Effect of Ketamine on Fatigue Following Cancer Therapy

Although the underlying mechanisms of fatigue have been studied in several disease conditions
(Bower et al., 2002; Brola et al., 2007), the etiology, mechanisms, and risk factors remain
elusive, and this symptom remains poorly managed. Fatigue is conceptualized as a
multidimensional symptom which incorporates temporal, sensory, cognitive/mental,
affective/emotional, behavioral, and physiological dimensions (Voss, et al., 2006). We
recently observed increased levels of neutrophic factors (brain-derived neurotrophic factor
(BDNF)), glial-cell line derived neurotrophic factor (GDNF) and synaptosomal-associated
protein (SNAP) from the serum samples of fatigued prostate cancer men receiving external beam
radiation therapy, suggesting that fatigue may be a component of depression and the
N-methyl-D-aspartate (NMDA) receptors may be involved in fatigue intensification during
cancer therapy. Ketamine is an NMDA receptor antagonist and has been reported to treat acute
depression (Berman et al., 2000; Prommer, 2012; Aan Het Rot et al., 2012). Depression and
cancer-related fatigue (CRF) are highly correlated during cancer therapy (Portenoy and Itri,
1999; Roscoe et al., 2002, Servaes et al., 2002, Aan Het Rot et al., 2012).

This double-blind, placebo-controlled, cross-over study will explore the effect of a single,
intravenous dose of ketamine in providing immediate reduction of fatigue following radiation
therapy. The primary objective of the study is to determine the immediate effect of a single
intravenous dose of ketamine in reducing clinically-significant worsening of fatigue
following radiation therapy. The secondary objectives of this study are to investigate the
levels of cytokines (i.e., tumor necrosis factor-alpha (TNFalpha), insulin-like growth factor
1 (IGF-I), interleukin (IL)-6, IL-8, transforming growth factors (TGF)alpha and beta),
neurotrophic factors (i.e., BDNF, GDNF, SNAP), metabolic (i.e., apoliprotein, arginine,
arginase), and mitochondrial (i.e., oxygen consumption rate, glycolysis rate) markers from
peripheral blood before and after treatment with ketamine or placebo and relate these levels
to self-reported fatigue, depression, and health-related quality of life (HRQOL) scores. This
study also aims to measure cognitive function and skeletal muscle strength of patients before
and after treatment with ketamine or placebo and relate these findings with self-reported
fatigue, depression, and HRQOL scores.

We will enroll 40 subjects who completed radiation therapy for cancer within at least 3
months. The primary outcome measure of the study is the change in self-reported fatigue score
after receiving a single intravenous dose (0.5 mg/kg) of ketamine or placebo. The secondary
outcomes of this study include: the cytokine profile (e.g. TNFalpha, IGF-I, IL-6, IL-8,
TGFalpha and TGFbeta), neurotrophic factors (e.g. BDNF, GDNF), metabolic (i.e., apoliprotein,
arginine, arginase), and mitochondrial markers (i.e., Complex I-V, manganese superoxide
dismutase (MnSOD), oxygen consumption rate, glycolysis rate) from blood samples; cognitive
function test scores; depression scores; HRQOL scores; and skeletal muscle strength of study
participants before and after a dose of ketamine or placebo.

- INCLUSION CRITERIA:

- Must be enrolled in 08-NR-0132.

- Had cancer as determined by diagnostic testing such as cytology and imaging and
confirmed from the oncologist s progress notes or reference letter;

- At least 3 months following localized radiation therapy (e.g. intensity-modulated
radiation therapy) for cancer;

- Total received radiation dose is 40-80 Gray (Gy);

- Able to provide written informed consent and must exhibit understanding of the study
during the informed consent process by passing at least 80% of the consent quiz;

- Greater than or equal to18 years of age;

- FACT-F score should be <43, to reflect that the study subjects fatigue symptoms are
worse than the general population (Cella et al., 2002).

In addition to the above inclusion criteria, in order to receive the study drug (ketamine
or placebo), the subject must have the following during the randomization visit:

-No clinically significant abnormal laboratory tests (i.e. absolute neutrophil count <1.5
thousand (K) cells/(micro)L, platelet <75K cells/(micro)L, hemoglobin <9 grams per
deciliter (g/dL).

EXCLUSION CRITERIA:

- Progressive or unstable disease other than cancer of any body system causing
clinically significant fatigue (e.g. class IV congestive heart failure, end-stage
renal disease, liver failure, stage IV chronic obstructive pulmonary disease)
including patients with systemic infections (e.g., human immunodeficiency virus (HIV),
active hepatitis); and those with chronic inflammatory disease (e.g. rheumatoid
arthritis, systemic lupus erythematosus);

- Uncontrolled hypertension and those with left ventricular dysfunction;

- Current psychotic features or a diagnosis of Schizophrenia or any other psychotic
disorder as defined in the Diagnostic and Statistical Manual (DSM-IV);

- Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for
caffeine or nicotine dependence) within the preceding 3 months. In addition, subjects
who currently are using illicit drugs (except for caffeine or nicotine) must not have
used illicit substances in the 2 weeks prior to screen and must have a negative
alcohol and drug (except for prescribed benzodiazepines) breathalyzer and urine test
at screening, respectively;

- Subjects with clinical hypothyroidism or hyperthyroidism;

- Subjects with one or more seizures, hallucinations, disorientation without a clear and
resolved etiology;

- Subjects with traumatic brain injury and/or post-traumatic stress disorder;

- Treatment with a reversible monoamine oxidase inhibitor (MAOI) within two weeks prior
to study drug administration;

- Treatment with fluoxetine within five weeks or aripiprazole within three weeks before
study drug administration;

- Treatment with any other concomitant medication known to interact with ketamine 14
days prior to study drug administration.

- Received total body irradiation or cranial irradiation for cancer;

- Pregnant or lactating women.