The BEACON Study (Breast Cancer Outcomes With NKTR-102)

Study Overview
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Brief Summary
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The study is designed as an open-label, randomized, parallel, two arm, multicenter, international Phase 3 study in patients with recurrent or metastatic breast cancer previously treated with cytotoxic chemotherapy regimens. The primary study objective is to compare overall survival of patients who receive NKTR-102 given once every 21 days to patients who receive treatment of Physician's Choice selected from a list of seven single-agent intravenous therapies.

Official Title
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The BEACON Study (Breast Cancer Outcomes With NKTR-102): A Phase 3 Open-Label, Randomized, Multicenter Study of NKTR-102 Versus Treatment of Physician's Choice (TPC) in Patients With Locally Recurrent or Metastatic Breast Cancer Previously Treated With an Anthracycline, a Taxane and Capecitabine

Conditions
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Locally Recurrent Breast Cancer, Metastatic Breast Cancer

Intervention / Treatment
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* Drug: NKTR-102
* Drug: Treatment of Physician's Choice (TPC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (major highlights): Patient is an adult female with histologically or cytologically confirmed carcinoma of the breast for whom single-agent cytotoxic chemotherapy is indicated Patient can have either measurable or non-measurable disease by RECIST. Patient has received prior therapy (administered in the neoadjuvant, adjuvant and/or metastatic setting) with an anthracycline, a taxane and capecitabine Patient has minimum of 2 and a maximum of 5 prior cytotoxic chemotherapy regimens with the last dose administered within 6 months. A minimum of two chemotherapy regimens had to be for locally recurrent and/or metastatic disease. All therapy received prior to a diagnosis of metastatic disease (eg, neoadjuvant, adjuvant or repeated adjuvant therapy following a second resection) is counted as one regimen. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate hematopoietic, liver and kidney functions. Exclusion Criteria (major highlights): Patient with chemotherapy within 21 days, radiotherapy within 14 days, biological therapy with 14 days, hormonal therapy within 7 days and investigational therapy within 21 days prior to randomization. Patient with any major surgery within 28 days prior to randomization. Patient with concurrent use of biologic agents for the treatment of cancer including antibodies or any investigational agent(s). Patient with prior treatment for cancer with a camptothecin derivative. Patient with chronic or acute GI disorders resulting in diarrhea of any severity grade; patients who are using chronic anti-diarrheal supportive care to control diarrhea in the 28 days prior to randomization. Patient received pharmacotherapy for hepatitis B or C, tuberculosis or HIV. Patient with known cirrhosis diagnosed with Child-PUGH Class A or higher liver disease. Patient with prior malignancy (other than breast cancer) except for non-melanoma skin cancer and carcinoma in situ (of the cervix or bladder), unless diagnosed and definitively treated more than 5 years prior to randomization. Patient requiring daily use of oxygen supplementation in the 28 days prior to randomization. Patients with significant cardiovascular impairment.

Ages Eligible for Study
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Minimum Age: 18 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: NKTR-102<br> | Drug: NKTR-102<br>* 145 mg/m2 NKTR-102 will be delivered q21day as a 90-minute intravenous (IV) infusion on day 1 of each treatment cycle.<br>|
| Active Comparator: Physician's Treatment of Choice<br> | Drug: Treatment of Physician's Choice (TPC)<br>* One of the following Treatment of Physician Choice will be administered per standard of care: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of Overall Survival: Intention to Treat (ITT) Population | Duration of OS was defined as the time from the date of randomisation to the date of death due to any cause. Subjects were followed until their date of death, loss to follow-up, withdrawal of consent for further follow-up for survival, or final database closure. OS was determined using the ITT population which included all subjects randomized into 1 of the 2 treatment arms. Subjects who were lost-to-follow-up or were not known to have died were censored at last date they were shown to be alive. Subjects who did not have any follow-up since the date of randomization were censored at the date of randomization. | 36 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of Progression-Free Survival (PFS): ITT Population | PFS was defined as the time from the date of randomization to the earliest date of disease progression (assessed by the investigator according to RECIST version 1.1) or death due to any cause. PFS was determined using the ITT population which included all subjects randomized into 1 of the 2 treatment arms. For subjects whose disease did not progress or who did not die, the PFS time was censored at the time of the last tumor assessment that demonstrated lack of disease progression. For subjects who received new anti-cancer therapy, the PFS time was censored at the start of the new anti-cancer therapy. | Up to 38 months. | 
| Clinical Benefit Rate (CBR): ITT Population | CBR was defined as the proportion of subjects with a CR, PR, or stable disease (SD) for at least 6 months (≥ 182 days). | Up to 38 months. | 
| Duration of Response (DOR): Efficacy Evaluable Population | DOR was defined as the time from first documented CR or PR until the earliest evidence of disease progression or death from any cause. Subjects who were alive without documented disease progression per RECIST version 1.1 were censored at the date of last tumor assessment without disease progression or start of new anti-cancer therapy for the study disease. | Up to 38 months. | 
| Incidence of Dose Reductions: Safety Population | Proportion of subjects who had a reduction in dose. | Up to 38 months. | 
| Quality of Life Questionnaire-Core 30 (QLQ-C30) Individual Scale, Overall Score: ITT Population | The QLQ-C30 is composed of 5 multi-item functional scales (physical, role, social, emotional and cognitive functioning), a global health status/QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (financial impact, appetite loss, diarrhoea, constipation, insomnia and dyspnoea). Most items are scaled 1 to 4 (1 = not at all, 2 = a little, 3 = quite a bit, 4 = very much) except the items contributing to the global health status/QoL, which are 7-point questions (1 = very poor to 7 = excellent). Raw scores were transformed using a linear transformation to standardize the results so that scores range from 0 to 100. n=number of subjects who completed each individual scale. Note that for scores measuring function, a higher score represented a higher better level of functioning, while for scores measuring symptoms, a higher score represented a lower worse level of symptoms. | Up to 39 months | 
| QLQ-C30 Individual Scale, Change Over Time: ITT Population | The QLQ-C30 is composed of 5 multi-item functional scales (physical, role, social, emotional and cognitive functioning), a global health status/QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (financial impact, appetite loss, diarrhea, constipation, insomnia and dyspnea). Most items are scaled 1 to 4 (1 = not at all, 2 = a little, 3 = quite a bit, 4 = very much) except the items contributing to the global health status/QoL, which are 7-point questions (from 1 = very poor to 7 = excellent). Raw scores were transformed using a linear transformation to standardize the results so that scores range from 0 to 100. n=number of subjects who completed each individual scale. Note that for scores measuring function, a higher score represented a higher better level of functioning, while for scores measuring symptoms, a higher score represented a lower worse level of symptoms. | From Baseline to Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 56. | 
| Quality of Life Questionnaire-breast Cancer-specific Module (BR23) Score Value: ITT Population | The QLQ-BR23 incorporates 5 multi-item scales to assess systemic therapy side effects, arm symptoms, breast symptoms, body image and sexual functioning, and 3 single items to assess sexual enjoyment, upset by hair loss and future perspective. Most items were scaled one to four except the items contributing to the global health status/QoL, which were seven-point questions. Raw scores were transformed using a linear transformation to standardize the results so that scores ranged from 0-100. Note that for scores measuring function, a higher score represented a higher better level of functioning, while for scores measuring symptoms, a higher score represented a lower worse level of symptoms. | Baseline | 
| BR23 Score Change Over Time: ITT Population | The QLQ-BR23 incorporates 5 multi-item scales to assess systemic therapy side effects, arm symptoms, breast symptoms, body image and sexual functioning, and 3 single items assess sexual enjoyment, upset by hair loss and future perspective. Most items were scaled one to four except the items contributing to the global health status/QoL, which were seven-point questions. Raw scores were transformed using a linear transformation to standardize the results so that scores ranged from 0-100. Note that for scores measuring function, a higher score represented a higher better level of functioning, while for scores measuring symptoms, a higher score represented a lower worse level of symptoms. | Up to 38 months. | 
| Population Mean ± Standard Deviation (SD) Area Under the Concentration-Time Curve (AUC) for NKTR-102 and Metabolites After Multiple Administration of 145 mg/m^2 NKTR-102 [25] | Plasma concentrations of NKTR-102 and its major metabolites irinotecan, SN38, SN38G, and APC were measured using validated analytical methods. The population pharmacokinetic (PK) model-derived mean AUC values were computed by integration from t = 0 (start of first dose) to 21 days after the last dose. Integration was implemented using a separate compartment defined as the amount of drug or metabolite in the central compartment divided by the model-estimated volume of distribution. | Up to 38 months. | 
| Population Mean ± SD Maximum Plasma Concentration (Cmax) for NKTR-102 and Metabolites After Multiple Administration of 145 mg/m^2 NKTR-102 [26] | Plasma concentrations of NKTR-102 and its major metabolites irinotecan, SN38, SN38G, and APC were measured using validated analytical methods. The population PK model-derived mean Cmax values were computed by integration from t = 0 (start of first dose) to 21 days after the last dose. Integration was implemented using a separate compartment defined as the amount of drug or metabolite in the central compartment divided by the model-estimated volume of distribution. | Up to 38 months. | 
| Population Mean ± SD Elimination Half-life (t½) for NKTR-102 After Multiple Administration of 145 mg/m^2 NKTR-102 [27] | Plasma concentrations of NKTR-102 and its major metabolites irinotecan, SN38, SN38G, and APC were measured using validated analytical methods. The population PK model-derived mean t½ values were computed by integration from t = 0 (start of first dose) to 21 days after the last dose. Integration was implemented using a separate compartment defined as the amount of drug or metabolite in the central compartment divided by the model-estimated volume of distribution. The t½ of all analytes was primarily driven by NKTR-102. Thus, the NKTR-102 t½ of 37 days also applies to all NKTR-102 metabolites. | Up to 38 months. | 
| Objective Response Rate (ORR): Efficacy Evaluable Population | ORR was defined as the proportion of subjects with a complete response (CR) or a partial response (PR), assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 The analyses were performed for subjects in the efficacy evaluable population who had measurable disease as determined by the investigator at baseline. | Up to 38 months. |