DARA BioSciences, Inc (NASDAQ: DARA) is a pharmaceutical development company that acquires promising therapeutic candidates and develops them through proof of concept (pre-phase III) in humans for subsequent sale or out-licensing to larger pharmaceutical companies. KRN5500* for the treatment of neuropathic pain in patients with cancer – successfully completed a phase II study. KRN5500 met its primary endpoints of reduction of pain and safety. It was statistically significantly better than placebo (p=0.03). The company plans to initiate a second phase II this year in conjunction with the National Cancer Institute focusing on the treatment and prevention of chemotherapy induced peripheral neuropathy (CIPN). The NCI will sponsor these studies with DARA only having to supply active drug and placebo.

1. Vol. - No. - - 2011 Journal of Pain and Symptom Management 1
Original Article
A Spicamycin Derivative (KRN5500) Provides
Neuropathic Pain Relief in Patients With
Advanced Cancer: A Placebo-Controlled,
Proof-of-Concept Trial
Sharon M. Weinstein, MD, Amy P. Abernethy, MD, Susan E. Spruill, PStat, MS,
Isadore M. Pike, MD, Andrea True Kelly, PhD, and Linda G. Jett, MSN
Pain Medicine and Palliative Care Program (S.M.W.), The Huntsman Cancer Institute, and
Department of Anesthesiology (S.M.W.), University of Utah, Salt Lake City, Utah; Duke Cancer Care
Research Program (A.P.A.), Duke Cancer Institute, Durham, North Carolina; Applied Statistics &
Consulting (S.E.S.), Spruce Pine, North Carolina; Izzy Pike MD Consulting (I.M.P.), Fairhope,
Alabama; ATK Clinical Consulting (A.T.K.), Charleston, South Carolina; and DARA BioSciences
(L.G.J.), Raleigh, North Carolina, USA
Abstract
Context. Neuropathic pain in patients with cancer can be difficult to treat
effectively.
Objectives. The purpose of the study was to determine safety and efficacy of
KRN5500, a novel, spicamycin-derived, nonopioid analgesic agent, in patients with
advanced cancer and neuropathic pain of any etiology.
Methods. The study was a Phase 2a, multicenter, double-blind, placebo-
controlled, dose escalation clinical trial. Patients with refractory neuropathic pain
and advanced cancer were randomly assigned 2:1 to receive a maximum of eight
single escalating doses of KRN5500 or placebo, ranging from 0.6 to 2.2 mg/m2.
The primary objective was safety and tolerability. The secondary objective was
efficacy, measured by change in average pain intensity on a 0e10 numeric rating
scale administered one week after the patient’s final dose.
Results. Nineteen patients received treatment (KRN5500 n ¼ 12; placebo
n ¼ 7). The most frequently reported adverse events were gastrointestinal
symptoms, which were more frequent and severe with KRN5500 than placebo; two
(17%) KRN5500 patients discontinued the study because of nausea and vomiting.
At study end point, KRN5500 exhibited a significant median decrease in pain
intensity from baseline of 24% compared with 0% for placebo (P ¼ 0.03). The
median for largest weekly reduction in target pain intensity was 29.5% for
KRN5500 and 0% for placebo patients (P ¼ 0.02).
Conclusion. This proof-of-concept study for KRN5500 in patients with advanced
cancer and any type of neuropathic pain found gastrointestinal adverse events to
be the predominant safety concern. The results also provided the first indication
Address correspondence to: Linda G. Jett, MSN, DARA Accepted for publication: May 5, 2011.
BioSciences, 8601 Six Forks Road, Suite 160, Raleigh,
NC 27615, USA. E-mail: ljett@darabio.com
Ó 2011 U.S. Cancer Pain Relief Committee 0885-3924/$ - see front matter
Published by Elsevier Inc. All rights reserved. doi:10.1016/j.jpainsymman.2011.05.003

2. 2 Weinstein et al. Vol. - No. - - 2011
of clinical and statistical efficacy in reducing pain intensity. J Pain Symptom
Manage 2011;-:-e-. Ó 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier
Inc. All rights reserved.
Key Words
Neuropathic pain, cancer, KRN5500, spicamycin, allodynia
Introduction nonopioid analgesics and adjuvant therapy
consisting of anticonvulsants, antidepressants,
Neuropathic pain is characterized by an ab-
and corticosteroids was successful for both
normal hypersensitivity to innocuous and nox-
types of pain, although the lack of controlled
ious stimuli and can persist long after the
treatment and comparison arms makes the re-
tissue damage and inflammation that induced
sults difficult to generalize.10,11
the pain have resolved. The International Asso-
KRN5500, a novel spicamycin derivative pro-
ciation for the Study of Pain defines neuro-
duced by Streptomyces alanosinicus, was discov-
pathic pain as ‘‘pain initiated or caused by
ered in an effort to identify new agents that
a primary lesion or dysfunction in the nervous
induced differentiation of myeloid leukemia
system’’1 and more recently, as ‘‘pain arising as
cells. KRN5500 failed to establish significant
a direct consequence of a lesion or disease
therapeutic efficacy as a potential antineo-
affecting the somatosensory system’’ in an
plastic agent in Phase 1 trials conducted
attempt to more effectively distinguish neuro-
under a cancer Investigational New Drug
pathic pain from nociceptive (e.g., inflamma-
application.12e14 However, clinical observa-
tory pain) and musculoskeletal or other types
tions of a patient who experienced remission
of pain that arise indirectly in the course of neu-
of severe neuropathic pain while receiving
rologic disorders.2
KRN5500 for metastatic cancer sparked inter-
Eleven million patients worldwide are af-
est in this drug as a possible neuropathic
flicted by neuropathic pain.3 The etiology of
pain treatment. For more than two decades,
neuropathic pain includes diverse conditions,
the patient, who was enrolled in a KRN5500
such as diabetic neuropathy, postherpetic neu-
cancer trial, had been treated for peripheral
ralgia, trauma, HIV/AIDS, and cancer-related
neuropathy and severe pain secondary to im-
neuropathy secondary to tumors, surgery, ra-
munoglobulin A monoclonal gammopathy
diotherapy, and chemotherapy, as well as toxic
and Raynaud’s disease. Surprisingly, although
effects from a number of medications.4 More
no pain response was anticipated, the patient’s
than one pathophysiologic mechanism may
neuropathic pain improved from the time of
underlie neuropathic pain symptoms in cancer
his first infusion with KRN5500. His progress
patients, making this population more difficult
was well documented and later published as
to treat effectively.5,6 In addition, some experts
a case history. He remained free of this long-
in the field consider neuropathic pain more
standing and severe neuropathic pain until
resistant than nociceptive or inflammatory
his death from cancer two months after stop-
pain to standard analgesic treatments.7,8 A
ping study treatment, although over the same
large prospective epidemiological study found
period of time, there was no apparent effect
that the proportion of neuropathic pain con-
on the patient’s upper quadrant pain, which
tributing to cancer pain was 33%, with opioid
was associated with liver metastases. The ab-
therapy effective in providing 50% relief for
dominal pain continued to worsen during
the neuropathic pain.9 Another large prospec-
the last months of his life, thus providing an
tive study surveyed routine clinical practice,
initial indication that KRN5500 may not be
based on the 1986 version of the World Health
effective for nociceptive pain.15
Organization cancer pain guideline, in a large
This serendipitous finding led to nonclinical
population of advanced cancer patients with
in vivo studies evaluating response to KRN5500
neuropathic or mixed (neuropathic and noci-
in rodent pain models. In three standard rat
ceptive) pain. A combination of opioid and

3. Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 3
models of nerve injury-induced neuropathic curative therapeutic option. There was no re-
pain, single doses of KRN5500 reversed pain striction on therapies that might contribute
hypersensitivity within two hours, with effects to patients’ comfort or quality of life. Palliative
lasting up to six weeks. KRN5500 had no ef- (noncurative) chemotherapy was allowed if
fects in uninjured rats or in a rat model of compatible with study drug in terms of dosing
acute inflammatory pain, suggesting specificity schedule and stable adverse event (AE) profile.
for pain that is neuropathic in nature and sup- Although the patient population comprised
porting earlier clinical observations of neuro- patients with advanced cancer, refractory neu-
pathic but not nociceptive pain relief.16e18 ropathic pain of any etiology was acceptable
KRN5500 inhibits acetylcholinesterase and for study entry. Refractory was defined as fail-
fatty acid amide hydrolase enzymes, both tar- ure to achieve adequate pain relief from at
gets that can modulate aspects of neuropathic least two commonly used treatments for neuro-
pain. KRN5500 lacks activity at 87 other evalu- pathic pain. The target neuropathic pain for
ated G protein-coupled receptor, ion channel, the study had to be characterized by at least
and enzyme targets. The prolonged duration two of the following symptoms: burning pain,
of action seen in the rat pain model studies shooting/lancinating pain episodes, dysesthe-
does not correlate with plasma pharmacokinet- sias, or allodynia at an overall pain score of
ics (terminal half-life ¼ 0.6e1.5 hours), sug- $4 on a 0e10 numeric rating scale (NRS), de-
gesting that KRN5500 might have disease spite any pain therapies patients were receiving
modifying activity through synergistic interac- at the time. Patients were allowed to continue
tions between the two identified mechanisms their usual pain treatments, including nonste-
or through an as yet unidentified mechanism. roidal anti-inflammatory, antidepressant, anti-
convulsant, and opioid medications if the
treatments were thought to be contributing
to partial pain relief for the target neuropathic
Methods pain or other pain conditions. Because each
Patients patient was likely to have more than one type
This Phase 2a study was a multicenter, and location of pain, the neuropathic pain
double-blind, randomized, placebo-controlled that was considered the primary complaint
dose escalation trial designed to evaluate the was identified as the target neuropathic pain
safety and efficacy of KRN5500 in patients for clinical assessments and patient self-
with advanced cancer and neuropathic pain evaluation; study staff recorded the targeted
of any etiology (Fig. 1). Advanced cancer was pain area in each diary NRS page as reinforce-
defined as cancer in which there was no ment for patients in rating their daily ‘‘target’’
Fig. 1. Schematic of dose escalation and treatment decisions.

4. 4 Weinstein et al. Vol. - No. - - 2011
pain. Eligibility was restricted to patients with Clinical personnel, monitors, patients, and
no radiation therapy to the target pain site the sponsor remained blinded throughout
within four weeks of screening and no major the study to treatment received.
surgery within two weeks. Patients were re-
quired to be at least five half-lives posttreat- Treatment Schedule
ment with any other investigational drugs. A maximum of eight single escalating doses
Eligibility was not restricted by type of cancer ranging from 0.6 to 2.2 mg/m2 were adminis-
or projected life expectancy. tered during weekly visits as an intravenous
(IV) infusion completed in one hour or less,
Study Design with a maximum of 5 mg established for any
The primary objective of this trial was to eval- single dose. KRN5500 (6-[4-Deoxy-4-[(2E,4E)-
uate the safety and tolerability of KRN5500 tetradecadienoylglycyl]amino-L-glycero-ß-L-man
for neuropathic pain in patients with advanced nohepto-pyranosyl]amino-9H-purine) was for-
cancer. Secondary objectives were to assess the mulated in a mixture of dehydrated alcohol;
analgesic activity and the dose-response rela- propylene glycol, NF; polysorbate 80, NF;
tionship of KRN5500. All investigative sites, N,N-dimethylacetamide (DMAC), monoetha-
the protocol, and study materials were ap- nolamine, NF; and normal saline and was ad-
proved by the investigator’s local or a central- ministered intravenously. Placebo was normal
ized Institutional Review Board. The study saline, indistinguishable visually from the
was independently monitored by i3Research, KRN5500 IV solution. Blinding was further
a contract research organization, and conduct- enhanced by covering IV bags with an opaque
ed in accordance with Good Clinical Practice material.
guidelines. Safety was assessed on an ongoing Patients were evaluated over a 14-week pe-
basis through monthly review of all available riod, inclusive of follow-up. At each clinic visit,
data by a safety committee comprising the the investigator evaluated whether to redose
study oncology adviser and medical monitor. the patient with the same dose, a lower dose,
Patients were randomly assigned to receive the next higher dose, or no dose, based on as-
up to eight doses of test article (KRN5500) sessments of tolerability, efficacy, and the pa-
or placebo over a 10-week treatment period tient’s desire for treatment. During each
from December 2006 to March 2009. The ran- clinic visit, diary 0e10 NRS pain scores were av-
domization schedule, generated by a third- eraged for the six days after the previous dose,
party statistician, assigned 24 patients to one and the percent change from the previous
of two treatment groups in a 2:1 ratio week’s average was calculated. This informa-
(KRN5500:placebo) using a block size of three tion was used clinically to determine the ap-
over all sites in an effort to obtain sufficient propriate dose for that visit. For dosing
data from at least 18 patients. The study was purposes, response to study drug was defined
not powered for prospective efficacy out- as at least a 20% decrease in target pain inten-
comes; rather, information regarding esti- sity from the previous week’s average NRS
mates of efficacy was to be used to make an scores. Before dosing, patients were asked,
informed decision regarding further develop- ‘‘Is your target pain still significant enough to
ment. As such, no formal sample size calcula- you that you’d like further treatment?’’ Fig. 1
tions were carried out for this study. The presents a schematic of dose escalation
sample size of 18 was considered typical for guidelines.
similar proof-of-concept/feasibility studies.19 During the course of treatment, if unaccept-
Patients were assigned to treatment in sequen- able treatment emergent AEs (TEAEs) oc-
tial order based on the randomization scheme curred, the patient could receive the next
using an automated web-based central ran- lower dose. If unacceptable TEAEs occurred
domization process accessed by site study per- at the minimum dose (0.6 mg/m2), the pa-
sonnel on obtaining signed informed consent tient was discontinued from the trial. Labora-
and verifying all eligibility criteria. Random- tory values and patient-reported AEs were
ized patients who discontinued study participa- considered when evaluating tolerability and
tion before being dosed were replaced with additional dosing. The patient’s overall physi-
new patients assigned to the same treatment. cal condition related to the patient’s cancer

5. Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 5
also was a factor in dosing. There were occa- from 0 to 10, where 0 represented ‘‘no pain’’
sions when dosing was withheld because of and 10 represented the ‘‘worst possible pain,’’
the need for respite from therapy or to accom- collected by a clinician at each weekly clinic
modate increased treatment for underlying visit. Secondary efficacy measurements in-
conditions. Patients were encouraged to com- cluded NRS scores recorded by patients each
plete at least four treatment visits to allow for evening in a diary. The mean change in scores
the possibility of full dose escalation but were for the six days after each dose was used for
instructed that they were not expected to par- dosing decisions and secondary end point
ticipate beyond that if they did not perceive analyses. Other secondary efficacy assessments
any benefit from study participation. included examinations and questionnaires for
measuring dimensions of neuropathic pain
Safety, Tolerability, and Pain Response and quality of life. These included the Neuro-
Evaluation of safety and tolerability of pathic Pain Questionnaire (NPQ), Brief Pain
KRN5500 was the primary objective of this Inventory-Short Form (BPI-SF), allodynia
study. To assess safety and tolerability, AEs, physical examination, Karnofsky Performance
clinical laboratory assessments, vital signs, Status (KPS), and the 12-item Short Form
and electrocardiogram data were collected at Health Survey (SF-12v2Ò).21e24 Patients also
each visit. TEAEs were defined as AEs with on- recorded all pain medication use in a diary.
set after the date and time of the first treat- Results were summarized by treatment
ment, or, if the event was present before group. Statistical tests, when performed, were
treatment, worsening after study intervention. two sided, nonparametric tests (Wilcoxon
TEAEs were assessed for intensity (mild, mod- Rank Sum Test), conducted at the a ¼ 0.05 sig-
erate, or severe) and relatedness to treatment nificance level. Data summaries and analyses
by the investigator. Levels of intensity were de- of results were generated using SASÒ version
fined as: milddthe symptom was barely notice- 8 or later (SAS Institute, Cary, NC). No interim
able to the patient, did not influence analyses were performed. All statistical analyses
performance or functioning, and generally were prospectively planned and documented
did not require prescription drug treatment; in an analysis plan before unblinding the data.
moderatedthe symptom was of sufficient sever-
ity to make the patient uncomfortable, perfor-
mance of daily activities was influenced, and
prescription of other treatment for the symp- Results
tom may have been needed; severedthe symp- Demographic and Baseline Characteristics
tom caused severe discomfort, sometimes of Nineteen male and female patients, aged
such severity that the patient could not con- 18 years or older with advanced cancer and re-
tinue in the study, and prescription or other fractory neuropathic pain of any etiology, were
treatment for the symptom was likely neces- enrolled at nine centers across the continental
sary. Serious adverse events (SAEs) were de- U.S. and Puerto Rico. Because of a randomiza-
fined per U.S. Food and Drug Administration tion error at one site, a patient who was to
guidelines as any AE meeting one or more of receive KRN5500 was given placebo, resulting
the following criteria: 1) was fatal or life- in 12 patients receiving KRN5500 and seven
threatening; 2) was permanently disabling; patients receiving placebo. Data presented
3) resulted in unplanned or prolongation of are based on treatment received (Fig. 2).
hospitalization; 4) resulted in persistent or Chemotherapy-induced peripheral neuropa-
significant disability/incapacity; 5) resulted thy was the most frequently recorded etiology
in birth defect/congenital anomaly; or 6) re- for patients’ neuropathic pain, followed by
quired medical intervention to prevent any of complex regional pain syndrome-Type II and
these outcomes.20 surgery-related neuropathic pain. Investigators
The secondary objective of this study was frequently documented more than one etiol-
evaluation of efficacy. The efficacy end point ogy. Patients most often identified lower limbs,
measurement was the average target pain in- followed by upper limbs, back, and face as the
tensity score over the previous 24 hours as site of the target neuropathic pain for the pur-
measured by an 11-point NRS score, ranging pose of assessing NRS scores, allodynia

6. 6 Weinstein et al. Vol. - No. - - 2011
Assessed for eligibility (n=25)
Excluded (n=6)
♦ Not meeting inclusion criteria (n=5)
♦ Declined to participate (n=0)
♦ Other reasons
Schedule conflict (n=1)
Randomized (n=19)
Allocated to KRN5500 (n=13) Allocated to placebo (n=6)
♦ Received KRN5500 (n=12) ♦ Received placebo (n=7)
♦ Did not receive KRN5500 (patient received ♦ Did not receive allocated intervention (n=0)
placebo in error) (n=1)
Lost to follow-up (n=0) Lost to follow-up (n=0)
Discontinued KRN5500 (n=9) Discontinued placebo (n=5)
♦ Adverse event (n=3) ♦ Adverse event (n=1)
♦ Withdrawal of consent (n=3) ♦ Protocol violation (n=1)
♦ Progression of disease (cancer) (n=2) ♦ Withdrawal of consent (n=3)
♦ Bed-rest ordered by oncologist (n=1)
KRN5500 patients analyzed (n=12) Placebo patients analyzed (n=7)
Excluded from analysis (n=1) Excluded from analysis (n=0)
♦ Intention to treat (n=13) ♦ Intention to treat (n=6)
♦ Modified efficacy (n=12) ♦ Modified efficacy (n=7)
Fig. 2. CONSORT diagram of patient disposition in the study.
examination scores, and all other assessments. study (10 treatment weeks), the protocol and
The same target neuropathic pain location, informed consent form specified that patients
specified at the initiation of the trial, was to were not expected to remain in the study be-
be consistently assessed for efficacy measure- yond its perceived benefit to them. Of the 14
ments throughout the study. Baseline patient patients who discontinued before receiving
demographics and neuropathic pain charac- their eighth possible dose, nine (75%) were
teristics are summarized in Table 1. treated with KRN550 and five (71%) were
treated with placebo.
Safety and Tolerability
Exposure to Study Drug. Table 2 provides data Adverse Events. A summary of TEAEs is pre-
on exposure to study drug and reasons for dis- sented in Table 3. All patients (100%) who
continuation. The median duration of expo- received KRN5500 had at least one TEAE, com-
sure was 40 days for the KRN5500 treatment pared with 86% who received placebo. Events
group compared with 29 days for the placebo of greater severity were more frequent in the
treatment group. On average, KRN5500 pa- KRN5500 group compared with placebo,
tients took 5.3 doses whereas placebo patients and more patients treated with KRN5500 dis-
took 4.4 doses. The highest dose of KRN5500 continued study participation because of
received was 2.2 mg/m2. Seven (58%) patients TEAEs (25%) compared with those treated
treated with KRN5500 were exposed to at least with placebo (14%). The most frequently re-
one dose at this level, and four (57%) placebo ported TEAEs were gastrointestinal (GI) in na-
patients were escalated to at least one dose of ture (primarily nausea and vomiting), which
normal saline at this level. occurred more often and with greater severity
Given the serious nature of patients’ ill- in the KRN5500 group than in the placebo
nesses and the relatively long length of the group. GI events in the KRN5500 treatment

7. Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 7
Table 1 Table 2
Baseline Patient Demographics and Exposure to Study Drug and Discontinuation
Characteristics KRN5500 Placebo
KRN5500 Placebo Metric (n ¼ 12) (n ¼ 7)
(n ¼ 12) (n ¼ 7)
Median number of 5.5 (3, 8) 4.0 (2, 8)
Variable Mean (SD) Mean (SD) doses (range)
Median days of 40 (14, 71) 29 (9, 64)
Age (years) 61 (12.0) 63 (13.4) exposure (range)a
Body surface area (m2) 1.9 (0.21) 1.7 (0.35) Median dose densities 1.27 (0.7, 1.5) 1.20 (0.6, 1.5)
(mg/m2/week)b
NRS 7.4 (1.62) 6.4 (1.90) (range)
Number (%) of patients
n (%) n (%) by dose levelc
0.6 mg/m2 12 (100) 7 (100)
Gender 1.2 mg/m2 12 (100) 6 (86)
Male 6 (50) 4 (57) 1.8 mg/m2 10 (83) 6 (86)
Race 2.2 mg/m2 7 (58) 4 (57)
Caucasian 9 (75) 5 (71) Patients completed $4 10 (83) 6 (86)
Black 1 (8) 1 (14) dosing visits
Other 2 (17) 1 (14) Patients completed all 3 (25) 2 (29)
a
dosing visits
Etiology of neuropathic pain Patients withdrawn 9 (75) 5 (71)
Chemotherapy induced 10 (83) 7 (100) Reason for early
Complex regional pain 4 (33) 0 withdrawal
syndrome-Type II AEd 3 (25) 1 (14)
Complex regional pain 1 (8) 0 Protocol violation 0 1 (14)
syndrome-Type I Lost to follow-up 0 0
Postherpetic 1 (8) 0 Withdrawal of 3 (25) 3 (43)
Cancer related 1 (8) 0 consente
Radiation induced 1 (8) 0 Death 0 0
Diabetic 1 (8) 0 Otherf 3 (25) 0
Surgery related 1 (8) 1 (14)
Carpal tunnel syndrome 1 (8) 0 AE ¼ adverse event.
a
Duration of exposure ¼ date of last dose À date of first dose þ 1 in
b
Target neuropathic pain the specified interval.
b
Lower extremity 7 (58) 5 (71) Dose density is calculated as average weekly dose, including rest
Upper extremity 3 (25) 1 (14) weeks.
c
Trunk 1 (8) 1 (14) The number of unique patients receiving each dose level. The per-
centage is calculated using the number of patients in each treat-
Face 1 (8) 0
ment group as the denominator.
d
SD ¼ standard deviation; NRS ¼ numeric rating scale. One KRN5500 SAE (seizures) and two KRN5500 AEs of nausea/
a
Most patients had more than one etiology recorded. vomiting led to withdrawal; one placebo SAE (stroke) led to
b
Target neuropathic pain identified as specific body area for all as- withdrawal.
e
sessments; recorded on the NPQ and diary NRS forms for patients No explanations were collected for ‘‘Withdrawal of Consent.’’ It is
to refer to. possible that some patients withdrew consent because of lack of
benefit (absence of pain relief).
f
Reasons for ‘‘Other’’ included: two KRN5500 for progression of dis-
ease; one KRN5500 attending oncologist recommended bed rest.
group were considered related to study drug
and required treatment with antiemetic medi- study drug; and 3) hospitalization 18 days after
cations. After the first study dose, antiemetics the last dose of study drug for convulsions and
could be provided prophylactically if clinically secondary memory loss (caused by the devel-
indicated. Two patients receiving KRN5500 opment of a new brain metastasis in a patient
withdrew from the study because of GI with head and neck cancer). All events were
symptoms. followed until resolution. One patient receiv-
A greater percentage of patients in the ing placebo experienced a stroke after the sec-
KRN5500 group (25%) experienced an SAE ond dose of placebo, which led to disability
compared with those in the placebo group and discontinuation from the study. This SAE
(14%). All SAEs in the KRN5500 group oc- was considered not related to treatment and
curred during the posttreatment follow-up pe- remained unresolved at the end of the
riod and were not considered related to study follow-up period.
drug. The following SAEs occurred in the
KRN5500 group: 1) hospitalization for conges-
tive heart failure and pneumonia 24 days after Other Safety Assessments. No significant labora-
the last dose of study drug; 2) hospitalization tory abnormalities related to study drug were
for dehydration 29 days after the last dose of observed in either treatment group. As a whole,

8. 8 Weinstein et al. Vol. - No. - - 2011
Table 3 NRS data plotted to show baseline, weekly, and
TEAEs and Organ System Most Affected end point scores and depicts positive or nega-
KRN5500 Placebo tive final outcome.
(n ¼ 12) (n ¼ 7)
The median greatest weekly reduction (i.e.,
TEAEs n (%) n (%) best response) in target pain intensity was
Patients with any TEAE 12 (100) 6 (86)
29.5% for KRN5500 patients, whereas the me-
Patients with any TEAE by gender dian in placebo patients was 0% (P ¼ 0.02)
Male 6 (100) 3 (75) (Fig. 4). Clinic NRS data also were evaluated
Female 6 (100) 3 (100)
for clinically meaningful levels of pain reduc-
Patients with an SAEa 3 (25) 1 (14) tion achieved during the study (Table 5).
Patients with an AE leading to 3 (25) 1 (14)
withdrawalb There was little difference between treatment
Patients with an AE outcome of 0 0 groups for patients that achieved $50% pain
death reduction; 25% of KRN5500 vs. 14% of pla-
By organ system most affectedc cebo patients achieved this level. However,
GI disorders 11 (92) 4 (57)
Mild 4 (33) 2 (29)
50% of KRN5500 vs. 14% of placebo patients
Moderate 3 (25) 2 (29) achieved $30% pain reduction. In addition,
Severe 4 (33) 0 83% of KRN5500 patients reached $20%
Related 11 (92) 1 (14)
Nervous system disorders 6 (50) 2 (29)
pain reduction compared with 29% of placebo
Infections and infestations 3 (25) 0 patients who reached this level.
Metabolism and nutrition 3 (25) 0 Daily patient diary NRS ratings were highly
disorders
Musculoskeletal and connective 3 (25) 2 (29)
correlated with in-clinic ratings (r ¼ 0.87;
tissue disorders P ¼ 0.007); however, there was no statistical dif-
Psychiatric disorders 3 (25) 0 ference between groups, with the KRN5500
Skin and subcutaneous tissue 3 (25) 4 (57)
disorders
group providing a median decrease from base-
General disorders and 2 (17) 0 line of 16% compared with 0% for placebo
administration site conditions (P ¼ 0.07) (Fig. 5). Investigator allodynia test-
TEAE ¼ treatment emergent adverse event; SAE ¼ serious adverse ing yielded a 33% median decrease in pain
event; AE ¼ adverse event; GI ¼ gastrointestinal.
a
All SAEs were assessed as not related to study drug.
for both mechanical and cold stimuli in the
b
One KRN5500 SAE (seizures) and two KRN5500 AEs of nausea/ KRN5500 group compared with 0% and 8%
vomiting led to withdrawal; one placebo SAE (stroke) led to
withdrawal.
decrease, respectively, in the placebo group.
c
Events experienced by two or more patients in either treatment There was no median change (0%) in KPS
group.
scores for either treatment group (Table 5).
no clinically relevant changes in vital signs or Additional Questionnaires and Assessments
negative changes in physical examinations In general, when a difference between treat-
were observed in either treatment group. Elec- ment groups was observed in patient self-rated
trocardiogram changes were within acceptable written questionnaires and assessments, the
limits for all parameters. results were mixed (Table 6). In the NPQ,
placebo patients had more reduced scores
for individual symptoms (seven of 10) than
Efficacy Assessments KRN5500 patients (two of 10). However, the
Analgesic Activity of KRN5500. Patients receiv- difference in symptom improvement between
ing KRN5500 exhibited a statistically significant the two groups was generally <12%, except
median decrease in average pain intensity of for Pain because of weather change, which pro-
24% based on baseline in-clinic NRS scores, vided the difference in favor of placebo with
whereas the median change in patients receiv- 21% improvement compared with 3% for
ing placebo was zero (P ¼ 0.03). There was no KRN5500 and Freezing pain, which showed
clear linear relationship between reduction in a larger decrease in the KRN5500 group at
pain intensity and increasing dose for either 33% compared with 0% in the placebo group.
group (Table 4). The median for absolute unit The BPI-SF also showed very little difference
decrease on the 11-point NRS scale was two between treatment groups, with the only nota-
units for KRN5500 and zero for placebo ble difference in favor of placebo for Pain relief
(Table 5). Fig. 3 provides individual patient in last 24 hours showing 32% improvement

9. Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 9
Table 4
Median Change From Baseline NRS in Target Pain Intensity and Median Best Response Across Dosesa
KRN5500 (mg/m2) Placebo (mg/m2)
Dose 0.6 1.2 1.8 2.2 Allb (range) 0.6 1.2 1.8 2.2 Allb (range)
n 1 2 3 6 12 1 0 2 4 7
Endpointc change (%) À25 À14 À30 À6 L24 (L100, 0) À20 d 0 0 0 (L20, 25)
one week after final dose
KRN5500 (mg/m2) Placebo (mg/m2)
Dose No dosed 0.6 1.2 1.8 2.2 Anye (range) No dosed 0.6 1.2 1.8 2.2 Anye (range)
n 3 4 1 2 2 12 2 3 1 0 1 7
Bestf response (%) one À29 À24 À13 À32 À92 L29 (L100, 0) 13 0.0 À60 d À13 0.0 (L60, 25)
week after any dose
NRS ¼ numeric rating scale.
a
Based on in-clinic NRS results.
b
Includes all final doses for endpoint analysis.
c
P ¼ 0.03, obtained from a Wilcoxon rank sum test.
d
Some patients achieved their best responses after the rest week, when no dose was given.
e
Denotes best response at any dose.
f
P ¼ 0.02, obtained from a Wilcoxon rank sum test.
compared with 6% in the KRN5500 group. as fibrosis or myelopathy post-radiotherapy,
The SF-12 quality-of-life instrument showed chemotherapy, surgery, or combinations
no difference between treatment groups, nor thereof.25 Treatment of neuropathic pain in
did two self-rated allodynia questions for cancer patients is even more complicated
touch- and cold-induced pain. given that epidemiological research is severely
lacking.26 Additionally, most agents devel-
oped for neuropathic pain have been studied
Discussion and Conclusions in noncancer patients, such as those with
Diagnosis and treatment of neuropathic postherpetic neuralgia or diabetic peripheral
pain in cancer patients remains challenging. neuropathy. Successful results in those set-
There are often multiple pathophysiologic tings may not always apply to the complex pa-
pain etiologies present in a single patient tient with advanced cancer and neuropathic
(neuropathic pain and nociceptive or inflam- pain.27
matory pain), often with multiple origins. For This Phase 2a randomized and controlled
example, neuropathic pain can be the result trial using NRS scores as a measure of efficacy
of nerve lesions caused by direct tumor inva- provides the first demonstration of safety and
sion or result from secondary causes, such efficacy for KRN5500 in a small cohort of
Table 5
Changes From Baseline by Treatment Group for NRS Absolute Units, Standard Percentage Reductions,
Allodynia Examinations, and Performance Status
Measure KRN5500 (n ¼ 12) Placebo (n ¼ 7)
Actual NRS unit change from baseline, median (range) À2 (À7, 0) 0 (À1, 1)
Clinic NRS: standard percentage reductions
Number (%) of patients who achieved $50% reduction 3 (25) 1 (14)
Number (%) of patients who achieved $30% reduction 6 (50) 1 (14)
Number (%) of patients who achieved $20% reduction 10 (83) 2 (29)
Allodynia physical examination, median (range)
Dynamic (mechanical)dtouch-induced pain À33 (À100, 0) 0 (À100, 300)
Thermaldcold-induced pain À33 (À100, 0) À8 (À100, 100)
KPS, median (range) 0 (À10, 30) 0 (À10, 0)
NRS ¼ numeric rating scale; KPS ¼ Karnofsky Performance Status.

10. 10 Weinstein et al. Vol. - No. - - 2011
Baseline Endpoint Weekly Visits Pain Improved
Pain Worsened
10
9
8
7
Clinic NRS
6
5
4
3
2
1
0
0 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7
|-------------------------KRN5500--------------------------| |-----------PLACEBO---------------|
Patients
Fig. 3. Absolute change in NRS scores for each patient by treatment group. (Total number of NRS weekly scores
per patient [up to 11] cannot be ascertained in this figure as duplicate scores are not depicted, with the exception
that a score [only 1] that overlays baseline and/or end point is visible.)
patients with treatment-resistant neuropathic significant GI symptoms emerging as the pre-
pain (of any etiology) and advanced cancer. dominant and only safety concern at dose
The KRN5500 safety profile showed clinically levels that notably reduced pain intensity.
Fig. 4. Maximum reduction in neuropathic pain score by patient ordered from greatest to least within treatment
group. (P ¼ 0.02 obtained from a Wilcoxon rank sum test.)

11. Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 11
Table 6
10 Median Percent Change From Baseline in
Patient-Rated Questionnaires One Week After
Final Dose
8
KRN5500 Placebo
(n ¼ 12) (n ¼ 7)
Clinic NRS
6
Patient self-rated
assessmentsa % change (range) % change (range)
4
r = 0.87 NPQ
Burning pain À15 (À100, 0.0) À7 (À100, 67)
2 Sensitive to À8 (À100, 100) À17 (À100, 0)
touch
Shooting pain 0 (À100, 200) À11 (À100, 20)
0 Numbness À5 (À100, 50) À7 (À40, 11)
0 2 4 6 8 10 Electric pain À14 (À100, 0) 20 (À100, 20)
Diary NRS
Tingling pain À14 (À100, 300) À23 (À100, 0)
Squeezing pain 0 (À100, 300) 0 (À100, 20)
Fig. 5. Correlation of weekly diary and clinic NRS Freezing pain À33 (À100, 0) 0 (À21, 0)
scores for all subjects. (Diary scores are plotted as Pain because À6 (À100, 700) À16 (À100, 100)
of touch
the mean of the first six daily NRS scores after
Pain because À3 (À100, 900) À21 (À100, 0)
each weekly visit.) of weather
changes
BPI-SF
Pain at its worst 0 (À100, 33) 0 (À25, 25)
Study safety data demonstrate that drug- in last 24 hours
Pain at its least À16 (À100, 20) 0 (À40, 300)
related GI symptoms of nausea, vomiting, in last 24 hours
and less frequently, diarrhea were a distressing, Pain on the 0 (À100, 100) 0 (À40, 13)
though temporary, adverse effect of KRN5500. average
Pain right now 0 (À100, 67) 0 (À43, 50)
Although these symptoms occurred in the pla- Pain relief in À6 (À50, 250) À33 (À100, 0)
cebo group as well, the frequency, severity, and last 24 hours
relatedness to study drug indicate that this may Mean of pain 2 (À100, 29) 0 (À29, 12)
severity
be a clinically significant problem associated Mean of pain À10 (À100, 131) 2 (À23, 51)
with the use of KRN5500. No other safety con- interference
cerns were identified. SF-12Ò
Certain excipients, namely DMAC and mono- Physical 0 (À2, 10) À1 (À3, 2)
ethanolamine, part of the Phase 1 anticancer component
summary
formulation that also was administered in this Mental 3 (À10, 11) 2 (À20, 8)
study, are known to cause nausea and vomit- component
ing;28,29 in addition, patients receiving placebo summary
were given normal saline without any of the for- Self-rated
allodynia
mulation excipients used with KRN5500. Thus, questionnaire
it is not possible at the present time to deter- Touch-induced À30 (À100, 60) À17 (À100, 33)
mine whether the GI effects are a result of the pain
Cold-induced À32 (À100, 29) À31 (À100, 0)
active pharmaceutical ingredient, formulation pain
excipients, or a combination thereof. In an ef-
NPQ ¼ Neuropathic Pain Questionnaire; BPI-SF ¼ Brief Pain
fort to better understand and decrease these Inventory-Short Form; SF-12Ò ¼ Short Form Health Survey.
a
side effects, reformulation efforts are underway For all assessments, decreases in scores indicate improvements,
except for SF-12, where higher scores indicate better health
to replace emetogenic components with ingre- status.
dients that are Generally Recognized as Safe
(GRAS).
KRN5500 yielded a significant median de-
crease in pain intensity from baseline when correlated with clinic NRS scores, and clinical
compared with placebo. Efficacy was further testing of allodynia yielded a substantial me-
supported by the significant difference in dian pain decrease for both mechanical and
the median best (largest) pain reduction per cold stimuli in the KRN5500 group and none
patient. Diary NRS scores were highly in the placebo group.

12. 12 Weinstein et al. Vol. - No. - - 2011
Study results also provided clinically mean- led to fatigue and confusion in scoring. It also
ingful decreases in absolute pain units on is possible that several versions of the same
a standard clinical 0e10-point pain intensity question served to divide the level of pain into
rating scale, with 10 of 12 KRN5500 patients smaller components, in much the same way
achieving a two-point reduction compared that the NPQ divides pain into symptom
with one of seven placebo patients (Fig. 3). components.
Six of 12 KRN5500 patients achieved $30% A major limitation of the study was its small
reduction in pain, whereas one of seven pla- sample size, making the study vulnerable to
cebo patients achieved this level. In similar variable outcomes. In particular, because pa-
studies, meeting a standard cutoff of 30% tients were allowed to escalate to an effective
for pain reduction or an absolute reduction dose, the number of patients in any particular
of two units on a standard 0e10-point pain dose level was too small to reliably estimate
intensity rating scale is considered clinically a dose-response relationship. Although it is
significant.30 possible that positive results in this study repre-
Except for the diary NRS scores, none of the sent a Type I error (false positive outcome),32
data collected entirely by patient self-rated in- there is strong evidence supporting the posi-
struments showed a trend for efficacy in either tive analgesic outcome, including both clini-
group. Results from the NPQ and BPI-SF were cally and statistically significant results, as well
varied and did not provide clinically significant as nonsignificant but positive trends.
differences in individual symptoms or overall It is notable that, except for diary NRS scores,
levels of pain or relief. Small differences and each of the positive efficacy results is based on
median scores with wide ranges make the data ascertained by clinician interview (asking
results difficult to interpret. Aside from the the patient to rate their pain) or clinician exam-
small sample size, the authors have no clear ination with an interview component, such as
explanation for these inconsistencies other the allodynia examination, which combined
than the possibility that some tools were mechanical and cold stimulation with verbal
more sensitive than others in detecting treat- collection of NRS pain scores before and after
ment differences in this particular group of the stimulation. The diary NRS question was
subjects. written with exactly the same wording as the ver-
The NPQ divides the overall target pain bally administered clinic NRS question, which
level into 12 components (symptoms). With likely contributed to its positive correlation
the exception of burning pain, changes from to primary efficacy end point results. None of
baseline on individual questions varied greatly the other data collected through patient-
from week to week, suggesting that the recorded outcomes provided meaningful
component questions were not a sensitive trends in either direction.
measure of treatment differences in this study. Patients did choose a ‘‘target neuropathic
Because the pattern of symptoms is different pain’’ site for focused assessment throughout
for each patient, it may not be reasonable to the study, and although there may be variability
expect component scores to show the same in the degree to which patients and clinicians
pattern or degree of change as the overall were able to separate one site and kind of
pain rating. The NPQ is designed as a diagnos- pain from another, tests, such as the allodynia
tic tool for confirming neuropathic pain and physical examination could only have pro-
has not been validated as an instrument for duced results by strictly focusing on the target
measuring efficacy through changes in symp- area. The fact that pain was significantly re-
tom scores.31 duced is in itself a positive finding, even if it rep-
The BPI-SF asks patients to rate pain in four resents a more nonspecific site or overall pain
different ways on the same 11-point NRS scale, relief in some patients. Careful selection of di-
as follows: ‘‘worst pain in the last 24 hours,’’ agnostic and neurological tests, more thorough
‘‘least pain in the last 24 hours,’’ ‘‘pain on the av- training for patients, and appropriate patient-
erage,’’ and ‘‘pain you have right now.’’ None of rated questionnaires will be important for
these is exactly the same wording used for the future studies.
clinic/diary NRS assessment. It is possible that Large placebo effect in pain trials often con-
asking so many versions of the same question tributes to difficulty in establishing significant

13. Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 13
differences between treatments.33 Placebo re- results or a positive trend not considered ro-
sponse, although present, was low in this study. bust enough. Given the burden of suffering as-
The reasons for this are not known, but the sociated with severe pain, resultant great
fact that patients were more or less near clinical need for new pain therapies, and the
the end of life, and were willing to enter into overwhelming odds against bringing new ther-
a placebo-controlled trial, may be an indica- apeutics to proof of concept, we believe that it
tion that pain was sufficiently severe to make is important to move forward with cautious op-
any sustained placebo response unlikely. timism to design a Phase 2b study. Future stud-
Though baseline pain levels were not unusu- ies of KRN5500 with modified formulation
ally high, it is possible that baseline and contin- excipients may shed additional light on
ued pain levels represented subjectively higher whether this investigational drug holds prom-
discomfort than would be the case in patients ise as a tool for oncologists and pain specialists
who have not endured as much physical and working with cancer patients or for those who
emotional stress. may have recovered from cancer only to find
High study withdrawal rate is another factor their quality of life seriously impaired by con-
that has repeatedly contributed to failure in tinued neuropathic pain.
oncology symptom control studies.34 Because In conclusion, KRN5500 demonstrated
this study was considered lengthy for patients safety at dose levels providing first therapeutic
with advanced cancer and a serious pain condi- evidence for treatment-resistant neuropathic
tion, an unusual approach was used to proac- pain in patients with advanced cancer, al-
tively address an anticipated high withdrawal though causing transient GI side effects
rate. In this study, over and above the usual that were generally manageable. Despite the
statement that participation is voluntary and relatively small sample size, statistically signifi-
patients can withdraw at any time, patients cant and clinically meaningful improvements
were explicitly told that they were not ex- in pain were observed in patients treated
pected to continue participation if the study with KRN5500 when compared with placebo.
was not beneficial or if other more pressing With continued formulation development,
needs presented. Patients were asked to com- better selection of diagnostic and efficacy as-
mit to at least four treatment visits if possible, sessment tools, and larger well-controlled tri-
to allow for the possibility of escalation to the als, KRN5500 may hold promise as a safe and
highest dose to assess for efficacy if it would oc- effective treatment, especially for patients
cur. This may have contributed to subjects re- with severe disabling neuropathic pain.
maining on study at least long enough to
reach an efficacious dose or to determine
that the study drug was not providing analgesia
(no response). Most patients stayed in the Disclosures and Acknowledgments
study for the minimum period requested. This study was funded by the sponsor,
The analysis plan called for data collected DARA Therapeutics, a subsidiary of DARA Bio-
one week after the last dose, no matter when Sciences (DARA). DARA personnel participated
it occurred, to serve as the efficacy end point, with industry advisers, investigators, and consul-
which resulted in no missing end points and tants in designing the study. i3Research, a con-
no data carried forward to fill in missing tract research organization under contract with
assessments. the sponsor, conducted the study, including
Given the difficulty in reproducing positive site monitoring, data management, and statisti-
outcomes in postmarketing and comparator cal analysis.
trials of analgesic medications (e.g., gabapen- Of the authors, Sharon M. Weinstein was an
tin), it is possible that pain studies may be par- investigator; Amy P. Abernethy was an investiga-
ticularly susceptible to a Type II error (false tor and has been a DARA consultant as well;
negative outcome) related to some of the is- Isadore M. Pike (oncologist), Susan E. Spruill
sues discussed above. As a result, potentially (statistician), and Andrea True Kelly (clinical
beneficial therapeutics may be abandoned adviser/medical writer) are DARA consultants.
too early in development because of negative Linda G. Jett is an employee of DARA.

14. 14 Weinstein et al. Vol. - No. - - 2011
The authors thank the patients, study coor- intravenous infusion for five consecutive days to pa-
dinators, and enrolling investigators: Ghassan tients with refractory solid tumors. Clin Cancer Res
Al-Jazayrly, Enser Cole, Thomas Cosgriff, Tanya 2003;9:5178e5186.
Dorff, Louis Rivera-Colon, Jack Saux, Leonard 14. Yamamoto N, Tamura T, Kamiya Y, et al. Phase 1
Sender, and Jose Stable. and pharmacokinetic study of KRN5500, a spicamy-
cin derivative, for patients with advanced solid tu-
mors. Jpn J Clin Oncol 2003;33:302e308.
15. Borsook D, Edward A. Antineuropathic effects
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