 
Naunyn Schmiedebergs Arch Pharmacol. 2004 Jan;369(1):89-104.  and 
[http://www.medicine.iupui.edu/flockhart/clinlist.htm as of July 13, 2006] 
a Strong inhibition/ induction (“strong inhibitor” implies that it can cause ≥5-fold increase in AUC or ≥80% decrease in 
clearance of sensitive CYP substrates; moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values, or 
50-80% decrease in clearance of sensitive CYP substrates.  Distinction is not always categorical as interaction can vary 
according to conditions). 


 
  
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Drugs that are CYP2D6 substrates 
If CYP2D6 substrates listed in Table 10 below are used concomitantly with panobinostat, patients 
should be carefully monitored and may require dose titration or dose reduction of the CYP2D6 
substrate.  
Beta blockers (listed below): 
Antipsychotics (listed below): 
carvedilol 
aripiprazole 
metoprolol 
haloperidol 
bufuralol 
perphenazine 
alprenolol 
risperidone 
nebivolol 
thioridazine 
propranolol 
chlorpromazine 
timolol 
duloxetine 
Antidepressants (listed below): 
fluoxetine 
amitriptyline 
fluvoxamine 
clomipramine 
venlafaxine 
desipramine 
Antiarrhythmics (listed below): 
imipramine 
encainide 
nortriptyline 
flecainide 
paroxetine 
lidocaine 
venlafaxine 
mexiletine 
Antiemetics (listed below): 
propafenone 
dolasetron 
Others: 
ondansetron 
amphetamine 
metoclopramide 
atomoxetine 
 
codeine 
 
hydrocodone 
 
dextromethorphan 
 
promethazine 
 
tamoxifen 
 
tramadol 
This is not a comprehensive list of CYP2D6 substrates.  Additional updated versions of this list, which are meant to be 
used as a guide, may be found at the following website: http://medicine.iupui.edu/flockhart/clinlist.htm