ASCO 2012 TIP Poster

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

Edith A. Perez1, Ahmad Awada2, Joyce O'Shaughnessy3, Hope S. Rugo4, Christopher Twelves5, Javier Cortes6, BEACON Study Group, Nektar Therapeutics7, 1Mayo Clinic, Jacksonville FL; 2Institut Jules Bordet, Brussels, Belgium; 3Baylor Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX; 4University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 5University of Leeds and St. James’s University Hospital, Leeds, United Kingdom; 6Vall d’Hebron University Hospital, Barcelona, Spain; 7Nektar Therapeutics, San Francisco, CA

Background Introduction The BEACON Study Key Patient Entry Criteria Statistical Plan and Methods

• Nektar Therapeutics is a biopharmaceutical company developing a pipeline • There are currently no topoisomerase I inhibitors approved by the FDA to treat • The BEACON study (BrEAst Cancer Outcomes with NKTR-102) is a phase 3 • Adult females with histologically or cytologically confirmed carcinoma of the • Approximately 840 patients (420 patients per treatment group) will be required for of drug candidates that utilizes its advanced polymer conjugate technology breast cancer. Nektar is currently evaluating the potential of etirinotecan pegol as randomized, open-label, international study of etirinotecan pegol in patients with breast: sufficient events to occur in the planned follow-up time. to improve the benefits of drugs for patients. a treatment option in breast cancer. MBC that will evaluate single agent etirinotecan pegol in patients who have – Patients: measurable or non-measurable disease by RECIST, locally • OS will be compared between treatment groups using a stratified two-sided previously received ATC versus a comparator arm consisting of an active single • Etirinotecan pegol (NKTR-102) is in clinical trials for patients with solid recurrent or metastatic disease. log-rank test. Stratification factors include: geographic region, prior eribulin use Topoisomerase I inhibition with irinotecan in MBC agent Treatment of Physician’s Choice (TPC). tumors, including breast, ovarian and colorectal cancers. and receptor status. – Prior therapy (administered in the neoadjuvant, adjuvant and/or metastatic • A previous phase 2 study3 looked at two irinotecan schedules – Based on better tolerability, OS and PFS, the q3w 145 mg/m2 treatment • Etirinotecan pegol is a next-generation topoisomerase I inhibitor with a setting) must include an anthracycline (unless not medically appropriate or • A single interim analysis is planned when approximately 50% of the total deaths (q3w and weekly) for patients with Metastatic Breast Cancer (MBC) refractory to schedule of etirinotecan pegol has been selected for the BEACON phase 3 unique pharmacokinetic (PK) profile that provides a continuous contraindicated for the patient), a taxane, and Xeloda® (capecitabine). have occurred. The purpose of this analysis is to determine whether early an anthracycline, a taxane or both: study in MBC. concentration of active drug with reduced peak concentrations (figure 1).1 termination of the study due to overwhelming efficacy, or due to futility can be – Patients must have received a minimum of 2 and a maximum of 5 prior supported. – Studies have shown etirinotecan pegol to have a markedly reduced cytotoxic chemotherapy regimens for the treatment of breast cancer, with the C (SN-38 peak concentration) that improves tolerability and a Table 1. Efficacy Results from Perez, et al. Randomized Phase II Study of Two last dose administered within 6 months of the date of consent for this trial. max Irinotecan Schedules for Patients with Metastatic Breast Cancer Refractory to continuous exposure to SN-38 compared to irinotecan. an Anthracycline, a Taxane or Both Study Design – Patients must have ECOG performance status of 0–1 with adequate organ Protocol Procedures • Etirinotecan pegol has demonstrated better efficacy as measured both by function. Overall Response Rate (ORR) 14% (q3w), 23% (weekly) tumor growth delay and regression rate compared to irinotecan against a • This study will randomize approximately 840 patients using a 1:1 randomization • Investigator determination of response and progression by RECIST v1.1. – Patients with brain metastases may be eligible, provided local therapy was wide range of human xenograft tumors, including a breast tumor model ratio. Prior to randomization of a patient, the Investigator must determine which Progression-Free Survival (PFS) 1.9 months (q3w), 2.8 (weekly) completed and use of corticosteroids for this indication discontinued for at (figure 2).2 TPC will be offered to the patient as part of the informed consent process and • Central imaging will not be used in this trial. must enter the chosen agent into the medical chart and the central randomization least 3 weeks prior to randomization with stable brain metastases (by Median Overall Survival (OS) 8.6 months (q3w), 9.7 (weekly) • Health-Related Quality of Life: every 8 weeks (prior to imaging). Figure 1. Comparison of SN-38 PK Upon Figure 2. MCF-7 Breast Cancer Tumor Model system. Randomization will be stratified by geographic region, prior use of symptoms and imaging). Etirinotecan Pegol or Irinotecan Administration eribulin, and receptor status. • Healthcare utilization: every 4 weeks. Doses 100

) 2000 3 Topoisomerase I inhibition with etirinotecan pegol in MBC • Data will be collected on subsequent anticancer therapies in both treatment arms • PK in a subset of patients.

SN38 T1/2~50 1500 10 Days after 4 from the time patients come off the study treatment until the time of primary data Exploratory Biomarkers Reduced Etirinotecan pegol Control • A previous phase 2 study evaluated etirinotecan pegol in two treatment regimens SN38 C max 1000 Irinotecan 40 mg/kg • Biomarkers in a subset of patients. NKTR-102 40 mg/kg 2 analysis for OS. 1 NKTR-102 90 mg/kg (145 mg/m q2w and q3w; n=70; 35 per treatment regimen), for patients with a 500 median of 2 cytotoxic regimens for MBC (100% prior taxane, 89% anthracycline; • Exploratory biomarkers in BEACON study: • Central laboratory for safety tests (in addition to local laboratories). Plasma SN38 Conc (ng/mL)

Median Tumor Volume (mm Volume Tumor Median • An independent data monitoring committee (DMC) will review the safety of 0.1 0 0 3 6 9 12 0 7 14 21 28 35 42 49 56 63 70 77 Days Post Initial Treatment 26% with prior ATC): etirinotecan pegol treatment in the study and will assess interim efficacy data. After irinotecan: SN38 T1/2 ~ 1-2 days; Time (weeks) – Nektar will work with ApoCell, a leader in the field for capturing and not detectable 5-6 days following dose – 29% ORR observed with single agent etirinotecan pegol (both schedules analyzing Circulating Tumor Cells (CTCs). Figure 4. Trial Schema Accrual showed similar ORR). – An increased harvest of CTCs compared to other technologies, enables • Etirinotecan pegol is a large molecule, and is believed to penetrate the Primary Endpoint – ORR was also maintained in other heavily pre-treated and poor prognosis Single Agent Etirinotecan pegol Nektar to analyze more biomarkers per sample and to monitor the change in • BEACON is open for enrollment and enrollment is expected to be completed by Patients with Arm A: Overall survival ‘leaky’ vasculature within the tumor environment more readily than normal (NKTR-102) biomarkers over time. patient subsets: 2 December 2013. vasculature, increasing exposure of tumor cells to the active anti-tumor metastatic breast cancer 145 mg/m q21d Secondary Endpoints Previously treated with an Progression-free survival agent SN-38 (figure 3). Treatment of Physician’s Choice (TPC) – Quantify CTCs, assess biomarkers of DNA damage, topoisomerase I/ • ER+ and/or PR+: 29%. anthracycline, a taxane, and Objective response rate • Regions: Approximately 160 sites in North America, Europe and Asia. Arm B: Single Agent Regimen:

Randomized 1:1 topoisomerase II, and apoptosis (figure 5). • Triple-negative: 39%. capecitabine (N=840) eribulin, ixabepilone, vinorelbine, gemcitabine, Clinical bene t rate • Comparison of SN-38 PK upon etirinotecan pegol or irinotecan administration: paclitaxel, docetaxel, or nab-paclitaxel Duration of response • Clincaltrials.gov • Visceral disease: 30%. – Reduced C Figure 3. Etirinotecan Pegol Mechanism of Action Figure 5. CTC Collection-At Baseline, Pre-cycle 2, Pre-cycle 4 and End of Treatment • Registration # NCT01492101 max – Side effects were generally manageable; most common severe toxicity was (infusional-related Other Endpoints diarrhea (G3 23% in q3w), typically occurring after 3 months of therapy. Health-Related Quality of Life (HRQoL) toxicities are not • Contact Information: Pharmacoeconomic implications using healthcare utilization measures 7.5 mL blood seen with Exploratory Objectives Alison Hannah, M.D. Gabriel Luciano etirinotecan pegol). Biomarkers (Topo I, Topo II, Markers of DNA damage/apoptosis) Table 2. Efficacy Results from Awada, et al. Significant Antitumor Activity in a Evaluation of biomarkers in CTC and tissue Medical Monitor Clinical Operations – Greatly prolonged Randomized Phase 2 Study Comparing Two Schedules of Etirinotecan Pegol CTC enrichment with Nektar Therapeutics Nektar Therapeutics elimination half-life in Patients With Pre-Treated Metastatic Breast Cancer ApoStream™ [email protected] [email protected] with etirinotecan Laser-scanning cytometric Overall Response Rate (ORR) 31% in ATC (N=16) pegol (50 days analysis Place cells on glass slide and compared to 2 days). SCAN TO Progression-Free Survival (PFS) 4.6 months (5.3 months in q3w) DOWNLOAD A PDF stain for markers References OF THIS POSTER • Topoisomerase I Quantify CTCs, inhibition may result Overall Survival (OS) 10.3 months (13.1 months in q3w) assess biomarkers of DNA damage, 1. Von Hoff DD, Jameson GS, Borad MJ, et al. First phase 1 trial of NKTR-102 (peg-irinotecan) reveals early topo I/topo II, and apoptosis evidence of broad antitumor activity in three different schedules. Presented at the 20th EORTC-NCI-AACR in improved antitumor symposium on Molecular Targets and Cancer Therapeutics meeting, Oct 21-24, 2008, Geneva, Switzerland, Poster activity due to lack of no. 595. 2. Persson H., et al. NKTR-102, a novel polyethylene glycol conjugate of irinotecan, has improved anti-tumor activity 'cross-resistance' to commonly used microtubule inhibitors. Data transfer from ApoCell to central database in three mouse xenograft models. Poster presented at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Oct 22-26, 2007, San Francisco, CA USA. Poster no. C10. 3. Perez E, et al. Randomized Phase II Study of Two Irinotecan Schedules for Patients with Metastatic Breast Cancer Refractory to an Anthracycline, a Taxane or Both. J Clin Oncol 22: 2849-2855., 2004. 4. Awada A, et al. Significant Antitumor Activity in a Randomized Phase 2 Study Comparing Two Schedules of NKTR-102 in Patients With Pre-Treated Metastatic Breast Cancer. Abstract 1034 – Poster #24 Poster presented at the 2011 American Society of Clinical Oncology Annual Meeting: Breast Cancer: Triple Negative/Cytotoxics/ Local Therapy Poster Session, June 3-6, 2011.