NOLAN: Naproxen or Loratadine and Neulasta

Study Overview
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Brief Summary
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The primary objective of the study is to estimate the difference in bone pain between breast cancer patients receiving chemotherapy and pegfilgrastim and either no prophylactic intervention, prophylactic naproxen, or prophylactic loratadine.

Detailed Description
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In this study, the investigational products are naproxen, a non-steroidal antiinflammatory drug (NSAID), and loratadine, an anti-histamine. Both agents are being investigated as prophylactic medications to reduce the incidence and/or severity of bone pain in breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy and pegfilgrastim prophylaxis. Pegfilgrastim treatment is used to stimulate bone marrow to produce more neutrophils to help fight infections in patients undergoing chemotherapy.

Official Title
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Randomized, Phase 2 Study to Estimate the Effect of Prophylactic Intervention With Naproxen or Loratadine on Bone Pain in Breast Cancer Subjects Receiving Chemotherapy and Pegfilgrastim

Conditions
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Bone Pain in Stage I - III Breast Cancer

Intervention / Treatment
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* Drug: Naproxen
* Drug: Loratadine
* Biological: Pegfilgrastim
* Drug: Chemotherapy


Participation Criteria
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Eligibility Criteria
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Age 18 years or over Eastern cooperative oncology group (ECOG) performance status 0-2 Female with newly diagnosed, not previously treated with chemotherapy, stage I-III breast cancer Medically eligible to safely receive adjuvant or neoadjuvant chemotherapy, pegfilgrastim, naproxen and loratadine as determined by the investigator Creatinine ≤ 1.5 X upper limit of normal (ULN) Planning to receive at least 4 cycles of adjuvant or neoadjuvant chemotherapy Planning to receive prophylaxis with pegfilgrastim starting in the first cycle and continuing throughout each chemotherapy cycle of the treatment period Subject has provided informed consent Exclusion Criteria History of other malignancy within the past 5 years, with the following exceptions: Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated cervical carcinoma in situ without evidence of disease Planning to receive weekly chemotherapy Ongoing chronic pain, or other painful conditions requiring treatment (including immediate post-operative treatment of surgical or procedural-associated pain) as determined by the investigator Chronic oral steroid use. Premedication related to the administration of chemotherapy, and use of anti-emetics is allowed, per usual clinical practice Chronic use of oral non-steroidal anti-inflammatory drug (NSAIDs) or oral antihistamines outside of those dictated by the randomization groups outlined in the protocol, with the following exception: - Chronic oral aspirin use for cardiovascular-related indications Prior chemotherapy treatment for cancer within 5 years of current breast cancer diagnosis Prior use of granulocyte colony stimulating factor (G-CSF) History of clinically significant gastrointestinal (GI) bleeding, history of GI ulcers or active GI bleeding within 6 months prior to randomization History of clinically significant bleeding disorders, thromboembolism within 6 months prior to randomization Currently enrolled in, or less than 30 days since ending, another clinical trial which includes language directing G-CSF (filgrastim, pegfilgrastim, other) or granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim) use Currently enrolled in, or less than 30 days since ending, another interventional clinical trial which includes a blinded treatment or blinded treatment arm (whether or not the subject is randomized to the blinded arm) Currently enrolled in, or less than 30 days since ending, another interventional clinical trial which includes the use of any agent not currently considered to be standard therapy for the adjuvant or neoadjuvant treatment of stage I-III breast cancer based on National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Breast Cancer Currently enrolled in, or less than 30 days since ending, any pain intervention study Female subjects who are pregnant or lactating or of reproductive potential not willing to employ an effective method of birth control during treatment and for 17 days after discontinuing study treatment History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the Investigator or Amgen, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prophylactic naproxen<br>Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration. | Drug: Naproxen<br> <br> Biological: Pegfilgrastim<br>* Commercially available pegfilgrastim (Neulasta®) will be used in the study, and is considered background therapy. Pegfilgrastim is administered as a single 6 mg subcutaneous injection 24 hours to 72 hours after completion of chemotherapy.<br>* Other names: Neulasta®;Drug: Chemotherapy<br>* The choice of chemotherapy regimen (agent, dose, and schedule) is at the discretion of the treating physician.<br>|
| Experimental: Prophylactic loratadine<br>Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration. | Drug: Loratadine<br> <br> Biological: Pegfilgrastim<br>* Commercially available pegfilgrastim (Neulasta®) will be used in the study, and is considered background therapy. Pegfilgrastim is administered as a single 6 mg subcutaneous injection 24 hours to 72 hours after completion of chemotherapy.<br>* Other names: Neulasta®;Drug: Chemotherapy<br>* The choice of chemotherapy regimen (agent, dose, and schedule) is at the discretion of the treating physician.<br>|
| Other: No prophylactic treatment<br>Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis. | Biological: Pegfilgrastim<br>* Commercially available pegfilgrastim (Neulasta®) will be used in the study, and is considered background therapy. Pegfilgrastim is administered as a single 6 mg subcutaneous injection 24 hours to 72 hours after completion of chemotherapy.<br>* Other names: Neulasta®;Drug: Chemotherapy<br>* The choice of chemotherapy regimen (agent, dose, and schedule) is at the discretion of the treating physician.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Bone Pain (All Grades) in Cycle 1 | Bone pain data were captured as part of standard adverse event (AE) reporting. | Cycle 1 (approximately 4 weeks, depending on the chemotherapy dosing interval) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Bone pain data were captured as part of standard adverse event (AE) reporting. | Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval) | 
| Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Bone pain data were captured as part of standard adverse event reporting. Severe bone pain is defined as grade 3 or 4 according to common terminology criteria for adverse events (CTCAE) version 3 grading criteria: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, and Grade 4 = Life-threatening or disabling. | Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval) | 
| Mean Patient-reported Bone Pain by Cycle and Across Cycles | Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Mean patient-reported bone pain values are the average of each participant's bone pain values across survey days 1-5 within each cycle. Across all cycles the mean is the average of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An analysis of variance (ANOVA) model with treatment as explanatory term was used. | Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle) | 
| Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Maximum patient-reported bone pain is the maximum of each participant's bone pain values across survey Days 1-5 within each cycle. Across all cycles the maximum is the maximum of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An ANOVA model with treatment as explanatory term was used. | Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle) | 
| Area Under the Curve (AUC) for Patient-reported Bone Pain | Patient-reported bone pain AUC was calculated using the trapezoidal rule with bone pain scores from day 1 to 5 for each cycle. The AUC across cycles is the average of AUCs across the cycle. | Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle) | 
| Number of Participants With Adverse Events (AEs) | Severity was graded using CTCAE version 3. A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal; • life threatening; • requires in-patient hospitalization or prolongation of existing hospitalization; • results in persistent or significant disability/incapacity; • congenital anomaly/birth defect; • other medically important serious event. The investigator assessed each adverse event for relatedness to investigational product(s) or other protocol-required therapies. | From first dose of investigational product (IP, naproxen or loratidine) or first dose of pegfilgrastim (Peg), whichever occurred first, until 30 days after last dose, up to 24 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Chemotherapy, Neulasta, Pegfilgrastim, Naproxen, Loratadine, Non-steroidal antiinflammatory drug (NSAID), Anti-histamine, Bone Pain