A Randomized Phase 2b Study Comparing Treatment with Aldoxorubicin Versus Doxorubicin First Line in Patients
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Aldoxorubicin p2-sts-01 ctos poster 10-31-13

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Aldoxorubicin p2-sts-01 ctos poster 10-31-13

  1. 1. A Randomized Phase 2b Study Comparing Treatment with Aldoxorubicin Versus Doxorubicin First Line in Patients with Advanced Soft Tissue Sarcomas Sant P. Chawla1, M.D., Zsuzsanna Pápai, M.D.2, Guzel Mukhametshina, M.D.3, Kamalesh Sankhala, M.D.4, Mamed Aliev, M.D.5, Kennith Khamly, M.D.6, Leonid Vasylyev, M.D.7, Rajnish Nagarkar, M.D.8, Kristen Ganjoo, M.D.9, Scott Wieland, Ph.D.10, and Daniel Levitt, M.D., Ph.D.10 1Santa Monica, CA, USA; 2Budapest, Hungary; 3Kazan, Russia; 4San Antonio, Texas, USA; 5Moscow, Russia; 6Victoria, Australia; 7Kharkiv, Ukraine; 8Maharashtra, India; 9Stanford, CA; 10CytRx Corp., USA. Abstract OBJECTIVE: Doxorubicin is the only approved chemotherapy for the treatment of most advanced soft tissue sarcomas. Aldoxorubicin consists of doxorubicin attached to an acid-sensitive linker that binds covalently and completely to circulating serum albumin in minutes. In this phase 2b study we compared the efficacy and safety of aldoxorubicin to doxorubicin as first line treatment for patients with advanced soft tissue sarcomas. METHODS: This multicenter, international, open label trial was initiated in January, 2012. Approximately 120 patients ages 18 to 80 with histologically confirmed metastatic, locally advanced or unresectable soft tissue sarcomas are randomized 2:1 to receive either 350 mg/m2 aldoxorubicin (260 mg/m2 doxorubicin equivalents) or 75 mg/m2 doxorubicin i.v. every 3 weeks for up to 6 cycles. No prior chemotherapy except for adjuvant chemotherapy (up to 225 mg/m2 total doxorubicin) is permitted. Tumor response by CT is being monitored every 6 weeks until end or completion of treatment, 2 months following the end of treatment, then every 3 months until tumor progression or withdrawal from the study. The primary endpoint is progression-free survival for each treatment group. Secondary endpoints include overall survival, tumor response and PFS at 4 and 6 months. A blinded, independent central radiology review is performed for each scan. RESULTS: As of June 26, 2013 107 patients had been randomized (aldoxorubicin 72: doxorubicin 35). 62 patients were still active (aldoxorubicin 47: doxorubicin 15). 41 patients who received aldoxorubicin had completed at least 4 cycles of therapy and 31 patients 6 cycles. 16 patients treated with aldoxorubicin received at least 4 cycles and 8 patients had received 6 cycles. 8 objective responses were documented for patients in the aldoxorubicin arm and 22 patients had ongoing stable disease. For doxorubicin-treated patients, there are no objective responses and 6 patients had stable disease. The major grade 3 or 4 adverse event has been neutropenia. The study is ongoing with final enrollment expected by late third quarter. CONCLUSION: Aldoxorubicin can be administered at doses greater than 3 1/2 x the standard doxorubicin dose with fewer systemic side effects. A higher percentage of patients receiving aldoxorubicin are still active, have received at least 4 or 6 cycles of treatment and have a greater number of tumor responses and stable disease. Preliminary results from the study should be available before the end of 2013. Structure of Aldoxorubicin Acid-sensitive bond O OH O O N C NH N Key Eligibility Criteria Albumin-binding group Age between 15-80 years (US only), and 18-80 (ROW), male or female. Adjuvant or neoadjuvant chemotherapy (including doxorubicin) allowed if no tumor recurrence for at least 12 months since the last measurement, beginning or end of last chemotherapy. O CH2OH OH OCH3 O OH CH3 Histologically or cytologically confirmed, locally advanced, unresectable, and/or metastatic soft tissue sarcoma of intermediate or high grade. OO HO NH2 Doxorubicin, the clinical standard Prior exposure to <3 cycles or <225 Doxil® cumulative dose. Proposed Mechanism of Action mg/m2 of either doxorubicin HCl or Subject Status (as of October 16, 2013) Aldoxorubicin Screened, n Screen Failure, n (%) 83 40 Thrombocytopenia 2 0 11 (28) Mucositis 2 2 Discontinued, n (%) 47 (57) 29 (73) Leucopenia 2 0 Completed Cycle 4, n 59 22 Vomiting 3 0 Completed Cycle 6, n 45 14 *number of subjects; #1 death Aldoxorubicin is a prodrug of the anticancer agent doxorubicin which is derivatized at its C-13 keto-position with a thiol-binding spacer molecule ( 6-maleimidocaproic acid hydrazide). Aldoxorubicin is quantitatively and selectively bound to the cysteine-34 position of endogenous albumin within a few minutes. The reaction follows second-order kinetics. Aldoxorubicin was superior to free doxorubicin in several human tumor xenograft models and in low dose combination studies.1,2 Toxicological studies in mice, rats, and dogs demonstrated a 3- to 5-fold increase in the MTD, moderate and reversible myelosuppression, no liver toxicity and immunotoxicity, and no new toxicity compared to doxorubicin.3 Aldoxorubicin is significantly less cardiotoxic in a chronic rat model when compared to doxorubicin at an equitoxic dose.4 Dose density of doxorubicin is important for response in sarcoma. Doxorubicin is limited to only 75-90 mg/m2 due to toxicity. 30 0 (0) 0 (0) 15 (22.1)+ 0 (0) 31 (45.6) 15 (50) Progressive Disease, n (%) 22 (32.4) 15 (50) *Data from blinded central imaging vendor; 7 Hungary 20 8 Russia 12 N India 11 Australia 12 +p=0.004 compared to doxorubicin 30 Romania Disease Progression (as of Sept. 27, 2013)* Characteristics Aldoxorubicin Tumor cells Doxorubicin Primary To evaluate the progression-free survival in subjects with metastatic, locally advanced, or unresectable soft tissue sarcomas. Secondary To evaluate the overall survival, progression-free survival at 4 and 6 months, and objective response rate (ORR; RECIST 1.1 criteria). To evaluate the treatment-related toxicities in this subject population. Study Design Aldoxorubicin was administered at 350 mg/m2 (260 mg/m2 doxorubicin equivalents) IV on Day 1 every 21 days for up to 6 consecutive cycles compared to doxorubicin administered at 75 mg/m2 for up to 6 consecutive cycles. Subjects were randomized 2:1 to received aldoxorubicin or doxorubicin. Tumor response was monitored every 6 weeks from Cycle 1-Day 1 during treatment, at End of Treatment, 2 months following the End of Treatment and then every 3 months until disease progression. Safety assessments including adverse events, physical exam, serum chemistry, CBC, urinalysis, and ECG were performed at each visit. Cardiac function was assessed using either MUGA or cardiac ultrasound. 18 ≥ 20% ↑ in Target Lesions 17 (50%)** 12 (66.7%) ≥ 20% ↑ in Non-target Lesions 10 (29.4%) 5 (27.8%) 7 (20.6%) 1 (5.6%) *Data from central imaging vendor; **n (%) Linker releases the drug payload due to acidic environment of the tumor Objectives 34 New Lesion(s) Background Aldoxorubicin Doxorubicin 68 Stable Disease, n (%) % of Total Enrolled Ukraine Recent estimates indicate that there will be 11,410 new cases of soft tissue sarcomas diagnosed in the United States in 2013, with almost 4,390 deaths. Doxorubicin, either alone or in combination with ifosfamide, is still considered the mainstay chemotherapeutic agent for the treatment of advanced, unresectable tumors. In a phase 1 study, good objective responses (38.5%), prolonged stable disease (53.8%), and tumor shrinkage (61.5%) were demonstrated in chemotherapy relapsed or refractory soft tissue sarcoma patients treated with aldoxorubicin. [2012 ASCO] A human PK study showed that aldoxorubicin has a relatively long circulating half-life, narrow volume of distribution, and slow clearance. Circulating free doxorubicin was <2% of total doxorubicin measured. [2013 ESMO] Aldoxorubicin Partial Response, n (%) USA Tumor cells Patient Characteristics Characteristics 2 36 (43) Characteristics Geographic Distribution Country 2 5 Active, n (%) Randomized and Dosed, n Complete Response, n (%) Albumin transports drug to the tumor 10 Anemia 14 (10) N Aldoxorubicin is infused into the patient Aldoxorubicin* Doxorubicin*# Febrile neutropenia 140 Best Response (as of Sept. 27, 2013)* ECOG performance status 0-2. Life expectancy >12 weeks. Linker rapidly binds to cysteine-34 residue of albumin in the blood stream Serious Adverse Events (treatment-related) Doxorubicin Conclusions • Patients treated with aldoxorubicin demonstrate significantly higher response rates than subjects treated with doxorubicin (blinded review). • Higher percentage of aldoxorubicin patients received 4 (59 patients, 1000 mg/m2 doxorubicin equivalents) and 6 (45 patients, 1500 mg/m2 doxorubicin equivalents) cycles of treatment with no clinically significant reduction in cardiac function. • Similar percentages of aldoxorubicin and doxorubicin patients experienced neutropenic fever. • Higher percentage of aldoxorubicin patients had grade 3 or 4 thrombocytopenia, mucositis or nausea or vomiting. • Tumor responses and PFS data are still being collected. Cardiac Evaluation Aldoxorubicin Doxorubicin Aldoxorubicin Doxorubicin 83 40 % subjects with ≥15% decrease in LVEF: 11% 22% Age, median (range) 52.5 (22-76) 56.1 (26-78) % subjects with ≥15% increase in LVEF: 15% 3% Male / Female, n (%) 38 (46) / 45 (54) 18 (45) / 22 (55) % subjects with <50% of expected value: 0% 9.4% 61 (74) 32 (80) 1 (1) 1 (2.5) Asian 16 (19) 6 (15) Other 5 (6) 1 (2.5) N Race, n (%) Caucasian Black or African American Grade 3/4 Treatment Emergent Adverse Events (regardless of relationship) Aldoxorubicin 0-1 2 Completed Cycles, median (range) Doxorubicin N=83 N=40 No. (%) No. (%) ECOG, n (%) 80 (25) 37 (92.5) 3 (75) 3 (7.5) Event Gr. 3 Gr. 4 Gr. 3 Gr. 4 6 (1-6) 4 (1-6) Neutropenia 14 (17) 9 (11) 2 (5) 3 (8) 81 38 Neutropenic fever 4 (5) 8 (10) 5 (13) 1 (3) Leiomyosarcomas, n (%) 24 (30) 11 (29) Thrombocytopenia 4 (5) 2 (2) 0 (0) 14 (17) 5 (13) Anemia 2 (2) 2 (2) 9 (23) 2 (5) Fibrosarcoma, n (%) 11 (14) 4 (11) Leucopenia 4 (5) 4 (5) 0 (0) 2 (5) 6 (7) 4 (11) Nausea/vomiting 5 (6) 0 (0) 0 (0) 0 (0) 25 (32) 14 (36) Mucositis 7 (8) 0 (0) 1 (3) 0 (0) 1. Kratz F, Beyer U. Serum proteins as drug carriers of anticancer agents: a review. Drug Delivery. 1998;5:281-299. 2. Kratz F, Azab S, et al. Combination therapy of doxorubicin and the acid-sensitive albumin-binding prodrug of doxorbucin INNO-206 induces complete regressions in a xenograft pancreatic carcinoma model demonstrating excellent tolerability. AACR, 2012. 3. Kratz F, Ehling G, Kauffman H. Acute and repeat-dose toxicity studies of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), an albuminbinding prodrug of the anticancer agent doxorubicin. Human Exp. Toxicol. 2007;1935. 4. Lebrecht D, Geist A, Ketelsen U, et al. The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage. Int J Cancer. 2007;120:927-934. 1 (3) Liposarcoma, n (%) References Unconfirmed Histopathology, N Synovial sarcoma, n (%) Others, n (%) Contact Details Sant P. Chawla, M.D. Sarcoma Oncology Center 2811 Wilshire Blvd., Suite 414 Santa Monica, CA 90403 (310) 552-9999 – phone (310) 201-6685 – fax E-mail santchawla@aol.com www.sarcomaoncology.com

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