Clinical trial NCT02506959
Conditions: Plasma Cell Leukemia Plasmacytoma Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-09-14; Completion date: 2024-06-03
Enrollment: 83 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well panobinostat, gemcitabine hydrochloride, busulfan, and melphalan before stem cell transplant work in treating patients with multiple myeloma that does not respond to treatment (refractory) or has returned (relapsed). Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving high-dose chemotherapy, such as gemcitabine hydrochloride, busulfan, and melphalan, before a peripheral blood stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Previously collected stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the progression-free survival (PFS) in patients with refractory or relapsed myeloma receiving panobinostat/gemcitabine hydrochloride (gemcitabine)/busulfan/melphalan (panobinostat/Gem/Bu/Mel) with autologous stem-cell transplant, either as a first or a salvage stem-cell transplant.

SECONDARY OBJECTIVES:

I. To evaluate the complete response (CR) rate. II. To determine the overall survival (OS). III. To determine the CR + very good partial remission (VGPR) rate. IV. To determine the overall response rate (ORR). V. To determine minimal residual disease posttransplant, measured by multiparametric flow cytometry (MFC).

VI. To describe the toxicity profile of panobinostat/Gem/Bu/Mel. VII. To analyze the predictive value of pretransplant levels in myeloma cells of X-box binding protein 1 (XBP1), inositol-requiring enzyme 1 (IRE1), unspliced XBP1 (XBP1u), sliced XBP1 (XPB1s), XBP1u/XPBs ratio and v-myc myelocytomatosis viral oncogene homolog (avian) (Myc), by analyzing their correlation with CR, VGPR+CR and response rate (RR).

VIII. To study the prognostic effect of pretransplant levels in myeloma cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, by analyzing their correlation with PFS and OS.

OUTLINE:

Patients receive panobinostat orally (PO) once daily (QD) on days -9 to -2, gemcitabine hydrochloride intravenously (IV) over 4 hours on days -8 and -3, busulfan IV over 3 hours on days -8 to -5, and melphalan IV over 30 minutes on days -3 and -2. Patients then undergo autologous peripheral blood stem cell transplant on day 0.

After completion of study treatment, patients are followed up at 1 month, 100 days, 6 months, 1 year, and then every 3-6 months for at least 2 years.

Arms: arm 1: Patients receive panobinostat PO QD on days -9 to -2, gemcitabine hydrochloride IV over 4 hours on days -8 and -3, busulfan IV over 3 hours on days -8 to -5, and melphalan IV over 30 minutes on days -3 and -2. Patients then undergo autologous peripheral blood stem cell transplant on day 0. arm 2: Patients receive panobinostat PO QD on days -9 to -2, gemcitabine hydrochloride IV over 4 hours on days -8 and -3, busulfan IV over 3 hours on days -8 to -5, and melphalan IV over 30 minutes on days -3 and -2. Patients then undergo autologous peripheral blood stem cell transplant on day 0.
Interventions: intervention 1: Autologous Hematopoietic Stem Cell Transplantation intervention 2: Busulfan intervention 3: Gemcitabine Hydrochloride intervention 4: Melphalan intervention 5: Panobinostat intervention 6: Peripheral Blood Stem Cell Transplantation intervention 7: Pharmacological Study
Intervention descriptions: intervention 1: Undergo autologous peripheral blood stem cell transplant intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given PO intervention 6: Undergo autologous peripheral blood stem cell transplant intervention 7: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
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Page 1 of 42 
 
 
 
 
Panobinostat Combined with High-Dose 
Gemcitabine/Busulfan/Melphalan with Autologous Stem Cell 
Transplant for Patients with Refractory/Relapsed Myeloma 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 The University of Texas MD Anderson Cancer Center, Stem Cell Transplantation and Cellular Therapy Department 
2 The University of Texas MD Anderson Cancer Center, Biostatistics Department 
3 The University of Texas MD Anderson Cancer Center, Lymphoma-Myeloma Department 
Institution Study Number:  2014-0516 
Financial Support:   Secura Bio, Inc. 
Principal Investigator:  Yago Nieto, MD, PhD 
The University of Texas MD Anderson Cancer Center  
Stem Cell Transplantation and Cellular Therapy Department 
1515 Holcombe Blvd, Unit 0432 
Houston, TX 77030 
Telephone: 713.794.1752 
Fax: 713.794.4902 
ynieto@mdanderson.org 
 
Collaborators:  Borje Andersson, MD, PhD1 
Qaiser Bashir, MD1 
Roland L. Bassett, Jr., MS2 
Richard E. Champlin, MD, PhD1 
Robert Orlowski, MD, PhD3 
Uday Popat, MD1 
Muzaffar H. Qazilbash, MD1 
Ben Valdez, PhD1 
 
   


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Table of Contents 
 
 
 
1.0   Objectives ................................................................................................................................. 3 
2.0   Background .............................................................................................................................. 3 
3.0    Patient Eligibility ....................................................................................................................... 7 
4.0   Pretreatment evaluation ............................................................................................................ 9 
5.0   Study Registration .................................................................................................................... 9 
6.0   Treatment Plan ......................................................................................................................... 9 
7.0   Post-Treatment Evaluation ..................................................................................................... 12 
8.0   Criteria for Response .............................................................................................................. 13 
9.0   Criteria for Removal from the Study ........................................................................................ 14 
10.0 Determination of Body Surface Area ....................................................................................... 14 
11.0   Reporting Requirements......................................................................................................... 14 
12.0 Correlative Studies ................................................................................................................. 16 
13.0 Statistical Considerations ....................................................................................................... 17 
14.0 Background Drug Information ................................................................................................. 19 
15.0 References ............................................................................................................................. 40 
 
 
 


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Protocol Body 
 
1.0 Objectives 
Primary endpoint: 
 
1. To determine the progression-free survival (PFS) in patients with refractory or 
relapsed myeloma receiving panobinostat/gemcitabine/busulfan/melphalan 
(panobinostat/Gem/Bu/Mel) with autologous stem-cell transplant, either as a first or 
a salvage stem-cell transplant. 
 
Secondary endpoints: 
 
1. To evaluate the complete response (CR) rate. 
2. To determine the overall survival (OS). 
3. To determine the CR + very good partial remission (VGPR) rate. 
4. To determine the overall response rate (ORR). 
5. To determine minimal residual disease posttransplant, measured by 
multiparametric flow cytometry (MFC). 
6. To describe the toxicity profile of panobinostat/Gem/Bu/Mel. 
7. To analyze the predictive value of pretransplant levels in myeloma cells of XBP1, 
IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, by analyzing their correlation 
with CR, VGPR+CR and RR. 
8. To study the prognostic effect of pretransplant levels in myeloma cells of XBP1, 
IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, by analyzing their correlation 
with PFS and OS. 
 
 
2.0 Background 
2.1. 
Current Status and Shortcomings of High-Dose Chemotherapy for Myeloma 
 
High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) support 
results in significant benefit as part of first-line treatment of myeloma.[1, 2] However, most 
patients eventually experience tumor relapse after HDC. In addition, high-dose melphalan 
induces only 5-10% of CR with a median PFS of around 12 months in patients with 
primary refractory disease or in refractory relapse.[3-5] These data underscore the need to 
develop more active HDC regimens. While maintenance post-transplant treatment with 
lenalidomide or bortezomib improves PFS,[7-9] it is likely that ultimate success of 
maintenance strategies, i.e., long-term OS benefit, will still largely depend on the depth of 
response previously achieved by HDC. Thus, further exploration of novel preparative 
regimens for single transplantations is necessary with the short-term goal of improving CR 
rate. 
 
Complete response is a major surrogate for long-term OS in myeloma. Achievement of a 
CR with HDC is a crucial step for long-lasting PFS and OS.[10, 11] This seems particularly 
critical in refractory or high-risk disease, whereas it may be less important in more 
smoldering tumors, who can still enjoy prolonged outcomes despite never achieving a 
CR.[12] 
 


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Multiparametric flow cytometry (MFC) of bone marrow exam to define immunophenotypic 
CR has gained acceptance in myeloma. This technique presents a sensitivity of 10
-4 to 10
-5, 
superior to that of immunofluorescence or immunohistochemistry, and broader 
applicability than PCR.[13] Minimal residual disease (MRD) status by MFC at day 100 
post-transplant has been shown to be a major prognostic factor after front-line HDC.[14] 
 
2.2. 
Gemcitabine/Busulfan/Melphalan 
 
As with most other tumors in which HDC plays a role, it is conceivable that an active drug 
combination will prove to be more effective than the current standard of single-agent 
melphalan. We have developed a combination of infusional gemcitabine, busulfan and 
melphalan (Gem/Bu/Mel), following these principles: 
 
1. Synergy between gemcitabine and alkylators, based on inhibition of DNA 
damage repair.[15] 
2. Gemcitabine infusions at FDR of 10 mg/m2/min avoid saturation of its intracellular 
metabolic activation, which results in improved antitumor activity and increased 
myelotoxicity compared to shorter infusions.[16] The increased myelotoxicity of FDR 
infusions is overcome by stem-cell support. 
3. Minimal overlapping dose-limiting toxicity of the three agents at high doses. 
4. Optimization of intravenous busulfan therapy by therapeutic drug monitoring.[17] 
 
In our phase 1 trial of this combination (MDA 2006-0803) we saw early signals of high 
activity in 7 patients with refractory myeloma enrolled in the trial.[18] Five of them had 
primary refractory disease and 2 had refractory relapse, all pretreated with a median 4 
prior regimens. Their disease status at transplant was progressive disease in 5 patients 
and stable disease or partial response in the remaining 2 patients. In this very poor 
prognosis small subgroup, 6 patients achieved a response, which met criteria for stringent 
CR in 3 of them. Three of these patients remain free of progression at more than 5 years. 
 
These observations led us to test Gem/Bu/Mel in a phase 2 trial in refractory/relapsed 
myeloma (MDA 2010-0506).[19] The primary endpoint was the CR rate, targeting a 20% 
CR rate, which was deemed to be clinically relevant in this population where single agent 
high-dose melphalan is expected to induce 10% or less CRs. We enrolled 74 patients, 
median age 45 (22-68), who had received a median prior 4 lines of therapy (range, 2-13). 
Sixteen patients had myeloma unresponsive to all prior treatments; 32 patients had failed 
prior HDC; 27 patients had high-risk cytogenetics. Disease status at HDC was CR (N=9), 
PR (N=38) and no response (N=27, including tumor progression in 20). The CR rate was 
24.6%, with 77.5% response rate. At median follow-up of 22 months (6-46), the PFS and 
OS rates are 45% and 69%, respectively. Among the 32 patients receiving Gem/Bu/Mel 
as a second salvage transplant, the median PFS was 21 months with 1-year PFS rate of 
59%, seemingly superior to our previously published experience with salvage 
transplants.[17] There were 3 treatment-related deaths (1 pneumonia, 1 sudden cardiac 
arrest of undetermined etiology with normal postmortem exam findings, and 1 E coli 
neutropenic sepsis). The toxicity profile included mucositis (49% grade 2, 20% grade 3), 
dermatitis (20% grade 2, 7% grade 3), asymptomatic transaminase elevations (17% grade 
2, 7% grade 3) and asymptomatic bilirubin elevations (3% grade2, 10% grade 3), with no 
cases of venoocclusive disease. There were no renal, cardiac, neurological or pulmonary 
toxicities. 
 


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2.3. 
Potentiation of Gem/Bu/Mel through Histone Deacetylase Inhibition 
 
A major factor affecting the activity of alkylating agents is their access to DNA, which 
largely depends on the configuration of chromatin. Acetylation of lysine residues in the 
histones leads to charge neutralization, decreased binding to the DNA backbone, 
changes in the conformation of DNA and gene expression, and relaxation of chromatin. 
Histone acetyltransferases (HAT) and histone deacetylases (HDACs) add and remove 
acetyl groups, respectively. Addition of 
acetyl groups by HATs or inhibition of HDACs results in the weakening of the bond 
between histones and DNA, increasing gene transcription and decondensing 
chromatin. 
 
Histone deacetylase inhibitors (HDACi) induce relaxation of the chromatin, rendering the 
DNA more accessible to DNA-targeting agents such as alkylators and nucleoside 
analogues. To this end we combined the first-generation HDACi vorinostat with 
Gem/Bu/Mel. Our preclinical experiments showed marked synergy when vorinostat was 
added to GemBuMel, as determined by apoptosis or survival readouts in lymphoma B-cell 
and T-cell (J45) lines, which were resistant to those agents when exposed to them 
separately.[18] 
 
Fig.1. Antitumor activity of vorinostat (SAHA) in concurrent exposure with 
gemcitabine/busulfan/melphalan in a chemotherapy-resistant T-cell line (J45). 
Fig. 1-A: Apoptosis (% cells in subG1) assay. Fig. 1-B: Cell survival assay. 
 
Fig. 1-A 
Fig. 3-B 
 


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In these experiments lymphoma cells exposed to 
vorinostat/gemcitabine/busulfan/melphalan experienced increased cleavage of PARP1 
and increase in gamma-H2AX, reflecting increased DNA damage (Fig. 2) 
 
 
Fig. 2. Western blots showing cleavage of PARP1, increase of gamma-H2AX and 
acetylated Histone 3. Lane1: control cells. Lanes 2-8: cells treated with SAHA or 
chemotherapy. Lane 9: SAHA + gemcitabine/melphalan. Lane 10: SAHA + 
gemcitabine/busulfan/melphalan. 
 
 
 
 
 
These observations led to our clinical trial 2011-0407, evaluating a short schedule of 
vorinostat concurrent with GemBuMel with autologous stem cell support.[19] We 
combined GemBuMel at full doses with escalated doses of vorinostat from 200 mg daily to 
the maximally planned dose of 1,000 mg daily with good tolerance and no dose-limiting 
toxicities. There was no QT prolongation after treatment. The toxicity profile of 
vorinostat/Gem/Bu/Mel was comparable to that of Gem/Bu/Mel alone. The regimen was 
highly active across all lymphoma histologies. 
 
2.4. 
Use of HDACi in Myeloma. 
 
Clinical trials have shown the safety and increased activity of combinations of HDACi with 
other agents.[20-22] Bortezomib/vorinostat resulted in a small prolongation of PFS 
compared to bortezomib alone (7.6 vs. 6.8 months, P=0.01) in patients with 
relapsed/refractory myeloma.[23] A larger benefit was observed with the use of 
panobinostat, which is substantially more potent than vorinostat. In a phase 2 trial in 
patients with relapsed and bortezomib-refractory MM, the combination of panobinostat with 
bortezomib and dexamethasone was able to recapture responses in 35% of patients.[24]. 
In a subsequent phase III randomized trial the combination of 
panobinostat/bortezomib/dexamethasone was compared to bortezomib/dexamethasone in 
relapsed/refractory disease.[25] The addition of panobinostat resulted in a significant 
improvement in median PFS of 12.0 months vs. 8.1 months (hazard ratio 0.63, P< 0.0001), 
CR/near CR rate (27.6% vs. 15.7%, respectively; p = 0.00006), duration of response, time 
to response and median time to progression (12.7 vs. 8.5 months). The addition of 
panobinostat was associated with an increased frequency of thrombocytopenia (grade 3/4 
in 67% vs. 31% of patients). Other grade 3/4 adverse events occurring more frequently in 
the panobinostat arm included lymphopenia (53% vs. 40%), neutropenia (34% vs. 11%), 
diarrhea (25% vs. 8%), and asthenia/fatigue (24% vs. 12%). However, these adverse 
events led to discontinuation in fewer than 5% of patients in the panobinostat arm. 


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On 02/23/2015 the FDA granted approval for panobinostat for patients with relapsed or refractor 
myeloma treated with at least two prior standard therapies, including bortezomib and an 
immunomodulatory agent. This is precisely the target population of this transplant study. 
 
2.5. STUDY RATIONALE/PURPOSE 
 
We wish to develop an effective high-dose regimen for refractory myeloma, building on 
our prior experience with SAHA/Gem/Bu/Mel, substituting panobinostat for SAHA. 
Panobinostat is a more effective drug for myeloma than vorinostat. Its toxicity profile 
suggests, as with vorinostat, the feasibility of its combination with Gem/Bu/Mel. 
 
We hypothesize that epigenetic modulation of Gem/Bu/Mel with panobinostat is feasible 
and will increase the activity of the regimen. To facilitate the addition of panobinostat we 
will decrease the dose of gemcitabine in Gem/Bu/Mel compared to the regimen we tested 
in the phase 2 trial. 
 
We will study the prognostic and predictive effect of study markers of unfolded protein 
response (UPR) in patients enrolled in this trial. As highly secretory immunoglobulin-
producing cells, myeloma cells require an increased capacity to handle unfolded proteins 
within the endoplasmic reticulum (ER) under conditions of stress. The UPR includes 
transmembrane ER proteins, such as IRE1, which has RNase activity and removes an 
intron from the XBP1 mRNA. The spliced XBP1 protein (XPB1s) is a potent transcription 
factor that controls genes involved in ER membrane biosynthesis, protein import, 
chaperoning and ER-associated degradation of unfolded proteins. Myeloma cells are 
prone to ER stress and have a highly active UPR. 
 
We will study panobinostat/GemBuMel in two separate cohorts of patients receiving a first or a 
salvage stem-cell transplant. 
 
3.0 Patient Eligibility 
3.1 Inclusion: 
1. 
Age 18 to 65 years. 
2. 
Refractory or relapsed myeloma, defined as one or more of the following: 
2.1. Treated with first-line therapy including at least 2 cycles of lenalidomide, 
bortezomib or thalidomide, and one or more of the following: 
2.1.1. 
Less than PR to first-line therapy. 
2.1.2. 
Relapse after 1st line therapy. 
2.2. High-risk cytogenetics, defined by del(13q) by conventional cytogenetics, 
or by del(17p), t(4;14), t(14;16), t(14;20) or 1q+ by FISH. 
2.3. Relapse after a prior ASCT. 
2.4. Plasma cell leukemia. 
2.5. Soft tissue plasmacytoma. 
3. 
Adequate renal function, as defined by serum creatinine </=1.8 mg/dL and/or 
estimated serum creatinine clearance >/=50 ml/min. 
4. 
Adequate hepatic function, as defined by SGOT and/or SGPT </=3 x upper limit of 
normal; serum bilirubin and alkaline phosphatase </=2 x upper limit of normal, unless 
proven to be due to disease involvement. 
 


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5. 
Adequate pulmonary function with FEV1, FVC and DLCO >/=50% of expected 
corrected for hemoglobin and/or volume. 
6. 
Adequate cardiac function with left ventricular ejection fraction >/=40%. No 
uncontrolled arrhythmias or symptomatic cardiac disease. 
7. 
Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone 
supplements to treat underlying hypothyroidism. 
8. 
Zubrod performance status < 2. 
9. 
Negative Beta-HCG test in a woman of child-bearing potential, defined 
as not post-menopausal for 12 months or no previous surgical 
sterilization. 
10. Availability of >/= 2.5 million CD34+ cells/kg previously apheresed. 
11. Ability to provide written informed consent. 
 
3.2. Exclusion criteria: 
 
1. 
Prior whole brain irradiation. 
2. 
Having received radiation therapy to head and neck (excluding eyes), and internal 
organs of chest, abdomen or pelvis in the month prior to enrollment. 
3. 
Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA 
>/=10,000 copies/mL, or >/= 2,000 IU/mL). 
4. 
Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic 
hepatitis C or positive hepatitis C serology. 
5. 
Active infection requiring parenteral antibiotics. 
6. 
Known positivity for human immunodeficiency virus (HIV). 
7. 
Autologous stem-cell transplant in the previous six months. 
8. 
Needing valproic acid for any medical condition during the study or within 5 days 
prior to first panobinostat treatment. 
9. 
Impairment of GI function or GI disease that may significantly alter the 
absorption of panobinostat. 
10. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled 
diabetes or active or uncontrolled infection) including abnormal laboratory values, that 
could cause unacceptable safety risks or compromise compliance with the protocol. 
11. Impaired cardiac function or clinically significant cardiac diseases, including any one 
of the following: 
11.1. History or presence of sustained ventricular tachyarrhythmia. (Patients with a 
history of atrial arrhythmia are eligible but should be discussed with Secura 
Bio, Inc. (Secura Bio) prior to enrollment). 
11.2 Any history of ventricular fibrillation or torsade de pointes. 
11.3. Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if 
HR >/= 50 bpm. 
11.4. Screening ECG with a QTc > 470 msec. 
11.5. Right bundle branch block + left anterior hemiblock (bifascicular block). 
11.6. Myocardial infarction or unstable angina </= 12 months prior to starting study drug. 
11.7. Other clinically significant heart disease (e.g., CHF NY Heart Association class 
III or IV , uncontrolled hypertension, history of labile hypertension, or history of 
poor compliance with an antihypertensive regimen). 
12. Have undergone major surgery </= 4 weeks prior to starting study drug or who 
have not recovered from side effects of such therapy. 
13. Prior malignancy with in the last 5 years (except for basal or squamous cell carcinoma, or 
in situ cancer of the cervix). 


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14. Any significant history of non-compliance to medical regimens or unwilling or 
unable to comply with the instructions given to him/her by the study staff. 
15. Received targeted agents within 2 weeks or within 5 half-lives of the agent and 
active metabolites (whichever is longer) and who have not recovered from side 
effects of those therapies. 
16. Having received immunotherapy or chemotherapy within 2 weeks; or radiation 
therapy to > 30% of marrow-bearing bone within  2 weeks prior to starting study 
treatment; or who have not yet recovered from side effects of such therapies. 
17. Grade >/= 3 nonhematological toxicity from prior therapy that has not resolved to </= 
grade 1. 
 
4.0 Pretreatment evaluation 
4.1. 
Within 30 days of study 
enrollment: Complete history and 
physical examination Assessment of 
performance status 
Bone survey (within 6 months of study entry unless clinically indicated) 
SPEP, UPEP, serum and urine immunofixation, serum free kappa and lambda light chain 
assay Beta-2 microglobulin 
Chest X-ray 
Echocardiogram or MUGA 
scan EKG 
Pulmonary function 
tests TSH and free T4 
 
4.2. Within 14 days of study enrollment: 
CBC with differential, electrolytes, BUN, creatinine, glucose, total protein, albumin, 
calcium, phosphorus, uric acid, total bilirubin, alkaline phosphatase, LDH, AST, ALT, 
magnesium, and serum HCG in all female patients of childbearing potential. 
 
4.3 Once enrolled, if not obtained within 30 days of study enrollment date: 
Bone marrow aspirate and biopsies for morphology, multiparametric flow cytometry, 
(CD19, CD20, CD28, CD38, CD56, CD117, CD138, cyKappa, cyLambda), cytogenetic 
and FISH studies. 
 
5.0 Study Registration 
Each patient will be evaluated and approved for enrollment by the primary attending 
physician and the Study Chairman (or his designee). The study research coordinator will 
register each patient on protocol in the institutional CORe system. 
6.0 Treatment Plan 
Treatment will not commence until resolution of prior toxicities to grade 1 or less. 
Acetaminophen (Tylenol) shall not be administered for 72 hr before and on the day of 
administration of Busulfan or Melphalan. Voriconazole, posaconazole, fluconazole, 
itraconazole and metronidazole will be avoided from 7 days before start of chemotherapy 
to day -1. 


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6.1. 
Outpatient Busulfan Test 
Dose: Day 
 
Treatment 
…… 
Outpatient Busulfan 32 mg/m2 IV Test Dose (PK Sampling) 
-12 
Palifermin 60 microgram/kg IV (outpatient), not starting on Mon/Tues/Wed 
-11 
Palifermin 60 microgram/kg IV (outpatient) 
-10 
Palifermin 60 microgram/kg IV (outpatient) 
-9 
Admit / Panobinostat 20 mg PO 
-8 
Panobinostat 20 mg PO / Gemcitabine 1,875 mg/m2 IV / Busulfan AUC 4,000 IV 
-7 
Panobinostat 20 mg PO / Busulfan AUC 4,000 IV 
-6 
Panobinostat 20 mg PO / Busulfan AUC 4,000 IV 
-5 
Panobinostat 20 mg PO / Busulfan AUC 4,000 IV 
-4 
Panobinostat 20 mg PO 
-3 
Panobinostat 20 mg PO / Gemcitabine 1875 mg/m2 IV / Melphalan 60 mg/m2 IV 
-2 
Panobinostat 20 mg PO / Melphalan 60 mg/m2 IV 
-1 
Rest 
0 
Stem Cell Transplant / Palifermin 60 microgram/kg IV 
+1 
Palifermin 60 microgram/kg IV 
+2 
Palifermin 60 microgram/kg IV 
 
Table 1. Treatment plan with outpatient busulfan test dose. 
Day 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Admission 
X 
Panobinostat 
X 
X 
X 
X 
X 
X 
X 
X 
Gemcitabine 
X 
X 
Busulfan 
X 
X 
X 
X 
Melphalan 
X 
X 
Peripheral Blood 
Progenitor Cell 
X 
 
6.2. 
Inpatient Busulfan Test Dose: 
 
Day 
-14 
Treatment 
Palifermin 60 microgram/kg IV (outpatient). Do not start on Monday/Tuesday 
-13 
Palifermin 60 microgram/kg IV (outpatient) 
-12 
Palifermin 60 microgram/kg IV (outpatient) 
-11 
Admit 
-10 
Inpatient Busulfan 32 mg/m2 IV Test Dose (PK Sampling) 
-9 
Panobinostat 20 mg PO 
-8 
Panobinostat 20 mg PO / Gemcitabine 1875 mg/m2 IV / Busulfan AUC 4,000 IV 
PK Sampling) 
 
-7 
Panobinostat 20 mg PO / Busulfan AUC 4,000 IV 
-6 
Panobinostat 20 mg PO / Busulfan AUC 4,000 IV 
-5 
Panobinostat 20 mg PO / Busulfan AUC 4,000 IV 
-4 
Panobinostat 20 mg PO 
-3 
Panobinostat 20 mg PO / Gemcitabine 1875 mg/m2 IV / Melphalan 60 mg/m2 IV 
-2 
Panobinostat 20 mg PO / Melphalan 60 mg/m2 IV 


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-1 
-1 
Rest 
 0 
Stem Cell Transplant / Palifermin 60 microgram/kg IV 
+1 
Palifermin 60 microgram/kg IV 
+2 
Palifermin 60 microgram/kg IV 
 
Table 2. Treatment plan with inpatient busulfan test dose. 
Day 
-11 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Admission 
X 
Panobinostat 
X 
X 
X 
X 
X 
X 
X 
X 
Gemcitabine 
X 
X 
Busulfan 
Test 
dose 
X 
X 
X 
X 
Melphalan 
X 
X 
Peripheral Blood 
Progenitor Cell 
X 
 
Oral panobinostat will be supplied as 20-mg capsules. During the study, panobinostat will 
be administered orally as once daily dose of 20 mg. Each dose of panobinostat should be 
taken with an 8 oz. / 240 ml glass of water. Patients should be instructed to swallow the 
capsules whole and not chew them. Patients must avoid grapefruit or grapefruit juice and 
seville (sour) oranges during the entire study. 
 
On days when panobinostat is to be administered with other drugs it will be administered 
within 1 hour before the next drug. Repeat a full dose if emesis occurs within 30 minutes 
and tablets/tablet fragments are found in the vomit. The time of administration will be in 
the early morning, and the patient may need to be woken up by the nurse. The nurse 
must stay and witness the patient taking the drug. 
 
Gemcitabine will be administered as a loading dose of 75 mg/m2 followed by continuous 
infusion of the remaining dose at 10mg/m2/minute. It will be followed immediately by 
busulfan on Day -8 and melphalan on Day -3. 
 
Busulfan test dose will be administered as an outpatient any day within 1 week of Day -12. 
If given as an inpatient, the test dose will be administered on Day -10. The busulfan test 
dose of 32 mg/m2 will be based on actual body weight to be administered over 60 
minutes. Busulfan pharmacokinetics will be done with the test dose and repeated with the 
first therapeutic dose on day-8. The doses of days -6 and -5 will be subsequently adjusted 
to target an AUC of 4,000 
microMol.min . In the event that PK adjusting was not possible a dose of busulfan of 100 
mg/m2 will be administered on days -6 and -5. 
 
Melphalan will be administered at 60 mg/m2 on Days -3 and -2. 
 
6.3 
Supportive Treatment 
Patients will receive standard supportive treatment as outlined below. 
 
1. 
Dexamethasone 8 mg IV BID from day -9 PM to day -2 PM. Omit any 
other dexamethasone for chemotherapy premedication. 
2. 
Mucositis supportive care: 


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2.1. Patients will receive a total of 6 doses of palifermin 60 mcg/kg IV daily. Three 
doses administrated prior to start chemo (a minimum of 24 hours must elapse 
between the last dose and first therapeutic dose of chemo) and three doses 
after the last chemo starting on day 0. Doses can be capped to vial size. 
2.2. Caphosol oral rinses 30 mL four times a day will be used from day -9 until discharge. 
2.3. Oral glutamine, 15 g four times a day, swished, gargled and spit will be started on day 
-9 until discharge. 
2.4 Pyridoxine 100 mg IV/PO TID from Day -1. 
 
G-CSF, antiemetics, infection prophylaxis, and other supportive care as per 
departmental standards. 
 
6.4 
Post-Transplant Therapies 
Post-transplant therapies will be left at the discretion of the primary physician. 
 
 
7.0 Post-Treatment Evaluation 
 
7.1. Toxicity Monitoring:  
During the treatment administration and until day +100 all patients will be monitored for toxicity, 
specifically for grade 3 or greater side effects, according to CTCAE v4.0. While admitted in 
hospital, patients will be monitored on a regular basis. Once discharged patient will return to 
clinic once a week or as determined by the primary physician until day +30.  
 
7.2. Disease restaging: 
 
7.2.1  Around 1 month post-transplant, day 100 (+/- 15 days), 6 months (+/- 30 days), 1 year (+/- 
30 days)  and about every 3-6 months thereafter for at least 2 years: 
 
Complete history and physical examination. 
 
SPEP, UPEP, serum and urine immunofixation, serum free kappa and lambda light chain 
assay. 
 
Serum albumin, LDH, and beta-2 microglobulin. 
 
7.2.2    On day +100 (+/- 15 days) post-transplant:  
 
Bone marrow aspirate and biopsies for morphology, multiparametric flow cytometry, 
(CD19, CD20, CD28, CD38, CD56, CD117, CD138, cyKappa, cyLambda), cytogenetic 
and FISH studies. Afterwards, once a year or earlier if clinically indicated. 
 
7.2.3    Bone survey: Only once per year 
 
 
 
 
 
 
 
 
 
 


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8.0 Criteria for Response 
We will use the International Myeloma Working Group (IMWG) uniform response criteria.[26] All 
response categories require no known evidence of progressive or new bone lesions. 
 
Complete response (CR): All of the following: 
1. Negative immunofixation in serum and urine. 
2. </= 5% plasma cells in the bone marrow. 
3. Disappearance of any soft tissue plasmacytomas. 
 
Note: While healing of preexisting bone lesions is not required, no new lytic lesions should 
appear. Further compression fracture of previously known spine lesion will not be 
considered as progressive disease. 
 
Stringent complete response (sCR): All of the following: 
1. CR as defined above. 
2. Normal free light chain ratio 
3. Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence (defined by absence of abnormal ê/ë ratio of >4:1 or <1:2) 
 
Very good partial response (VGPR): One or more of the following: 
1. Serum and urine M protein detectable by immunofixation but not by electrophoresis 
2. 90% or greater reduction in serum M protein plus urine M protein level <100 mg 
per 24 hours. 
 
 
Partial response (PR): All of the following: 
1. Reduction by > 50% in serum monoclonal protein. 
2. Reduction of urinary monoclonal protein to < 200 mg/24 or >90%. 
 
Progressive disease (PD): Any one or more of the following: 
1. Increase of >/= 25% from baseline in: 
1.1. Serum M protein (absolute increase must be >= 0.5 g/dL). 
1.2. Urine M component (absolute increase must be >= 200 mg/24h). 
1.3. (Only in patients without measurable serum and urine M protein levels) 
Difference between involved and uninvolved FLC levels (absolute increase must 
be > 10 mg/dL). 
1.4. Bone marrow plasma percentage (absolute % must be >=10%). 
2. Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas. 
3. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65 
mmol/L) that can be solely attributed to the myeloma. 
 
Stable disease: Not meeting criteria for CR, VGPR, PR or PD. 
 
Clinical relapse: One or more of the following direct indicators of increasing disease 
and/or end-organ dysfunction: 
1. Development of new soft tissue plasmacytomas or bone lesions on skeletal survey, MRI 
or other imaging. 
2. Increase in the size of existing plasmacytomas or bone lesions: 50% (and at least 1 


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cm) increase as measured by the sum of the products of the cross-diameters of the 
measurable lesion. 
3. Hypercalcemia (> 11.5 mg/dL). 
4. Decrease in hemoglobin of > 2 g/dL) or to < 10 g/dL. 
5 Rise in serum creatinine by >/=2 mg/dL. 
6. Hyperviscosity. 
7. Bone pain without imaging confirmation is not adequate to meet these criteria in trials. 
 
Biochemical relapse (in patients who do not have clinical relapse): 
1. Doubling of the M-component in 2 consecutive measurements separated by </=2 months. 
2. Incr in the absolute levels of serum M protein by >/= 1 g/dL. 
3. Increase of urine M protein by >/= 500 mg/24 hours. 
4. Increase of involved FLC level by >/= 20 mg/dL (plus an abnormal FLC 
ratio) in 2 consecutive measurements separated by </= 2 months. 
9.0 Criteria for Removal from the Study 
 
1. Patient’s withdrawal of the informed consent. 
2. Patient's inability or unwillingness to have follow-up visits and/or laboratory tests 
required by this protocol. 
3. An unexpected toxicity that is deemed unacceptable by the study PI. 
4. Disease progression or relapse. 
5. After two years of treatment completion. 
 
10.0 Determination of Body Surface Area 
For patients whose actual body weight is < 20% above ideal body weight (defined by the 
MD Anderson dosing calculator), the actual body weight is used to calculate the body 
surface area (BSA). The actual body weight will also be used to calculate the BSA for the 
busulfan test dose. For purposes of gemcitabine and melphalan dosing, patients whose 
actual body weight is >20% above ideal body weight, an “adjusted body weight” is 
calculated using the midpoint between the actual and ideal body weight, and defining that 
as the adjusted body weight. That adjusted body weight is then used to calculate an 
“adjusted body surface area” that is used for chemotherapy dosing calculation purposes. 
11.0 Reporting Requirements 
Patients will be monitored for toxicity until day +100 or until documentation of reversal of 
toxicities related to this treatment. The intensity of adverse events (AE) will be assessed 
according to the Common Terminology Criteria v4.0 (CTCAE). Adverse events and 
protocol deviations will be reported accordingly to MDACC policy and procedures. 
Collection of adverse events will reflect the onset and resolution date and maximum 
grade. Intermittent events should be labeled as such and followed until resolution. If a 
patient is taken off study while an event is still ongoing, this will be followed until resolution 
unless another therapy is initiated. Pre-existing medical conditions will be recorded only if 
an exacerbation occurs during the active treatment period. Co-morbid events will not be 
scored separately. 
 
 
 
 


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11.1 Adverse events (toxicities) known to be produced by the chemotherapy regimen: 
 
Gastrointestinal: Diarrhea (FDA boxed warning), nausea and vomiting, oral mucositis 
Hepatic: Self-limited elevations of liver function enzymes; veno-occlusive disease 
Hypersensitivity: Acute hypersensitivity reactions characterized by urticaria, pruritus, 
edema, and in some patients, tachycardia, hypotension and bronchospasm (rare) 
Pulmonary: Pulmonary fibrosis and interstitial 
pneumonitis. Skin: Rash. 
Endocrine abnormalities: Hypothyroidism. 
Cardiac abnormalities: QTc prolongation, arrhythmias. 
 
11.2. Adverse events (toxicities) known to be produced by other treatment components: 
 
The following events are not considered to be significant in relationship with the study 
treatment, will not be considered adverse events and will not be collected in the study 
database. 
 
Myelosuppression-related: neutropenia, anemia, thrombocytopenia, platelet and RBC 
transfusions. 
Flu-like symptoms: low grade fever, headache, chills, cough, rhinitis, myalgia, fatigue, 
sweating and insomnia. 
Mood alteration: depression, anxiety, and agitation 
Readmissions (lasting <10 days) 
Low blood pressure due to dehydration requiring fluid 
replacement Fluid overload. 
Fatigue. 
Laboratory serum metabolic values not reflecting end-organ (hepatic, renal) function 
and or those considered associated to the original disease 
Events that are identified to be related to the supportive treatment, e.g., 
steroids, palifermin, antibiotics. 
 
11.3 Adverse Events Considered Serious (SAEs): 
 
1. Graft failure/rejection 
2. Prolonged hospitalization due to infections and/or organ failure requiring 
extensive supportive care (i.e. dialysis, mechanical ventilation) 
3. Readmissions from any cause resulting in a prolonged hospitalization (>10 days). 
4. Any expected or unexpected event resulting in an irreversible condition and/ or 
leading to death. 
 
Serious adverse events (SAE) will be reported to the PI or his designate, who in turn will 
notify the IRB following institutional policy. 
 
11.4. 
Secura Bioinstructions for rapid notification of serious adverse events: 
This is an investigator-initiated study sponsored by Secura Bio. The principal investigator 
has the obligation to report all serious adverse events to Secura Bio. This includes serious, 
related, labeled (expected) and serious, related, unlabeled (unexpected) adverse 
experiences. All deaths during treatment or within 30 days following completion of active 
protocol therapy must be reported within 24 hours. 
Any serious adverse event occurring after the patient has provided informed consent and 


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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. 
 
11.5. 
Protocol amendments or changes in study conduct 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by Novartis and the investigator before implementation. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or 
the scientific quality of the study require additional approval by the IRB at each study center. 
A  copy of the written approval of the IRB must be provided to Novartis. Examples of 
amendments requiring such approval are: 
1. Increases in drug dose or duration of exposure of subjects, 
2. Significant changes in the study design (e.g. addition or deletion of a control group), 
3. Increases in the number of invasive procedures, 
4. Addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from 
being taken by the investigator or by Novartis in the interests of preserving the safety of all 
patients included in the trial. If an immediate change to the protocol is felt to be necessary 
by the investigator and is implemented for safety reasons Novartis must be notified and 
the IRB at the center must be informed immediately. 
 
 
12.0 Correlative Studies 
These correlative studies will be optional for patients participating in this trial. We will 
measure by RT-PCR the pretransplant levels of the following markers of UPR in myeloma 
cells extracted from a bone marrow aspirate: XBP1, IRE1, XBP1u, XPB1s, and Myc. 
Myeloma cells will be purified as described and cryopreserved until analysis.[27] 
 
1. We will study the prognostic effect of pretransplant levels in myeloma cells of XBP1, 
IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, by analyzing their correlation 
with PFS and OS. 
 
2. We will determine the predictive value of pretransplant levels in myeloma cells of 
XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, by analyzing their 
correlation with CR, VGPR+CR and RR. 
 
Correlative studies will be conducted in the laboratory of Ben Valdez, Ph.D. at MD Anderson. 
 
 
 
 
 
 


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13.0 Statistical Considerations 
Overview: 
 
This is a Phase II clinical trial examining the effect of panobinostat + Gemcitabine/Busulfan/ 
Melphalan (Gem/Bu/Mel) with hematopoietic cell support in patients with refractory or relapsed 
myeloma. There will be two parallel cohorts: 1) patients with refractory disease receiving their 
first transplant, and 2) patients receiving a second salvage transplant. We expect to enroll 40 
patients in each cohort and a total of 80 patients in the study. The primary objective in each 
cohort is to assess whether progression-free survival (PFS) can be improved over historical 
patients treated with Gem/Bu/Mel. Secondary objectives include assessing overall survival, 
response rates, toxicity, and various biomarkers. Study endpoints will only be assessed among 
patients who have received the study treatment. 
 
Primary Endpoint 
 
Progression-free survival. 
Secondary Endpoints 
1. Complete response (CR) rate 
2. Overall survival (OS) 
3. CR + very good partial remission (VGPR) rate 
4. Response rate (RR) 
5. Minimal residual disease post-transplant measured by multiparametric flow cytometry 
6. To describe the toxicity profile 
7. To analyze the predictive value of pretransplant levels in myeloma cells of XBP1, 
IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, by analyzing their correlation 
with CR, VGPR+CR and RR. 
8. To study the prognostic effect of pretransplant levels in myeloma cells of XBP1, 
IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, by analyzing their correlation 
with PFS and OS. 
 
Sample Size and Power 
The 1-year PFS rate in cohort 1 (refractory, 1st transplant) associated with GemBuMel is 
62%. With 40 patients in this cohort, assuming exponentially-distributed PFS times, 1.5 
years of accrual followed by 2 years of follow-up, and a one-sided 5% Type I error rate, 40 
patients provides more than 80% power to detect an increase in one-year PFS to 75% in 
this cohort. 
 
In cohort 2 (2nd transplant), the historical 1-year PFS rate is 55%. Under the same 
assumptions, 40 patients will provide more than 80% power to detect an increase in 1-
year PFS to 69%. 
 
Patients lost to follow-up before 1 year will be censored at the time of their last follow-
up.  
 
Safety Monitoring Endpoints 
To ensure patient safety in this trial, we will monitor the rate of treatment-related mortality 
(TRM). We target a maximum TRM rate of no more than 5%. The method of Thall et al 
will be employed to perform interim safety monitoring.[28]. 


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During the treatment administration and until day +100 all patients will be monitored for 
toxicity, specifically for grade 3 or greater side effects, according to CTCAE v4.0. 
Response will be assessed by day +100 using the International Myeloma Working Group 
(IMWG) uniform response criteria. 
 
Safety Monitoring Rule 
To monitor the treatment-related mortality (TRM) rate, a binary outcome, there are two 
possible elementary outcomes. They are 1 = [treatment-related death], 2 = [alive or death 
due to other causes]. We denote the probability vector with the experimental treatment by 
qE.  We assume a Beta (0.1, 1.9) prior on qE, which corresponds to a mean TRM rate of 
5%. Because we expect the TRM rate not to differ between the two cohorts of patients, 
this monitoring rule will be applied overall rather than by cohort. 
 
The following decision criteria will be applied after a minimum of 2 patients has been 
evaluated, up to the last patient. Targeting a 5% TRM rate as a trade-off, the trial will be 
stopped early if: 
 
Pr[qE(TRM rate) > 5% | data] > 0.975 
 
That is, if at any time during the trial we determine that we have greater than 97.5% posterior 
probability that the TRM rate is higher than 5%, we will stop enrollment into the trial. Stopping 
boundaries corresponding to this probability criterion are found in the following table. 
 
TRM Monitoring Rule Stopping Boundaries 
 
Total number of patients: 
Stop if this many patients have TRM: 
1 
Never stop with this many patients 
2-4 
2-4 
5-12 
3-12 
13-22 
4-22 
23-33 
5-33 
34-45 
6-45 
46-58 
7-58 
59-71 
8-71 
72-79 
9-79 
80 
Always stop at 80 patients 
 
 


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This stopping rule was simulated using the program Multc Lean Desktop version 2.1.0, 
available from the MDACC Department of Biostatistics. This leads to the operating 
characteristics found in the table below. 
Operating Characteristics for Monitoring Rule 
 
True Pr (TRM) 
Early Stopping 
Probability 
Sample Size Quartiles 
25th 
50th 
75th 
0.025 
0.008 
80 
80 
80 
0.05 
0.075 
80 
80 
80 
0.075 
0.269 
70 
80 
80 
0.10 
0.542 
29 
69 
80 
0.125 
0.773 
18 
40 
74 
 
Secondary Analyses 
 
Summary statistics will be provided for continuous variables. Frequency tables will be 
used to summarize categorical variables. Response rates (CR; CR/VGPR; RR) will be 
reported along with corresponding 95% confidence intervals. Logistic regression will be 
used to model the association between response rates and prognostic factors. Overall 
survival (OS) and progression free survival (PFS) will be estimated by the Kaplan-Meier 
method. Comparison of time to event endpoints by subgroups will be made using the log-
rank test. Cox proportional hazards regression will be employed for univariate and 
multivariate analysis on time-to-event outcomes. The treatment-related morality rate will 
be computed and presented with 95% confidence interval. Adverse events will be 
tabulated for all patients. 
 
We will analyze the correlation with PS and OS of pretransplant levels in myeloma cells of 
XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, using the log-rank test. We will 
analyze the correlation with CR, VGPR+CR and RR of pretransplant levels in myeloma 
cells of XBP1, IRE1, XBP1u, XPB1s, XBP1u/XPBs ratio and Myc, using Fisher’s F test. 
 
14.0 Background Drug Information 
14.1. Panobinostat 
 
Panobinostat is a HDACi belonging to a structurally novel cinnamic hydroxamic acid class 
of compounds. It is a potent class I/II pan-HDACi with 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. 
 
Clinical development of panobinostat focuses on the oral formulation. The clinical 
program for the i.v. formulation is completed with no further company-sponsored studies 
currently planned. As of 31 December 2013, 36 clinical studies, including clinical 
pharmacology, phase I and phase II trials, as well as two randomized phase III studies 
have either been completed or are ongoing. A total of 2428 patients were enrolled, 235 
for i.v. and 2193 for oral, who received at least one dose of panobinostat either as a 
single agent or in combination with other agents. 


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Patients were treated with panobinostat either TIW QW (666 patients) or TIW QOW (96 
patients) in single agent trials. These patients comprise the pooled safety population 
experiencing adverse (AE) events during study treatment. The most frequent non-
hematologic AE included gastrointestinal events (diarrhea, nausea, vomiting), mostly of 
grade 1-2, in both  groups. Blood and lymphatic system disorders were the second most 
often reported specific system organ class, with dose-related thrombocytopenia being the 
most frequent AE. Fatigue, mostly grade 1-2, was also common among patients treated 
for TIW QW and TIW QOW. 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. 
 
Table 4  All grade adverse events regardless of causality in patients receiving oral 
panobinostat three-times-a-week every-week (TIW QW) 
 
Primary system organ 
class Preferred term 
20 mg 
(N=309 
N      % 
30 mg 
(N=81) 
N      % 
40 mg 
(N=163) 
N      % 
60 mg 
(N=113) 
N      % 
TOTAL 
(N=666) 
N      % 
-Any primary system 
organ class 
 
 
 
 
 
-Total 
307 (99.4) 
81 (100.0) 
163(100.0) 
113(100.0) 
664 (99.7) 
Blood and lymphatic 
system disorders 
 
 
 
 
 
-Total 
193 (62.5) 
50 (61.7) 
145 (89.0) 
87 (77.0) 
475 (71.3) 
Anemia 
63 (20.4) 
32 (39.5) 
65 (39.9) 
35 (31.0) 
195 (29.3) 
Febrile neutropenia 
9 (2.9) 
0 (0.0) 
7 (4.3) 
33 (29.2) 
49 (7.4) 
Leukopenia 
19 (6.1) 
1(1.2) 
18 (11.0) 
4 (3.5) 
42 (6.3) 
Neutropenia 
53 (17.2) 
4 (4.9) 
48 (29.4) 
29 (25.7) 
134 (20.1) 
Thrombocytopenia 
133 ( 43.0) 
31(38.3) 
137(84.0) 
58 (51.3) 
359 (53.9) 
Endocrine disorders 
 
 
 
 
 
-Total 
21 (6.8) 
7 (8.6) 
27 (16.6) 
9 (8.0) 
64 (9.6) 
Hypothyroidism 
15 (4.9) 
3 (3.7) 
21 (12.9) 
4 (3.5) 
43 (6.5) 
Gastrointestinal disorders 
 
 
 
 
 
-Total 
246 (79.6) 
76 (93.8) 
152 (93.3) 
107(94.7) 
581(87.2) 
Abdominal pain 
33 (10.7) 
11 (13.6) 
30 (18.4) 
23 (20.4) 
97 (14.6) 
Abdominal pain upper 
26 (8.4) 
5 (6.2) 
24 (14.7) 
9(  8.0) 
64(  9.6) 
Constipation 
46 (14.9) 
15 (18.5) 
32 (19.6) 
24 (21.2) 
117( 17.6) 
Diarrhea 
158 (51.1) 
46 (56.8) 
117 (71.8) 
85 (75.2) 
406 (61.0) 
Dry mouth 
17 (5.5) 
6 (7.4) 
22 (13.5) 
9 (8.0) 
54 (8.1) 
Nausea 
142( 46.0) 
51( 63.0) 
112( 68.7) 
67( 59.3) 
372( 55.9) 
Vomiting 
68( 22.0) 
33( 40.7) 
73( 44.8) 
47( 41.6) 
221( 33.2) 
General disorders and 
administration site 
conditions 
 
 
 
 
 
-Total 
229( 74.1) 
70( 86.4) 
137( 84.0) 
98( 86.7) 
534( 80.2) 
Asthenia 
52( 16.8) 
6(  7.4) 
29( 17.8) 
21( 18.6) 
108( 16.2) 
Chills 
19(  6.1) 
4(  4.9) 
13(  8.0) 
17( 15.0) 
53(  8.0) 
Fatigue 
126( 40.8) 
56( 69.1) 
85( 52.1) 
59( 52.2) 
326( 48.9) 
Edema peripheral 
62( 20.1) 
21( 25.9) 
30( 18.4) 
24( 21.2) 
137( 20.6) 
Pyrexia 
61( 19.7) 
18( 22.2) 
67( 41.1) 
47( 41.6) 
193( 29.0) 
Infections and infestations 
 
 
 
 
 


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-Total 
152( 49.2) 
40( 49.4) 
101( 62.0) 
76( 67.3) 
369( 55.4) 
Sepsis 
6(  1.9) 
3(  3.7) 
4(  2.5) 
13( 11.5) 
26(  3.9) 
Upper respiratory tract 
infection 
12(  3.9) 
5(  6.2) 
24( 14.7) 
4(  3.5) 
45(  6.8) 
Urinary tract infection 
23(  7.4) 
11( 13.6) 
10(  6.1) 
7(  6.2) 
51(  7.7) 
Investigations 
 
 
 
 
 
-Total 
143( 46.3) 
40( 49.4) 
71( 43.6) 
57( 50.4) 
311( 46.7) 
Blood creatinine increased 
37( 12.0) 
7(  8.6) 
13(  8.0) 
13( 11.5) 
70( 10.5) 
Platelet count decreased 
13(  4.2) 
14( 17.3) 
4(  2.5) 
7(  6.2) 
38(  5.7) 
Weight decreased 
44( 14.2) 
12( 14.8) 
30( 18.4) 
22( 19.5) 
108( 16.2) 
Metabolism and nutrition 
disorders 
 
 
 
 
 
-Total 
179( 57.9) 
56( 69.1) 
92( 56.4) 
83( 73.5) 
410( 61.6) 
Anorexia 
45( 14.6) 
10( 12.3) 
16(  9.8) 
24( 21.2) 
95( 14.3) 
Decreased appetite 
49( 15.9) 
30( 37.0) 
49( 30.1) 
31( 27.4) 
159( 23.9) 
Dehydration 
12(  3.9) 
12( 14.8) 
13(  8.0) 
19( 16.8) 
56(  8.4) 
Hypocalcemia 
22(  7.1) 
3(  3.7) 
8(  4.9) 
21( 18.6) 
54(  8.1) 
Hypokalemia 
33( 10.7) 
11( 13.6) 
28( 17.2) 
35( 31.0) 
107( 16.1) 
Hypophosphatemia 
25(  8.1) 
1(  1.2) 
9(  5.5) 
14( 12.4) 
49(  7.4) 
Musculoskeletal and 
connective tissue 
disorders 
 
 
 
 
 
-Total 
114( 36.9) 
29( 35.8) 
90( 55.2) 
43( 38.1) 
276( 41.4) 
Back pain 
35( 11.3) 
8(  9.9) 
30( 18.4) 
13( 11.5) 
86( 12.9) 
Muscle spasms 
19(  6.1) 
6(  7.4) 
32( 19.6) 
2(  1.8) 
59(  8.9) 
Myalgia 
16(  5.2) 
1(  1.2) 
17( 10.4) 
2(  1.8) 
36(  5.4) 
Nervous system disorders 
 
 
 
 
 
-Total 
147( 47.6) 
36( 44.4) 
86( 52.8) 
52( 46.0) 
321( 48.2) 
Dizziness 
42( 13.6) 
14( 17.3) 
15(  9.2) 
10(  8.8) 
81( 12.2) 
Dysgeusia 
44( 14.2) 
13( 16.0) 
28( 17.2) 
22( 19.5) 
107( 16.1) 
Headache 
49( 15.9) 
14( 17.3) 
34( 20.9) 
16( 14.2) 
113( 17.0) 
Psychiatric disorders 
 
 
 
 
 
-Total 
65( 21.0) 
17( 21.0) 
43( 26.4) 
38( 33.6) 
163( 24.5) 
Anxiety 
12(  3.9) 
3(  3.7) 
18( 11.0) 
9(  8.0) 
42(  6.3) 
Insomnia 
20(  6.5) 
10( 12.3) 
14(  8.6) 
19( 16.8) 
63(  9.5) 
Respiratory, thoracic and 
mediastinal disorders 
 
 
 
 
 
-Total 
117( 37.9) 
42( 51.9) 
97( 59.5) 
53( 46.9) 
309( 46.4) 
Cough 
30(  9.7) 
11( 13.6) 
48( 29.4) 
19( 16.8) 
108( 16.2) 
Dyspnea 
49( 15.9) 
28( 34.6) 
32( 19.6) 
20( 17.7) 
129( 19.4) 
Epistaxis 
16(  5.2) 
3(  3.7) 
22( 13.5) 
20( 17.7) 
61(  9.2) 
Skin and subcutaneous 
tissue disorders 
 
 
 
 
 
-Total 
147( 47.6) 
21( 25.9) 
73( 44.8) 
38( 33.6) 
279( 41.9) 
Pruritus 
56( 18.1) 
3(  3.7) 
22( 13.5) 
3(  2.7) 
84( 12.6) 
Vascular disorders 
 
 
 
 
 
-Total 
61( 19.7) 
17( 21.0) 
26( 16.0) 
33( 29.2) 
137( 20.6) 
Hypotension 
18(  5.8) 
4(  4.9) 
10(  6.1) 
18( 15.9) 
50(  7.5) 
Includes only events 
occurring in ≥10% of 
patients 
 
 
 
 
 


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A patient with multiple 
occurrences of an AE is 
counted only once in that AE 
category. 
A patient with multiple 
adverse events within a 
primary system organ class 
is counted only once in the 
total row. 
If an AE frequency matches 
the criteria in one dose 
category, the frequency of 
that event is shown for all 
doses. 
Primary system organ 
classes are presented 
alphabetically; preferred 
terms are sorted within 
primary system organ class 
alphabetically. 
 
As shown above, AEs regardless of causality for TIW QW dosing were reported in 664 
patients, 99.7% of the safety population for this dosing schedule. The most commonly 
reported AEs across doses were gastrointestinal: diarrhea in 406 patients (61.0%) and 
nausea in 372 patients (55.9%). Thrombocytopenia was the third most frequent AE in 359 
patients (53.9%) with the highest frequency in the 40 mg dose level (137 patients; 84%). 
Fatigue also was commonly seen across dose levels in 326 patients (48.9%) overall. Of 
note hypothyroidism was reported in 12.9% of patients treated at the dose level of 40 mg, 
mostly deriving from study [CLBH589E2214] in HL patients who are known to have an 
increased risk for hypothyroidism. 
 
Table 5. Grade 3-4 adverse events regardless of causality in patients receiving 
oral panobinostat three-times-a-week every-week (TIW QW)  
 
Primary system organ class 
20 mg 
30 mg 
40 mg 
60 mg 
Total 
Preferred term 
N=309 
N=81 
N=163 
N=113 
N=666 
 
N  (%) 
N  (%) 
N  (%) 
N  (%) 
N  (%) 
-Any primary system organ class 
 
 
 
 
 
-Total 
209( 67.6) 
70( 86.4) 
150(92.0) 
105(92.9) 
534( 80.2) 
Blood and lymphatic system 
disorders 
 
 
 
 
 
-Total 
120( 38.8) 
26( 32.1) 
138(84.7) 
84( 74.3) 
368( 55.3) 
Anemia 
29( 9.4) 
8( 9.9) 
35( 21.5) 
31( 27.4) 
103( 15.5) 
Febrile neutropenia 
9( 2.9) 
0( 0.0) 
6( 3.7) 
31( 27.4) 
46(  6.9) 
Leukocytosis 
4( 1.3) 
2( 2.5) 
0( 0.0) 
3(2.7) 
9( 1.4) 
Leukopenia 
2( 0.6) 
0( 0.0) 
11(  6.7) 
4(  3.5) 
17(  2.6) 
Neutropenia 
42( 13.6) 
4( 4.9) 
39( 23.9) 
26( 23.0) 
111( 16.7) 
Thrombocytopenia 
66( 21.4) 
21( 25.9) 
129( 79.1) 
56( 49.6) 
272( 40.8) 
Gastrointestinal disorders 
 
 
 
 
 
-Total 
24( 7.8) 
20( 24.7) 
24( 14.7) 
31( 27.4) 
99( 14.9) 
Abdominal pain 
5(  1.6) 
3(  3.7) 
7(  4.3) 
2(  1.8) 
17(  2.6) 


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Ascites 
0(  0.0) 
4(  4.9) 
0(  0.0) 
0(  0.0) 
4(  0.6) 
Diarrhea 
10(  3.2) 
6(  7.4) 
6(  3.7) 
18( 15.9) 
40(  6.0) 
Nausea 
6(  1.9) 
6(  7.4) 
2(  1.2) 
7(  6.2) 
21(  3.2) 
Vomiting 
4(  1.3) 
3(  3.7) 
4(  2.5) 
3(  2.7) 
14(  2.1) 
General disorders and 
administration site conditions 
 
 
 
 
 
-Total 
35( 11.3) 
25( 30.9) 
38( 23.3) 
41( 36.3) 
139( 20.9) 
Asthenia 
8(2.6) 
2(2.5) 
7(4.3) 
10(8.8) 
27( 4.1) 
Fatigue 
13(4.2) 
19( 23.5) 
26( 16.0) 
24( 21.2) 
82( 12.3) 
General physical health deterioration 
6(1.9) 
2(2.5) 
0(0.0) 
1(0.9) 
9(1.4) 
Pain 
3(1.0) 
0(0.0) 
0(0.0) 
3(2.7) 
6(0.9) 
Pyrexia 
4(1.3) 
1(1.2) 
4(2.5) 
2(1.8) 
11(1.7) 
Hepatobiliary disorders 
 
 
 
 
 
-Total 
3(1.0) 
3( 3.7) 
6(3.7) 
3(2.7) 
15(2.3) 
Hyperbilirubinemia 
2(0.6) 
0(0.0) 
4(2.5) 
2(1.8) 
8(1.2) 
Infections and infestations 
 
 
 
 
 
-Total 
37( 12.0) 
12( 14.8) 
27( 16.6) 
49( 43.4) 
125( 18.8) 
Bacterial infection 
0(0.0) 
0(0.0) 
1(0.6) 
5(4.4) 
6(0.9) 
Infection 
1(0.3) 
2(2.5) 
1( 0.6) 
1(0.9) 
5(0.8) 
Pneumonia 
7( 2.3) 
2(2.5) 
6(3.7) 
6 ( 5.3) 
21(3.2) 
Sepsis 
5(1.6) 
3( 3.7) 
4( 2.5) 
9( 8.0) 
21(3.2) 
Septic shock 
2(0.6) 
1(1.2) 
1(0.6) 
3(2.7) 
7(1.1) 
Urinary tract infection 
1( 0.3) 
3(3.7) 
0( 0.0) 
3( 2.7) 
7(1.1) 
Investigations 
 
 
 
 
 
-Total 
39( 12.6) 
14( 17.3) 
22( 13.5) 
26( 23.0) 
101( 15.2) 
Alanine aminotransferase increased 
1(0.3) 
1(1.2) 
4(2.5) 
1(0.9) 
7(1.1) 
Aspartate aminotransferase increased 
1(0.3) 
0(0.0) 
5(3.1) 
1(0.9) 
7(1.1) 
Electrocardiogram qt prolonged 
6(1.9) 
1(1.2) 
0(0.0) 
4(3.5) 
11(1.7) 
Platelet count decreased 
8(2.6) 
7(8.6) 
3(1.8) 
6(5.3) 
24(3.6) 
Weight decreased 
2(0.6) 
1(1.2) 
4(2.5) 
1(0.9) 
8(1.2) 
Metabolism and nutrition disorders 
 
 
 
 
 
-Total 
42( 13.6) 
16( 19.8) 
27( 16.6) 
38( 33.6) 
123( 18.5) 
Anorexia 
3(1.0) 
1(1.2) 
2(1.2) 
5(4.4) 
11(1.7) 
Decreased appetite 
2(0.6) 
0( 0.0) 
5(3.1) 
3( 2.7) 
10(1.5) 
Dehydration 
2(0.6) 
4(4.9) 
2(1.2) 
5( 4.4) 
13( 2.0) 
Failure to thrive 
1(0.3) 
2(2.5) 
0(0.0) 
0( 0.0) 
3( 0.5) 
Hyperglycemia 
6(1.9) 
1(1.2) 
3(1.8) 
5(4.4) 
15(2.3) 
Hypoalbuminemia 
1(0.3) 
2(2.5) 
1(0.6) 
0( 0.0) 
4(0.6) 
Hypocalcemia 
4(1.3) 
0(0.0) 
1( 0.6) 
5(4.4) 
10(1.5) 
Hypokalemia 
10(3.2) 
3(3.7) 
9(5.5) 
15( 13.3) 
37(5.6) 
Hyponatremia 
7(2.3) 
3(3.7) 
2(1.2) 
2(1.8) 
14(2.1) 
Hypophosphatemia 
7(2.3) 
1(1.2) 
5(3.1) 
10(8.8) 
23(3.5) 
Musculoskeletal and connective 
tissue disorders 
 
 
 
 
 
-Total 
18(  5.8) 
2(  2.5) 
12(  7.4) 
7(  6.2) 
39(  5.9) 
Back pain 
5(  1.6) 
1(  1.2) 
4(  2.5) 
2(  1.8) 
12(  1.8) 
Nervous system disorders 
 
 
 
 
 
-Total 
24(  7.8) 
4(  4.9) 
16(  9.8) 
14( 12.4) 
58(  8.7) 
Lethargy 
1(  0.3) 
0(  0.0) 
5(  3.1) 
4(  3.5) 
10(  1.5) 
Respiratory, thoracic and 
mediastinal disorders 
 
 
 
 
 


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-Total 
17(  5.5) 
14( 17.3) 
18( 11.0) 
10(  8.8) 
59(  8.9) 
Dyspnea 
10(  3.2) 
8(  9.9) 
8(  4.9) 
1(  0.9) 
27(  4.1) 
Hypoxia 
0(  0.0) 
2(  2.5) 
2(  1.2) 
3(  2.7) 
7(  1.1) 
Pleural effusion 
3(  1.0) 
2(  2.5) 
1(  0.6) 
0(  0.0) 
6(  0.9) 
Pulmonary embolism 
1(  0.3) 
2(  2.5) 
3(  1.8) 
0(  0.0) 
6(  0.9) 
Skin and subcutaneous tissue 
disorders 
 
 
 
 
 
-Total 
20(  6.5) 
1(  1.2) 
6(  3.7) 
4(  3.5) 
31(  4.7) 
Pruritus 
9(  2.9) 
0(  0.0) 
3(  1.8) 
1(  0.9) 
13(  2.0) 
Vascular disorders 
 
 
 
 
 
-Total 
8(  2.6) 
5(  6.2) 
9(  5.5) 
8(  7.1) 
30(  4.5) 
Hypertension 
1(  0.3) 
2(  2.5) 
1(  0.6) 
1(  0.9) 
5(  0.8) 
Hypotension 
3(  1.0) 
1(  1.2) 
4(  2.5) 
5(  4.4) 
13(  2.0) 
Includes only events occurring ≥ 2% of 
patients in any dose group. 
A patient with multiple occurrences of 
an AE is counted only once in that AE 
category. 
A patient with multiple adverse events 
within a primary system organ class is 
counted only once in the total row. 
Primary system organ classes are 
presented alphabetically; preferred 
terms are sorted 
within primary system organ class 
alphabetically. 
If an AE frequency matches the criteria 
in one dose category, the frequency of 
that event is shown for all doses. 
 
 
 
 
 
 
 
As shown above, grade 3-4 AEs regardless of causality were reported in 534 patients, 
80.2% of the safety population for the QW schedule. The most commonly reported 
grade 3-4 AEs across doses were thrombocytopenia in 272 patients (40.8%), 
neutropenia in111 patients (16.7%), anemia in 103 patients (15.5%), fatigue in 82 
patients (12.3%) and febrile neutropenia in 46 patients (6.9%). There were more grade 
3-4 hematologic AEs at higher dose levels, with the highest incidences at 40 and 60 mg. 
The highest incidence of febrile neutropenia was seen at the dose level of 60 mg 
(27.4%) compared to the other dose levels where the incidence was  3.7%. This could 
be because this dose level was only tested in leukemia patients, in whom febrile 
neutropenia is a common AE. Grade 3-4 thrombocytopenia, grade 3-4 neutropenia and 
grade 3-4 anemia accounted for 75.7% (272/359), 82.8% (111/134) and 52.8% 
(103/195) of their respective all grade events. 
Grade3-4 diarrhea, grade 3-4 vomiting and grade 3-4 nausea accounted for less than 
10% of their respective all grade events. For the TIW QOW dosing schedule, AEs 
regardless of causality were reported in 96 patients, which is 100% of the safety 
population. The most commonly reported AEs (all grades) across doses were diarrhea in 
65 patients (67.7%), nausea in 60 patients (62.5%), fatigue in 54 patients (56.3%), 
vomiting in 42 patients (43.8%), thrombocytopenia in 41 patients (42.7%), pyrexia in 35 
patients (36.5%) and anorexia in 33 patients (34.4%). 
 
In the TIWQOW schedule, Grade 3-4 AEs regardless of causality were reported in 81 


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patients, 84.4% of the safety population. The most commonly reported Grade 3-4 AEs 
across doses were thrombocytopenia in 35 patients (36.5%), neutropenia in 25 patients 
(26.0%), fatigue in 
14 patients (14.6%), diarrhea in 11 patients (11.5%), anemia in 10 patients (10.4%), 
and febrile neutropenia in 8 patients each (8.3%). 
 
Overall, the most frequent Grade 3-4 AEs regardless of causality for both schedules 
(TIWQW and TIWQOW) were ascribed to the same SOC, namely blood and lymphatic 
system disorders. 
 
FDA boxed warning for Panobinostat: 
a. Warning: Fatal and Serious Toxicities: Severe Diarrhea and Cardiac Toxicities 
b. Severe diarrhea occurred in 25% of panobinostat treated patients. 
c. Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes 
have occurred in patients receiving panotbinostat. Arrhythmias may be exacerbated by 
electrolyte abnormalities 
 
Human pharmacokinetics 
After oral administration, panobinostat is rapidly absorbed with no observed lag phase. 
Maximum plasma concentrations were generally reached within 1 hour after oral dosing. 
The absolute bioavailability was 30% and the mean (SD) half-life of panobinostat was 
comparable following i.v. and oral dosing ~15.0 hours. Moderate drug accumulation was 
observed with oral three-times-a-week schedule but not with the weekly i.v. schedule 
(1.4-fold drug accumulation with oral three-times-a-week dosing), consistent with the 
terminal half-life of 15 hours and dosing interval. 
 
In vitro experiments suggested that the hepatic oxidative metabolism of panobinostat is 
mediated primarily by cytochrome P450 (CYP3A4), and to a lesser extent by CYP2D6 and 
CYP2C19. In addition to monooxygenation, hydrolysis of the hydroxamic chain were also 
found to be mediated (at least in-part) by the CYPs. 
 
Dose proportionality 
A positive and linear dose-exposure relationship was found following single i.v. 
administration (1.2 to 20 mg/m2, Rs = 0.83; p<0.0001). After oral dosing with 15 mg to 80 
mg of panobinostat, dose-proportionality analysis indicated that systemic exposure 
increased nearly 
dose-proportionally at doses below 60 mg and there is less than proportional increase in 
AUC after 60 mg and 80 mg doses of panobinostat. It appears that absorption may become 
limiting at doses ꞏ 60 mg of panobinostat. 
 
Food Effect 
Influence of food on panobinostat PK was evaluated in patients with advanced cancer who 
received 20 mg panobinostat twice a week and were randomized to receive panobinostat 
under fasting, high fat, and normal breakfast conditions. The overall exposure and inter-
patient variability (CV 59%) in 34 patients remained unchanged with or without food, 
whereas Cmax was transiently reduced by <45% and Tmax prolonged by food (i.e., both 
normal and high fat breakfast). Since food did not alter the overall extent of absorption, 
food is unlikely to significantly impact panobinostat systemic exposure in cancer patients. 
Therefore, panobinostat can be administered without regard to food. 
 


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Electrocardiographic experience and cardiac safety of with panobinostat. 
Cardiac safety in patients with hematologic malignancies 
As of 31 December 2013, cardiac safety data for 666 patients treated with oral 
panobinostat TIW QW are available. All patients underwent intensive pre- and post-dose 
ECG monitoring. The most common finding is a post-baseline QTc increase of >30 and 
ꞏ60 msec in approximately 22%. No cases of torsades de pointes have been observed. A 
post-baseline increase of >60 msec was less frequent (27 patients, 4.1%). QTc 
prolongation translating into an absolute value of 450 to 480 msec and of > 480 - 500 
msec was measured in 88 patients (13.4%) and in 17 patients (2.6%), respectively. 
Absolute QTc prolongation > 500 msec was uncommon (6 patients, 0.9%), mostly 
referred to 5 patients treated at 60 mg weekly dose level. 
The maximum change of QTc from baseline does not coincide with the peak 
plasma concentration-time course of panobinostat suggesting a possible 
delayed effect. 
 
Drug interactions 
Panobinostat is a CYP3A substrate and inhibits CYP2D6. Panobinostat is a P-
glycoprotein (P-gp) transporter system substrate. 
a. Agents that May Increase panobinostat Blood Concentrations 
b. CYP3A Inhibitors: Coadministration of panobinostat with a strong CYP3A inhibitor 
increased the Cmax and AUC of panobinostat by 62% and 73% respectively, compared 
to when panobinostat was given alone. 
c. Reduce dose to 10 mg when coadministered with strong CYP3A inhibitors (e.g., 
boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole). Instruct patients to avoid star fruit, pomegranate or 
pomegranate juice, and grapefruit or grapefruit juice because these foods are known to 
inhibit CYP3A enzymes. 
d. Agents that May Decrease panobinostat Plasma Concentrations 
e. CYP3A Inducers: Coadministration of panobinostat with strong CYP3A inducers was 
not evaluated in vitro or in a clinical trial however, a reduction in panobinostat exposure is 
likely. An approximately 70% decrease in the systemic exposure of panobinostat in the 
presence of strong inducers of CYP3A was observed in simulations using mechanistic 
models. Therefore, the concomitant use of strong CYP3A inducers should be avoided. 
f. Agents whose Plasma Concentrations May be Increased by panobinostat 
g. CYP2D6 Substrates: 
Panobinostat increased the median Cmax and AUC of a sensitive substrate of 
CYP2D6 by approximately 80% and 60%, respectively; however this was highly 
variable. Avoid coadministrating 
panobinostat with sensitive CYP2D6 substrates (i.e., atomoxetine, desipramine, 
dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and venlafaxine) or 
CYP2D6 substrates that have a narrow therapeutic index (i.e., thioridazine, pimozide). If 
concomitant use of CYP2D6 substrates is unavoidable, monitor patients frequently for 
adverse reactions. 
h. Drugs that Prolong QT interval 
i. Concomitant use of anti-arrhythmic medicines (including, but not limited to 
amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that 
are known to prolong the QT interval (including, but not limited to chloroquine, 
halofantrine, clarithromycin, methadone, moxifloxacin, bepridil and pimozide) is not 


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recommended. Anti-emetic drugs with known QT prolonging risk, such as dolasetron, 
ondansetron, and tropisetron can be used with frequent ECG monitoring. 
 
Hepatic Impairment 
a. The safety and efficacy of panobinostat in patients with hepatic impairment has not 
been evaluated. 
b. In a pharmacokinetic trial, patients with mild (bilirubin ꞏ1xULN and AST >1xULN, or bilirubin 
>1.0 to 1.5x ULN and any AST) or moderate (bilirubin >1.5x to 3.0x ULN, any AST) 
hepatic impairment (NCI-ODWG criteria) had increased AUC of panobinostat by 43% and 
105%, respectively. Reduce the starting dose of panobinostat in patients with mild or 
moderate hepatic impairment. Avoid use in patients with severe hepatic impairment. 
Monitor patients with hepatic impairment frequently for adverse events. 
Renal Impairment 
d. Mild [creatinine clearance (CrCl) ꞏ50 to <80 mL/min] to severe renal impairment (CrCl 
<30 mL/min) did not impact the plasma exposure of panobinostat. Panobinostat has not 
been studied in patients with end stage renal disease (ESRD) or patients on dialysis. The 
dialyzability of panobinostat is unknown. 
Monitoring parameters: 
a. Complete Blood Count (CBC): Obtain a CBC before initiating treatment. Verify that 
the baseline platelet count is at least 100 x 109/L and the baseline absolute neutrophil 
count (ANC) is at least 1.5 x 109/L. Monitor the CBC weekly (or more often as clinically 
indicated) during treatment. 
b. ECG: Perform an ECG prior to the start of therapy and repeat periodically during 
treatment as clinically indicated. Verify that the QTcF is less than 450 msec prior to 
initiation of treatment with 
panobinostat . If during treatment with panobinostat , the QTcF increases to ꞏ480 msec, 
interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not 
resolve, permanently discontinue treatment with panobinostat. During the clinical trial, 
ECGs were performed at baseline and prior to initiation of each cycle for the first 8 cycles. 
c. Serum Electrolytes: Obtain electrolytes, including potassium and magnesium, at 
baseline and monitor during therapy. Correct abnormal electrolyte values before 
treatment. During the trial, monitoring was conducted prior to the start of each cycle, at 
Day 11 of cycles 1 to 8, and at the start of each cycle for cycles 9 to 16. 
 
14.2. Gemcitabine 
Synonyms: Gemcitabine hydrochloride, difluorodeoxycytidine, 2',2'-
difluorodeoxycytidine, dFdC, LY 188011 
 
Common Trade Name(S): Gemzar® 
 
Classification: Antimetabolite, cytotoxic 
 
Special pediatric considerations are noted when applicable, otherwise adult provisions apply. 
 
Mechanism of Action: 
 
Gemcitabine, a pyrimidine analog, is structurally similar to cytarabine, but has a wider 
spectrum of antitumor activity due to its different cellular pharmacology and mechanism of 
action. 
Gemcitabine is metabolized intracellularly to two active metabolites, Gemcitabine 


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diphosphate (dFdCDP) and Gemcitabine triphosphate (dFdCTP). The cytotoxic effects of 
Gemcitabine are exerted through incorporation of dFdCTP into DNA with the assistance of 
dFdCDP, resulting in inhibition of DNA synthesis and induction of apoptosis. Gemcitabine 
is a radiation-sensitizing agent.5 It is cell-cycle phase specific (S and G1/S-phases). 
 
 
Pharmacokinetics:  
Interpatient variability 
3- to 4-fold interpatient and intrapatient variability 
Oral absorption 
No information found 
Distribution 
Widely distributed into tissues; also present in ascitic fluid. 
Cross blood brain barrier: No information found 
volume of distribution: IV infusion < 70 min: 50 L/m2; 
IV infusion 70-285 min: 370 L/m2 
plasma protein binding< 10% 
Metabolism 
Metabolized intracellularly by nucleoside kinases to active metabolites 
dFdCDP and dFdCTP; also metabolized intracellularly and extracellularly 
by cytidine deaminase to inactive metabolite difluorodeoxyuridine (dFdU) 
Active metabolites: dFdCDP, dFdCTP 
Inactive metabolites: dFdU 
Excretion 
Mainly renal excretion 
Urine 92-98% over one week (89% as dFdU, < 10% as Gemcitabine) after 
a single dose of 1000 mg/m2 given over 30 minutes. 
Terminal half-life: IV infusion < 70 min: 0.7-1.6 h 
IV infusion 70-285 min: 4.1-10.6 h  
Clearance: IV infusion < 70 min: 41-92 L/h/m2 (male), 31-69 L/h/m2 
(female) 
Gender 
Decreased volume of distribution and clearance in women 
Elderly 
Decreased clearance and increased half-life with increasing age 
Children 
No information found 
Ethnicity 
No information found 
 
 
 
Special Precautions: 
Carcinogenicity: No information found. 
Mutagenicity: Not mutagenic in Ames test but mutagenic in mammalian in vitro mutation test. 
Gemcitabine is lactogenic in mammalian in vitro and in vivo chromosome tests. 
Fertility: Decreased spermatogenesis and fertility in male mice. 
Pregnancy: FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the 


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benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed 
in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are 
ineffective). Breastfeeding is not recommended due to the potential secretion into breast milk. 
Side Effects:  
ORGAN SITE 
SIDE EFFECT 
ONSET 
 
 
 
Dose-limiting side effects are in bold, italics 
I = immediate (onset in 
hours to days); 
E = early (days to weeks); 
D = delayed (weeks to 
months); 
L = late (months to years) 
Allergy/Immunology 
allergic reaction (4%, severe 0.2%) 
I 
anemia (68%, severe 8%) 
E 
Leucopenia (62%, severe 9%) 
E 
neutropenia (63%, severe 25%)  
nadir 7-10 days, recovery within 7 days 
E 
Blood/Bone marrow 
Febrile Neutropenia 
thrombocytopenia (24%, severe 5%)  
nadir 7-10 days, recovery within 7 days 
E 
cardiac arrhythmia (2%, severe 0.2%) 
E 
Cardiovascular  
edema/peripheral edema (28%, severe 3%) 
ED 
Coagulation 
hemolytic uremic syndrome (0.3%) 
D 
asthenia (42%, severe 2%) 
E 
Constitutional symptoms 
fever (37%, severe < 1%) 
IE 
extravasation hazard: none 
 
alopecia (14%) 
D 
Dermatology 
skin rash (25%, severe < 1%) 
IE 
emetogenic potential: low moderate 
 
constipation (8%, severe < 1%) 
E 
diarrhea (12%, severe < 1%) 
E 
nausea and vomiting (64%, severe 18%) 
I 
Gastrointestinal 
stomatitis (8%, severe < 1%) 
E 
Hemorrhage 
hematuria (31%, severe < 1%) 
E 
elevated alkaline phosphatase (55%, severe 9%) 
E 
elevated AST (67%, severe 9%) 
E 
elevated ALT (68%, severe 10%) 
E 
Hepatic 
elevated bilirubin (13%, severe 2%) 
E 
Infection 
infection (9%, severe 1%) 
E 
decreased level of consciousness (9%, severe < 1%) 
E 
Neurology 
peripheral neuropathy (3%) 
ED 
Pain 
pain (16%, severe 1%) 
ED 
Pulmonary 
dyspnea (8%, severe 1%) 
IE 
elevated BUN (16%, severe 0%) 
E 
elevated creatinine (7%, severe < 1%) 
E 


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Renal/genitourinary 
Proteinuria (36%, severe < 1%) 
E 
Syndromes 
flu-like symptoms (19%, severe 1%)30 
E 
 
 
Hemolytic uremic syndrome has been infrequently reported and is characterized by 
microangiopathic hemolytic anemia, thrombocytopenia and renal failure. The syndrome 
can present either acutely with severe hemolysis, thrombocytopenia and rapidly 
progressive renal failure, or more insidiously with mild or no thrombocytopenia and slowly 
progressive renal failure. The etiology of hemolytic uremic syndrome is unknown. The 
onset of the syndrome has been reported to occur during and shortly after gemcitabine 
therapy. If not treated promptly, the syndrome may result in irreversible renal failure 
requiring dialysis. Therefore, patients with impaired renal function should be monitored 
closely while being treated with gemcitabine. 
Elevated liver enzymes: Gemcitabine causes transient and reversible elevations of liver 
function enzymes in about two-thirds of patients. However, these increases are rarely of 
clinical significance and there is no evidence of increasing hepatic toxicity with either 
longer duration of Gemcitabine treatment or cumulative dose. 
Fever/Flu-like symptoms: Fever of any severity was reported in 37% of patients. It is 
frequently associated with other flu-like symptoms such as headache, chills, cough, 
rhinitis, myalgia, fatigue, sweating and insomnia. These symptoms are usually mild and 
transient, and rarely dose-limiting. The use of acetaminophen may provide symptomatic 
relief. 
Severe pulmonary toxicity: Acute dyspnea may sometimes occur with gemcitabine 
therapy, but is usually self-limiting. However, severe pulmonary toxicities such as 
pulmonary edema, interstitial pneumonitis and adult respiratory distress syndrome have 
rarely been reported. The symptoms are manifested as progressive dyspnea, tachypnea, 
hypoxemia and pulmonary infiltrates on chest radiograph that are sometimes 
accompanied by fever and cough. Pulmonary toxicities usually occur after several cycles 
of gemcitabine, but have also been seen as early as the first cycle. Risk factors for 
pulmonary toxicities include prior radiation to the mediastinum. 
Because of its structural similarities to cytarabine, gemcitabine is thought to cause lung 
injury by the same mechanism by inducing pulmonary capillary leakage. Management of 
pulmonary toxicities consists of discontinuation of gemcitabine and early supportive care 
with bronchodilators, corticosteroids, diuretics, and/or oxygen. Although pulmonary 
toxicities may be reversible with treatment, fatal recurrence of severe pulmonary symptoms 
was reported in one patient upon rechallenge with gemcitabine. 
Skin rash: Typically mild to moderate in severity, with macular or finely granular 
maculopapular pruritic eruption on the trunk and extremities. It is not dose-limiting and 
usually responds to topical corticosteroids If needed, antihistamines such as 
diphenhydramine can be used. 
Drug Interactions 
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid 
combination 
Bleomycin: Gemcitabine may enhance the adverse/toxic effect of Bleomycin. The risk 
of pulmonary toxicity may be increased. Risk D: Consider therapy modification 
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, 
the risk for serious infections may be increased. Risk C: Monitor therapy 
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: 
Consider therapy modification 
Fluorouracil: Gemcitabine may increase the serum concentration of Fluorouracil. Risk 


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C: Monitor therapy 
Fluorouracil (Systemic): Gemcitabine may increase the serum concentration of 
Fluorouracil (Systemic). Risk C: Monitor therapy 
Fluorouracil (Topical): Gemcitabine may increase the serum concentration of 
Fluorouracil (Topical). Risk C: Monitor therapy 
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. 
Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, 
and/or thrombocytopenia may be increased. Management: Consider not using a 
leflunomide loading dose in patients receiving other immunosuppressants. Patients 
receiving both leflunomide and another immunosuppressant should be monitored for bone 
marrow suppression at least monthly. Risk D: Consider therapy modification 
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. 
Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination 
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid 
combination 
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: 
Avoid combination 
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: 
Monitor therapy 
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk 
X: Avoid combination 
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: 
Monitor therapy 
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines 
(Inactivated). Risk C: Monitor therapy 
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines 
(Live). Vaccinial infections may develop. Immunosuppressants may diminish the 
therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines 
with immunosuppressants; live-attenuated vaccines should not be given for at least 3 
months after immunosuppressants. 
Risk X: Avoid combination 
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the 
anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the 
anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy 
 
Ethanol/Nutrition/Herb Interactions 
Ethanol: Avoid ethanol (due to GI irritation). 
 
Monitoring Parameters 
CBC with differential and platelet count (prior to each dose); hepatic and renal function (prior to 
initiation of therapy and periodically, thereafter); monitor electrolytes, including potassium, 
magnesium, and calcium (when in combination therapy with cisplatin) 
 
Administration 
 
Infuse over 30 minutes. Note: Prolongation of the infusion time > 60 minutes has been shown to 
increase toxicity (some unlabeled protocols may include infusion times > 30 minutes). 
Gemcitabine is being investigated in clinical trials for fixed dose rate (FDR) infusion 
administration at doses from 1000-2200 mg/m2 at a rate of 10 mg/m2/minute. Prolonged 
infusion times increase the accumulation of the active metabolite, gemcitabine 
triphosphate. Patients who receive gemcitabine FDR experience more grade 3/4 


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hematologic toxicity. 
 
For intravesicular (bladder) instillation, gemcitabine was diluted in 50-100 mL normal 
saline; patients were instructed to retain in the bladder for 1 hour. 
Dosage Forms 
 
Powder for injection, lyophilized: 20 mg/mL (200-mg and 1000-mg vial) 
 
Reconstitute 200 mg vial with 5 mL of NS without preservative and 1000 mg vial with 25 
mL of NS without preservative to yield a Gemcitabine concentration of 38 mg/mL. 
Reconstitution of concentrations greater than 40 mg/mL may result in incomplete 
dissolution and should be avoided. Reconstituted solution is stable for 24 hours at room 
temperature and should not be days at room temperature and under refrigeration. However, 
the manufacturer recommends that the admixture be used within 24 hours since the 
solution does not contain preservatives. 
Bacterial challenge: Gemcitabine 2.4 mg/mL diluted in NS did not exhibit a 
substantial antimicrobial effect on the growth of four organisms inoculated into the 
solution. Diluted solutions should be stored under refrigeration whenever possible and 
that the potential for microbiological growth should be considered when assigning 
expiration periods. 
Compatibility: The following are compatible via Y-site injection: amifostine, bleomycin, 
carboplatin, carmustine, cisplatin, cyclophosphamide, cytarabine, dactinomycin, 
daunorubicin, dexamethasone, dexrazoxane, diphenhydramine, docetaxel, dopamine, 
doxorubicin, etoposide, fludarabine, fluorouracil, granisetron, heparin, hydrocortisone, 
hydromorphone, idarubicin, ifosfamide, leucovorin, lorazepam, mannitol, meperidine, 
mesna, metoclopramide, mitoxantrone, morphine, ondansetron, paclitaxel, plicamycin, 
potassium chloride, ranitidine, sodium bicarbonate, streptozocin, teniposide, thiotepa, 
topotecan, vinblastine, vincristine, vinorelbine. 
Incompatibility: The following are incompatible via Y-site injection: furosemide, irinotecan, 
methotrexate, methylprednisolone, mitomycin, prochlorperazine. 
 
14.3. Busulfan 
 
Therapeutic Classification: Antineoplastic Alkylating agent 
 
Pharmaceutical data: Busulfan injection is a sterile, pyrogen-free solution provided in a 
mixture of dimethylacetamide (DMA) and polyethyleneglycol 400 (PEG400). It is supplied 
in 10 ml single use ampoules at a concentration of six (6) mg busulfan per ml. Each 
ampoule contains 60 mg of busulfan in 3.3 ml of DMA and 6.7 ml of PEG400. When 
diluted in normal saline or D5W to a concentration of 0.5 mg/ml, the resulting solution 
must be administered within eight 
(8) hours of preparation including the three (3) hour infusion of the drug. 
 
Stability and storage: Ampoules should be stored refrigerated at 2-8oC (35-46
oF).  Stable 
at 4
oC for at least twelve (12) months. Additional stability studies are in progress. DO NOT 
use beyond the expiration date. DO NOT use if the solution is cloudy or if particulates are 
present. 
 
Break off the top of the ampoule and use a syringe needle to remove the calculated 
volume of busulfan from the primary container. Remove the needle, replace with a new 


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needle which has been fitted with a 5.0 micron nylon filter (provided with packaged drug) 
and transfer the contents of the syringe into the calculated amount of either normal saline 
or D5W making sure that the drug flows into and through the solution. Do not put the 
busulfan solution into a syringe or IV bag, which does not contain the normal saline or 
D5W. Mix by inverting the container numerous times to ensure a homogenous solution. 
Place an appropriate label on the container with an expiration time of eight (8) hours from 
the time of preparation with directions to store at room temperature. Do not use if solution 
contains visible particulates. Record the actual volume on the label. 
 
Place a suitable (non-vented or universal) intravenous administration set (gravity flow) into 
the outflow port of the container of the infusion solution. 
 
Route of Administration: It is to be noted, that a sufficient amount of diluted busulfan 
should be added to compensate for the amount needed to prime the IV tubing; when 
hanging the infusate, the tubing should be primed with the busulfan solution and 
connected as close to the patient as possible, i.e. by a 3-way connector at the level of the 
central venous catheter. After completed infusion, the tubing with remaining busulfan 
(approximately 12 mL) should be disconnected and discarded. All busulfan infusions 
should be performed by programmable, controlled-rate pump. 
 
The busulfan will be given by slow intravenous infusion over three (3) hours into a 
central venous catheter. 
 
CAUTION: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
 
An infusion pump will be used with the busulfan solutions as prepared above. A new 
infusion set must be used for administration of each dose. Prior to and following each 
infusion, flush the catheter line with normal saline or (approximately 5 ml). Start the three-
hour infusion at the calculated flow rate. 
DO NOT infuse concomitantly with another intravenous solution of unknown compatibility. 
 
If a delay in administration occurs after the infusion solution is prepared, the properly 
identified container should be kept at room temperature (20-25oC), but administration 
must be completed within eight (8) hours of preparation including the three (3) hour drug 
infusion. 
 
Side effects: Dose limiting toxicity is expected to be hematological when used without 
stem cell support. Other toxicities seen frequently following high-dose busulfan in 
preparative regimens for bone marrow transplantation include: VOD, nausea, vomiting, 
pulmonary fibrosis, seizures, rash, and an Addison’s-like syndrome. 
 
Mechanism of action: Interferes with DNA replication and transcription of RNA through 
DNA alkylation, and ultimately results in the disruption of nucleic acid function. 
 
Animal Tumor Data: Busulfan has been shown to be active against a variety of animal 
neoplasm in vivo, including mouse sarcoma 180 and Ehrlich’s mouse ascites tumor. 
 
Animal Toxicology: Busulfan fed to rats in an amount equivalent to about 0.5 mg/kg of final 
body weight per day slowed weight gain and produced bone marrow depression, pancytopenia 
and cataracts after about 10 weeks. In rats, LD5O was found to be 34 mg/kg intraperitoneally.  
When the drug was administered on day 13, 14, or 15 of gestation at a dose of 10 mg/kg to 


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rats, the progeny were prematurely sterile. 
 
Human Pharmacology: Limited pharmacology data are available for the parenteral 
formulation to be used in this study and is detailed in Attachment II, Preliminary 
Pharmacokinetic Evaluation of Busulfan in a Phase II human Trial. The pharmacokinetic 
data suggests that the plasma decay of the formulation fits a two-compartment model. 
The oral formulation is absorbed from the gastrointestinal tract, and measurable blood 
levels are obtained within one-half to two 
(0.5-2.0) hours after ingestion. Within three (3) minutes after IV administration in rats, 90% 
of the drug disappears from the blood; similar rapid decreases in blood concentrations 
have been reported in man. Busulfan is reported to be extensively metabolized; twelve 
(12) metabolites have been isolated, but most have not been identified. The drug is slowly 
excreted in the urine, chiefly as methanesulfonic acid. Ten to fifty percent (10-50%) of a 
dose is excreted as metabolites within twenty-four (24) hours. 
 
Drug interactions: 
Metabolism/Transport 
Effects Substrate of 
CYP3A4 (major) Drug 
Interactions 
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Busulfan. 
Risk C: Monitor therapy 
 
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid 
combination 
 
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: 
Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating 
therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification 
 
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk 
C: Monitor therapy 
 
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk 
C: Monitor therapy 
 
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. 
Risk D: Consider therapy modification 
 
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: 
Monitor therapy 
 
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: 
Monitor therapy 
 


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Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, 
the risk for serious infections may be increased. Risk C: Monitor therapy 
 
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: 
Consider therapy modification 
 
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk 
C: Monitor therapy 
 
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. 
Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, 
and/or thrombocytopenia may be increased. Management: Consider not using a 
leflunomide loading dose in patients receiving other immunosuppressants. Patients 
receiving both leflunomide and another immunosuppressant should be monitored for bone 
marrow suppression at least monthly. Risk D: Consider therapy modification 
 
MetroNIDAZOLE: May increase the serum concentration of Busulfan. Risk D: Consider therapy 
modification 
 
MetroNIDAZOLE (Systemic): May increase the serum concentration of Busulfan. Risk 
D: Consider therapy modification 
 
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of 
Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: 
Avoid combination 
 
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid 
combination 
 
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: 
Avoid combination 
 
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: 
Monitor therapy 
 
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk 
X: Avoid combination 
 
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: 
Monitor therapy 
 
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines 
(Inactivated). Risk C: Monitor therapy 
 
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines 
(Live). Vaccinial infections may develop. Immunosuppressants may diminish the 
therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines 
with immunosuppressants; live-attenuated vaccines should not be given for at least 3 
months after immunosuppressants. 
Risk X: Avoid combination 
 


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7
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the 
anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the 
anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy 
 
Ethanol/Nutrition/Herb Interactions 
 
Ethanol: Avoid ethanol due to GI irritation. 
 
Food: No clear or firm data on the effect of food on busulfan 
bioavailability. Herb/Nutraceutical: Avoid St John's wort (may decrease 
busulfan levels). Please add: 
Monitoring Parameters 
 
CBC with differential and platelet count, liver function tests (evaluate transaminases, alkaline 
phosphatase, and bilirubin daily for at least 28 days post transplant) 
 
Administration 
 
Intravenous busulfan should be administered as a 2-hour via central line. 
 
Premedicate with prophylactic anticonvulsant therapy (e.g., phenytoin or Keppra) 
prior to high-dose busulfan treatment. 
 
14.4. Melphalan 
 
Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its 
cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, 
probably by binding at the N position of guanine. Like other bifunctional alkylating agents, 
it is active against both 
resting and rapidly dividing tumor cells. 
 
Formulation: Melphalan for injection is supplied as a sterile, nonpyrogenic, freeze-dried 
powder. Each single-use vial contains melphalan hydrochloride equivalent to 50 mg 
melphalan and 20 mg povidone. 
 
Preparation: Melphalan for injection must be reconstituted by rapidly injecting 10 mL of 
the supplied diluent directly into the vial of lyophilized powder using a sterile needle and 
syringe. This provides a 5 mg/mL solution of melphalan. Immediately dilute the dose to be 
administered in 0.9% Sodium Chloride Injection, USP, to a concentration not greater than 
0.45 mg/mL. Administer the diluted product over a minimum of 15 minutes. Complete the 
administration within 60 minutes of reconstitution. 
 
Storage and stability: Melphalan for injection vials should be stored at controlled room 
temperature 15
o to 30
o C (59
o to 86
o F) and protected from light.  The time between 
reconstitution/dilution and administration of melphalan should be kept to a minimum 
because reconstituted and diluted solutions of melphalan are unstable. Over as short a 
time as 30 minutes, a citrate derivative of melphalan has been detected in reconstituted 


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material from the reaction of melphalan with the diluent. Upon further dilution with saline, 
nearly 1% label strength of melphalan hydrolizes every 10 minutes. A precipitate forms if 
the reconstituted solution is stored at 5
o C.  Do not refrigerate the reconstituted product. 
Adverse events associated with melphalan: The following information on adverse 
reactions is based on data from both oral and IV administration of melphalan as a single 
agent, using several different dose schedules for treatment of a wide variety of 
malignancies. Please refer to the Adverse Reactions and Warnings sections of the 
product package insert. 
 
Hematologic: The most common side effect is bone marrow suppression. White blood 
cell count and platelet count nadirs usually occur 2 to 3 weeks after treatment, with 
recovery in 4 to 5 weeks after treatment. Irreversible bone marrow failure has been 
reported. 
 
Gastrointestinal: Gastrointestinal disturbances such as nausea and vomiting, diarrhea, 
and oral ulceration occur infrequently. Hepatic toxicity, including veno-occlusive disease, 
has been reported. 
Drug Interactions 
 
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid 
combination 
 
Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac 
Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor 
therapy 
 
Carmustine: Melphalan may enhance the adverse/toxic effect of Carmustine. 
Specifically, melphalan may sensitize patients to carmustine lung toxicity. Risk C: 
Monitor therapy 
 
CycloSPORINE: Melphalan may enhance the nephrotoxic effect of CycloSPORINE. 
Risk C: Monitor therapy 
 
CycloSPORINE (Systemic): Melphalan may enhance the nephrotoxic effect of CycloSPORINE 
(Systemic). Risk C: Monitor therapy 
 
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, 
the risk for serious infections may be increased. Risk C: Monitor therapy 
 
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: 
Consider therapy modification 
 
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. 
Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, 
and/or thrombocytopenia may be increased. Management: Consider not using a 
leflunomide loading dose in patients receiving other immunosuppressants. Patients 
receiving both leflunomide and another immunosuppressant should be monitored for bone 
marrow suppression at least monthly. Risk D: Consider therapy modification 
 
Nalidixic Acid: May enhance the adverse/toxic effect of Melphalan. Necrotic enterocolitis 


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has been reported in pediatric patients. Risk X: Avoid combination 
 
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of 
Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: 
Avoid combination 
 
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid 
combination 
 
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: 
Avoid combination 
 
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: 
Monitor therapy 
 
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk 
X: Avoid combination 
 
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: 
Monitor therapy 
 
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines 
(Inactivated). Risk C: Monitor therapy 
 
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines 
(Live). Vaccinial infections may develop. Immunosuppressants may diminish the 
therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines 
with immunosuppressants; live-attenuated vaccines should not be given for at least 3 
months after immunosuppressants. 
Risk X: Avoid combination 
 
Vitamin K Antagonists (e.g., warfarin): Antineoplastic Agents may enhance the 
anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the 
anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy 
 
Ethanol/Nutrition/Herb Interactions 
Ethanol: Avoid ethanol (due to GI 
irritation). Food: Food interferes with 
oral absorption. 
Pharmacodynamics/Kinetics 
Note: Pharmacokinetics listed are for FDA-approved 
doses. Absorption: Oral: Variable and incomplete 
Distribution: Vd: 0.5-0.6 L/kg throughout total body water; low penetration into 
CSF Protein binding: 60% to 90%; primarily to albumin, 20% to a1-acid 


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glycoprotein 
Metabolism: Hepatic; chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan 
Bioavailability: Unpredictable; 61% ± 26%, decreasing with repeated doses 
Half-life elimination: Terminal: I.V.: 75 minutes; Oral: 1-2 
hours Time to peak, serum: ~1-2 hours 
Excretion: Oral: Feces (20% to 50%); urine (~10% as unchanged drug) 
 
Hypersensitivity: Acute hypersensitivity reactions including anaphylaxis were reported in 
2.4% of 425 patients receiving melphalan for myeloma. These reactions were 
characterized by urticaria, pruritus, edema, and in some patients, tachycardia, 
hypotension and bronchospasm. 
These patients appeared to respond to antihistamine and corticosteroid therapy. If a 
hypersensitivity reaction occurs, IV or oral melphalan should not be readministered 
since hypersensitivity reactions have also been reported with oral melphalan. 
 
Carcinogenesis: Secondary malignancies, including acute nonlymphocytic leukemia, 
myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer 
treated with alkylating agents (including melphalan). 
 
Other: Other reported adverse reactions include skin hypersensitivity, skin ulceration at 
injection site, skin necrosis rarely requiring skin grafting, vasculitis, alopecia, hemolytic 
anemia, pulmonary fibrosis and interstitial pneumonitis. 
 
Monitoring Parameters 
CBC with differential and platelet count, serum electrolytes, serum uric acid 
Administration 
Oral: Administer on an empty stomach (1 hour prior to or 2 hours after meals) 
Parenteral: Due to limited stability, complete administration of I.V. dose should occur within 60 
minutes of reconstitution 
I.V.: Infuse over 15-30 minutes. Extravasation may cause local tissue damage; 
administration by slow injection into a fast running I.V. solution into an injection port or via 
a central line is recommended; do not administer by direct injection into a peripheral vein. 
BMT only: Saline-based hydration preceding (2-4 hours), during, and following (6-12 hours) 
administration reduces risk of drug precipitation in renal tubules. Hydrolysis causes loss of 1% 
melphalan injection per 10 minutes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15.0 References 
1. 
Attal M, Harousseau JL, Stoppa AM, et al. A prospective randomized trial of 
autologous bone marrow transplantation and chemotherapy in multiple myeloma. N 
Engl J Med 1996; 335: 91–7. 
 
2. 
Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with 
hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 
348: 1875–83. 
 
3. 
Vesole DH, Crowley JJ, Catchatourian R, et al. High-dose melphalan with 
autotransplantation for refractory multiple myeloma; Results of a Southwest 
Oncology Group phase II trial. J Clin Oncol 1999; 17: 2173-9. 
 
4. 
Shimoni A, Smith TL, Aleman A, et al. Thiotepa, busulfan, cyclophosphamide 
(TBC) and autologous hematopoietic transplantation: an intensive regimen for the 
treatment of multiple myeloma. Bone Marrow Transplant 2001: 27: 821-8. 
 
5. 
Agnastopoulos A, Aleman A, Ayers G, et al. Comparison of high-dose melphalan 
with a more intensive regimen of thiotepa, busulfan, and cyclophosphamide for 
patients with multiple myeloma. Cancer 2004; 100: 2607-12. 
 
6. 
McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell 
transplantation for multiple myeloma. N Engl J Med 2012;366(19):1770-81. 
 
7. 
Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after 
stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 
10;366(19):1782-91. 
8. 
Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and 
maintenance treatment in patients with newly diagnosed multiple myeloma: results 
of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol 
2012;30(24):2946-55. 
 
9. 
Lahuerta JJ, Mateos MV, Martínez-López J, et al. Influence of pre- and 
post-transplantation responses on outcome of patients with multiple myeloma: 
sequential improvement of response and achievement of complete response are 
associated with longer survival. J Clin Oncol 2008;26:5775–82. 
 
10. 
Van de Velde HJK, Liu X, Chen G, et al. Complete response correlates with 
long-term survival and progression-free survival in high-dose therapy in multiple 
myeloma. Haematologica. 2007; 92:1399–406. 
 
11. 
Barlogie B, Tricot G. Complete response in myeloma: a Trojan horse? 
Blood 2006;108:2134. 
 
12. 
Harousseau J-L, Attal M, Avet-Loiseau H. The role of complete response in 
multiple myeloma. Blood 2009;114:3139-46. 
 
13. 
Rawstron AC, Orfao A, Beksac M, et al. Report of the European Myeloma Network 
on multiparametric flow cytometry in multiple myeloma and related disorders. 


2014-0516  Version 16                                            25 February 2020 
Page 41 of 42 
 
 
Haematologica 2008;93:431-8. 
 
14. 
Paiva B, Vidriales M-B, Cerveró J, et al. Multiparameter flow cytometric remission 
is the most relevant prognostic factor for multiple myeloma patients who undergo 
autologous stem cell transplantation. Blood 2008;112:4017-23. 
 
15. 
Plunkett W, Huang P, Searcy CE, Gandhi V. Gemcitabine: preclinical 
pharmacology and mechanisms of action. Semin Oncol 1996;23(5 Suppl 10):3-15. 
 
16. 
Gandhi V, Plunkett W, Du M, Ayres M, Estey EH. Prolonged infusion of 
gemcitabine: Clinical and pharmacodynamic studies during a phase I trial in 
relapsed acute myelogenous leukemia. J Clin Oncol 2002;20:665-73. 
 
17. 
Kebriaei P, Madden T, Kazerooni R, et al. Intravenous busulfan plus melphalan is a 
highly effective, well-tolerated preparative regimen for autologous stem cell 
transplantation in patients with advanced lymphoid malignancies. Biol Blood Marrow 
Transplant 2011;17:412-20. 
 
18. 
Nieto Y, Thall P, Valdez B, et al. High-dose infusional gemcitabine combined with 
busulfan and melphalan with autologous stem-cell transplantation in patients with 
refractory lymphoid malignancies. Biol Blood Marrow Transplant 2012;18:1677-86. 
 
19. 
Nieto Y, Shah N, Popat U, et al. High-Dose Gemcitabine Combined With Busulfan 
and Melphalan (Gem/Bu/Mel) With Autologous Stem-Cell Transplant (ASCT) In 
Refractory and Relapsed Myeloma. Blood 2013 122:3346. 
 
20. 
Valdez BC, Nieto Y, Murray D, et al. Epigenetic modifiers the synergistic 
cytotoxicity of combined nucleoside analog-DNA alkylating agents in lymphoma cell 
lines. Exp Hematol. 2012;40:800-810. 
 
21. 
Nieto Y, Thall PF, Valdez BC, et al. Vorinostat (SAHA) Combined With High-
Dose Gemcitabine/Busulfan/Melphalan (SAHA/Gem/Bu/Mel) With Autologous 
Stem-Cell Transplant (ASCT) In Patients With Refractory Lymphomas. Blood 
2013 122:2095. 
 
22. 
Badros A, Burger AM, Philip S, et al. Phase I study of vorinostat in 
combination with bortezomib for relapsed and refractory multiple myeloma. 
Clin Cancer Res 2009;15(5250-7). 
 
23. 
Richardson P, Mitsiades C, Colson K, et al. Phase I trial of oral vorinostat 
(suberoylaniilide hydroxamic acid, SAHA) in patients with advanced multiple 
myeloma. Leuk Lymphoma 2008;49:502-7. 
 
24. 
Weber DM, Graef T, Hussein M, et al. Phase I trial of vorinostat combined with 
bortezomib for the treatment of relapsing and/or refractory multiple myeloma. Clin 
Lymphoma Myeloma Leuk 2012;12:319-24. 
 
 
 
 


2014-0516  Version 16                                            25 February 2020 
Page 42 of 42 
 
 
25. 
Dimopoulos MA, Jagannath S, Yoon S-S, et al. Vantage 088: Vorinostat in 
combination with bortezomib in patients with relapsed/refractory multiple myeloma: 
Results of a global, randomized phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1129-
40. 
 
26. 
Richardson PG1, Schlossman RL, Alsina M, et al. PANORAMA 2: 
panobinostat in combination with bortezomib and dexamethasone in 
patients with relapsed and bortezomib-refractory myeloma. Blood. 
2013;122(14):2331-7. 
 
27. 
Richardson PG, Hungria V, Yoon S-S, et al. Panorama 1: A randomized, double-
blind, phase 3 study of panobinostat or placebo plus bortezomib and 
dexamethasone in relapsed or relapsed and refractory multiple myeloma. J Clin 
Oncol 32:5s, 2014 (suppl; abstr 8510). 
 
28. 
Durie BGM, Harousseau J-L, San Miguel J, et al. International uniform response 
criteria for multiple myeloma. Leukemia 2006;20:1467-73. 
 
29. 
Ling SCW, Lau EKK, Al-SHAbeeb A, et al. Response of myeloma to the 
proteasome inhibitor bortezomib is correlated with the unfolded protein 
response regulator XBP-1. Haematologica 2012:97;64-72.