Presentation on theme: "Targeting Tumors Using Endogenous Albumin"— Presentation transcript:
0 Randomized phase 2b trial comparing first-line treatment with aldoxorubicin versus doxorubicin in patients with advanced soft tissue sarcomasSant Chawla, M.D.Principal InvestigatorDirector, Sarcoma Oncology CenterSanta Monica, California
1 Targeting Tumors Using Endogenous Albumin Acid-sensitive linker coupled to doxorubicinbinds covalently to circulating albumin in < 5 minutesDrugLinkerPredeterminedBreaking pointAlbuminAfter infusion, linker forms covalent bond to cysteine-34 on albuminAble to deliver several times more drug because drug is inactive until released at the tumorLinker can be used with many types of cancer drugs: anthracyclines, taxanes, camptothecins, platinums, etc.
2 Aldoxorubicin First-line STS Phase 2b Trial Design ScreenedN=14014 screen failures2:1 Randomization N=1233 subjects randomized but not dosedAldoxorubicin350mg/m2(260mg/m2 dox equiv.)Every 3wk up to 6 cyclesN=83Doxorubicin75mg/m2Every 3wk up to 6 cyclesN=40CT Scans every 6 weeks
3 Patient Characteristics AldoxorubicinDoxorubicinN8340Age, median (range)54.0 (21-77)54.0 (23-77)Male / Female, n (%)46 / 5445 / 55Race, n (%)Caucasian7480Black or African American12.5Asian1915Other6ECOG, n (%)0-19692248Completed Cycles, median (range)6 (1-6)4 (1-6)
5 Primary Endpoint: PFS All Subjects Intent-to-treat P Value Scans Read by InvestigatorAldoxorubicin8.4 monthsP=0.0004Doxorubicin4.7 monthsImprovement over dox3.7 mos. (79%)Hazard ratio0.419 ( )P=0.0007Scans Read by Blinded Central Lab5.7 monthsP=0.0142.8 months2.9 mos. (104%)0.584 ( )P=0.024
8 PFS at 6 Months Results All Subjects Intent-to-Treat P Value Scans Read by InvestigatorAldoxorubicin68.1%P=0.002Doxorubicin36.6%Improvement over dox86.1%Scans Read by Blinded Central Lab45.7%P=0.0222.9%99.6%
9 Overall Response Rate Results AldoxorubicinDoxorubicinScans Read by InvestigatorComplete Response2.4%0%Partial Response19.3%5.0%Overall Response Rate21.7%Scans Read by Central Lab23.8%
10 Waterfall Plot - Investigator Aldoxorubicin64.5% had tumor shrinkageDoxorubicin41.2% had tumor shrinkage
11 Waterfall Plot – Blinded Central Lab Aldoxorubicin60.8% had tumor shrinkageDoxorubicin39.4% had tumor shrinkage
12 Overall Survival - Preliminary Too early to determine OS due to prolonged survival of patients in study.As of September 15, 2014:Higher % deaths and lower % still being followed in doxorubicin-treated subjects.Lower % deaths and higher % still being followed in aldoxorubicin-treated subjects.% Deaths% Lost to F/U% Still FollowedAldoxorubicin421939Doxorubicin551827
13 Comparison to Current STS Treatments CytRx Phase 2bInvestigator assessedEORTC Phase 3Dox vs. dox+ ifosfamideAldoxDoxDox+ ifosN8340215217Age54 (21-77)54 (23-77)48 (18-60)47 (18-63)PFS (months)126.96.36.199.6P value0.00040.003OS (months)NA14.312.80.076ORR21.7%5.0%26.5%13.6%
16 Minimal Alopecia Even After 8 Cycles of Aldoxorubicin
17 Cardiac Evaluation Aldoxorubicin Doxorubicin Median Cumulative Dose (mg/m2) [range]2,100* [350-2,800]300* [75-450]% subjects with ≥15% decrease in LVEF8%34%% subjects with ≥15% increase in LVEF15%3%% subjects with ≤45% of expected value0%5.7%*Maximum of 6 cycles allowed per protocol
18 ConclusionsAldoxorubicin significantly increases PFS, PFS at 6 months and ORR compared to doxorubicin therapy for first line STS.Grade 3 or 4 neutropenia, mucositis and nausea/vomiting are higher in aldoxorubicin-treated patients but are not treatment limiting.The aldoxorubicin patients received more than 5 times the cumulative amount of doxorubicin in this study than the doxorubicin patients without any evidence of clinically relevant decreased LVEF, and in more instances an increase in LVEF, either by MUGA or echocardiogram.A phase 3 pivotal trial under a SPA is ongoing for relapsed/refractory STS.Presented by: Sant Chawla, M.D.
19 Phase 3 Trial Design: 2nd-line STS Soft tissue sarcoma patients that have relapsed or are refractory to prior chemotherapy1:1 RandomizationN=400Aldoxorubicin350mg/m2(260mg/m2 dox equiv.)Every 3weeks until disease progressionN=200Physicians Choice:DoxorubicinDacarbazineIfosfamideGemcitabine+docetaxelPazopanibN=200Primary Endpoint: PFS
20 Aldoxorubicin + Ifosfamide Study A Single Center, Open-Label Phase 1b/2 Study to Investigate the Preliminary Safety and Activity of Aldoxorubicin plus Ifosfamide/Mesna in Subjects with Metastatic, Locally Advanced, or Unresectable Soft Tissue SarcomaAldoxorubicin administered at either 170, 250 or 350 mg/m2 (125, 185 and 260 mg/m2 doxorubicin equivalents) intravenously on Day 1 every 28 days plus 1 gm/m2 ifosfamide by continuous intravenous infusion for 14 days via a portable/ambulatory infusion pump every 28 days until disease progression, unacceptable toxicity or withdrawal of consent.Tumor response will be monitored every 8 weeks from Cycle 1-Day 1 through week 33, and then every 12 weeks until disease progression using the RECIST 1.1 criteria.