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Long Acting Methylphenidate for Cancer Related Fatigue:

NCCTG trial N05C7

Long Acting Methylphenidate for Cancer Related Fatigue:

NCCTG trial N05C7

DL Barton AR Moraska A Sood S Dakhil JA Sloan K Rowland JD Bearden AM Bernath GS Soori CL Loprinzi

Supported by a CCOP research base grant from the NCI, CA37404

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DisclosuresDisclosures

Long acting methylphenidate and matching placebo for this study was supplied by Ortho-McNeil-Janssen

Scientific Affairs, LLC.

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What is Cancer Related Fatigue? What is Cancer Related Fatigue?

• Subjective, multi-dimensional experience (cognitive, physical, social, emotional)

• Sense of fatigue, tiredness, exhaustion, lack of energy, pep and/or motivation

• Not justified by activity level

• Not relieved by sleep (Olson, Support Care Cancer, 2008; Barsevick, ONF, 2001; Prue, Eur J Ca, 2006)

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The Problem of Cancer-Related Fatigue

The Problem of Cancer-Related Fatigue

• Present throughout the cancer experience

• Up to 90% experience fatigue

• Increases throughout treatment

• Can persist several years beyond treatment in 19-82% of survivors

(Prue, Eur J Ca, 2006; Bower, Cancer, 2006)

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Current Evidence Based TreatmentCurrent Evidence Based Treatment

• Treating comorbidities such as anemia (Minton, JNCI, 2008)

• Exercise (Cramp, Daniel, Cochrane, 2008)

• Psychostimulants:• Methylphenidate

• Modafinil (Minton, JNCI, 2008; Morrow, JCO, 26(15S):9512, 2008)

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MethylphenidateMethylphenidate

• Central nervous system stimulant

• Related to amphetamine

• Schedule II agent

• Equal mixture of d and l- isomers, with d-isomer being active compound

• FDA approved: narcolepsy, ADHD

• Non-approved: neurobehavioral function, depression, fatigue, pain, cognition

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Mechanism of ActionMechanism of Action

•Activates brainstem arousal system, cortex and subcortical structures, including thalamus

•Blocks reuptake of dopamine, norepinephrine

Micromedex®, accessed on line, May, 2010

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Studies leading to trial development (1)Studies leading to trial development (1)

• Positive data as adjuvant to narcotics in chronic pain (Bruera, Ca Tr Rep, 1987; Wilwerding, Supp Care Ca, 1995; Westberg, Clin J Onc Nurs, 2004)

• Pilot study (Bruera et al, JCO, 2003)

• N=30• 5 – 20 mg/day x 7 days• 0-10 fatigue scale• Base: 7.2, 7-day: 3.0 (p<.001)

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•RCT

•N=112

•5-20 mg/day x 7 days

•FACIT-F change of 9.6 (m) vs 7.5 (p) (p=.31)

(Bruera, JCO, 2006)

Studies leading to trial development (2)Studies leading to trial development (2)

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Rationale of current trialRationale of current trial

• 20 mg/day provided only 10 mg of d-isomer

• This study proposed to study 54 mg/day to provide 27 mg of d-isomer

• Sustained release formulation a benefit to avoid peaks and troughs

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SchemaSchema

R

4 weeks

Placebo; titrated from 1 to 3 tablets/day

Long acting methylphenidate 54 mg/day; titrated from 1 to 3 tablets/day

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ObjectivesObjectives

• To evaluate the efficacy of long acting methylphenidate for cancer related fatigue (primary goal)

• To evaluate the tolerability and adverse effects

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Eligibility InclusionEligibility Inclusion

• History of cancer

• Fatigue rating ≥ 4 on a scale of 0 to 10

• Performance scale 0-2

• Life expectancy 6 months

• Hgb ≥ 10 g/dl

• Treatment for cancer, depression, anemia allowed

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Eligibility ExclusionEligibility Exclusion

• Prior use of methylphenidate

• Use of stimulants or other agents, herbs, dietary supplements for fatigue

• Uncontrolled pain (≥ 4 of 10)

• Neurologic progression or organ failure

• Contraindications to use of methylphenidate (disease or other pharmacologic agents)

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Primary EndpointPrimary Endpoint

Usual Fatigue as measured by the Brief Fatigue Inventory

Please rate your fatigue (weariness/tiredness) by circling the one number that best describes your usual level of fatigue over the past 24 hours?

0 1 2 3 4 5 6 7 8 9 10

None As bad as

you can imagine

(Mendoza, Cancer 85, 1997 )

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AnalysisAnalysis

• AUC over 4 weeks, two sample t-test

• 64 patients per arm provided 80% power to detect a half standard deviation difference

• Secondary endpoints: • Other BFI items, vitality subscale

SF-36 (Ware, Med Care, 1992)

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Randomized:148 Participants

Feb. 29, 2008 – August 8, 2008

Long acting methylphenidate: 74 participants

Placebo: 74 participants

5 cancels

69 participantsstarted study drug

62 participants evaluable

4 cancels

70 participantsstarted study drug

49 participants completed per protocol

56 participants completed per protocol

63 participants evaluable

10 refusals10 AE’s

9 refusals5 AE’s

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Patient CharacteristicsPatient CharacteristicsMethylphenidate

(N=69)

Placebo

(N=70)

P- value

Mean Age 59.2 years 60.6 years 0.263

Race 0.605

White 96% 91%

Black/African American

4% 7%

Unknown 0% 1.4%

Female 64% 57% 0.425

Current Chemotherapy 64% 64% 0.949

Concurrent Radiation 13% 10% 0.574

Concurrent Biological Therapy

25% 24% 0.962

Fatigue Scale 0.954

4-7 68% 69%

8-10 32% 31%

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Patient Characteristics cont.Patient Characteristics cont.Methylphenidate

(N=69)

Placebo

(N=70)

P-value

Stage 0.954

0/I/II 32% 31%

III/IV 68% 69%

Type of cancer 0.497

Breast 38% 29%

Lung 15% 11%

Colon 6% 6%

Prostate 3% 9%

Combined/Other 39% 46%

Average pain over the last 24 hours (0-100, best)

0.399

Mean (SD) 87 (13.88) 86 (12.58)

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RESULTS

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BFI Question

Usual Fatigue

Mean

95% Confidence Intervals for the

Mean

Wilcoxon Rank Sum p-value

Methylphenidate

N=62

50.33 (45.17, 55.49)

0.317Placebo

N=63

47.15 (42.86, 51.43)

Primary Endpoint AUC(higher scores are better)Primary Endpoint AUC(higher scores are better)

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Usual fatigue AUC (higher numbers are better)

Usual fatigue AUC (higher numbers are better)

A= LA methylphenidate; B=placebo

LA MPH

Placebo

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BFI Question Arm Mean

95% confidence intervals

Wilcoxon Rank Sum p-

value

Fatigue Right Now

Methylphenidate

N=62

49.34 (43.84, 54.84)

0.684Placebo

N=63

47.90 (42.93, 52.87)

Worst Fatigue

Methylphenidate

N=62

39.65 (34.25, 45.05)

0.167Placebo

N=63

34.60 (29.84, 39.36)

BFI Fatigue Average AUC(higher scores are better)

BFI Fatigue Average AUC(higher scores are better)

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Success of BlindSuccess of BlindGuessed

Correctly

LA Methylphenidate

Placebo P-value

Yes 28% 32%

0.82

No

18% 20%

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Satisfaction with TreatmentSatisfaction with Treatment

Satisfied with

treatment

LA Methylphenidate

Placebo P-value

No 21% 34%

0.04

Yes 25% 18%

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Results by Fatigue SeverityChange from baseline to week 4

Results by Fatigue SeverityChange from baseline to week 4

BFI Usual Fatigue 8-10

Methylphenidate

N=10

Placebo

N=12

P -value

Mean: 47.0

SD: (40.01)

Mean: 33.3

SD: (30.85)

0.39

BFI Usual Fatigue 4-7

Methylphenidate

N=34

Placebo

N=38

Mean: 17.4

SD: (20.20)

Mean: 7.1

SD: (29.67)

0.11

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Results by Stage Change from baseline to week 4

Results by Stage Change from baseline to week 4

Stage 0/I/II Stage III/IV

Usual Fatigue

LA MPH

(N = 22)

Placebo

(N= 22)

P-value LA MPH

(N = 47)

Placebo

(N= 48)

P- value

Mean

(SD)

16.7

(20.24)

29.4

(33.07)

0.27 19.7

(38.61)

2.1

(28.20)

0.02

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Symptom Methylphenidate (N=49)

Placebo (N=56)

P-value

Nervousness -2.7 9.5 0.003

Appetite decrease

-5.2 6.6 0.034

Sex drive -0.9 9.8 0.062

Abdominal pain

-3.5 3.6 0.078

Symptom Experience Diary – Symptom Experience Diary – Mean Change from BaselineMean Change from Baseline

Higher numbers represent decreased symptoms over the baseline periodHigher numbers represent decreased symptoms over the baseline period

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Symptom Methylphenidate (N=49)

Placebo (N=56)

P-value

Dizziness -2.2 2.1 0.145

Shakiness -0.6 1.4 0.284

Heartbeat -2.0 -1.6 0.538

Vomiting -0.8 0.4 0.635

Headaches -0.8 3.9 0.718

Trouble sleeping

10.6 11.1 0.858

Symptom Experience Diary – Symptom Experience Diary – Mean Mean

Change from BaselineChange from Baseline

No significant differences or concerning trends by CTC grades

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RCT Summary TableRCT Summary TablePopulation Dose of d-

isomerMeasure Outcome

Effect Size

Bruera, JCO, 2006

N = 112

Adv. ca

10 mg/day

X 7 days

Facit – F

NS

.20

Mar Fan, Supp Care Ca, 2008

N = 57

BC, TX

early stage

20 mg/day

X 8 weeks

Facit – F

NS

.19

Lower, JPSM, 2009

N = 154

Post TX

BC/ovarian

27.7 mg/day

X 8 weeks

(range 10 – 70 mg/day)

Facit – F

p=.02

.37

Current Study, JCO, in press

N = 148;

Heterogeneous population

27 mg/day

X 4 weeks

BFI, usual fatigue

NS

.17

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ConclusionsConclusions

• This study failed to show a significant effect for long acting methylphenidate in this heterogeneous population

• More toxicities were experienced by those on active agent versus placebo

• Generates hypothesis about potential benefit in specific subgroup

• Long term use not evaluated

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THANK YOU