S1202: Duloxetine Hydrochloride for Muscle/Joint Pain in Early-Stage Breast Cancer Receiving Hormone Therapy

OBJECTIVES:

Primary

- To assess whether daily duloxetine hydrochloride (duloxetine) decreases average joint
pain in women with aromatase inhibitor-associated musculoskeletal syndrome (AIMSS), as
measured at 12 weeks by the modified Brief Pain Inventory Short Form (BPI-SF).

Secondary

- To assess whether daily duloxetine decreases worst joint pain in women with AIMSS, as
measured at 12 weeks by the modified BPI-SF.

- To assess whether daily duloxetine decreases pain interference in women with AIMSS, as
measured at 12 weeks by the modified BPI-SF.

- To investigate whether daily duloxetine improves functioning, pain, and stiffness in the
knees/hips according to the Western Ontario and McMaster Universities Osteoarthritis
(WOMAC) scale. (Exploratory)

- To investigate whether daily duloxetine improves function, pain, and stiffness in the
hands according to the Modified Score for the Assessment and Quantification of Chronic
Rheumatoid Affections of the Hands (M-SACRAH). (Exploratory)

- To investigate whether daily duloxetine improves functional quality of life as measured
by the Functional Assessment of Cancer Therapy-Endocrine Scale (FACT-ES). (Exploratory)

- To investigate whether daily duloxetine improves the proportion of patients reporting
changes for the better versus worst as measured by the Global Rating of Change Scale.
(Exploratory)

- To investigate whether daily duloxetine decreases analgesic use.

- To investigate whether daily duloxetine increases adherence to, and reduces the
discontinuation rate for, aromatase inhibitor (AI) therapy. (Exploratory)

- To assess whether patients receiving duloxetine as compared to placebo have improved
depression as measured by the Patient Health Questionnaire (PHQ-9) at Weeks 6 and 12.
(Exploratory)

- To explore the relationship between inherited variants in genes responsible for
duloxetine metabolism and activity (COMT, HTR3A, SLC6A2, SLC6A4, CYP1A2, CYP2D6) and
aromatase (CYP19A1) and change in pain with 12 weeks of treatment. (Exploratory)

- To explore the impact of treatment on serum inflammatory cytokine levels with 12 weeks
of treatment at baseline and 12 weeks. (Exploratory)

- To bank blood samples for future correlative analyses. (Exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to baseline pain
score (4-6 vs 7-10), and prior taxane use (yes vs no). Patients are randomized to 1 of 2
treatment arms.

- Arm I: Patients receive duloxetine hydrochloride orally (PO) once daily (QD) on days
1-7, twice daily (BID) on days 8-84, and then QD on days 85-91.

- Arm II: Patients receive placebo PO QD on days 1-7, BID on days 8-84, and then QD on
days 85-91.

Patients complete the modified Brief Pain Inventory Short Form (BPI-SF) questionnaire at
baseline and periodically during study treatment. Patients may also complete the Western
Ontario and McMaster Universities Osteoarthritis (WOMAC) scale, the Modified Score for the
Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH), the
Functional Assessment of Cancer Therapy-Endocrine Scale (FACT-ES), Global Rating of Change
Scale, and the patient Health Questionnaire (PHQ-9).

Patients undergo blood sample collection at baseline and periodically during treatment for
correlative studies, including biomarker and genetic studies.

After completion of study treatment, patients are followed up for 168 days.

DISEASE CHARACTERISTICS:

- Patients must be women with histologically confirmed estrogen receptor (ER)- and/or
progesterone receptor (PgR)-positive invasive carcinoma of the breast with no evidence
of metastatic disease (M0)

- Patients must have completed mastectomy or breast-sparing surgery and must have
recovered from all side effects of the surgery

- Patients must have aromatase inhibitor (AI)-associated musculoskeletal symptoms that
began or increased after starting AI therapy; new musculoskeletal pain must not be due
specifically to fracture or traumatic injury

- Patients must have completed the S1202 Brief Pain Inventory-Short Form (BPI-SF) within
7 days prior to registration; patients must have an "average pain" of at least 4 on
the BPI-SF

PATIENT CHARACTERISTICS:

- Patients must be post-menopausal, as defined by at least one of the following:

- At least 12 months since the last menstrual period

- Prior bilateral oophorectomy

- Previous hysterectomy with one or both ovaries left in place (or previous
hysterectomy in which documentation of bilateral oophorectomy is unavailable) AND
follicle-stimulating hormone (FSH) values consistent with the institutional
normal values for the post menopausal state; if patient is under the age of 55,
FSH levels must be obtained within 28 days prior to registration OR

- Have been on LHRH agonist therapy for at least 3 months and estradiol levels
drawn within 28 days prior to registration are consistent with the institutional
normal values for post-menopausal state.

- Patients must have Zubrod performance status of 0-2

- Patients must have no known allergy or hypersensitivity to duloxetine or any of the
inactive ingredients in the matching placebo

- Patients must not have any contraindicated concurrent illnesses listed on the
duloxetine package insert including:

- Current primary psychiatric diagnosis (schizophrenia, psychosis) or suicidal
ideation, history of bipolar disorder, or seizure disorder

- History of alcohol or other substance abuse or dependence within 365 days prior
to registration

- Chronic liver disease

- End-stage renal disease

- Uncontrolled narrow-angle glaucoma

- Clinically significant coagulation disorder

- Creatinine clearance > 30 mL/min

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both within 3 x
upper limit of normal

- Total bilirubin within the upper limit of normal

- Patients must be able to complete study questionnaires in English or Spanish

- Patients must not have concurrent medical/arthritic disease that could confound or
interfere with evaluation of pain or efficacy including: inflammatory arthritis
(rheumatoid arthritis, systemic lupus, spondyloarthropathy, psoriatic arthritis,
polymyalgia rheumatica), or cancer involving the bone

- Patients must be willing to submit blood samples for correlative studies; baseline
samples must be obtained prior to beginning protocol treatment

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- If patients were treated with chemotherapy and/or radiation therapy, these treatments
must be completed at least 28 days prior to study registration

- Concurrent bisphosphonate and trastuzumab therapies are allowed

- Patients should have recovered from all Grade 2 or higher side effects of chemotherapy
and/or radiation therapy with the exception of alopecia and peripheral neuropathy

- Patients must currently be taking one of the following aromatase inhibitor (AI) doses
for at least 21 days, but no longer than 12 months, prior to registration and plans to
continue for at least an additional 180 days after registration

- Anastrozole (Arimidex®) 1 mg daily

- Letrozole (Femara®) 2.5 mg daily

- Exemestane (Aromasin®) 25 mg daily

- Patients must not be taking any contraindicated medications listed on the duloxetine
package insert including the following: treatment with phenothiazines, propafenone,
flecainide, or linezolid; treatment with monoamine oxidase (MAO)-inhibitor within 14
days prior to registration; or current use of anticoagulation medication (e.g.,
heparin, warfarin)

- Patients must not require selective serotonin reuptake inhibitors (SSRIs), serotonin
and norepinephirine reuptake inhibitors (SNRIs), or tricyclic antidepressants during
study participation; patients must have been able to taper and discontinue treatment
with these medications at least 7 days prior to registration; patients must not have
taken duloxetine or milnacipran within 90 days prior to registration

- Patients who are receiving treatment with narcotics, tramadol, gabapentin, and/or
pregabalin must have been taking a stable dose for at least 30 days prior to
registration