Tandem Autologous Hematopoietic Stem Cell Transplant With Melphalan Followed by Melphalan and Bortezomib in Patients With Multiple Myeloma
Phase: PHASE3
Conditions: Multiple Myeloma, Auto Stem Cell Transplant
Sponsor: Hackensack Meridian Health

Protocol IRB # Pro00001295
Tandem Autologous Hematopoietic Stem Cell Transplantation with
Melphalan Followed by Melphalan and Bortezomib in Patients with Multiple
Myeloma
Protocol Version:
Date of Protocol
Original Version
25Feb2010
Amendment 1
03Aug2010
Amendment 2
`
02Nov2010
Amendment 3
16Oct2012
Amendment 4
29May2013
Amendment 5
19Jun2014
Amendment 6
17Nov2016
Amendment 7
06Jun2018
Amendment 8
08Nov2019
BLOOD AND MARROW TRANSPLANTATION PROGRAM
HACKENSACK UNIVERSITY MEDICAL CENTER
Principle Investigator:
Michele L. Donato, M.D. (551) 996-5900
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TABLE OF CONTENTS
1
INTRODUCTION AND STUDY RATIONALE
6
1.1
Overview of the Disease
6
1.2
Melphalan
9
1.3
VELCADE (bortezomib) for Injection
11
1.4
Combination of Bortezomib and Other Agents
15
2
STUDY OBJECTIVES
18
2.1
Primary Objective
18
2.2
Secondary Objectives
18
3
INVESTIGATIONAL PLAN
19
3.1
Overall Design and Plan of the Study
19
3.2
Patient Selection
19
3.3
Inclusion Criteria
19
3.4
Exclusion Criteria
19
3.5
Patient Evaluations - First Transplant
21
3.6
Patient Evaluations - Second Transplant
22
3.7
Analysis of PBSC and Marrow Compontents
23
3.8
Post Transplant Evaluation
23
3.9
Post-Transplant re-staging of disease
23
3.10
Study Treatments
23
3.11
Outline of Treatment Plan
26
3.12
Conditioning Regimens
27
3.13
Second Transplant
27
3.14
Bortezomib
27
3.15
Stem Cell Infusion
28
3.16
Post-transplant Cytokine Administration
28
3.17
Post-transplant Supportive Care
28
3.18
Disease Response.
29
3.19
Timing between Transplant Procedures
29
3.20
Dosing Agents
30
3.21
Pre-Transplant Therapy
31
3.22
Treatment Assignment
31
3.23
Blinding, Packaging, and Labeling
31
3.24
Concomitant Treatment
32
3.25
Treatment Compliance
32
3.26
Duration of Treatment and Patient Participation
32
3.27
Termination of Treatment and/or Study Participation
32
4
ADVERSE EVENTS
33
4.1
Definitions
33
4.2
Procedures for AE and SAE Reporting
34
4.3
Assessment of Toxicity
34
5
Statistical Evaluation
36
5.1
Endpoint
36
5.2
Secondary endpoints
36
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5.3
Accrual, Registration and Follow-up
36
5.4
Sample Size and Power Calculations
37
5.5
Efficacy analysis
37
5.6
Statistical Hyopthesis
38
5.7
Primary Endpoint
38
5.8
Secondary endpoints
38
5.9
Safety Analysis
39
5.10
Stopping Rules
39
5.11
Monitoring Compliance
40
5.12
Data Management and Analysis
40
6
ADMINISTRATIVE REQUIREMENTS
41
6.1
Good Clinical Practice
41
6.2
Ethical Considerations
41
6.3
Patient Information and Informed Consent
41
6.4
Protocol Registration
41
6.5
Patient Confidentiality
41
6.6
Record Retention
42
6.7
Investigation New Drug Exemption
42
7
KARNOFSKY PERFORMANCE STATUS SCALE
43
8
BODY SURFACE AREA AND CREATININE CLEARANCE
CALCULATIONS
44
9
DECLARATION OF HELSINKI
45
10
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS
49
11
REFERENCES
49
Abbreviation
Definition
°C
degrees Celsius
μM
Micromolar
20S
20S proteasome subunit
AE
adverse event
ANC
absolute neutrophil count
Bc1-2
B-cell lymphoma-2; a gene that inhibits apoptosis
BSA
body surface area
CAM
cell adhesion molecules
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Abbreviation
Definition
cm
Centimeter
CR
Complete Response
CTCAE
(NCI) Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
dL
Deciliter
DLT
Dose Limiting Toxicity
DNA
deoxyribonucleic acid
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
ht
Height
IκB
I kappa B kinase; cytokine response kinase that activates
transcription factor NF-kappa b at serine 32 and 36
ICAM-1
intercellular adhesion molecule 1
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
IV
Intravenous
IB
I kappa B alpha-associated protein kinase
kg
Kilogram
Ki
inhibitory constant
lbs
Pounds
m2
square meters
mg
Milligram
min
Minute
mL
Milliliter
mm3
cubic millimeters
mmol
Millimole
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NF-κB
nuclear factor-κB
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Abbreviation
Definition
ng
Nanogram
nM
Nanomole
p21
p21(ras) farnesyl-protein transferase
p27
cyclin-dependent kinase inhibitor
p53
tumor suppressor protein with molecular weight of 53 kDa
SAE
serious adverse event
US
United States
USP
United States Pharmacopeia
VCAM-1
vascular cell adhesion molecule 1
w/w
weight-to-weight ratio
wt
Weight
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1
INTRODUCTION AND STUDY RATIONALE
Background
1.1
Overview of the Disease
Multiple myeloma is the second most common hematological malignancy, affecting about 55,000
Americans. Limited control of disease can be achieved with conventional dose chemotherapy
but randomized studies reported improved response rates for patients who are treated with
dose-intense therapy and autologous hematopoietic stem cell (HSC) transplantation. However,
most patients who undergo dose-intense therapy will require salvage therapy at a median of two
to three years after transplantation. High-dose melphalan (200 mg/m2) appears to be the most
effective conditioning regimen but the potentially greater tumor cell kill of dose-intense
melphalan in synergistic combination with other drugs is only now being studied.
1.1.1
Multiple Myeloma
Multiple myeloma is a malignancy of plasma cells and belongs in a family of diseases
known as plasma cell dyscrasias. It accounts for about 1% of all cancers and 10% of all
hematological malignancies. Thus, it is the second most common “blood cancer,”
affecting approximately 55,000 Americans. The annual incidence is about 20,000 cases;
the annual death rate is about 11,000. The median age at diagnosis is 65 years old. The
disease is more common in males (1.3 to 1) and the frequency doubles in
African-Americans compared to Caucasians.
1.1.2
Clinical Studies of High-Dose Therapy of Multiple Myeloma
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Standard dose therapy for most plasma cell disorders includes regimens such as low-dose
melphalan (32 mg/m2/month) with prednisone. For patients with multiple myeloma, this
regimen results in a 40% overall response rate, but few patients achieve a complete
remission and the median duration of response is only 2 years. The median survival is in
the range of 3 years and few (<15%) survive 5 years. More aggressive chemotherapy
regimens, including VAD, VBMCP and M2, induce remissions more quickly but overall
survival rates are not substantially improved (Alexanian and Dimopoulos, 1994).
These poor outcomes led many investigators explored high-dose chemotherapy regimens.
In 1983, McElwain used melphalan 140 mg/m2 without stem cell support as a salvage
therapy in nine patients with refractory myeloma and noted all patients responded to
treatment with five patients achieving complete biochemical and bone marrow responses
(McElwain and Powles, 1983). This observation of dose-response led to a series of phase
I/II trials with and without stem cell support in both newly diagnosed and refractory
disease (Attal et al., 1992; Harousseau et al, 1995).
A matched-pair analysis by the Arkansas group and SWOG comparing dose-intense with
standard-dose therapy demonstrated the benefit of autologous HSC transplantation for the
treatment of multiple myeloma (Barlogie et al., 1997). Event-free (49 vs 27 months) and
overall survivals (62+ vs 48 months) were improved for patients treated with dose-intense
therapy as part of the initial treatment.
A number of randomized studies comparing dose-intense therapy with autologous stem
cell support to standard therapy regimens have been conducted. The French Myeloma
Intergroup reported a large-scale randomized trial (IFM 90) that randomized two hundred
patients to either conventional dose VMCP/VBAP or autologous bone marrow
transplantation with melphalan and total body irradiation after four cycles of induction
treatment (Attal et al., 1996). The findings were strikingly in favor of the dose-intense
approach with improvements in complete response rates (22% vs 5%) and median
probabilities of event-free (27 months vs 18 months) and overall-survivals (60+ months vs
37 months). In contrast, the USIG found no difference in overall survival using the same
transplant conditioning regimen but a much more intensive “standard” non-transplant
chemotherapy regimen (Barlogie et al., 2006). These authors also acknowledged that the
combination of melphalan and TBI is now recognized as an inferior transplant regimen.
The French group Myelome Autogreffe (MAG) achieved results comparable to the IFM
90 trial; however, there was no significant difference in overall survivals as a result of
unexpected prolonged survivals in the chemotherapy arm (Fermand et al., 2005). The
Spanish PETHEMA group did not find a statistically significant difference in EFS and OS
between chemotherapy and dose-intensive therapy (Blade et al., 2005). However, only
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patients who responded (CR: 15%; PR: 68%; MR: 17%) to conventional dose
chemotherapy were randomized and patients in the chemotherapy arm were allowed to
cross over into the dose-intensive therapy group. The Italian MMSG compared
melphalan-prednisone to two courses of melphalan at 100 mg/m2 with autologous stem
cell support (Palumbo et al., 2004). They found significant improvement in CR and EFS
in the transplant arm. The Medical Research Council Myeloma VII trial of 407 patients
reported similar results for a comparison of six cycles of BCNU, doxorubicin,
cyclophosphamide and melphalan to at least three cycles of doxorubicin, vincristine,
methylprednisolone, and cyclophosphamide followed by melphalan at 200mg/m2 and
autologous stem cell transplant (Child et al., 2003). This trial deserves special
consideration in that it is the most recent of the randomized trials and was carried out in
the era of more advanced supportive care and the availability of newer therapeutic agents.
It still showed a statistically significant advantage for HDT in terms of CR, EFS and OS.
In addition, it did not show any increase in treatment-related mortality relative to
conventional therapy. These randomized trials, all of which showed a trend to, or
significantly improved results for patients treated with dose-intense therapy, with the
support of numerous phase II trials, clearly indicate that dose–intense therapy with
autologous HSCT should be offered to appropriate patients as part of their initial
treatment. The median EFS is remarkably constant (25-31 months). It is more difficult to
analyze OS results since OS partly depends on subsequent salvage therapy. However,
median OS was significantly longer in the three studies where differences in EFS were
more marked. In all studies, procedure-related death rate was <5% and not greater than
that observed with conventional chemotherapy.
1.1.3
Tandem Autologous Transplantation as Initial Therapy
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Table 1: Randomized Trials Comparing Conventional Chemotherapy vs. High-dose Therapy
N
Age
MedianF/U
CR rate (%)
Median EFS (m)
Median OS (m
CC
HDT
P
CC
HDT
P
CC
HDT
IFM 90
200
<65
7 yr
5
22
<0.001
18
28
0.01
44
57
0.
MAG91
190
55-6
5
56 m
NE
NE
19
25
0.05
45
42
N
PETHEMA
164
≤65
42 m
11
30
0.002
34
42
NS
67
65
N
Italian MMSG
195
50-7
0
2 yr
7
26
<0.001
16
28
0.0036
43
58+
0.0
USIG
50
15
17
NS
21
25
0.05
53
58
N
MRC7
407
<65
42 m
8
44
<0.001
19.6
31.6
<0.0001
42
54
<0.
Abbreviations: CC=conventional chemotherapy, CR=complete remission, EFS=event free survival, HDT=high-dose
therapy, OS=overall survival, NE=not evaluated, NS=difference not statistically significant.

About 10 years ago, the Arkansas transplant program showed the feasibility of 2
consecutive autologous transplants (Vesole et al., 1994). They described 42 patients who
received two consecutive autologous PBSC transplants using melphalan 200mg/m2. In
patients that were capable of receiving 2 transplants, the CR rate increased from 24%
after the first transplant to 43% after 2 transplants. This experience has now been
extended in over 1000 patients with overall complete remission rates of 40% and
projected 5 year event-free and overall survivals of 25% and 40% respectively (Desikan
et al., 2002). The French Intergroup randomized 399 newly diagnosed myeloma patients
under age 60 to single versus tandem transplants (Attal et al, 2003). They found similar
CR rates between the two groups (42% single transplant vs. 50% tandem transplant), but
superior seven year event-free (10% vs. 20%, P=0.03) and overall survivals (21% vs.
42%, P=0.01) for the tandem transplant group. For patients who did not achieve a very
good partial response (less than 90% reduction in serum or urine paraprotein) after one
transplant, the improvement in seven year overall survival was more dramatic (11% vs.
43%, P<0.01). These results support tandem autologous transplants for patients with a
diagnosis of multiple myeloma who do not show disease progression after the first
transplant.
1.1.4
Impact of Impaired Renal Function on Dose-Intense Therapies
Many patients with plasma cell dyscrasias have renal impairment as a result of their
disease; early studies of dose-intense therapy tended to exclude these patients. However,
the favorable characteristics of melphalan permits transplant therapy to be extended to
patients with renal impairment including patients with end-stage renal failure (ESFR).
Pharmacokinetic studies of melphalan show comparable clearance rates regardless of
renal function (Tricot et al., 1996). The Arkansas group compared 42 patients with renal
failure (including 19 requiring dialysis) with 84 patients matched for other prognostic
features. Regimen-related mortality was 7% for the group with renal impairment
compared to 6% for those with normal renal function. Engraftment kinetics and
probabilities of event-free and overall survivals were also similar. This group reported a
subsequent series involving 81 patients with renal insufficiency that showed no
difference in quality of stem cell collection and engraftment, even for patients on dialysis
(Badros et al., 2001).
1.1.5
Age as a Limiting Factor
The plasma cell disorders strike older populations of patients; multiple myeloma is rare
for patients under the age of 40 years. The Arkansas group reported a slight increase in
60-day mortality for patients over the age 65 undergoing transplantation for the treatment
of myeloma (8% vs 2%). However, median event-free (1.5 vs. 2.8 years) and overall
survivals (3.3 vs. 4.8 years) were statistically similar (Siegel et al., 1999).
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Age has also not been found to be a significant predictor of transplant related mortality
in other series. An analysis of 383 consecutive transplants at Temple University actually
noted poorer survival of younger patients compared to older patients, presumably a
result of the willingness of physicians to offer aggressive treatment to younger patients
with higher risk disease or co-morbid illnesses (Goldberg et al., 1998). Conflicting data
on this subject in at least 14 studies (6 no effect, 8 adverse) point to the need for patient
selection criteria other than chronological age.
1.2
Melphalan
1.2.1
Melphalan Non-clinical Pharmacology
Melphalan is a bifunctional alkylating agent that acts principally through covalent
reactions with DNA, resulting in the formation of drug-DNA adducts with cross-linking of
DNA strands (Samuels and Bitran, 1995). Melphalan’s cytotoxic effects are related to its
concentration and the duration of exposure to melphalan of the cell (Hall and Tilby, 1992).
Enhanced repair of DNA interstrand crosslinks may be a mechanism of resistance that
develops after prior exposure to this drug (Spanswick et al., 2002). Melphalan is actively
transported into cells by the high-affinity L-amino acid transport system; glutamine and
leucine compete for carrier uptake and high levels of these amino acids can reduce drug
uptake. Other drugs such as tamoxifen, chlorpromazine, and indomethacin can also impair
melphalan uptake and accumulation.
1.2.2
Clinical Pharmacokinetics and Pharmacodynamics
Studies of the pharmacokinetics of oral melphalan were complicated by the highly
variable absorption of the drug. Moreover, studies of intravenous melphalan have also
showed considerable inter-patient variability in plasma clearance. Pinguet et al studied the
pharmacokinetics of melphalan administered at a dose of 140 mg/m2 in combination with
other chemotherapeutic agents to 20 patients undergoing autologous PBSC transplantation
(Pinguet et al., 1997). The medians time to neutrophil and platelet recoveries were 16 and
14.6 days, and the majority of patients (80%) developed WHO grade 3/4 stomatitis. Plasma
concentration profiles were biphasic and fitted with a two-compartment model. The
maximal concentration at the end of infusion averaged 7.94±3.73 mg/l (range, 1.65-14.5).
The mean elimination half-life and the mean residence time were 83.1±27.1 minutes (range,
51.6-16681) and 98.7±26.9 minutes (range 59.5-166.9), respectively. The volume of
distribution averaged 1.00±0.62 l/kg (range 0.46-3.12) and total plasma clearance
548.3±300.0 ml/min/m2 (range, 218.6-1378.8). Plasma levels were below the limits of
detection for all patients by 24 hours after melphalan administration. These authors noted
large inter-individual variability of these pharmacokinetic parameters. Total clearance of
melphalan was significantly correlated with creatinine clearance (r=0.49, p<0.05). A
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relationship between melphalan clearance and renal function was also described by
Kergueris et al., but this relationship did not explain the large variation in inter-individual
overall clearance of the drug (Kergueris et al., 1994). Similar pharmacokinetic results were
reported for 20 pediatric and 10 adult patients treated with melphalan 140 mg/m2 as a single
agent (infused rapidly over 5 minutes; Gouyette et al., 1986). For the adult patients, the
elimination half-life (t½β) was 50±7 minutes for patients treated with 140 mg/m2 dose and
41±12 minutes for the higher dose of 180 mg/m2. Plasma clearance averaged 525
ml/min/m2 at 140 mg/m2 and 532 ml/min/m2 at 180 mg/m2.
Melphalan undergoes hydrolysis in the circulation and the amount cleared by the
kidneys is not well defined. However, the toxicity of melphalan (hematological or
gastrointestinal) is reported higher for patients with diminished renal function. A study of
nine patients given a melphalan dose of 5 mg/m2 (four of whom subsequently treated with
220 mg/m2) showed highly variable renal clearance of melphalan with the percentage of
dose excreted unchanged in the urine ranging from 2.5% to 92.8% (Reece et al., 1988).
These authors speculated that the variation in renal clearance observed for these patients
could account for the large variation in plasma clearance observed in all studies of
melphalan pharmacokinetics.
1.2.3
Clinical Toxicities of Melphalan
Dose-related leukopenia, thrombocytopenia, anemia, usually with nadir 2-3 weeks and
with recovery 4-5 weeks after dosing (without HSC support) will occur with moderate
melphalan dose schedules. Hematological toxicity is the most prominent serious toxicity
associated with the use of high-dose melphalan regimens, with neutrophil counts falling to
<100/uL about 7 days after administration. However, initial hematological recovery occurs
about 3 to 5 days later for patients given hematopoietic stem cell and cytokine support.
About 50% of patients will require blood component (red blood cells and/or platelet) support
or will develop neutropenic fevers during the period of marrow hypoplasia.
Dose-related nausea and vomiting beginning 2-4 hrs after dosing, peaking at 12 hrs, and
persisting for several days, and delayed nausea and vomiting starting 24-48 hrs after
administration and persist for multiple days to 3 or 4 weeks occurs with high doses of
melphalan. Stomatitis will occur in most patients can be almost completely prevented by
prophylactic cooling of the mouth with ice during the infusion of melphalan. A small
proportion of patients will develop diarrhea.
Melphalan is associated with a number of rare complications including: hemolytic
anemia, abnormal liver function tests with jaundice, renal insufficiency, atrial fibrillation,
pulmonary fibrosis and interstitial pneumonitis, skin hypersensitivity, seizures (described in
patients with renal failure receiving melphalan, hyponatremia and SIADH, secondary
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leukemia and myelodysplastic syndromes, anaphylaxis (rare), and potentially irreversible
sterility.
1.3
VELCADE (bortezomib) for Injection
1.3.1
Scientific Background
VELCADE™(bortezomib) for Injection is a small molecule proteasome inhibitor
developed by Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat
human malignancies. Bortezomib is currently approved by the United States Food and Drug
Administration (US FDA) and it is registered in Europe for the treatment of multiple
myeloma patients who have received at least one prior therapy.
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple
signaling pathways. The anti-neoplastic effect of bortezomib likely involves several distinct
mechanisms, including inhibition of cell growth and survival pathways, induction of
apoptosis, and inhibition of expression of genes that control cellular adhesion, migration and
angiogenesis. Thus, the mechanisms by which bortezomib elicits its antitumor activity may
vary among tumor types, and the extent to which each affected pathway is critical to the
inhibition of tumor growth could also differ. Bortezomib has a novel pattern of cytotoxicity
in National Cancer Institute (NCI) in vitro and in vivo assays (Adams et al., 1999). In
addition, bortezomib has cytotoxic activity in a variety of xenograft tumor models, both as a
single agent and in combination with chemotherapy and radiation (Steiner et al., 2001;
Teicher et al., 1999; Cusack et al., 2001; LeBlanc et al., 2002; Pink et al., 2002). Notably,
bortezomib induces apoptosis in cells that over express bcl-2, a genetic trait that confers
unregulated growth and resistance to conventional chemotherapeutics (McConkey et al.,
1999).
Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear
factor κB (NF-κB) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a
direct apoptotic effect, and possibly anti-angiogenic and other effects (Hideshima et al.,
2001).
1.3.2
Non-clinical Pharmacology
Pharmacokinetic (PK) and pharmacodynamic studies were conducted in the rat and
cynomolgus monkey. Upon intravenous (IV) bolus administration, bortezomib displays a
rapid distribution phase (t½α <10 minutes) followed by a longer elimination phase (t½β
5–15 hours). Bortezomib has a large volume of distribution (range 5–50 L/kg). The plasma
PK profile is well described by a 2-compartment model.
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The pharmacodynamic action of bortezomib is well established and can be measured
through an ex vivo assay (20S proteasome activity) (Lightcap et al., 2000). This assay was
used to determine the duration of drug effect in lieu of the PK data in the early preclinical
toxicology studies as well as to set a guide for dose escalation in humans. Following dosing
with bortezomib in the rat and cynomolgus monkey, proteasome inhibition in peripheral
blood had a half-life less than 24 hours, with proteasome activity returning to pretreatment
baseline within 24 hours in monkey and within 48 to 72 hours in rat after a single dose of
bortezomib. Further, intermittent but high inhibition (>70%) of proteasome activity was
better tolerated than sustained inhibition. Thus, a twice-weekly clinical dosing regimen was
chosen in order to allow return of proteasome activity towards baseline between dose
administrations.
1.3.3
Non-clinical Toxicity
Single-dose IV toxicity studies were conducted with bortezomib in the mouse, rat, dog,
and monkey to establish the single-dose maximum tolerated dose (MTD). The MTDs were
0.25 mg/kg (1.5 mg/m2) and 0.067 mg/kg (0.8 mg/m2) in the 2 most sensitive species, rat
and monkey, respectively.
Repeat-dose multi-cycle toxicity studies of 3 and 6 months in the rat and 9 months in the
monkey, each with 8-week recovery periods, were conducted to characterize the chronic
toxicity of bortezomib when administered by the clinical route and regimen of
administration. The MTD in the 6-month rat study was 0.10 mg/kg (0.6 mg/m2) and the key
target organs were the gastrointestinal (GI) tract, hematopoietic and lymphoid systems. The
MTD in the 9-month monkey study was 0.05 mg/kg (0.6 mg/m2) and the key target organs
were the GI tract, hematopoietic and lymphoid systems, peripheral nervous system, and
kidney. Full or partial reversibility was observed for each of the toxicities described to date.
In general, the nature of the toxicity of bortezomib is similar across species, and target
organs of toxicity in animals have been largely predictive of human toxicity. The toxicity of
bortezomib in animals is characterized by a steep dose-response with mortality seen at
dosages above the MTD. The cause of death at acutely lethal dosages is considered to be
related to indirect cardiovascular (CV) effects of hypotension and vascular changes with
secondary bradycardia and the cause of death in long-term studies has been attributed to GI
or hematologic toxicity. The pharmacologic effects of bortezomib on the CV system have
been extensively characterized and have demonstrated that indirect effects on CV function
occur only at acutely lethal dosages and are abrogated by routine supportive care.
Additional detailed information regarding the nonclinical pharmacology and toxicology
of bortezomib may be found in the 2006 Investigator’s Brochure.
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1.3.4
Clinical Pharmacokinetics and Pharmacodynamics
The clinical pharmacology characterization of bortezomib has been determined from
phase 1 studies in subjects with solid tumors and hematological malignancies, and
confirmed in phase 2 studies in subjects with multiple myeloma.
Bortezomib demonstrates multi-compartmental pharmacokinetics. Following
intravenous administration of 1.0 mg/m2 and 1.3 mg/m2 dose, the mean first-dose maximum
observed plasma concentrations of bortezomib were 57 and 112 ng/mL, respectively in 11
patients with multiple myeloma and creatinine clearance values >50 mL/min participating in
a pharmacokinetics study. In subsequent doses, mean maximum observed plasma
concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m2 dose and 89 to 120 ng/mL
for the 1.3 mg/m2 dose. The mean elimination half-life of bortezomib upon multiple dosing
ranged from 40 to 193 hours. Bortezomib is eliminated more rapidly following the first
dose. Mean Total Body Clearances were 102 and 112 L/h following the first dose for doses
of 1.0 mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following
subsequent doses for doses of 1.0 and 1.3 mg/m2, respectively. Clinical experience has
shown that the change in clearance does not result in overt toxicity from accumulation in
this multidose regimen in humans.
In subjects with advanced malignancies, the maximum pharmacodynamic effect
(inhibition of 20S activity) occurred within 1-hour post dose. At the therapeutic dose of 1.3
mg/m2 in subjects with multiple myeloma, the mean proteasome inhibition at 1-hour post
dose was approximately 61%.
The time course of proteasome inhibition in subjects is characterized by maximum
inhibition observed within the first hour after administration, followed by partial recovery of
proteasome activity over the next 6 to 24 hours to within 50% of the pretreatment activity.
On the Day 1, 4, 8, and 11 schedule, variable (10%–30%) levels of proteasome inhibition
have been observed at next scheduled dosing. In theory, this advantage allows cells to
recover proteasome activity for normal cellular housekeeping functions between doses.
The relationship between bortezomib plasma concentrations and proteasome inhibition
can be described by a maximum effect (Emax) model. The Emax curve is initially very steep,
with small changes in plasma bortezomib concentration over the range of 0.5 to 2.0 ng/mL
relating to large increases in the percent inhibition (0–60%). After that, a plateau occurs
where marginal increases of proteasome inhibition are observed in spite of large changes in
plasma bortezomib concentrations.
1.3.5
Clinical Experience
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It is estimated that more than 55,000 patients have been treated with bortezomib,
including patients treated through Millennium-sponsored clinical trials, Investigator-Initiated
Studies, the US NCI Cancer Therapy Evaluation Program (CTEP), and with commercially
available drug. Bortezomib has been commercially available since 13 May 2003.
The overall goal of the Millennium phase 1 program was to determine the MTD and
dose-limiting toxicity (DLT) of bortezomib in a number of therapeutic settings involving
subjects with various advanced malignancies. In a Phase I trial in patients with refractory
hematologic malignancies, the MTD for a twice weekly for 4 weeks of a 42 day cycle was
1.04 mg/m2/dose, with DLTs of thrombocytopenia, hyponatremia, hypokalemia, fatigue, and
malaise (Orlowski et al., 2002). The toxicity was greatest during the third and fourth weeks
of therapy. In the 3-week schedule of bortezomib monotherapy (4 doses, given on Days 1, 4,
8, and 11 of a 21-day treatment cycle), the DLT occurred at 1.56 mg/m2/dose (3 subjects
with Grade 3 diarrhea and 1 with peripheral sensory neuropathy). Therefore, the MTD at
this schedule was 1.3 mg/m2/dose. In a 35-day treatment cycle with 4 weekly doses of
bortezomib monotherapy, the MTD was 1.6 mg/m2/dose and DLT included hypotension,
tachycardia, diarrhea, and syncope.
In phase 1 clinical studies, anti-tumor activity was reported in subjects with NHL,
multiple myeloma, Waldenström’s Macroglobulinemia, squamous cell carcinoma of the
nasopharynx, bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate
cancer.
The safety and efficacy of bortezomib in subjects with multiple myeloma were
investigated in two phase 2 clinical studies, studies M34100-024 (subjects with first relapse)
(Jagannath et al, 2004) and M34100-025 (subjects with second or greater relapse and
refractory to their last prior therapy) (Richardson et al, 2003). In M34100-025, 202 heavily
pre-treated subjects with refractory multiple myeloma after at least 2 previous treatments
received bortezomib, 1.3 mg/m2 on Days 1, 4, 8, and 11 of a 21-day treatment cycle. The
European Group for Blood and Marrow Transplant (EBMT) response criteria, as described
by Blade (Blade et al., 1998) were utilized to determine disease response. CRs were
observed in 4% of subjects, with an additional 6% of patients meeting all criteria for CR but
having a positive immunofixation test. PR or better was observed in 27% of subjects, and
the overall response rate (CR, PR and minor response [MR] combined) was 35%. Seventy
percent of subjects experienced stable disease or better.
The phase 3 study (M34101-039) (Richardson et al, 2005), also referred to as the APEX
study, was designed to determine whether bortezomib provided benefit (time to progression
[TTP], response rate, and survival) to patients with relapsed or refractory MM relative to
treatment with high-dose dexamethasone. The study was also designed to determine the
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safety and tolerability of bortezomib relative to high-dose dexamethasone, and whether
treatment with bortezomib was associated with superior clinical benefit and quality of life
relative to high-dose dexamethasone. A total of 669 patients were enrolled and 663 patients
received study drug (bortezomib: 331; dexamethasone: 332). Patients randomized to
bortezomib received 1.3 mg/m2 I.V. push twice weekly on days 1, 4, 8, and 11 of a 3-week
cycle for up to eight treatment cycles as induction therapy, followed by 1.3 mg/m2
bortezomib weekly on days 1, 8, 15, and 22 of a 5-week cycle for three cycles as
maintenance therapy. Patients randomized to dexamethasone received oral dexamethasone
40 mg once daily on days 1 to 4, 9 to 12, and 17 to 20 of a 5-week cycle for up to four
treatment cycles as induction therapy, followed by dexamethasone 40 mg once daily on days
1 to 4 followed of a 4-week cycle for five cycles as maintenance therapy. The European
Group for Blood and Marrow Transplant (EBMT) response criteria, as described by Blade
(Blade et al., 1998) were utilized to determine disease response. There was a 78% increase
in TTP for the bortezomib arm. Median TTP was 6.2 months for the bortezomib arm and 3.5
months for the dexamethasone arm (P<.0001). CR (complete response) + PR (partial
response) was 38% with bortezomib vs. 18% with dexamethasone (P<.0001). CR was 6%
with bortezomib vs. <1% with dexamethasone (P<.0001). The CR + nCR rate was13% with
bortezomib vs. 2% with dexamethasone. In patients who had received only one prior line of
treatment (bortezomib: 132; dexamethasone: 119), CR + PR was 45% with bortezomib vs.
26% with dexamethasone (P=.0035). With a median 8.3 months of follow-up, overall
survival was significantly longer (P=.0013) for patients on the bortezomib arm vs. patients
on the dexamethasone arm. The probability of survival at one year was 80% for the
bortezomib arm vs. 66% for the dexamethasone arm, which represented a 41% decreased
relative risk of death in the first year with bortezomib (P=.0005). In patients who had
received only one prior line of treatment, the probability of survival at one year was 89% for
the bortezomib arm vs. 72% for the dexamethasone arm, which represented a 61% decreased
relative risk of death in the first year with bortezomib (P=.0098). (Richardson et al., 2005).
Updated response rates and survival data were reported for M34101-039 (Richardson ASH,
2005). The updated CR (complete response) + PR (partial response) rate was 43% with
bortezomib. The CR + nCR rate was 16% with bortezomib. With a median 22 months of
follow-up, overall survival was significantly longer for patients on the bortezomib arm vs.
patients on the dexamethasone arm. The median overall survival was 29.8 months (95% CI:
23.2, not estimable) for the VELCADE arm vs. 23.7 months (95% CI: 18.7, 29.1) for the
dexamethasone arm (hazard ratio = 0.77, P= 0.0272). The probability of survival at one year
was 80% for the bortezomib arm vs. 67% for the dexamethasone arm (P=0.0002).
Studies using bortezomib as monotherapy and in combination with other chemotherapy
agents are continuing. Potential Risks of bortezomib (this section reflects updates to our
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standard risks language that have been updated since I gave the modified version of the
protocol several months ago.
1.4
Combination of Bortezomib and Other Agents
A pre-clinical study reported by the Dana Farber Jerome Lipper Multiple Myeloma
Center demonstrated synergy in cell line kill between bortezomib and other agents such as
doxorubicin and melphalan (Mitsiades et al., 2003). Synergy was found with co-incubation
of bortezomib with doxorubicin, or with pre-exposure to either of the drugs. Bortezomib
exposure after prior doxorubicin exposure achieved the greatest cell kill. Myeloma cell lines
known to be resistant to doxorubicin or melphalan confirmed sensitization by bortezomib, as
did studies involving freshly isolated myeloma cells from patients known to be resistant to
bortezomib or doxorubicin. A proposed mechanism for this enhancement of
chemosensitivity is the down-regulation of several effectors involved in the cellular response
to genotoxic stress, restoring sensitivity to DNA-damaging chemotherapeutic agents.
Berenson et al recently published a phase I/II trial of bortezomib and low-dose
melphalan combination therapy for the treatment of patients with relapsed or refractory
multiple myeloma (Berenson et al., 2006). Bortezomib was administered from 0.7 to 1.0
mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles, and oral melphalan
was administered in escalating doses form 0.025 to 0.25 mg/kg on days 1 to 4. Thirty-five
patients were enrolled and dose-limiting grade 4 neutropenia in two of six patients in the
highest dose cohort led to the assignment of bortezomib 1.0 mg/m2 and melphalan 0.10
mg/kg as the maximum-tolerated dose. Responses were observed in 23 of 34 evaluable
patients. Myelosuppression was the most prominent toxicity; Grade 1/2 neurotoxicity
developed in 8 patients and worsened in 4 of 15 patients with pre-existing neurotoxicity.
Diarrhea and nausea/vomiting were observed at all dose levels and no relationship to drug
dosage was evident.
Hollmig et al described treatment of 37 patients with bortezomib and high-dose melphalan
(Hollmig et al., 2004). Bortezomib was dosed at 1.0 mg/m2 or 1.3 mg/m2 on days -4 and -1
before autologous HSC transplantation, with melphalan (50-200 mg/m2) given on the same
days for 26 patients and on day -1 only for 11 patients. All patients achieved granulocyte
(median, 13 days) and platelet (median, 17 days) recoveries.
Serious (grade 3/4) mucositis
and/or diarrhea occurred in 14% and 29% of patients, respectively. No transplant-related
deaths were reported.
A partial or better response was observed in 73% of evaluable
patients. This same group also reported the use of 3 or 4 fractions of high-dose melphalan
given along with bortezomib (1.0 or 1.3 mg/m2) in a standard day 1, 4, 7, ±10 fashion
(Pineda-Roman et al., 2006). Maximum doses of melphalan reached 240-250 mg/m2. Only
1 of 22 patients treated experienced significant (grade 2) mucositis with grade 3/4 diarrhea
(primarily infectious) in 8 patients. These reports suggest a safe starting dose of bortezomib
in combination with high-dose melphalan of 1.0 mg/m2.
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A similar phase I trial of bortezomib and pegulated liposomal doxorubicin (PegLD)
enrolled 42 patients (24 with multiple myeloma) with advanced hematological malignancies
(Orlowski et al., 2005). Bortezomib dosing started at 0.9 mg/m2and was advanced in a
modified Fibonacci escalation with subsequent steps of 1.05, 1.2, 1.3, 1.4, and 1.5 mg/m2,
and was given on days 1, 4, 8, and 11 of each 21-day cycle. PegLD, 30 mg/m2, was given
on day 4 of each cycle. A bortezomib dose of 1.3 mg/m2was recommended for further study
because of frequent dose reductions and delays at the MTD of 1.5 mg/m2. Hematological
toxicities were the most common, with fatigue being the most-common non-hematological
toxicity. Again, diarrhea was observed at all dose levels. Of the 22 evaluable patients
treated for myeloma, 8 achieved a CR or very good PR, and another 8 achieved a PR.
The combination of bortezomib and carboplatin was studied in a phase I trial involving
15 patients with recurrent ovarian or primary peritoneal cancer (Aghajanian et al., 2005).
Carboplatin was administered on day 1 at a dose of 5 (AUC), and bortezomib on days 1, 4,
8, and 11 of each three week cycle at dose levels of 0.75, 1, 1.3, and 1.5 mg/m2. No
dose-limiting hematological toxicities were observed; dose-limiting non-hematological
toxicities were diarrhea, skin rash, and sensory peripheral neuropathy (all grade 3) and the
highest dose level of 1.5 mg/m2, and the MTD was determined to be 1.3 mg/m2. An overall
response rate of 47% was demonstrated, and one patient with platinum-resistant disease
achieved a CR.
We are conducting a phase I/II clinical study of bortezomib with dose-intense melphalan
with autologous peripheral blood stem cell transplantation in patients with disease
progression or less than partial response after a prior PBSCT (Rowley, et al, 2009).  Primary
exclusion criteria are active infection at time of PBSCT, cardiac amyloid deposition, and
creatinine clearance of <20 ml/min. Peripheral neuropathy of less than grade 4 is not an
exclusion. Bortezomib is given on days -4 and -1 with melphalan 200 mg/m2 (actual
weight) given on day -2 before PBSCT. For the phase I study, bortezomib was given at
rising doses of 1.0, 1.3, and 1.6 mg/m2. Three patients were to be enrolled at each dose
level, with an additional 3 patients enrolled in case of a serious toxicity event at any level.
An additional 20 patients are being enrolled in the phase II portion of the study with 15
patients enrolled as of 12/1/09 (patient accrual will be completed before enrollment into this
study).
Twelve patients (median age, 58 yrs) were treated in the phase I study with 6 patients treated
at the 1.0 mg/m2 level after 1 patient experienced a serious adverse event (SAE) of
prolonged diarrhea, and 3 patients treated at each of the subsequent levels. Eleven patients
had 1 prior and 1 patient tandem prior cycles of dose-intense melphalan. All patients
experienced the expected pancytopenia requiring red cell and/or platelet support.  Ten
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patients had febrile neutropenia with bacteremia identified in 3 patients. One patient had
mild tumor lysis not requiring medical intervention. Mucositis was minimal and comparable
to PBSCT with melphalan alone. All patients engrafted at a median time to ANC>500/uL of
11 days (range, 9-19) and platelet>20,000/uL of 14 days (range, 11-27). No other SAEs
occurred in the phase I study beyond the usual events of high-dose therapy. No neurological
SAEs, including severe peripheral neuropathies, were observed. A bortezomib dose of 1.6
mg/m2 was chosen for the phase II study.
Fifteen patients (median age, 56 yrs) are now treated in the phase II study. Six patients had
disease progression and 9 patients had less than a partial response (PR) after a prior PBSCT.
All patients experienced pancytopenia and evaluable patients engrafted with median time to
ANC>500/uL of 10 days (range, 8-13) and platelet>20,000 of 11 days (range, 9-65).  Eleven
patients had febrile neutropenia with 3 patients with positive blood cultures and 1 patient
with RSV bronchitis.  Three SAEs are reported in the phase II portion: 1 patient expired of
complications of Candida krusei infection and 1 of MRSA sepsis (before ANC recovery). A
third patient developed tumor lysis requiring dialysis. One patient had a dysphoric reaction
to anti-emetics and did not receive the 2nd bortezomib dose. No neurological SAEs
attributable to this regimen were observed in this population.
Patients underwent restaging studies at monthly intervals after transplantation with marrow
examination at 3 and 12 months.  Response classification is in accordance to standard
definitions. Three patients underwent subsequent allogeneic PBSC and 2 patientss died of
transplant-related complications and are not evaluable for response. Two patients succumbed
to progressive disease. The remaining 20 patients are in ongoing follow-up. Eight patients
including 6 of 11 patents with stable disease or minimal response after prior dose-intense
melphalan achieved a CR. Six patients remain in continuous CR at 11+ to 23+ months
(median, 15+ months) after PBSCT with 2 patients having disease progression at 12 and 26
months after PBSCT.
These data indicate that bortezomib can be added to dose-intense melphalan in this schedule
with acceptable toxicities. Strikingly, 8 of 22 pts achieved CR after minimal response to
dose-intense melphalan alone or disease progression after a prior PBSCT, and 2 patients
showed tumor lysis, indicating a synergistic effect of adding bortezomib to dose-intense
melphalan.
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2
Study Objectives
2.1 Primary Objective:
To determine the progression-free survivals of patients with multiple myeloma treated with
tandem cycles of high-dose melphalan followed by high-dose melphalan in combination with
bortezomib with autologous HSC transplantation.
2.2 Secondary Objectives:
To determine the response rate, overall survival, and regimen-related toxicities of patients with
multiple myeloma treated with high-dose melphalan or high-dose melphalan in combination
with bortezomib given in tandem transplants
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3
Investigational Plan
3.1 Overall Design and Plan of Study
This is a multi-institution phase II non- randomized study
3.2
Patient Selection
3.3
Inclusion Criteria (1st and 2nd transplants)
3.3.1
Confirmed diagnosis of multiple myeloma with either a
Durie-Salmon stage I, II, or III or ISS stage I, II or III, less than 12
months since initiation of systemic therapy
3.3.2
≥8x106 CD34+cells/kg available in cryopreservation in
aliquots
appropriate for tandem transplants
3.3.3
Age: 18-75 years at time of transplantation
3.3.4
KPS 70-100%
3.3.5
Recovery from complications of prior therapies
3.3.6
Gender: There is no gender restriction
3.4
Exclusion Criteria (1st and 2nd transplants)
Patients meeting any of the following exclusion criteria are not to be enrolled in
the study.
3.4.1
Diagnosis other than multiple myeloma
3.4.2
Chemotherapy or radiotherapy within 8 days of initiating treatment in this
study
3.4.3
Prior autologous or allogeneic transplantation (except as enrolled into this
study)
3.4.4
Uncontrolled bacterial, viral, fungal or parasitic infections
3.4.5
Uncontrolled CNS metastases
3.4.6
Known amyloid deposition in heart
3.4.7
Organ dysfunction
3.4.7.1 LVEF <40% or cardiac failure not responsive to therapy
3.4.7.2 FVC, FEV1, or DLCO <40% of predicted and/or receiving
supplementary continuous oxygen
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3.4.7.3 Evidence of hepatic synthetic dysfunction, or total bilirubin >2x
or AST >3x ULN
3.4.7.4 Calculated creatinine clearance <20 ml/min
3.4.8
Sensory peripheral neuropathy grade 4 within 14 days of enrollment
3.4.9
Karnofsky score <70% unless a result of bone disease directly caused by
myeloma
3.4.10 Life expectancy limited by another co-morbid illness
3.4.11 Diagnosed or treated for another malignancy within 3 years of
enrollment, with the exception of complete resection of basal cell
carcinoma or squamous cell carcinoma of the skin, an in situ malignancy,
or low-risk prostate cancer after curative therapy
3.4.12 Female subject is pregnant or breast-feeding (women) or unwilling to use
acceptable birth control methods (men or women) for twelve months after
treatment. Confirmation that the subject is not pregnant must be
established by a negative serum β-human chorionic gonadotropin
(β-hCG) pregnancy test result obtained during screening. Pregnancy
testing is not required for post-menopausal or surgically sterilized
women.
3.4.13 Documented hypersensitivity to melphalan or to bortezomib, boron or
mannitol or any components of the formulation
3.4.14 Patients unable or unwilling to provide consent
3.4.15 Myocardial infarction within 6 months prior to enrollment or has New
York Heart Association (NYHA) Class III or IV heart failure (see
section 8.4), uncontrolled angina, severe uncontrolled ventricular
arrhythmias, or electrocardiographic evidence of acute ischemia or active
conduction system abnormalities. Prior to study entry, any ECG
abnormality at screening has to be documented by the investigator as not
medically relevant
3.4.16 Patient has received other investigational drugs with 14 days before
enrollment
3.4.17 Serious medical or psychiatric illness likely to interfere with participation
in this clinical study
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3.5 Patient Evaluations – First Transplant
3.5.1
Pre-transplant evaluation must be performed within 60 days of
transplant, except for HLA, ABO and Rh typing
3.5.2
History with full details of the patient’s prior treatments and
responses
3.5.3
Careful physical exam with determination of Karnofsky score
and findings related to underlying malignancy
3.5.4
Chemistry profile to include serum creatinine, AST, alkaline
phosphatase, and bilirubin
3.5.5
CBC with differential
3.5.6
ABO, Rh, red cell antibody screen
3.5.7
PT, PTT
3.5.8
Serum pregnancy test, if female gender with child-bearing
potential
3.5.9
HIV, Hepatitis B, Hepatitis C and CMV serology
3.5.9.1
Infectious disease testing, if previously
documented positive, need not be repeated to
comply with this requirement.
3.5.10 Creatinine clearance (calculated)
3.5.11 Disease Staging
3.5.11.1
Serum and urine protein electrophoreses and
immunofixation with measurement of monoclonal
protein
3.5.11.2
ß2M
3.5.12 Radiological studies of any sites of bone pain or bone scan
abnormalities
3.5.13 Skeletal survey if not performed within 6 months of start of
study treatment
3.5.14 Pulmonary function tests with DLCO
3.5.15 MUGA scan or cardiac echo
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3.5.16 Patients with a suspected diagnosis of amyloidosis will
undergo echocardiography for the detection of cardiac
involvement
3.5.17 EKG
3.6 Patient Evaluations – Second Transplant
3.6.1
History with full details of the patient’s prior treatments and
responses
3.6.2
Careful physical exam with determination of Karnofsky score
and findings related to underlying malignancy
3.6.3
Chemistry profile to include serum creatinine, AST, alkaline
phosphatase, and bilirubin
3.6.4
CBC with differential
3.6.5
ABO, Rh, red cell antibody screen
3.6.6
PT, PTT
3.6.7
Serum pregnancy test, if female gender with child-bearing
potential
3.6.8
HIV,, Hepatitis B, Hepatitis C and CMV serology
3.6.8.1 Infectious disease testing, if previously documented
positive, need not be repeated to comply with this
requirement.
3.6.9
Creatinine clearance (calculated)
3.6.10 Disease Staging
3.6.10.1
Serum and urine protein electrophoreses and
immunofixation with measurement of monoclonal
protein
3.6.10.2
β2m
3.6.10.3
Radiological studies of any sites of bone pain or
bone scan abnormalities
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3.7 Analysis of PBSC and Marrow Components
3.7.1
TNC and CD34+ cell count
3.8 Post-Transplant Evaluation
3.8.1
Physical exam, daily until hematological recovery and
resolution of serious regimen-related complications
3.8.2
Daily assessment of toxicity from day-1 until resolution of all
Grade 3/4 treatment-related toxicities
3.8.2.1 Presence assessed and scored in accordance with NCI
toxicity guidelines
3.8.3
CBC daily from day 0 until ANC ≥500/ul on two sequential
days after nadir reached (engraftment). Thereafter, CBC at
least weekly until documentation of transfusion independence
(platelet count ≥20,000/ul without transfusion for ≥7 days)
3.8.4
Chemistry profile including magnesium t.i.w. until
documentation of engraftment, and then at least weekly until
stabilization of electrolytes is documented
3.8.5
Record of all medications administered during inpatient course
3.9 Post transplant re-staging of disease
3.9.1
Restaging by serum and urine should be done at 4 weeks
intervals (±7 days) starting at day +28 after transplantation for
3 months and then at 3 months intervals until 3 years after
transplantation or demonstration of disease progression
requiring therapy, if earlier.
3.9.1.1 Staging studies will be obtained after both 1st and 2nd
transplants.
3.9.2
24 hour urine for creatinine clearance, total protein, protein
electrophoresis with quantitation of monoclonal protein by
immunofixation, serum free light chain measurements at 4
week intervals (±7 days) starting at day +28 after
transplantation for 3 months and then at 3 month intervals (or
more frequently as clinically necessary) until demonstration of
disease progression
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3.9.2.1 Staging studies will be obtained after both 1st and 2nd
transplants.
3.10Study Treatments
3.10.1 Study Medications
3.10.1.1
Bortezomib (VELCADE) for Injection is a sterile
lyophilized powder for reconstitution and is supplied in
vials containing bortezomib and mannitol at a 1:10 ratio.
For example, vials containing 3.5 mg of bortezomib
contain 35 mg of mannitol. Vials containing lyophilized
bortezomib for Injection should be stored according to the
label requirements.  For the United States, store at USP
Controlled Room Temperature which is 25ºC (77ºF);
excursions permitted from 15 to 30ºC (59 to 86ºF).  For
Europe, do not store above 30ºC (86ºF).  To date, stability
data indicate that the lyophilized drug product is stable
for at least 18 months when stored under the
recommended conditions. Stability studies are ongoing,
and Millennium Pharmaceuticals, Inc. will notify the
investigator should this information be revised during the
conduct of the study. bortezomib is cytotoxic.  As with all
cytotoxic drugs, caution is required when preparing and
handling bortezomib solutions.  Cytotoxic drugs should
only be handled by staff specially trained in the safe
handling of such preparations. The use of gloves and
other appropriate protective clothing is recommended.  In
case of skin contact, wash the affected area immediately
and thoroughly with soap and water for at least 15
minutes.  If product contacts eye, immediately flush eye
thoroughly with water for at least 15 minutes.  Always
contact a physician after any form of body contact. All
materials that have been used for preparation should be
disposed of according to standard practices. A log must
be kept of all disposed materials. The drug is available in
sterile, single use vials containing 3.5 mg of bortezomib. 
Each vial of bortezomib for Injection should be
reconstituted under a laminar flow biological cabinet
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(hood) within eight hours before dosing with 3.5 mL of
normal (0.9%) saline, Sodium Chloride Injection USP, so
that the reconstituted solution contains bortezomib at a
concentration of 1 mg/mL.  Prior to reconstitution the
vials should remain in the cartons to protect them from
light.  Dissolution is completed in approximately 10
seconds.  The reconstituted solution is clear and colorless,
with a final pH of 5 to 6.  Reconstituted bortezomib
should be administered promptly and in no case more
than 8 hours after reconstitution.  All materials that have
been used for preparation should be disposed of
according to standard practices.  A log must be kept of all
disposed material.
3.10.1.2
Melphalan for Injection is a sterile lyophilized powder for
reconstitution and will be obtained from the manufacturer
in accordance with standard pharmacy purchasing
criteria. Melphalan will be reconstituted by pharmacy
staff, in accordance with usual pharmacy practices,
immediately before patient infusion. Melphalan is a
bifunctional alkylating agent that acts principally through
covalent reactions with DNA, resulting in the formation
of drug-DNA adducts with cross-linking of DNA strands.
Melphalan’s cytotoxic effects are related to its
concentration and the duration of exposure to melphalan
of the cell. Enhanced repair of DNA interstrand
crosslinks may be a mechanism of resistance that
develops after prior exposure to this drug. Melphalan is
actively transported into cells by the high-affinity
L-amino acid transport system; glutamine and leucine
compete for carrier uptake and high levels of these amino
acids can reduce drug uptake. Other drugs such as
tamoxifen, chlorpromazine, and indomethacin can also
impair melphalan uptake and accumulation. Studies of
the pharmacokinetics of oral melphalan were complicated
by the highly variable absorption of the drug. Moreover,
studies of intravenous melphalan have also showed
considerable inter-patient variability in plasma clearance.
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Pinguet et al studied the pharmacokinetics of melphalan
administered at a dose of 140 mg/m2 in combination with
other chemotherapeutic agents to 20 patients undergoing
autologous PBSC transplantation. The medians time to
neutrophil and platelet recoveries were 16 and 14.6 days,
and the majority of patients (80%) developed WHO grade
3/4 stomatitis. Plasma concentration profiles were
biphasic and fitted with a two-compartment model. The
maximal concentration at the end of infusion averaged
7.94±3.73 mg/l (range, 1.65-14.5). The mean elimination
half-life and the mean residence time were 83.1±27.1
minutes (range, 51.6-166.81) and 98.7±26.9 minutes
(range 59.5-166.9), respectively. The volume of
distribution averaged 1.00±0.62 l/kg (range 0.46-3.12)
and total plasma clearance 548.3±300.0 ml/min/m2
(range, 218.6-1378.8). Plasma levels were below the
limits of detection for all patients by 24 hours after
melphalan administration. These authors noted large
inter-individual variability of these pharmacokinetic
parameters. Total clearance of melphalan was
significantly correlated with creatinine clearance (r=0.49,
p<0.05). A relationship between melphalan clearance
and renal function was also described by Kergueris et al.,
but this relationship did not explain the large variation in
inter-individual overall clearance of the drug (Kergueris
et al., 1994). Similar pharmacokinetic results were
reported for 20 pediatric and 10 adult patients treated with
melphalan 140 mg/m2 as a single agent. For the adult
patients, the elimination half-life (t½β) was 50±7 minutes
for patients treated with 140 mg/m2 dose and 41±12
minutes for the higher dose of 180 mg/m2. Plasma
clearance averaged 525 ml/min/m2 at 140 mg/m2 and 532
ml/min/m2 at 180 mg/m2.
3.11 Outline of Treatment Plan
Patients will sequentially undergo two transplants in this order.
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Figure 1: Outline of Treatment Schema First Transplant
Melphalan 200 mg/m2 day -1
⇓
Autologous HSCT
Figure 2: Outline of Treatment Schema Second Transplant
Bortezomib 1.6 mg/m2 d-4
⇓
Melphalan 200mg/m2 d-2
⇓
Bortezomib 1.6mg/m2 d-1
⇓
Autologous HSCT
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3.12Conditioning Regimens
3.12.1 First Transplant
3.12.2 Melphalan
3.12.2.1
Melphalan is administered by rapid intravenous
infusion via a central vein over one hour
3.12.2.2
The final dilution of melphalan is physically and
chemically stable for 60 minutes and therefore will
be administered within that time period
3.12.2.3
Melphalan will be given as a single dose (not split
over 2 or more days)
3.12.2.4
Patients are encouraged to “chew” ice for 15
minutes before through 1 hour after administration
of melphalan
3.12.2.5
Dosing will be based on body surface area
calculated using actual body weight
3.12.2.6
Patients will be hospitalized starting at least 1 hr
before melphalan administration and continuing for
at least 10 days after melphalan infusion (may be
discharged home on day +10). Aggressive
hydration will be used for uro-protection during the
time of melphalan administration and for 24 hours
after the completion of melphalan infusion
3.13Second Transplant
3.14 Bortezomib
3.14.1 Bortezomib is administered by rapid I.V. push (over 3-5
seconds) via a central or peripheral vein into a flowing saline
line
3.14.2 Bortezomib will be administered any time on day -4, at least
20 hrs after the start of the melphalan infusion on day -1
3.14.3 Dosing will be based on body surface area calculated using
actual body weight
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3.14.4 Dexamethasone is administered at a dose of 20 mg i.v. daily
on days -4 and -1 (with bortezomib). Dexamethasone is
administered at a dose of 10 mg i.v. as a component of the
anti-nausea regimen on day -2 before melphalan
administration
3.15Stem Cell Infusion
3.15.1 Day 0 is defined as the day of first stem cell infusion.
3.15.2 Additional cells may be infused on subsequent days if the
volume of the HSC components is deemed too large for a
single infusion
3.15.3 HSC will be infused at least 18 hrs or later after bortezomib
infusion
3.15.4 Day 0 should be fixed on a Monday – Friday, when possible
3.15.5 All patients will receive unmodified HSCT (other than
cryopreservation). These components will not be irradiated
3.15.6 Cells will be infused according to HUMC Standard Practice
guidelines
3.16Post-transplant Cytokine Administration.
3.16.1 Patients will routinely receive filgrastim, 5 ug/kg sc, on days
3, 5, 7, 9 and 10+ after stem cell transplantation. Filgrastim
dose may be rounded to vial size (e.g., <70kg: 300 ug, 70-90
kg: 480 ug, >90 kg: 600 ug)
3.17Post-transplant Supportive Care
3.17.1 Hospitalization: Patients will cared for in the inpatient or
outpatient transplant units. Patients will be discharged from
the transplant unit when hematological recovery occurs, the
patient is clinically stable, and all grade 3/4 toxicities have
resolved, but not before day +10 of transplantation
3.17.2 Mucositis
3.17.2.1
Patients may receive any anti-emetic regimen
determined to be clinically appropriate
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3.17.2.2
Patients may receive any anti-diarrhea regimen
determined to be clinically appropriat
3.17.3 Central line: Patients will have central venous access suitable
for TPN and blood component support and maintained
according to HUMC Standard Practice guidelines
3.17.4 Infection prophylaxis: Patients will receive prophylaxis for
PCP, HSV, bacterial, and fungal infections according to
HUMC Standard Practice guidelines
3.17.5 Blood component support: Patients will receive transfusions
in accordance with HUMC Standard Practice guidelines
3.17.6 Nutrition: Patients may receive enteral or parenteral
alimentation if caloric or protein intake falls below daily basal
needs
3.17.7 Post-transplant treatment: There are no restrictions for
administration of involved field radiation, chemotherapy,
maintenance therapy, or surgical interventions after
transplantation
3.17.8 Bisphosphinates: Monthly infusions of bisphosphinate therapy
after transplantation should be considered for all patients
3.17.9 Post-transplant vaccinations: Vaccinations will be
administered after transplantation in accordance with HUMC
Standard Practice guidelines
3.18Disease Response
3.18.1 Patients should undergo restaging of disease at 4 week
intervals starting one month after transplant as defined in
section 3.9
3.19Timing between Transplant Procedures
Patients will undergo 2nd transplant (day 0) no earlier than day 84 and no later than
day 180 after the 1st transplant (day 0)
3.20Dosing of Agents
3.20.1 Melphalan dosing will be based on actual body weight.. The
amount (in mg) of drug to be administered will be determined
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based on body surface area. Body surface area is to be
calculated based on body weight using a standard nomograM
3.20.2 Bortezomib dosing will be based on actual body weight. The
amount (in mg) of drug to be administered will be determined
based on body surface area. Body surface area is to be
calculated based on body weight using a standard nomogram
3.20.3 Patient weight will be determined by the nursing or nutrition
staff within 7 days of start of conditioning
3.20.4 Administration of Melphalan
3.20.4.1
Melphalan will be dosed based on actual body
weight at a dose of 200 mg/m2 and infused on day
-1 (first transplant) or day -2 (second transplant)
3.20.4.2
Administer melphalan IV over one hour through a
central catheter. Rapid infusion may result in
dizziness, nasal stuffiness, rhinorrhea, or nasal
congestion during or immediately after infusion
3.20.4.3
Administer early in the day
3.20.4.4
Have patient empty bladder frequently
3.20.4.5
Patients will receive hydration before and after
administration of melphalan
3.20.4.6
“Chewing” on ice may decrease the severity of oral
mucositis and is encouraged for all patients starting
15 minutes before, during, and for 60 minutes after
the infusion of melphalan
3.20.4.7
Patients will receive an anti-emetic regimen of
dexamethasone 10 mg i.v., and ondansetron 12 mg
i.v. 30 minutes before melphalan infusion
3.20.5 Administration of Bortezomib
3.20.5.1
Bortezomib will be dosed based on actual body
weight and infused on day -4, and day -1 before
HSC infusion
3.20.5.2
Bortezomib is supplied as a lyophilized white
powder in 3.5 mg single-dose vials
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3.20.5.3
Bortezomib is reconstituted with 1.2 ml sterile
water for injection, without shaking
3.20.5.4
Administration
3.20.5.4.1 Rapid I.V. push over 3-5 seconds via a
central or peripheral vein. Each vial is for a
single use administration.
3.20.5.4.2 Second dose of bortezomib will be no less
than 20hrs after melphalan administration
3.20.5.4.3 Dexamethasone, 20 mg i.v., will be given as
a pre-medication.
3.21Pre-Transplant Therapy
Chemotherapy and/or radiation therapy may be given to reduce tumor bulk as
determined on clinical grounds. The referring oncologist may be asked to administer
this therapy. The prior therapies are not specified by this protocol
3.21.1 Patients will not proceed to dose-intense therapy any sooner
than 8 days after completion of the most recent cycle of
chemotherapy or radiotherapy
3.21.1.1
The timing of therapy is in reference to the dose of
melphalan
3.21.1.2
Therapy with thalidomide and/or corticosteroids
may be discontinued no less than 7 days before
initiation of bortezomib
3.21.2 Collection of Autologous Hematopoietic Stem Cells
The methods of collection of hematopoietic stem cells are not specified by this
protocol
3.22Treatment Assignment
All patients will undergo the same treatment regimen
3.23Blinding, Packaging, and Labeling
VELCADE will be supplied in vials as open-label stock. Both the box label and
vial label will fulfill all requirements specified by governing regulations.
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Melphalan will be supplied in vials as open-label stock. Both the box label and vial label
will fulfill all requirements specified by governing regulations.
3.24Concomitant Treatment
3.24.1 Required Concurrent Therapy
Not applicable. Patients will receive standard care
3.24.2 Prohibited Concurrent Therapy
Any investigational agent
3.25Treatment Compliance
All drug will be administered to eligible patients under the supervision of the
investigator or identified sub-investigator(s). The pharmacist will maintain records of
drug receipt (if applicable), drug preparation, and dispensing, including the applicable
lot numbers, patients’ height, body weight, and body surface area, and total drug
administered in milliliters and milligrams. Any discrepancy between the calculated dose
and dose administered and the reason for the discrepancy must be recorded in the source
documents.
3.26Duration of Treatment and Patient Participation
Patients will be hospitalized until at least day +10 after transplantation and resolution of
serious adverse events. Patients will then be followed, indefinitely, for survival and
duration of response to the treatment received.
3.27Termination of Treatment and/or Study Participation
Patients will be informed that they have the right to withdraw from the study at any time
for any reason, without prejudice to their medical care. The investigator also has the
right to withdraw patients from the study for any of the following reasons:
●
Intercurrent illness
●
Occurrence of an unacceptable adverse event
●
Patient request
●
Protocol violations
●
Non-compliance
●
Administrative reasons
●
Failure to return for follow-up
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●
General or specific changes in the patient’s condition unacceptable for further treatment
in the judgment of the investigator
●
Progressive disease at any time
At the time of withdrawal, all study procedures outlined for the End of Study visit should be
completed. The primary reason for a patient’s withdrawal from the study is to be recorded in
the source documents.
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4
Adverse Events
4.1 Definitions
4.1.1
Adverse Event Definition
An adverse event (AE) is any untoward medical occurrence in a patient administered a
pharmaceutical product, which does not necessarily have a causal relationship with the
treatment. An adverse event can be any unfavorable and unintended sign (eg, including an
abnormal laboratory finding), symptom, or disease temporally associated with the use of the
drug, whether or not it is considered to be drug related. This includes any newly occurring
event or previous condition that has increased in severity or frequency since the
administration of drug.
4.1.2
Serious Adverse Event Definition
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of
causality that:
●
Results in death.
●
Is life-threatening. Life-threatening means that the patient was at immediate risk of
death from the reaction as it occurred, i.e., it does not include a reaction which
hypothetically might have caused death had it occurred in a more severe form.
●
Requires
inpatient
hospitalization
or
prolongation
of
existing
hospitalization.
Hospitalization admissions and/or surgical operations scheduled to occur during the
study period, but planned prior to study entry are not considered AEs if the illness or
disease existed before the patient was enrolled in the trial, provided that it did not
deteriorate in an unexpected manner during the trial (eg, surgery performed earlier than
planned).
●
Results in persistent or significant disability/incapacity. Disability is defined as a
substantial disruption of a persons’ ability to conduct normal life functions.
●
Is a congenital anomaly/birth defect.
●
Is an important medical event. An important medical event is an event that may not
result in death, be life-threatening, or require hospitalization but may be considered an
SAE when, based upon appropriate medical judgment, it may jeopardize the patient or
subject and may require medical or surgical intervention to prevent one of the outcomes
listed in the definitions for SAEs. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or at home, blood
dyscrasias or convulsions that do not result in inpatient hospitalization, or the
development of drug dependency or drug abuse.
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Clarification should be made between the terms “serious” and “severe” since they ARE NOT
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of
relatively minor medical significance (such as a severe headache). This is NOT the same as
“serious,” which is based on patient/event outcome or action criteria described above and are
usually associated with events that pose a threat to a patient’s life or functioning. A severe
adverse event does not necessarily need to be considered serious. For example, persistent nausea
of several hours duration may be considered severe nausea but not an SAE. On the other hand, a
stroke resulting in only a minor degree of disability may be considered mild, but would be defined
as an SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for
defining regulatory reporting obligations.
4.2 Procedures for AE and SAE Reporting
Investigator-sponsor must report all serious adverse event (SAE) regardless of relationship with any
study drug or expectedness to the IRB as required by the institution.
Intensity for each adverse event, including any lab abnormality, will be determined by using the
NCI CTCAE, version 3.0, as a guideline, wherever possible. The criteria are available online at
http://ctep.cancer.gov/reporting/ctc.html.
4.3 Assessment of Toxicity
4.3.1. Common Terminology Criteria for Adverse Events (CTCAE) will be used for the
assessment and grading of all toxicities experienced by patients enrolled into this
study (htt;:///ctep.cancer.gov/forms/CTCAE_Index.pdf).
a.
If the nature of the adverse experience is listed in the CTCAE, the maximum
grade and time of maximum grade will be reported.
b. If the adverse experience is not listed on the NCI CTG Expanded Toxicity
Criteria Appendix D, report the toxicity grade using the following criteria:
Grade 1= Mild: an adverse experience which is easily tolerated by the
patient, causing minimal discomfort and not interfering with
everyday activities.
Grade 2 = Moderate: an adverse experience which is sufficienty
discomforting to interfere with normal every day activities.
Grade 3 = Severe: an adverse experience which is incapacitating and
prevents normal every day activities.
Grade 4 = Life Threatening: an adverse experience which places the patient
at immediate risk of death.
4.3.2. Assessment of Causality
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a.
Every effort should be made by the investigator to explain each adverse
experience and assess its relationship, if any, to study drug treatment.
Causality should be assessed using the following categories: Not Related,
Unlikely, Suspected (Reasonable Possibility), Probable.
Not related: The adverse experience is definitely not related to the test drug.
Unlikely: There are other, more likely causes and the drug is not suspected as
a cause.
Suspected (reasonable possibility): A direct cause and effect relationship
between the drug and the adverse experience has not been demonstrated but
there is a reasonable possibility that the experience was caused by the drug.
Probable: There probably is a direct cause and effect relationship between the
adverse experience and the study drug.
b. The degree of certainty with which an adverse experience is attributed to
drug treatment (or alternative causes, e.g.: natural history of the underlying
diseases, concomitant therapy, etc.) will be determined by how well the
experience can be understood in terms of one or more of the following.
Known pharmacology of the drug
Reaction of similar nature being previously observed with this drug or class
of drug. The experience having often been reported in literature for similar
drugs as drug related e.g.: skin rashes, blood dyscrasia. The experience being
related by time to drug ingestion terminating with drug withdrawal
(dechallenge) or reproduced on rechallenge.
4.3.3. Follow-up of Adverse Experiences
a.
Patients with adverse experiences will be actively followed until the event
has subsided (disappeared) or until the condition has stabilized.
b.
Adverse events, both serious and non-serious, and deaths that occur
during the patient’s study participation will be recorded in the source
documents. All SAEs should be monitored until they are resolved or are
clearly determined to be due to a patient’s stable or chronic condition or
intercurrent illness(es).
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5
Statistical Evaluation
This is a phase II study to determine the progression-free survivals of patients with multiple
myeloma treated with tandem cycles of high-dose melphalan followed by high-dose melphalan
in combination with bortezomib with autologous HSC transplantation.
5.1
Endpoint
5.1.1
Primary Objective
5.1.1.1 The main primary endpoint of this study is three-year progression free survival.
Patients are considered a failure with respect to PFS if they die or experience disease
progression or relapse. The time to this event is the time from transplantation to
relapse/progression, initiation of non-protocol anti-myeloma therapy, or death from any
cause. Subjects alive without confirmed disease progression will be censored at the
time of last disease evaluation. Deaths without progression are treated as failures no
matter when they occur.
5.1.2
Secondary Objective
5.2
5.2.1.1 To determine the response rate, overall survival, and regimen-related toxicities of
patients with multiple myeloma treated with high-dose melphalan or high-dose melphalan
in combination with bortezomib given in tandem transplants
5.2
Secondary endpoints will include:
a.
Overall response rates: Defined as the composite endpoint of response to treatment which
includes Complete Response (CR), Partial Response (PR), stable disease (SD) as defined
in International Response Criteria. We will also analyze Complete Response rate.
b. Overall survival (OS): Defined as time from the first dose of administration to death
from any cause.
c.
Univariate analysis of risk of progression/relapse and mortality: To examine the
univariate effects of the prognostic features on the outcomes EFS and OS for patients
using this modality with respect to risk of relapse/progression and death from any cause.
d. Univariate analysis of the risk of progression/relapse and mortality: In addition,
multivariate analysis of the risk of progression/relapse and overall mortality will be
conducted to assess influence of variables measured after the start of treatment.
e.
Regimen-related toxicity: Graded and presented in a descriptive nature.
Descriptive analysis of baseline characteristics and demographics in this study will be
performed in the following manner. Continuous measurements will be summarized as mean
(SD) or median (inter-quartile range) based on whether or not the data come from a normal
distribution as validated by Shapiro-Wilks test of normality. Categorical measurements will be
summarized as frequency (percentage). Proportion of overall survival will be estimated by the
Kaplan-Meier product limit method. The univariate probability of the relapse and
treatment–related mortality (TRM) will be calculated using cumulative incidence function.
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5.3 Accrual, Registration and Follow-up
The targeted sample size for the single arm is 97 subjects that successfully undergo the 2nd
transplant.  It is estimated that eight years 1 month (97 months) of accrual will be necessary to
enroll this number of subjects.   The Blood and Marrow Transplantation Program at HUMC
treats over 120 patients with this diagnosis every year. In the last two years, an estimated 50
multiple myeloma patients each year underwent tandem autologous hematopoietic stem cell
transplantation using the high-dose melphalan conditioning regimen. It is assumed that patients
will enroll into the study uniformly over the accrual period at the rate 1 patient per month.
After eligibility is established, subjects will be enrolled into the single arm using high-dose
melphalan and high-dose melphalan-bortezomib as a conditioning regimen.
All subjects will be “on-study” for three years post-transplant, during which they will be
monitored for the effects of treatment through regular clinic. With four years of planned
accrual, and a minimum of three years of additional follow-up post-transplant, subjects will be
followed for progression-free survival for at least 36 months.
5.4    Sample Size and Power Calculations
In this section, the power of the analysis of time to progression or death is considered and
performed based on the proportion surviving without progression at three years.  The standard
tandem autologous HSCT with high-dose melphalan conditioning regimen is assumed to have
PFS of 56%. It is posited that the high-dose melphalan and melphalan-bortezomib conditioning
regimen will increase the three-year PFS to 76%. To estimate the 3-year PFS in tandem
autologous HSCT followed by high dose Mel-Vel based on an anticipated advantage over 3-PFS
observed in historical controls, the method of Simon and Dixon (9) was used to derive the
sample size. At the design stage, it was stated that there were 150 patients in the historical
control cohort who had received tandem auto HSCT with HD melphalan. Median event-free
survival in the 150 was 3.58 years (42.96 months) and 44%(66 of 150) had had progression of
disease. Hazard rate in the HC is 0.44 and hazard rate in the experimental arm (with
melphalan-bortezomib) is 0.24 thus the ratio of the hazard rates is 1.8333. However, to adjust
for the dropout due to MD decision, Patient decision, PD before 2nd transplant, or loss of
insurance averaging to a rate 0.3, the hazard rate is (.44+.3)/(.24+.3)=1.37. If we assume
accrual rate of 1 patient per month, 5% level of significance and 80%, a sample of 97 patients
that successfully undergo the 2nd transplant will be required and this calculation will achieve
80.17% power to show that PFS is at least 76% in the single arm.
Adjusted Sample Size
This is adjustment was not preplanned, however, after observing the slower accrual of 1 patient
per month and the larger than anticipated dropouts post-first transplant, it was deemed necessary
to employ an adjustment with respect to dropout, for the single arm versus historical control if
the power to detect the efficacy of high-dose melphalan and high-dose melphalan-bortezomib
were to be preserved.
5.5   Efficacy analysis
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This is a phase II study comparing the progression-free survival after tandem autologous HSCT
with high-dose melphalan to high-dose melphalan and bortezomib in patients with a diagnosis
of multiple myeloma. 
5.6   Statistical Hypothesis
The null hypothesis is that the three-year progression free survival rate in multiple
myeloma patients receiving tandem autologous HSCT with high-dose melphalan
(control arm) is 56%. The alternative hypothesis for this study posits that the treatment
plan consisting of tandem autologous HSCT with high-dose melphalan followed by
high-dose melphalan-bortezomib (experimental arm) will increase the 3 year progression
free survival to 76%, which is 20 % more than PFS in the historical arm. Note that the
hazard rate for progression in historical tandem cohort, λc, is 0.44 (1-0.56) and the
experimental arm with HD Mel-Vel has a hazard rate, λE, of 0.24 (1-0.76), so that the
minimum hazard ratio, δ = λc/ λE, is 0.44/0.24=1.833. Thus this single arm trial of
increased PFS at 3 years post-HSCT is equivalent to evaluating
hypotheses:
HO: δ (3)≤1
 HA: δ (3) > 1 SE(3)
where δ (3) = the three-year progression of disease hazard ratio Thus, a one-sided log-rank test
stratified on risk status will be conducted to determine if tandem autologous HSCT with
high-dose melphalan and melphalan-bortezomib improves the progression free survival over
that in historical controls using high-dose mephalan alone using a 5% level of significance.
Equivalently, estimating a 90% confidence interval of the 3 year progression-free survival
would achieve the desired goal.
5.7 Primary endpoint
The primary analysis will include all eligible autologous transplantation subjects that receive the
high-dose Mel-MelVel conditioning regimen and historical control of standard tandem HSCT
recipients using high-dose melphalan conditioning regimen. 3 –year PFS and corresponding
90% confidence interval will be estimated using Kaplan-Meier method. It is anticipated that the
estimated 90% confidence interval should include 76% and exclude 56% to show evidence that
tandem autologous HSCT with high-dose melphalan and melphalan-bortezomib improves the
progression-free survival in this patient population.
5.8
Secondary endpoints
5.8.1
Response to Treatment
The rates of complete remission (CR), and very good partial remission (VGPR) according to the
International Uniform Response Criteria (Section 3.2) will be calculated at two years after
transplantation. The analyses of the two-year response rates are planned as soon as those data
become available in all subjects, at one and two years after the close of accrual. Estimated
proportions or response and their corresponding exact binomial 95% confidence interval will be
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reported for these endpoints. Fisher’s exact test will be used to compare response to treatment
for both CR and VGPR endpoints between any groups using 5% level of significance.
5.8.2
Overall Survival
The event is death from any cause. The time to this event is the time from transplantation to
death, loss to follow-up or the end of the study, whichever comes first. Patients alive at the time
of last observation are considered censored. The Kaplan-Meier estimate of survival, along with
corresponding with 90% confidence interval, will be computed at 1 year, 2 year and 3 year post
tandem transplant for all patients and separately for any group. For any group comparisons, a
log-rank test, conducted at a one-sided significance level of 0.05.
5.8.3
Association between Prognostic factors and EFS and OS
Ananalysis of risk outcomes relapse/progression, transplant-related mortality, and overall
mortality will be conducted while adjusting for imbalance in other risk factors using a Cox
proportional hazards model (10). To fit the multivariate model, a stepwise backward selection
procedure will be used while considering relapse risk status (low risk, high risk), age at
transplant and Karnosfky performance score (<90 versus ≥90 ). An examination of the
goodness-of-fit will be performed using Grambsch-Therneau and Martingale residual plots (11)
and Loess smooth of Cleveland (12). Covariates yielding a p-value of 0.05 or less will be an
indication of statistical significance. The proportionality assumption for Cox regression will be
validated by introducing a time-dependent covariate for each risk factor and outcome. This
analysis will be presented in terms of relative risks (RR) along with the corresponding p values
for each covariate.
5.9
Safety Analysis
Safety Analysis will be performed on all patients who have at least one dose of medication on
either treatment arms over the course of this study. The severity of the toxicities will be graded
according to the NCI CTCAE v3.0 whenever possible. Events during the first 100 days after
transplantation will be considered possibly related to the transplant for this analysis.
Regimen-related toxicity will be graded and presented in a descriptive nature as incidence rates
and corresponding exact binomial 95% confidence intervals.
5.9.1
Safety Monitoring Endpoints
The incidence of toxicities of grade 3 or higher toxicities (CTCAE version 3.0), the incidence of
probable viral fungal and bacterial infections, and the incidence of treatment-related morality,
i.e., from causes other than relapse or progression, will be recorded for each patient at set
intervals over the course of the study. Safety data will be described in a variety of ways, both
graphical and tabular, and incidence will be compared across time points and treatment arms.
The Data and Safety Monitoring Board will be presented with a comprehensive semi-annual
report that will contain both solicited and unsolicited adverse event reports.
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5.10 Stopping rules
If the non-relapse mortality rate in the experimental group receiving high-dose melphalan and
bortezomib within the first 28 days after transplantation exceeds 10% then the study will be
stopped. Resumption of patient accrual will only be permitted after review of interim results by
the Institutional Review Board and the Data Safety Monitoring Board.
5.11 Monitoring Compliance.
Patients enrolled into the study will monitored for treatment actually received. Failure to comply
with study conditioning regimen would first trigger an intervention to improve compliance.
5.12 Data Management and Analysis
Case report forms will be created for management of data collected during this study. A
database in Access will be created based on the case report forms. All study data will be
imported into SAS and data management will be utilized to flag, and generate queries on out of
range data issues until they are resolved. All analysis will be performed using SAS software
version 9.2 (SAS Institute Inc. Cary, NC).
6.0 Administrative requirements
6.1
Good Clinical Practice
The study will be conducted in accordance with the International Conference on
Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory
requirement(s). The investigator will be thoroughly familiar with the appropriate use of
the drug as described in the protocol and Investigator’s Brochure. Essential clinical
documents will be maintained to demonstrate the validity of the study and the integrity
of the data collected. Master files should be established at the beginning of the study,
maintained for the duration of the study and retained according to the appropriate
regulations.
6.2
Ethical Considerations
The study will be conducted in accordance with ethical principles founded in the
Declaration of Helsinki. The IRB/IEC will review all appropriate study documentation
in order to safeguard the rights, safety and well-being of the patients. The study will
only be conducted at sites where IRB/IEC approval has been obtained. The protocol,
informed consent, advertisements (if applicable), written information given to the
patients (including diary cards), safety updates, annual progress reports, and any
revisions to these documents will be provided to the IRB/IEC by the investigator.
6.3
Patient Information and Informed Consent
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After the study has been fully explained, written informed consent will be obtained from
either the patient or his/her guardian or legal representative prior to study participation.
The method of obtaining and documenting the informed consent and the contents of the
consent will comply with ICH-GCP and all applicable regulatory requirement(s).
A conference will be held with the patient and family to discuss this study and
alternative treatments available for treatment of the underlying disease. All potential
risks associated with the use of bortezomib, melphalan and HSCT will be discussed as
objectively as possible. It will be explained that patients offered this treatment have
advanced malignancy with life expectancy of months to no more than 1-2 years with
conventional treatments. Informed consent from the patient will be obtained using the
IRB-approved consent form describing this protocol. The patient has the right to review
and correct the results of the pre-transplant evaluation.
6.4
Protocol Registration
All patients will be assigned a unique patient number (UPN) in accordance with HUMC
Standard Practice.
6.5
Patient Confidentiality
In order to maintain patient privacy, all data capture records, drug accountability records,
study reports and communications will identify the patient by initials and the assigned
patient number. The patient’s confidentiality will be maintained and will not be made
publicly available to the extent permitted by the applicable laws and regulations.
6.6
Record Retention
The investigator will maintain all study records according to ICH-GCP and applicable
regulatory requirement)s). The licensed medical records department, affiliated with the
institution where the patient receives medical card, maintains all original inpatient and
outpatient chart documents.
6.7 Investigation New Drug Exemption
All of the drugs employed in this protocol are commercially available and an IND
exemption is not required for the conduct of this study. The study will be conducted in
accordance with current Good Clinical Practice guidelines.
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7.0
Karnofsky Performance Status Scale
The following table presents the Karnofsy performance status scale1:
Points
Description
100
Normal, no complaints, no evidence of disease
90
Able to carry on normal activity
80
Normal activity with effort; some signs or symptoms of disease
70
Cares for self; unable to carry on normal activity or to do active work
60
Requires occasional assistance but is able to care for most of his/her needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization indicated. Death not imminent
20
Very sick; hospitalization necessary; active support treatment necessary
10
Moribund; fatal processes progressing rapidly
0
Dead
Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale: an
examination of its reliability and validity in a research setting. Cancer 1984;53:2002-2007.
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8.0
Body Surface Area and Creatinine Clearance Calculations
Body surface area (BSA) should be calculated using a standard nomogram that yields the
following results in meters squared (m2):
BSA =
or
BSA =
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows:
CrCl (ml/min) = (140-age) (actual wt in kg)
72 x serum creatinine (mg/dl)
For females use 85% of calculated CrCl value.
Note: In markedly obese patients, the Cockroft-Gault formula will tend to overestimate the
creatinine clearance. (Adipose tissue tends to contribute little creatinine requiring renal
clearance.) 12.0 New York Heart Association Classification of Cardiac Disease
The following table presents the NYHA classification of cardiac disease:
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of
physical activity. Ordinary physical activity does not cause undue
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence
of cardiovascular
disease.
II
Patients with cardiac disease resulting in slight limitation of physical
activity. They are comfortable at rest. Ordinary physical activity
results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of
minimal
cardiovascular disease.
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III
Patients with cardiac disease resulting in marked limitation of
physical activity. They are comfortable at rest. Less than ordinary
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of
moderately severe
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any
physical activity without discomfort. Symptoms of heart failure or
the anginal syndrome may be present even at rest. If any physical
activity is undertaken, discomfort is increased.
Objective evidence of
severe cardiovascular
disease.
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria
for Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown &
Co; 1994:253-256.
9.0 Declaration of Helsinki
World Medical Association Declaration of Helsinki:
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by
the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly,
Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th
WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 52nd
WMA General Assembly, Edinburgh, Scotland, October 2000
INTRODUCTION
1. The World Medical Association has developed the Declaration of Helsinki as a statement of
ethical principles to provide guidance to physicians and other participants in medical
research involving human subjects.
Medical research involving human subjects includes
research on identifiable human material or identifiable data.
2. It is the duty of the physician to promote and safeguard the health of the people. The
physician's knowledge and conscience are dedicated to the fulfillment of this duty.
3. The Declaration of Geneva of the World Medical Association binds the physician with the
words, "The health of my patient will be my first consideration," and the International Code
of Medical Ethics declares that, "A physician shall act only in the patient's interest when
providing medical care which might have the effect of weakening the physical and mental
condition of the patient."
4. Medical progress is based on research which ultimately must rest in part on experimentation
involving human subjects.
5. In medical research on human subjects, considerations related to the well-being of the
human subject should take precedence over the interests of science and society.
6. The primary purpose of medical research involving human subjects is to improve
prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology
and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic
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methods must continuously be challenged through research for their effectiveness,
efficiency, accessibility and quality.
7. In current medical practice and in medical research, most prophylactic, diagnostic and
therapeutic procedures involve risks and burdens.
8. Medical research is subject to ethical standards that promote respect for all human beings
and protect their health and rights.
Some research populations are vulnerable and need
special protection. The particular needs of the economically and medically disadvantaged
must be recognized. Special attention is also required for those who cannot give or refuse
consent for themselves, for those who may be subject to giving consent under duress, for
those who will not benefit personally from the research and for those for whom the research
is combined with care.
9. Research Investigators should be aware of the ethical, legal and regulatory requirements for
research on human subjects in their own countries as well as applicable international
requirements.
No national ethical, legal or regulatory requirement should be allowed to
reduce or eliminate any of the protections for human subjects set forth in this Declaration.
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
1. It is the duty of the physician in medical research to protect the life, health, privacy, and
dignity of the human subject.
2. Medical research involving human subjects must conform to generally accepted scientific
principles, be based on a thorough knowledge of the scientific literature, other relevant
sources of information, and on adequate laboratory and, where appropriate, animal
experimentation.
3. Appropriate caution must be exercised in the conduct of research which may affect the
environment, and the welfare of animals used for research must be respected.
4. The design and performance of each experimental procedure involving human subjects
should be clearly formulated in an experimental protocol. This protocol should be submitted
for consideration, comment, guidance, and where appropriate, approval to a specially
appointed ethical review committee, which must be independent of the investigator, the
sponsor or any other kind of undue influence. This independent committee should be in
conformity with the laws and regulations of the country in which the research experiment is
performed. The committee has the right to monitor ongoing trials. The researcher has the
obligation to provide monitoring information to the committee, especially any serious
adverse events. The researcher should also submit to the committee, for review, information
regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and
incentives for subjects.
5. The research protocol should always contain a statement of the ethical considerations
involved and should indicate that there is compliance with the principles enunciated in this
Declaration.
6. Medical research involving human subjects should be conducted only by scientifically
qualified persons and under the supervision of a clinically competent medical person. The
responsibility for the human subject must always rest with a medically qualified person and
never rest on the subject of the research, even though the subject has given consent.
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7. Every medical research project involving human subjects should be preceded by careful
assessment of predictable risks and burdens in comparison with foreseeable benefits to the
subject or to others. This does not preclude the participation of healthy volunteers in
medical research. The design of all studies should be publicly available.
8. Physicians should abstain from engaging in research projects involving human subjects
unless they are confident that the risks involved have been adequately assessed and can be
satisfactorily managed. Physicians should cease any investigation if the risks are found to
outweigh the potential benefits or if there is conclusive proof of positive and beneficial
results.
9. Medical research involving human subjects should only be conducted if the importance of
the objective outweighs the inherent risks and burdens to the subject. This is especially
important when the human subjects are healthy volunteers.
10. Medical research is only justified if there is a reasonable likelihood that the populations in
which the research is carried out stand to benefit from the results of the research.
11. The subjects must be volunteers and informed participants in the research project.
12. The right of research subjects to safeguard their integrity must always be respected. Every
precaution should be taken to respect the privacy of the subject, the confidentiality of the
patient's information and to minimize the impact of the study on the subject's physical and
mental integrity and on the personality of the subject.
13. In any research on human beings, each potential subject must be adequately informed of the
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations
of the researcher, the anticipated benefits and potential risks of the study and the discomfort
it may entail. The subject should be informed of the right to abstain from participation in
the study or to withdraw consent to participate at any time without reprisal. After ensuring
that the subject has understood the information, the physician should then obtain the
subject's freely-given informed consent, preferably in writing.
If the consent cannot be
obtained in writing, the non-written consent must be formally documented and witnessed.
14. When obtaining informed consent for the research project the physician should be
particularly cautious if the subject is in a dependent relationship with the physician or may
consent under duress.
In that case the informed consent should be obtained by a
well-informed physician who is not engaged in the investigation and who is completely
independent of this relationship.
15. For a research subject who is legally incompetent, physically or mentally incapable of
giving consent or is a legally incompetent minor, the investigator must obtain informed
consent from the legally authorized representative in accordance with applicable law. These
groups should not be included in research unless the research is necessary to promote the
health of the population represented and this research cannot instead be performed on legally
competent persons.
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent to
decisions about participation in research, the investigator must obtain that assent in addition
to the consent of the legally authorized representative.
17. Research on individuals from whom it is not possible to obtain consent, including proxy or
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advance consent, should be done only if the physical/mental condition that prevents
obtaining informed consent is a necessary characteristic of the research population. The
specific reasons for involving research subjects with a condition that renders them unable to
give informed consent should be stated in the experimental protocol for consideration and
approval of the review committee. The protocol should state that consent to remain in the
research should be obtained as soon as possible from the individual or a legally authorized
surrogate.
18. Both authors and publishers have ethical obligations.
In publication of the results of
research, the investigators are obliged to preserve the accuracy of the results. Negative as
well as positive results should be published or otherwise publicly available. Sources of
funding, institutional affiliations and any possible conflicts of interest should be declared in
the publication. Reports of experimentation not in accordance with the principles laid down
in this Declaration should not be accepted for publication.
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL
CARE
1. The physician may combine medical research with medical care, only to the extent that the
research is justified by its potential prophylactic, diagnostic or therapeutic value. When
medical research is combined with medical care, additional standards apply to protect the
patients who are research subjects.
2. The benefits, risks, burdens and effectiveness of a new method should be tested against
those of the best current prophylactic, diagnostic, and therapeutic methods. This does not
exclude the use of placebo, or no treatment, in studies where no proven prophylactic,
diagnostic or therapeutic method exists.
3. At the conclusion of the study, every patient entered into the study should be assured of
access to the best proven prophylactic, diagnostic and therapeutic methods identified by the
study.
4. The physician should fully inform the patient which aspects of the care are related to the
research. The refusal of a patient to participate in a study must never interfere with the
patient-physician relationship.
5. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods
do not exist or have been ineffective, the physician, with informed consent from the patient,
must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in
the physician's judgment it offers hope of saving life, re-establishing health or alleviating
suffering. Where possible, these measures should be made the object of research, designed
to evaluate their safety and efficacy. In all cases, new information should be recorded and,
where appropriate, published. The other relevant guidelines of this Declaration should be
followed.
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10.0Common Terminology Criteria for Adverse Events 3.0
http://ctep.cancer.gov/reporting/ctc.html
11.0
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