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Background Although hypomethylating agents (HMAs) are effective and approved therapies for patients with myelodysplastic syndromes (MDS), many patients do not benefit from treatment, and nearly all ultimately stop responding to HMAs. The incidence and cost burden of HMA failure are unknown yet needed to appreciate the magnitude and significance of such failure. Methods We analyzed a de-identified dataset of over 5 million individuals with private health insurance in the U.S. to estimate MDS incidence, prevalence, and treatments. Based on MDS provider interviews, a conceptual model of MDS patient management was constructed to create a new, claims-relevant and drug development-relevant definition of HMA treatment failure. This algorithm was used to define resource encumbrance of MDS patients in whom HMA treatment failed. Results We estimated an MDS incidence rate of ~70 cases per 100,000 enrollees per year and a prevalence of 155 cases per 100,000 enrollees. The proportion of MDS patients receiving HMA treatment was low (~3%), and treatment was typically initiated within 1 year of the first MDS claim. Notably, HMA-treated individuals were older and had more comorbidities than the overall MDS cohort. Total health care costs of managing MDS patients after HMA failure were high (~$77,000 during the first 6 months) and were driven primarily by non-pharmacy costs. Conclusion This study quantifies for the first time the burden of significant unmet need in caring for MDS patients following HMA treatment failure.

To evaluate optimal salvage therapy in high-risk myelodysplastic syndromes patients who have failed a first-line hypomethylating agent (HMA) therapy, given that treatment choice is challenging.Using published literature and expert opinion, we developed a Markov model to evaluate the cost-effectiveness of current treatments for patients who failed first-line HMA therapy. The model predicted costs, life years, quality-adjusted life years and incremental cost-effectiveness ratios. Sensitivity analyses were conducted to assess the impact of uncertainty in model inputs.Supportive care was the least expensive option ($65,704/patient) with the shortest survival (0.48 years). Low- and high-intensity chemotherapies and hematopoietic cell transplantation increased survival and costs with incremental cost-effectiveness ratios of $108,808, 306,103 and 318,163/life year, respectively. Switching HMA was more costly and less efficacious than another treatment option, namely low-intensity chemotherapy.Subsequent treatments in myelodysplastic syndrome patients who failed first-line HMA significantly increase costs, while only providing marginal clinical benefit and substantially increasing treatment-related morbidities. Additional treatment options would benefit resource allocation, clinical decision-making and patient outcomes.

This Phase 1/2, dose-escalating study of rigosertib enrolled 22 patients with higher-risk myelodysplastic syndromes (MDS) (n=9) and acute myeloid leukemia (AML; n=13) who had relapsed or were refractory to standard therapy and for whom no second-line therapies were approved. Patients received 3- to 7-day continuous intravenous infusions of rigosertib, an inhibitor of Ras-effector pathways that interacts with the Ras-binding domains, common to several signaling proteins including Raf and PI3 kinase. Rigosertib was administered at doses of 650-1700mg/m2/day in 14-day cycles. Initial dose escalation followed a Fibonacci scheme, followed by recommended phase 2 dose confirmation in an expanded cohort. Rigosertib was well tolerated for up to 23 cycles, with no treatment-related deaths and 18% of patients with related serious adverse events (AEs). Common AEs were fatigue, diarrhea, pyrexia, dyspnea, insomnia, and anemia. Rigosertib exhibited biologic activity, with reduction or stabilization of bone marrow blasts and improved peripheral blood counts in a subset of patients. Ten of 19 evaluable patients (53%) demonstrated bone marrow/peripheral blood responses (n=4 MDS, n=1 AML) or stable disease (n=3 MDS, n=2 AML). Median survival was 15.7 and 2.0 months for responders and non-responders, respectively. Additional studies of rigosertib are ongoing in higher-risk MDS (NCT00854646).

Introduction: Rigosertib is a small molecule inhibitor of cellular signaling pathways in cancer cells by acting as a Ras mimetic. The inhibitory effect is mediated by Rigosertib binding to the Ras-binding domain found in many Ras effector proteins (Athuluri-Divakar SK, Cell 2016). Oral administration of Rigosertib was initially evaluated in lower risk MDS patients. The drug, administered as 560 mg BID (q12hr; 2/3 wks), was associated with high rates of transfusion independence but with significant GU AEs (Raza, et al, Blood 2017 130:1689). Subsequently, a reduction in the PM dose to 280 mg led to a decrease in GU AEs, suggesting a causal relationship with nocturnal bladder drug concentration. When oral administration of Rigosertib was tested with standard dose of parenteral Azacitidine in a Phase I/II trial (NCT01926587) at a dose of 560/280 mg (Q12hrs, 3/4 weeks), the ORR was 77%; with 60% for the HMA relapsed/refractory group for the high risk MDS patients. The impressive response rate, in the combination treatment, was also associated with significant GU AEs. Hence, it is important to understand the underlying cause and devise ways to maximize response rates with minimization of GU AEs. Previously, it was established that GU AEs were unlikely to be related to the higher systemic exposure of the drug (Maniar, et al ASH 2018, Abstract submitted) but attributed to the nocturnal dwell time of high drug concentration in the bladder of patients treated with continuous oral administration (3/4 weeks). In this investigation, we developed a pharmacokinetic model to simulate the systemic and bladder exposure of Rigosertib after repeated oral dosing. The overall aim was to identify and implement an oral dosing regimen for Rigosertib that would maximize the systemic exposure with minimization of nocturnal bladder concentration, thereby potentially mitigating or eliminating the GU AE's. Methods: A 2-compartment model with 1st order absorption and elimination (Figure 1) was fitted to data collected from patients with solid malignancies at a 560 mg dose (n=25). Model parameter estimates were then used to generate a virtual population of 100 patients. Each virtual patient was randomly assigned parameter values based on the 95% confidence interval for each parameter estimate obtained through the modeling analysis. Model simulations were then performed to evaluate the steady state systemic and urinary exposure of Rigosertib in the virtual population after treatment with different dosing schedules (Figure 2). Besides plasma exposure (Cmax, AUC), the predicted rigosertib bladder concentration during the sleep-cycle was also assessed. From this analysis, optimal dosing regimens were selected for evaluation in a Phase 2 study in HR-MDS patients in combination with Azacitidine. The model was validated by comparing the predicted systemic exposure with observed data using these optimal dosing regimens, and by comparing Grade 3 GU AE's events from the pre- and post-optimization of dosing regimen (NCT01926587). Results: The model-predicted steady state plasma concentration-time profile of Rigosertib for different dosing regimens is shown in Figure 3. The duration of exposure of drug above minimum effective concentration (MEC, 0.175 ug/ml) was not changed by varying the dosing regimen. Importantly, model simulations demonstrated that BID dosing, with the dosing interval of 8 hours, would reduce the bladder concentration of Rigosertib by as much as 70% during sleep without compromising systemic drug exposure (Table 1). As illustrated in Table 2, model simulated Rigosertib exposure (Cmax, AUC) compared favorably with data from patients treated with the novel twice daily dosing regimens (560mg/560mg and 840 mg/280mg, dosing interval of 8 hours), thereby validating the model. Preliminary safety data from the on-going trial demonstrates that the Grade 3 GU AEs were significantly reduced (12%) with the optimized dosing regimen compared to the pre-optimized dosing regimen (29%) despite using a higher total dose of drug (1120 mg vs 840 mg). Conclusions: This study demonstrates the utility of pharmacokinetic modeling for designing a dosing regimen directed at reducing the incidence of toxicity. The identified dosing regimen, along with mitigation strategies, successfully reduced the risk of Grade 3 GU AEs of rigosertib without compromising the duration of systemic exposure of Rigosertib above MEC in HR MDS patients. Disclosures Taft: Onconova Therapeutics, Inc: Research Funding. Ren:Onconova Therapeutics, Inc: Employment, Equity Ownership. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Morgan:Onconova Therapeutics, Inc: Consultancy. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Maniar:Onconova Therapeutics, Inc: Employment, Equity Ownership.

Introduction: Oncogenic mutations of Ras genes have been implicated in number of human cancers whereby the cells grow uncontrollably, and evade death signals (Ledford, Nature, 520, 278, 2015). Rigosertib is a small molecule that inhibits cellular signaling in cancer cells by acting as a Ras mimetic (Athuluri-Divakar SK, Cell 2016). Rigosertib, as a single agent, was evaluated in a Phase III clinical trial in refractory MDS patients where the drug was administered as a 3 day continuous IV infusion every other week (NCT01241500). Rigosertib has also been evaluated in Phase I/II trials via oral route of administration in patients with solid malignancies (NCT01168011); and with myelodysplastic syndromes (NCT01926587). We performed pharmacokinetic and safety analysis of 253 patients across three different trials. The pharmacokinetics and safety profile of orally administered Rigosertib was evaluated in patients with MDS and solid malignancies. The results were compared to data obtained from high risk MDS patients receiving intravenous rigosertib therapy. In this investigation, we present evidence that differential GU toxicity of Rigosertib is probably related to the route of administration and dosing regimen; and independent of the underlying disease state. Methods: Data was analyzed from three clinical studies. Study NCT01241500 was conducted with MDS patients (n = 184) who were administered Rigosertib by continuous IV infusion (1800 mg/day for 72 hours) every 2 weeks. Blood samples were collected at 6, 24, 30, 48, 56 and 72 hours after infusion initiation. In Study NCT01168011, patients with advanced solid tumors (n=33) received oral Rigosertib (560 mg) Q12 hours of a 28-day cycle (3 weeks on, 1 week off). Study NCT01926587, conducted in MDS patients (n=36) with oral administration Rigosertib in combination with parenteral Azacitidine, evaluated the same AM dose but a lower 280 mg PM dose. In both studies, pharmacokinetic assessment was conducted after administration of the AM dose (560 mg) on day 1 of cycle 1. Blood samples were collected predose and 0.5, 1, 1.5, 2, 4, 6 and 8 hours after administration. For Study NCT01168011, urine was collected for 24 hours (0-4, 4-8 and 8-24 hrs) to determine the percent of dose excreted in urine. Rigosertib concentrations in plasma and urine were determined by a validated LC/MS-MS method. Rigosertib pharmacokinetic parameters were estimated using non-compartmental analysis. Treatment emergent adverse events were recorded throughout each study. Results: There was no difference in Rigosertib pharmacokinetic parameters between the two patient populations (Table 1) upon oral administration, and the plasma concentration-time profiles were super imposable (Figure 1). Approximately 2% of the orally administered dose was recovered in the urine. In both studies, the most common AEs observed were GU AEs (dysuria, hematuria). The incidence of grade ≥2 GU toxicity observed with oral dosing was 17 of 33 (52%) and 17 of 36 (47%) in Study NCT01168011 and NCT01926587, respectively. The incidence of GU AEs in both the studies was comparable even though the PM dose was lower (560 mg vs 280mg) in study NCT01926587. Peak plasma concentration and AUC0-∞ were similar in patients with or without urinary symptoms. Compared to oral dosing, the incidences of GU AEs were dramatically lower (10%) following IV infusion despite 8-fold higher and more prolonged systemic exposure (Table 2). Conclusions: This study demonstrates that the urinary adverse events and systemic exposure are similar in patients with either solid malignancies or MDS treated with orally administered rigosertib. The incidence of GU AEs is relatively high in spite of the very low amount (2%) of the administered dose eliminated through the renal route. In contrast, the GU AEs are significantly lower when Rigosertib is administered by IV infusion despite of 8 fold higher exposure. This is probably due to the short half-life of drug and dosing holiday of 12 days between two doses within the cycle. The higher incidence of GU AE upon oral administration is likely related to the dwell time of high concentration of drug in the bladder at night in patients treated daily for 3/4 weeks. This was successfully addressed in the clinical trial, NCT01926587 expansion with risk mitigation strategies, by deploying a novel dosing regimen derived through pharmacokinetic modeling and simulation (Taft, et al; ASH 2018 Abstract Submitted). Disclosures Maniar: Onconova Therapeutics, Inc: Employment, Equity Ownership. Ren:Onconova Therapeutics, Inc: Employment, Equity Ownership. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Taft:Onconova Therapeutics, Inc: Research Funding.

Introduction: CXCL12 (stromal cell derived factor-1, SDF-1), an 8 kDa peptide chemokine, ligates chemokine receptor 4 (CXCR4) and activates migration of normal and leukemic stem cells from the bone marrow into the blood. Rigosertib is a synthetic benzyl styrene sulfone with evidence of activity in certain subsets of patients with MDS and AML (Garcia-Manero et al., Lancet Oncology 2016; 17; 496). Objective: To characterize and quantify intact CXCL12 and its protease-induced truncation products in plasma of MDS and AML patients before and after treatment with Rigosertib in Phase I/II dose escalation trials. Methods: Rigosertib was infused continuously for three days (dose: 650-1,700 mg/m2/d), and samples were obtained from patients with MDS (n=8) or AML (n=12). Plasma samples were taken at 0 and 72 h and centrifuged at 300 g for 10 min. After dilution with equal volume of water, plasma was ultrafiltered (30 kDa exclusion). Aliquots of the ultrafiltrates were analyzed by liquid chromatograph/mass spectrometry (LC/MS). LC: Tosoh C18 column (TSK gel, ODS-100V), gradient elution. MS: positive electrospray ionization (ESI) with selected ion monitoring, m/z 980 for intact CXCL12, m/z 952, 940, 929, and 914 for -2 amino acids (aa, KP removed), -3 aa (KPV removed), -4 aa (KPVS removed), and -5 aa (KPVSL removed) truncation products, respectively. The presence of truncates was confirmed using standards incubated with various proteases by determining molecular masses using ESI. Calibration curves for quantification were established using synthetic standards. Results & Discussion: In normal subjects (n=10), the concentration of intact CXCL12 was 16.6±9.4 ng/m, compared to 3.1± 3.2 ng/mL in MDS patients (n=8) and 2.4±1.7 ng/mL in AML patients (n=12) prior to therapy with Rigosertib. No truncation products (≤1.0 ng/mL) were detected in normal subjects, despite the relatively high concentration of intact CXCL12. In contrast, truncation products, corresponding to the removal of 2, 3, 4 and 5 amino acids, were detected in all patients prior to treatment: 2.5±1.6 ng/mL, 2.7±2.1 ng/mL, 2.4±1.7 ng/mL, 4.2± 3.6 ng/mL in MDS patients; 3.3±2.9 ng/mL, 2.4±1.7 ng/mL, 3.1±2.5 ng/mL, 2.2±1.7 ng/mL in AML patients. The total concentration of all truncation products was ~12 ng/mL in MDS patients and ~11ng/mL in AML patients. We have also reported CXCL12 truncation products in patients with primary myelofibrosis (~29 ng/mL) and polycythemia vera (~31 ng/mL) (SC, JR et al., Cancer Res. 70, 3402, 2010). Of the 20 AML and MDS patients treated with rigosertib, six attained partial or complete bone marrow remission, based on the International Working Group criteria. Among the responding patients, intact CXCL12 concentration increased from 3.4±3.6 ng/mL to 5.6±3.7 ng/mL. Among non-responders, intact CXCL12 underwent little change, from 2.7±2.2 to 2.9±2.3 ng/mL. Conclusion: Proteolytic degradation of CXCL12 may be characteristic of the pathobiology of homing and release from the marrow niche in patients with myeloid malignancies and this process changes in response to treatment. Our findings suggest that CXCL12 may be a biomarker for patients with MDS or AML who respond to rigosertib on clinical trials. Further investigation of the potential role of intact CXCL12 and its truncation products in plasma as a biomarker in these diseases is warranted. Disclosures Roboz: Onconova Therapeutics: Consultancy, Honoraria; Mount Sinai School Medicine: Employment. Navada:Onconova: Research Funding. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Silverman:Mount Sinai School of Medicine: Employment; Medimmune: Research Funding; Onconova Therapeutics Inc.: Patents & Royalties, Research Funding; Celgene: Research Funding; Johnson and Johnson: Research Funding; Bayer: Research Funding.

Background: AZA is first line therapy for pts with HR-MDS with an overall response rate (ORR) between 35 and 60% in various publications; with CR/PR rates ranging between 23 and 29% in 3 randomized phase II/III studies (Silverman et al., JCO 2002; Fenaux et al., Lancet Oncol 2009; Sekeres, JCO 2017). AZA also has demonstrated efficacy in older pts with AML (Dombret et al., Blood 2015; Fenaux et al., JCO 2010). Rigosertib interferes with the RAS-binding domains of RAF kinases and inhibits the RAS-RAF-MEK and the PI3Ks pathways (Athuluri-Divakar, Cell 2016). RAS and other genes in this pathway are frequently mutated in HR MDS and putatively drive the malignant clone (Sperling et al., Nat Rev CA 2017). In vitro, the combination of rigosertib with AZA synergistically inhibits growth and induces apoptosis of leukemic cells in a sequence-dependent fashion (Skidan et al; AACR 2006 Abstract 1310). In a trial in lower-risk MDS, oral rigosertib was studied as a single agent at various doses including 560 mg BID for 14-21 days in 28 day cycles and yielded a transfusion independence (TI) rate of 44% - the highest reported TI rate (Raza, ASH Abstract #108660 2017). Based on this observation we expanded the ongoing Phase I/II trial and tested rigosertib at a total of 1120 mg per day with standard dose parenteral AZA (75mg/m2 x 7 days q28 days) in two different schemes as described in methods (NCT01926587). At a dose of 560 mg AM, 280 mg evening the ORR was 77%; 88% for the HMA naïve group and importantly 60% for the HMA Rel/Ref group. Of note, adverse events of interest have been genitourinary (GU) toxicities, particularly hematuria and dysuria. Thus, risk-mitigation strategies (Table 1) were employed to minimize hematuria with higher dose rigosertib at 1120 mg; including the rationale for the lower afternoon (280 mg) dose. We report here the initial results of efficacy and safety. Methods: In the Phase II Expansion cohort, up to 45 pts with HR MDS/RAEB-t/non-proliferative AML were randomized 1:1 into 2 cohorts both to receive 1120 mg of rigosertib over 24 hours: either 560 mg in the morning and 560 mg in the afternoon, or 840 mg in the morning and 280 mg in the afternoon (part of hematuria/dysuria risk mitigation; moving second dose from evening to afternoon to minimize overnight bladder dwell time as permitted by PK analysis (Maniar, ASH Abstract 2018). Each cohort is stratified among HMA naïve and HMA Rel/Ref pts. Hematologic response is determined per IWG 2006. Results: As of July 2018 in the rigosertib 1120 mg cohort in combination with AZA, 45 pts were enrolled; 43 treated, 31 evaluable for response; 14 pts continue on treatment, and 31 pts discontinued (includes 2 enrolled but not treated). To be evaluable for response, a minimum of 12 weeks of the doublet was required. Of the 31 pts evaluable for response, 17 pts are prior Rel/Ref, 14 pts are HMA naïve. The # of prior HMA cycles is 2-15; 13 failed AZA; 1 failed DAC; 2 failed both; and 1 failed other (experimental). The median duration of treatment at this time point for the overall population is 5 months (1-14+). The ORR (Table 2) for the all patients is 68%; 59% for the prior Rel/Ref cohort and 79% for the HMA naïve cohort. For responding patients, responses are seen in both 1120 mg cohorts as shown. Safety: In 43 patients treated with oral rigosertib at 1120 mg and AZA, with risk-mitigating strategies to minimize hematuria, Grade 1 & 2 hematuria = 16%; ≥3 Grade Hematuria = 5% have been seen to date (Table 3). This compares to an incidence of 12 % Gr 3 hematuria at a lower dose of rigosertib (840 mg); and prior to risk mitigation strategies. Incidence of hematuria of any grade with single agent AZA is 6.3 % & Grade ≥3 2.3% (VIDAZA, package insert 2004). Conclusion: The combination of oral rigosertib and AZA in HMA naïve patients with HR-MDS is encouraging compared to single agent AZA. The combination also has activity and reverses the HMA clinical resistance in a substantial number of patients after Rel/Ref, a finding with potentially significant clinical implications. Dose exploration with a higher dose of oral rigosertib (1120mg) administered in different dosing schemes in combination with standard dose AZA continues to be studied to optimize safety and efficacy. By employing risk mitigation strategies, the incidence of GU AEs, including hematuria, has been substantially reduced. We will update the safety and efficacy data at the time of presentation. Based on this data a pivotal trial is planned. Disclosures Navada: Onconova: Research Funding. Atallah:Pfizer: Consultancy; Abbvie: Consultancy; Jazz: Consultancy; BMS: Consultancy; Novartis: Consultancy. Shammo:Incyte: Consultancy, Honoraria, Research Funding; Onconova: Other: research support; Alexion: Honoraria, Other: research support; Novartis: Consultancy, Honoraria; Celgene: Other: research support. Griffiths:Novartis, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Alexion Inc.: Honoraria, Research Funding. Khaled:Juno: Other: Travel Funding; Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy. Pemmaraju:abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; Affymetrix: Research Funding; samus: Research Funding; SagerStrong Foundation: Research Funding; cellectis: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; plexxikon: Research Funding. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Maniar:Onconova Therapeutics, Inc: Employment, Equity Ownership. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Silverman:Johnson and Johnson: Research Funding; Onconova Therapeutics Inc.: Patents & Royalties, Research Funding; Bayer: Research Funding; Celgene: Research Funding; Medimmune: Research Funding; Mount Sinai School of Medicine: Employment.

Purpose: The study aimed to assess the pharmacokinetic behavior of satraplatin under fasted and fed conditions, and its safety and preliminary antitumor activity in adults with advanced solid tumors. Experimental Design: Satraplatin was administered orally at 80 mg/m2 once daily with prophylactic antiemetics for 5 consecutive days every 5 weeks. Patients were randomized to receive day 1 and day 5 doses of satraplatin in either the fed or fasted state, the order being reversed for cycle 2. Pharmacokinetic sampling was done during the first two cycles. For all subsequent cycles, patients received satraplatin in the fasted state. Results: Seventeen patients were treated with 60 total cycles of satraplatin. There was no dose-limiting toxicity during cycle 1. Severe hematologic toxicity was rare and the hematologic nadir occurred during week 4. Nausea, vomiting, and diarrhea were grade 1/2. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The hypothesis that food decreased ultrafiltrate platinum bioavailability could not be rejected, as the lower limit of the 90% confidence intervals for peak plasma concentration and area under the concentration-time curve from time 0 to 24 hours were 56.14% and 73.53%, respectively, both below the 80% bioequivalence acceptance criterion. One partial response (hormone refractory prostate cancer) and four durable stable diseases (breast, ovarian, parotid, and hormone refractory prostate cancer) were confirmed. Conclusions: There is an effect of food on the pharmacokinetics of satraplatin, the clinical significance of which is unclear. It is recommended that satraplatin be administered in the fasting state. This 5-week interval schedule of satraplatin was well tolerated in heavily pretreated patients.

7056 Background: No therapies are approved for MDS after HMA failure. 04-24 was a single-arm study to evaluate best BMBL response as a potential surrogate for OS in higher-risk (HR) MDS pts who progressed on or after an HMA. Rigo is a Ras-mimetic that inhibits the RAS-RAF-MEK pathway, which is frequently activated in HR MDS (Athuluri-Divakar Cell 2016; Gil-Bazo Cancer Biol Ther 2016). Methods: Eligible MDS pts had 5-30% BMBL confirmed within 6 wks pre-study and progression per International Working Group (IWG) 2006 criteria on or after HMAs within 2 yrs. Rigo 1800 mg/24 hrs was continuously infused over 72 hrs q 2 wks × 8 cycles, then q 4 wks until progression or unacceptable toxicity. Primary endpoint was relationship of best BMBL IWG response to OS by Kaplan Meier method. Results: 64 pts were treated (median 5 cycles, range 1-32+), with 61% male, median age 73 (range 47-87), median prior HMA duration 10.8 mos (range 1.2-70.2). Revised International Prognostic Scoring System scores were low 2%, intermediate 11%, high 27%, very high 53%, and unknown 8%. ≥Grade 3 adverse events in ≥10% of pts were anemia 19%, thrombocytopenia 19%, and febrile neutropenia 16%. At the analysis time 40 pts (63%) had died. Best BMBL IWG response was marrow complete response (mCR) 14 pts (22%), stable disease (SD) 30 (47%), progressive disease (PD) 15 (23%), and failure (early death/withdrawal) 5 (8%); 2 mCR pts had transplant. Median OS was 7.0 mos (95% confidence interval 4.8-10.8). Landmark median OS (from day of best BMBL response) was mCR not reached; SD 6.3 mos; PD 3.3 mos. Median OS of mCR+SD was 8.5 mos, with log-rank p = 0.011 (mCR+SD OS to PD OS). Conclusions: BMBL response is a predictor of survival for MDS pts receiving Rigo after HMA failure, confirming findings in earlier Phase 1/2 studies (Silverman ASCO 2015 Abstr 7017). Based on earlier results identifying an MDS subset benefitting from Rigo (Garcia-Manero Lancet Oncol 2016; ASCO 2016 Abstr 165681), a randomized Phase 3 trial of Rigo vs physician’s choice (INSPIRE) is ongoing to determine if Rigo improves survival after HMA failure within 9 cycles. Clinical trial information: NCTO 1928537.

Background: Rigosertib (RIG) is a RAS-mimetic interacting with the RAS-binding domains of RAF kinases, preventing their binding to RAS and inhibiting the RAS-RAF-MEK pathway. Rigosertib also binds to the RAS-binding domains of Ral-GDS and PI3Ks (Athuluri-Divakar, et al, Cell 165:643, 2016). Mutations of RAS are involved in proliferative processes important in neoplastic transformation (Gil-Bazo, et.al, Cancer Biology and Therapy 17:719, 2016). As of May 2016, 557 patients with MDS or AML received IV (N=335) or oral (N=222) rigosertib. All IV rigosertib was administered as monotherapy. Oral rigosertib was administered as monotherapy (N=168) or in combination with injectable azacitidine (AZA; N=54). Safety results across this rigosertib development program have not been presented. Methods: We reviewed all treatment-emergent adverse events (TEAEs) among patients with MDS/AML treated with rigosertib IV monotherapy, rigosertib oral monotherapy, or in combination therapy, overall and by grade of severity, and serious TEAEs and TEAEs leading to discontinuation. Due to the unexpected observation of urinary AEs, including occasional gross hematuria, we analyzed urinary AEs in greater detail. Results: Rigosertib IV monotherapy: The most common TEAEs were fatigue (33%), nausea (33%), diarrhea (27%), constipation (25%), anaemia (24%) and pyrexia (24%). The most common ≥Grade 3 AEs were anaemia (21%), febrile neutropenia (13%), pneumonia (12%) and thrombocytopenia (11%). The most common serious AEs were febrile neutropenia (10%), pneumonia (9%), and sepsis (7%). The most common AEs leading to discontinuation of IV rigosertib were sepsis and pneumonia (3% each) (Table 1). Rigosertib oral monotherapy: The most common TEAEs were pollakiuria (increased urinary frequency) (35-%), fatigue (32%), diarrhoea (26%), dysuria (29%) and haematuria (24%). The most common ≥Grade 3 AEs were anaemia (17%), thrombocytopenia (5%), haematuria (4%) and urinary tract infection (4%). The most common serious AE was pneumonia (6%). The most common AEs leading to discontinuation of patients receiving oral rigosertib as monotherapy were (dysuria [8%], urinary tract pain [7%], haematuria [5%] and urinary frequency [5%] (Table 2). Rigosertib oral in combination with azacitidine (AZA): The most common TEAEs were nausea (41%), fatigue (39%), diarrhea (37%), constipation (37%) and dysuria (28%). The most common serious AEs were pneumonia (11%) and febrile neutropenia (7%). The most common AEs leading to discontinuation were AML (4%) and pneumonia (4%) (Table 3). In patients fully evaluable for gross hematuria the cause of bleeding was bladder inflammation. Urinary and plasma concentration of RIG were examined to assess dose relationship. According to the azacitidine package insert, the incidence of gross hematuria of any grade with single agent azacitidine is 6.3 % and Grade 3-4 of 2.3%. Evaluations performed of hematuria among 5 studies of oral rigosertib (4 monotherapy and 1 in combination with AZA) in patients with MDS/AML (Table 4). Conclusions: Rigosertib IV or oral formulations were generally well tolerated in clinical trials in over 500 patients with MDS/AML. Gastrointestinal AEs were most frequently reported with IV rigosertib and genitourinary AEs were seen more often with oral than IV dosing. The greater rate of urinary AEs in the oral than in the IV studies indicates a need for close monitoring of these patients and proactive risk management, such as adequate hydration, timing of administration of the second dose, and bladder emptying prior to sleep. Studies are being designed to optimize dosing and schedule to maximize efficacy and minimize hematuria of single agent oral rigosertib. A randomized trial of oral rigosertib/azacitidine versus azacitidine will be required to optimize the clinical benefit and safety in the management of higher-risk patients with MDS. Disclosures Fenaux: Celgene: Honoraria, Research Funding; Janssen: Research Funding; Novartis: Honoraria, Research Funding; Astex: Research Funding; Teva: Honoraria, Research Funding. Al-Kali:Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding. Navada:Onconova Therapeutics, Inc.: Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Platzbecker:Onconova, Teva, Celgene, Janssen, Novartis, Amgen: Honoraria, Research Funding. Petrone:Onconova Therapeutics, Inc.: Employment. Brownstein:Onconova Therapeutics, Inc.: Consultancy. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Maniar:Onconova Therapeutics, Inc.: Employment. Silverman:Onconova Therapeutics, Inc.: Patents & Royalties: Co-Patent holder for the combination of azacitidine and rigosertib, Research Funding.

Background: Lower risk non-del5q MDS patients (pts) have limited treatment options and majority pts are transfusion dependent. Erythropoiesis stimulating agents (ESA) are first line of therapy for LR-MDS pts but almost half are resistant to ESA or become resistant after responding. Hence, LR-MDS represents an area of unmet medical need for novel agents to improve hematopoiesis and reduce transfusion dependency. Rigosertib (RIG) blocks RAS-mediated activation of proteins containing a common RAS binding domain, or RBD (Athuluri-Divaker, et al; Cell 165; 643'16). Since many pathways include proteins that employ RBD (i.e. ras, raf PI3-Kinase), interference with RBD provides a novel approach to block proliferation. While RIG showed encouraging response in LR-MDS pts (Tycko, et al; Blood 2013; 122:2745), there is a need for a biomarker that can differentiate responders from non-responders. To correlate genomics with response to RIG, we employed computational tools to integrate molecular data and observed responses. Aim: To determine predictive value of a computational biology derived genomic signature in LR-MDS pts who are treated with RIG. Methods: Materials were derived from Phase I and II studies of RIG in LR-MDS pts. Efficacy was reported as transfusion independence. Bone marrow samples were collected and processed using standard methods. DNA was extracted from bone marrow mononuclear cells or T-cells (germline control) purified from peripheral blood samples. Exome sequencing was performed using Agilent SureSelect Human All Exon v4 - 51Mb kit and HiSeq 2000. Raw sequences were aligned to the human genome build hg19 using BWA software; SNPs and In/Dels analysis was performed using PICARD, SAMTOOLS and GATK. These results, entered into predictive computational biology software (Cellworks Group), generated disease-specific protein network maps using PubMed and other online resources. Digital drug simulations are conducted by measuring drug effect on a score: a composite of cell proliferation, viability and apoptosis. Each patient-specific network map was screened for RIG reduced progression in a dose-respondent manner. Computer predictions were blindly correlated with clinical outcomes. Results: Predicted response was blindly correlated with the clinical outcome for 19 pts: Results showed 16 matches and 3 mismatches; and the following predictive test statistics: PPV - 81.25%, NPV - 100%, Sensitivity - 100%: accuracy of the predictive test at 84.21%. Modeling of LR-MDS pts predicted amplification of genes MYC, FNTA on chromosome 8; amplification of genes LGALS3, AJUBA, MAX on chromosome 14; TIAM1 on chromosome 21; HMGCR, on chromosome 5; PDPK1, MAPK3, PLK1 on chromosome 16 and PIK3CA, RAF1 on chromosome 3 correlated with increased response to RIG. Aberrations that enhanced the downstream of RAS signaling via the RAF-ERK or PI3K-AKT-MTOR pathway increased the signal flow through the drug response paths. MYC amplification on chromosome 8 via increasing the Purine synthesis pathway and production of GTP increased the RAS-ERK and RHEB-MTOR signaling. MYC also enhanced CCND1 production/proliferation. Prenylation pathway genes FNTA and HMGCR amplification also affect RAS and RHEB; enhance the drug response pathways. Another pathway that was found to be significant in the drug response, reducing proliferation, was inhibition of PLK1 and AURKA. Amplification of AJUBA, PLK1 made this pathway more significant and improved drug response via inhibition of proliferation via TIAM1-RAC1-PAK1-AURKA-PLK1 and RAF-PLK1 pathway. Deletion of TP53 and NF1 on chromosome 17 did not correlate with response. MYC amplification was seen in LR and HR MDS pts and correlated with response to RIG. However, the computational biology method showed that MYC amplification alone is not a predictor for response since there were non-responder profiles with MYC amplification and responder profiles with MYC deletion that had other aberrations in genes on chromosomes 3, 14, 16 or 21. Conclusions: A predictive method that models multiple genomic abnormalities simultaneously showed greater than 80% correlation between RIG mediated protein network perturbations and clinical outcomes in LR-MDS. The method also explained lack of response and highlighted resistance pathways that could be targeted to recover sensitivity. We also established eligibility criteria for greater precision enrollment in future trials. Disclosures Fruchtman: Onconova: Employment. Petrone:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Hoffman:Onconova Therapeutics, Inc.: Employment. Vali:Cellworks Group: Employment. Singh:Cellworks Group: Employment. Usmani:Cellworks: Employment. Grover:Cellworks Group: Employment. Abbasi:Cellworks: Employment.

Background: Based on a model suggesting leukemia can be driven by combined effect of mutations in an epigenetic gene (DNMT3) and Ras, the combination of a hypomethylating agent (HMA) such as azacitidine (AZA) and a Ras mimetic such as rigosertib (RIG) may have enhanced activity in both MDS and AML. The mechanism of action for RIG (Athuluri-Divakar et al, Cell 2016) documents its interference with the RAS-binding domains of RAF kinases and inhibition of the RAS-RAF-MEK and the PI3Ks pathways. In vitro, the combination of RIG with AZA was found to act synergistically to inhibit growth and to induce apoptosis of leukemic cells in a sequence-dependent manner (exposure to RIG first, followed by AZA) (Skidan et al, AACR 2006). Rigosertib's low bone marrow toxicity in pre-clinical assays, effective inhibition of human hematopoietic tumor cell lines, and its synergy with AZA suggests the potential value of combination treatment for patients (pts) with MDS. Phase I results of the current clinical study in pts with MDS or AML showed the combination of oral RIG and standard-dose AZA to be well-tolerated with evidence of efficacy (Navada et al, Blood 2014). The phase II portion of the study was initiated to further evaluate the combination in pts with MDS. Methods: Phase II results are presented for HMA-treatment-naïve MDS pts and for those with MDS failing to respond to or progressed on a prior HMA. Oral RIG was administered twice daily on Day 1-21 of a 28-day cycle at the recommended Phase II dose (RPTD: 560 mg qAM and 280 mg qPM). AZA 75 mg/m2/d SC or IV was administered for 7 days starting on Day 8. A CBC was performed weekly and a bone marrow aspirate and/or biopsy were performed at baseline, D29, and then every 8 weeks thereafter. Results: The combination of oral RIG and injectable AZA has been administered to a total of 54 pts, of whom 40 were pts with MDS including HMA-treatment-naïve (N=23) and previously HMA treated pts (N=17). Median age was 66 years (range 25-85); 73% of pts were male; and ECOG performance status was 0, 1, and 2 in 23%, 73%, and 5%, respectively. 17 pts received prior HMA therapy: 12 AZA, 4 decitabine, and 1 both. Patients have received 1-36+ cycles of treatment (median, 6 cycles), with a median duration of treatment of 25 weeks (range 4 to 145+ weeks). 8 (20%) and 2 (5%) of pts have been treated for more than 1 and 2 years, respectively. Table 1 shows the response per IWG 2006 criteria (Cheson, Blood 2006) among 33 evaluable patients. The response per IWG 2006 was complete remission (CR) in 8 (24%), concurrent marrow CR and hematologic improvement (HI) in 9 (27%), marrow CR alone in 7 (21%), and HI alone in 1 (3%). When overall response is defined as CR plus PR plus HI - responses with improvement in marrow function and thus either normalization of the peripheral blood count or lineage improvement - defined here as Clinical Benefit Response - 55% of all evaluable pts and 70% of the evaluable HMA-treatment-naïve patients showed responses meeting these criteria. Median time to initial response was 2 cycles (2.2 months), and median time to best response was 3 cycles (3.3 months). Median duration of response was 8 months for CR, 14.3 months for marrow CR, 7.4 months for erythroid response, 8 months for platelet response, and 6.2 months for neutrophil response. Clinical response is classified by IPSS-R risk categories below. The most frequently reported adverse events are nausea (41%), fatigue (39%), diarrhoea (37%), constipation (37%), dysuria (28%), decreased appetite (28%), haematuria (24%, 8% Grade 3), pyrexia (24%), dizziness (22%), thrombocytopenia (20%), back pain (20%), dyspnoea (20%), and cough (20%). Eight deaths were reported on study with most common causes including infection and progression of disease. Conclusions: The combination oforalRIG and standard-dose AZA was well tolerated in repetitive cycles in pts with MDS. Response per IWG 2006 criteria was observed both in HMA-treatment-naïve patients (85%) and in patients after failure of prior HMA therapy (62%); employing Clinical Benefit Response as the criteria, these groups had 70% and 31% response, respectively. These clinical results confirm the preclinical synergistic interaction with the combination of RIG and AZA reported by Skidan et al, and suggest that the combination can overcome clinical resistance to HMAs. Based on these results, a Phase III study of the combination of oral RIG and AZA in patients with MDS is planned. Disclosures Navada: Onconova Therapeutics, Inc.: Research Funding. Daver:Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Ariad: Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; BMS: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Petrone:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova: Employment. Silverman:Onconova Therapeutics, Inc.: Patents & Royalties: Co-Patent holder for the combination of azacitidine and rigosertib, Research Funding.

Background: MDS is a marrow stem cell disorder with limited treatments. Due to outcome heterogeneity of MDS, it is imperative to identify prognostic tools for patients in clinical trials. Rigosertib (RIG) is a RAS-mimetic that inhibits cellular signaling pathways by binding to the RAS-binding Domain found in RAS effector proteins. No approved treatment options are available for Higher-risk myelodysplastic syndromes (HR-MDS) pts after Hypomethylating Agent (HMA) failure. The "ONTIME" trial was a Phase III, randomized study of rigosertib in a heterogeneous population of HR-MDS pts who failed to respond to or progressed on HMAs. Aim: To determine the predictive value of a genomics-informed computational biology method and to design a patient selection signature in HR-MDS patients who are treated with RIG. Methods: ONTIME trial included HR-MDS pts who had progressed on (37% of total enrollment), failed to respond to (25%), or relapsed after (38%) HMA treatment. Patients were randomized 2:1 to receive RIG (199 pts) or best supportive care (BSC) (100 pts) (Garcia-Manero et al, Lancet Oncology, 2016).The primary endpoint was overall survival, analyzed on an intention-to-treat basis using the Kaplan-Meier method. Genomic DNA was isolated from single microscopic slides from 153 pts and subjected to sequence analysis of a "myeloid panel" comprising of 24 selected loci frequently mutated in MDS and AML. Standardized cytogenetic investigations were performed. The chromosome aberrations and clone definition followed the International System for Cytogenetic Nomenclature. Depending on the aberrations detected during karyotyping, further probes were applied. A complex karyotype was defined as ≥3 independent aberrations within 1 clone. These genomic results were input into predictive computational biology software (Cellworks Group, Fig. 1), which generates disease-specific dysregulated protein network maps using PubMed and other resources. Digital drug simulations are conducted by quantitatively measuring drug effect on a cell growth score, which is a composite of cell proliferation, viability and apoptosis. Each patient-specific protein network map was digitally screened for the extent by which RIG reduced disease growth in a dose-respondent manner. Clinical outcomes were prospectively recorded. Results: Based on input data from cell-culture studies the predicted response was blindly correlated with the clinical outcome for 54 patients with the following predictive test statistics: positive predictive value (PPV) - 85%, negative predictive value (NPV) - 94.12%, Sensitivity - 89.47%, Specificity - 91.43% and an accuracy of the predictive test at 90.74%. The accuracy of the genomics-informed computer method was significantly greater than empiric drug administration. New genomic signature rules were discovered to correlate with clinical response after RIG treatment. The predictive computational analysis identified a novel signature for selecting HR-MDS patient's responding to RIG. We identified patients with either trisomy 8 or trisomy 21 that also do not have any of the following aberrations including: Del 5q or Del 7/7q or Del 3 or Del 14 or Del 16 or Del 20, would be responders to the drug (Trisomy 8 OR Trisomy 21) AND NOT (Del 5 q OR (Del 7/7q OR Del 3 OR Del 14 or Del 16 or Del 20). We validated this patient selection rule prospectively via statistical correlation methods and through a computer based simulation of a clinical trial generated predicted Kaplan-Meir curve with a significant p-value of 0.003 (Fig. 2). Conclusions: A predictive computational method that models multiple high-risk MDS genomic abnormalities simultaneously showed greater than 90% correlation between protein network perturbations and clinical outcomes. The computational method also helps explain reasons for lack of response to RIG and highlights resistance pathways that could be targeted to recover chemo-sensitivity. This technology also established eligibility criteria for precision enrollment in drug development trials. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Petrone: Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova: Employment. Brownstein:Onconova Therapeutics, Inc.: Consultancy. Loferer:Onconova Therapeutics, Inc.: Employment. Azarnia:Onconova Therapeutics, Inc.: Employment. Vali:Cellworks Group: Employment. Singh:Cellworks Group: Employment. Usmani:Cellworks: Employment. Grover:Cellworks Group: Employment. Abbasi:Cellworks: Employment. Silverman:Onconova Therapeutics, Inc.: Patents & Royalties: Co-Patent holder for the combination of azacitidine and rigosertib, Research Funding.

Purpose This multinational, double-blind, randomized, placebo-controlled, phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic castrate-refractory prostate cancer (CRPC) experiencing progression after one prior chemotherapy regimen. Patients and Methods Nine hundred fifty patients were randomly assigned (2:1) to receive oral satraplatin (n = 635) 80 mg/m2 on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily or placebo (n = 315) and prednisone 5 mg twice daily. Primary end points were progression-free survival and overall survival (OS). The secondary end point was time to pain progression (TPP). Results A 33% reduction (hazard ratio [HR] = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo. This effect was maintained irrespective of prior docetaxel treatment. No difference in OS was seen between the satraplatin and placebo arms (HR = 0.98; 95% CI, 0.84 to 1.15; P = .80). Compared with placebo, satraplatin significantly reduced TPP (HR = 0.64; 95% CI, 0.51 to 0.79; P < .001). Satraplatin was generally well tolerated, although myelosuppression and GI disorders occurred more frequently with satraplatin. Conclusion Oral satraplatin delayed progression of disease and pain in patients with metastatic CRPC experiencing progression after initial chemotherapy but did not provide a significant OS benefit. Satraplatin was generally well tolerated. These results suggest activity for satraplatin in patients with CRPC who experience progression after initial chemotherapy.

The demographic characteristics of 242 clinic outpatients evaluated for dementia were examined. Each individual received a comprehensive assessment of medical status, psychological functioning, and social abilities. Diagnoses were arrived at by consensus, and appropriate treatment plans and follow-up recommendations were generated, with comprehensive feedback provided to family members and other caregivers. The results of this study help increase our knowledge of the characteristics of individuals with Alzheimer's disease, multi-infarct dementia, or other related disorders.

Background: The aging marrow stem cell demonstrates more somatic mutations when compared to younger marrow stem cells. These abnormalities have been noted in pts with MDS, as well as in patients with normal peripheral blood counts (Steensma et al, Blood 2015; Jaiswal et al, N Engl J Med 2014). Mutations are rarely detected in people 1 (Figure 1). Table 1 shows the most frequent clonal myeloid mutations in ONTIME, based on age above and below 75 years (the median age in ONTIME).Table 3.Incidence (%) of Patients with Specific Mutations, Age Above and Below 75 YearsMutation< 75 years (N=60)≥ 75 years (N=51)Total (N=111)Fisher's Exact Test P-valueSRSF22729280.83TP532518220.37ASXL12018190.81SF3B11316140.79U2AF11212121.00TET21216140.59RUNX1814110.38DNMT3A812100.75In a separate analysis, the number of months from diagnosis of MDS and duration of prior HMA treatment did not appear to influence the pattern of mutations (Table 2). Table 2.Mutations by Months Since MDS Diagnosis and Duration of Prior HMAMutationNMonths from MDS Diagnosis median (range)Duration of HMA (mo) median (range)All analyzed pts11118.5 (0.1-116)8.9 (1.2-65)TP532414.9 (0.7-116)13.0 (1.2-36)SF3B11629.4 (7.5-63)13.0 (1.2-36)TET21522.6 (0.1-63)11.4 (2.0-36)SRSF23117.2 (6.6-116)6.4 (3.0-35)ASXL12115.7 (4.9-66)8.2 (2.8-44)DNMT3A1115.1 (7.4-36)6.5 (4.2-30)Conclusions: Somatic mutations are common in marrow stem cells from patients with HR-MDS. Over 45% of patients had 1 mutational abnormality, and 44% had >1. Of note, patients under and over the median age of pts with MDS had a similar mutational pattern, which was not influenced by either length of time since diagnosis of MDS or prior treatment with an HMA. In this analysis, the mutational genomic abnormalities in the MDS marrow stem cell were similar among younger and older patients with MDS, suggesting the underlying pathogenic mechanisms causing these abnormalities are also similar irrespective of patient age. Figure 1. Number of Mutations Per Patient Figure 1. Number of Mutations Per Patient Figure 2. Overall Survival in ONTIME by Number of Marrow Stem Cell Mutations Figure 2. Overall Survival in ONTIME by Number of Marrow Stem Cell Mutations Disclosures Mufti: Onconova Therapeutics Inc: Research Funding. Silverman:Onconova Therapeutics Inc: Honoraria, Patents & Royalties: co-patent holder on combination of rigosertib and azacitdine, Research Funding. Best:Onconova Therapeutics Inc: Research Funding. Fructman:Onconova Therapeutics Inc: Employment. Azarnia:Onconova Therapeutics Inc: Employment. Petrone:Onconova Therapeutics Inc: Employment.

7017 Background: BMBL % is the prognostic variable with the greatest impact on outcome in MDS patients at diagnosis and subsequent time points. Current composite response criteria (IWG, Cheson 2006...

Management Choice • Supportive care is the initial treatment option for patients with low IPSS-R scores (≤3) • Transplantation was providers’ preferred treatment choice for newly-diagnosed, young and otherwise healthy high-risk patients • In line with findings from published literature, providers: Reported that only HMAs and lenalidomide were proven to delay MDS progression and/or improve survival in patients who are not eligible for transplant Expressed belief that HMAs are effective for a period of time, but eventually fail

Background: The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic malignancies that primarily affect older adults. Although first-line therapies are available for treating MDS, the majority of patients will not achieve clinical improvements and nearly all MDS patients suffer from refractory disease. The health resource burden of MDS patients who fail first-line therapies is unknown, but estimated to exceed $24,000 (Craig et al, Leuk Res 2011). Methods: To more accurately estimate burden, we examined healthcare resource utilization (HRU) and costs in MDS patients before and after failure of 1st line therapy with hypomethylating agents (HMAs) azacitidine and decitabine. We conducted a retrospective cohort study of US commercial health insurance claims data to describe, among patients considered to have failed initial HMA treatment, the economic burden and health resource utilization associated with MDS. We identified patients with an MDS-associated medical claim (ICD-9-CM diagnosis codes 238.7x) using an HMA in the identification (ID) period (1/1/2009–12/31/2011). The index date was the date on which patients were defined as eligible for 2nd-line therapy (ie, initiated HMA treatment but then stopped treatment for ≥ 2 months, switched to another HMA, or > 7 months of using the same HMA). Patients were followed for ≥ 6 months after they became candidates for 2nd-line treatment. Outcomes of interest included MDS-specific and overall HRU and costs. HRU included physician office visits, emergency department (ED) visits, hospitalizations, and hospital length of stay. MDS-related events were defined as claims with a primary diagnosis of MDS, acute myeloid leukemia, anemia, neutropenia, thrombocytopenia, or pancytopenia. We examined outcomes during the 1 year before and 6 months immediately after the index date. Results: We identified 402 MDS patients who failed 1st-line therapy. Mean age was 72.9 years; 39.8% were female. Mean Charlson comorbidity index was 3.6, and patients had a mean of 6.8 chronic conditions. Three hundred eighty-six (96.0%) patients had a cytopenia (e.g., anemia, neutropenia, etc.). During the 1 year prior to 1st-line treatment failure, the 402 patients in the cohort had a mean 42.7 MDS-specific office visits. Patients with ≥ 1 MDS-specific ED visit comprised 7.7% of the cohort; 3.0% had an ED visit due to hemorrhage, and 4.2% due to infection. Patients with ≥ 1 MDS-specific hospitalization comprised 29.6% of the cohort; 3.0% were hospitalized due to hemorrhage, and 8.7% due to infection. Mean length of stay for MDS-specific hospitalizations was 8.7 days. Mean MDS-specific healthcare costs totaled $80,673, or 63.4% of total costs. MDS-specific treatment accounted for 60.2% of MDS-specific costs, including those for chemotherapy and hematologic supportive care agents such as erythropoietin-stimulating agents, growth factors, and blood transfusions. During the initial 6 months after 1st-line treatment failure, the 402 patients in the cohort had a mean 18.9 MDS-specific office visits. Patients with ≥ 1 MDS-specific ED visit comprised 6.7% of the cohort; 1.0% had an ED visit due to hemorrhage, and 2.5% due to infection. Patients with ≥ 1 MDS-specific hospitalization comprised 16.9% of the cohort; 1.0% was hospitalized due to hemorrhage, and 6.0% due to infection. Mean length of stay for MDS-specific hospitalizations was 12.9 days. Mean 6-month MDS-specific healthcare costs totaled $45,564, or 59.2% of total costs. MDS-specific treatment accounted for 46.3% of MDS-specific costs. Conclusions: The healthcare and economic burden of illness of MDS patients is substantial after 1st-line HMA treatment failure. The costs of care of commercially insured MDS patients in this study were approximately 3 times higher than previously published costs in Medicare patients. Disclosures Cogle: Partnership for Health Analytic Research (PHAR): Consultancy, I was paid as a consultant for my expert opinion while developing the analyses Other. Mukherjee:Partnership for Health Analytic Research (PHAR): Consultancy, I was paid as a consultant for my expert opinion while developing the analyses Other. Bentley:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Broder:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Chang:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Lawrence:Onconova Therapeutics, Inc.: Employment. McKearn:Onconova Therapeutics, Inc. : Employment. Megaffin:Onconova Therapeutics, Inc.: Employment. Percy:Onconova Therapeutics, Inc.: Employment. Petrone:Onconova Therapeutics, Inc.: Employment, Stock Options Other. Sun:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other.

Background: The myelodysplastic syndromes (MDS) include a group of hematopoietic malignancies that typically affect older individuals. Healthcare claims data have not been previously used to describe treatment patterns of MDS patients who progressed while on, failed to respond to, or became intolerant to hypomethylating agents (HMA; azacitidine [AZA] and decitabine [DEC]) and were eligible for 2nd-line therapy. Methods: We conducted a retrospective cohort study using a US commercial health insurance claims database. The database contained adjudicated pharmacy and medical claims on 13 million annual lives submitted by providers, healthcare facilities, and pharmacies and included data on physician visits, medical procedures, hospitalizations, dispensed drugs, and performed tests. We identified patients with MDS (ICD-9-CM diagnosis code 238.7x) who were using an HMA in the identification (ID) period (1/1/2009–12/31/2011). The index date was the date on which the patient had used the same HMA for > 7 months, discontinued HMA treatment for ≥ 2 months, or switched to another HMA. Patients were defined as eligible for 2nd-line therapy after reaching the index date and were followed for ≥ 6 months after they became candidates for 2nd-line treatment until the end of enrollment or study end (12/31/2012). We examined treatment use patterns from 1/1/2008 to the index date. MDS-specific chemotherapy included AZA, DEC, and lenalidomide (LEN). We defined AZA or DEC cycles as continuous treatment periods without a gap of >7 days, and the gap between observed cycles could not be ≥ 60 days. Hematologic supportive care agents included erythropoiesis-stimulating agents (ESA), growth factors (ie, granulocyte and granulocyte-macrophage colony-stimulating factors), and blood transfusions. Results: Of 38,702 patients diagnosed with MDS in the ID period, we identified 1,366 who used an HMA. Three hundred eighty-six (96.0%) patients had a cytopenia potentially associated with HMA use, including anemia (92.8%), neutropenia (53.0%), and thrombocytopenia (52.7%). Of this group, 402 patients were eligible for 2nd-line MDS therapy: 283 (70.4%) had used AZA, 123 (30.6%) DEC, and 16 (4.0%) LEN. Patients averaged 6.1 HMA treatment cycles (6.4 for AZA, 5.4 for DEC) prior to being considered potential candidates for 2nd-line therapy. One hundred ninety-three (48.0%) patients had “early” discontinuation, defined as Conclusions: About half of patients completed < 5 HMA treatment cycles before discontinuation. AZA was used more often than DEC as 1st-line MDS therapy. These data suggest that a significant number of patients treated with AZA and DEC discontinue and become candidates for 2nd-line MDS therapy. The clinical reasons for early HMA discontinuation warrant further investigation; effective 2nd-line therapies for these patients are needed. Figure: Patient Selection Flowchart. Figure:. Patient Selection Flowchart. Disclosures Mukherjee: Partnership for Health Analytic Research (PHAR): Consultancy, I was paid as a consultant for my expert opinion while developing the analysis Other. Cogle:Partnership for Health Analytic Research (PHAR): Consultancy, I was paid as a consultant for my expert opinion while developing the analysis Other. Bentley:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Broder:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Chang:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Lawrence:Onconova Therapeutics, Inc.: Employment. McKearn:Onconova Therapeutics, Inc.: Employment. Megaffin:Onconova Therapeutics, Inc.: Employment. Percy:Onconova Therapeutics, Inc.: Employment. Petrone:Onconova Therapeutics, Inc.: Employment, Stock Options Other. Sun:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other.

Background: The choice of optimal salvage therapy in patients with MDS is challenging due to a current lack of therapeutic options and a lack of data in regard to the risks and benefits of existing disease management. We undertook this study with the aim of evaluating the clinical outcomes, economic impact, and cost effectiveness of currently available treatment options for MDS patients who failed first-line hypomethylating agent (HMA) therapy. Methods: We developed a Markov model to compare five second-line MDS treatment options: low- and high-intensity chemotherapy; switching HMA treatment; hematopoietic stem cell transplant (HSCT); and best supportive care (BSC). Hypothetical cohorts of patients who had failed a first-line HMA were simulated, and initiated each of these strategies. During each four-week cycle, patients could progress to acute myeloid leukemia (AML), experience a treatment- or disease-related adverse event (thrombocytopenia, anemia and neutropenia), discontinue treatment, or die (Figure 1). Costs were considered from the payer perspective and included those related to drug acquisition and administration, adverse event treatment, hospitalization, and supportive care. Inputs were based on published literature and expert opinion. Results were reported as lifetime costs (2013 USD), life expectancy in life years (LY), and incremental cost-effectiveness ratios (ICERs). Figure 1: Model Schematica Figure 1:. Model Schematica AML, acute myeloid leukemia; HMA, hypomethylating agent; MDS, myelodysplastic syndrome. a Green circles represent model health states. b MDS patients who have failed initial HMA therapy. c Second-line treatments considered for model strategies/comparators are: best supportive care (BSC), HMA, low or high intensity chemotherapy, or hematopoietic stem cell transplant. d Adverse events: thrombocytopenia, anemia, and neutropenia. Results: The model predicted that treating patients who had failed a first-line HMA with BSC was the least expensive option ($55,343 per person) but provided the shortest survival: 0.48 years. Switching patients to a second HMA increased costs to $84,625 and could extend survival modestly. Patients treated with low- and high-intensity chemotherapy had lifetime costs of $89,877 and $146,519 and life expectancy of 0.88 and 1.08 years, respectively. HSCT patients had the highest lifetime costs ($492,359) and survival (2.26 years). Compared with BSC, the ICER for low intensity chemotherapy was $87,343/LY gained, while high intensity chemo and transplant had ICERs of $284,303 and $291,375/LY, respectively. The strategy of switching patients to a second HMA was removed during the calculation of ICERs due to extended dominance, i.e., there was another strategy, namely low intensity chemotherapy, that provided greater clinical benefit and had a more attractive ICER. Conclusions: For MDS patients who had relapsed after, failed to respond, or progressed during administration of a first-line HMA, subsequent alternative active treatments provide some clinical benefit. However, such therapies substantially increase costs and a relatively small population of patients may be eligible due to functional status or matching donors. Although our results suggest that high intensity chemotherapy and transplant provide the greatest clinical benefits, they may cause substantial treatment-related morbidity. The increases in cost of care could thus be interpreted as an inefficient use of resources according to current societal standards, especially as the availability of these therapies is restricted to a limited number of patients. These findings suggest that there is an unmet need among MDS patients failing first-line HMA therapy; more research and treatment options would benefit clinical decision-making, patient outcomes, and healthcare resource allocation. Disclosures Cogle: Partnership for Health Analytic Research (PHAR): Consultancy, I was paid as a consultant for my expert opinion while developing the analyses Other. Mukherjee:Partnership for Health Analytic Research: Consultancy, I was paid as a consultant for my expert opinion while developing the analyses Other. Lawrence:Onconova Therapeutics, Inc. : Employment. McKearn:Onconova Therapeutics, Inc. : Employment. Percy:Onconova Therapeutics, Inc. : Employment. Petrone:Onconova Therapeutics, Inc. : Employment, Stock Options Other. Megaffin:Onconova Therapeutics, Inc. : Employment. Anene:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Ortendahl:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Romanus:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Bentley:Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other.

Background: The myelodysplastic syndromes (MDS) include a group of malignancies characterized by myeloid stem cell origin and increasing incidence with age. Although treatment is available with hypomethylating agents (HMAs), 80% of patients fail to achieve remission and nearly all patients eventually develop chemoresistant disease. The incidence of MDS 1st-line HMA treatment failures has not been previously reported. Methods: We examined US commercial health insurance claims data to estimate the annual incidence of MDS and the number of MDS patients potentially eligible for 2nd-line therapy. We conducted a retrospective cohort study of patients with an MDS-associated medical claim (ICD-9-CM diagnosis code 238.7x) in the identification (ID) period (calendar year 2009). The subgroup of newly diagnosed patients had no prior MDS diagnosis in the pre-ID period (calendar year 2008); patients newly treated with HMA had a claim for HMA in the ID but not pre-ID periods. Using expert input, we defined MDS patients as potential candidates for 2nd-line therapy if they used an HMA in the ID period and stopped for ≥2 months, switched to another HMA, or remained on the first HMA for >7 months. MDS incidence rates were stratified by age (≤49, 50-64, 65-74, and ≥75 years) and sex. Results: We identified 9,209 patients with an MDS-associated claim. There were 4,151 patients newly diagnosed with MDS, yielding an overall MDS incidence of 69.9/100,000 enrollees ( Table ). Incidence was slightly higher among women (75.7/100,000) than men (63.1/100,000). Women between the ages of 50 and 64 years had the highest incidence (111.5/100,000) among all newly diagnosed patients stratified by age and sex. The incidence of newly treated MDS patients was 2.8/100,000 enrollees. Among this group, incidence was higher among men (3.6/100,000) than women (2.1/100,000), and when stratified by age and sex the incidence was highest among men aged 75 years or older (10.5/100,000). For each 100,000 enrollees, there were 3 new 2nd-line therapy candidates. Conclusions: The estimated incidence of MDS in the United States was 69.9 per 100,000 insured enrollees in 2009, similar to results found in other epidemiological databases (Cogle et al, Blood 2011; Goldberg et al, J Clin Oncol 2010). The incidence of MDS patients identified as eligible for 2nd-line therapy was 3/100,000. In this commercially insured patient population we estimate that approximately 9,500 people per year in the United States may be candidates for 2nd-line therapy for MDS. These data can be used to inform population-based estimates that would include Medicare patients in addition to those commercially insured of the medical and economic burden of disease faced by MDS patients. | Gender | Age Group, years | Newly Diagnosed Patients | Newly Treated Patients | Potential 2nd Line Treatment Candidates | |:------:| ---------------- | ------------------------ | ---------------------- | --------------------------------------- | | Female | All ages | 75.7 | 2.1 | 2.0 | | ≤49 | 56.6 | 0.1 | 0.0 | | 50-64 | 111.5 | 2.1 | 1.1 | | 65-74 | 101.2 | 4.0 | 5.3 | | ≥75 | 68.5 | 4.4 | 4.4 | | Male | All ages | 63.1 | 3.6 | 4.1 | | ≤49 | 29.6 | 0.2 | 0.1 | | 50-64 | 86.5 | 2.5 | 3.8 | | 65-74 | 106.1 | 8.5 | 8.5 | | ≥75 | 97.1 | 10.5 | 11.7 | | All | All ages | 69.9 | 2.8 | 3.0 | Table: Incidence of MDS Stratified by Age and Gender Note: Results are expressed as number of cases per 100,000 enrollees. Disclosures Cogle: Partnership for Health Analytic Research (PHAR): Consultancy, I was paid as a consultant for my expert opinion while developing the analyses Other. Kurtin: Celgene, Millenium, Onyx, TEVA, Onconova, Incyte: Consultancy. Bentley: Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Broder: Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Chang: Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other. Lawrence: Onconova Therapeutics, Inc. : Employment. McKearn: Onconova Therapeutics, Inc. : Employment. Megaffin: Onconova Therapeutics, Inc. : Employment. Percy: Onconova Therapeutics, Inc. : Employment. Petrone: Onconova Therapeutics, Inc. : Employment, Stock Options Other. Sun: Partnership for Health Analytic Research (PHAR): Employment, I am an employee of PHAR, LLC, which was paid by Onconova Therapeutics to conduct the analyses described in this abstract. Other.

Background : The incidence of myelodysplastic syndromes (MDS) - a heterogeneous group of malignant myeloid stem cell disorders - increases with age and commonly affects older people. The prevalence of MDS in the US has been constantly rising as a result of increasing longevity of the overall population. Analyses of healthcare claims data using associated medical claims information (ICD-9-CM diagnosis codes) are a common way to estimate the number patients (pts) receiving care in specific disease states. We examined the total of unique US claims for MDS submitted over a 3-year period and also analyzed the claims according to type of treatment. Methods : We conducted a retrospective cohort study of patients (pts) with an MDS-associated medical claim (ICD-9-CM diagnosis code 238.7x) in the observation (OB) period (calendar years 2009-2011). In each year of the OB period, pts were classified according to type of treatment: watch and wait (ie, receiving no drug therapy) or interventional treatment [ie, supportive care treatment with erythropoietin stimulating agents (ESA) or growth factors (GF) and active drug treatment (ie, the hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DEC) and the immunomodulating agent lenalidomide (REV)]. A subgroup of newly diagnosed MDS pts was also identified in Years 2 and 3, but this group was not included in Year 1 of the OB period (calendar year 2009); this group of new-to-treatment patients had a claim for MDS in Years 2 and 3 of the OB period. MDS incidence rates were then determined within Years 2 and 3 of the OB period for this group. The total number of physicians treating pts coded for MDS was also collected. Results : We identified more than 100,000 unique pts with an MDS-associated claim in each of the 3 years of the OB period. Our calculated incidence of newly treated MDS pts (34,000) in Years 2 and 3 is consistent with recently reported estimates (Cogle et al, Blood 2011; Goldberg et al, J Clin Oncol 2010) but higher than the SEER database. Over the 3-year OB period, the number of diagnosed and treated MDS pts grew year on year and grew at a slower rate than that of the US population. Watch-and-wait is the mainstay treatment for 47% of MDS pts. We found that 6000 pts per month are treated with an HMA by 2100 physicians, or 2.8 pts per physician and 14,000 pts receive therapy for MDS comprised of ESA, GF, AZA, DEC or REV per year. AZA and DEC were the predominant HMA treatments prescribed for higher-risk MDS. Approximately 30% of HMA-treated reached the target number of 6 cycles. HMA therapies were used in 13.1% of pts. A larger percentage of the AZA- and DEC-treated pts (69.1%) stopped therapy before reaching the target number of doses, with approximately 32% of pts who initiated therapy dropping out after the first cycle. Conclusions : The total number of pts coded for MDS-associated ICD-9 billing in the US each year is substantial. The estimated incidence of 34,000 patients per year with MDS in the US in 2010 and 2011 is similar to results found in other epidemiological databases. The majority of pts are not treated with the optimal number of cycles with an HMA. The average physician treats only a limited number of pts with MDS, which may influence treatment decisions. These data suggest a need for further educational efforts to optimize care with additional insight into past population-based estimates of diagnosis and treatment (Cogle et al, Blood 2011; Goldberg et al, J Clin Oncol 2010). The data showing early discontinuation or failure of HMA therapy accentuates the poor prognosis of patients post-HMA, who have a predicted median survival of 4-6 months (Prebet et al, J Clin Oncol 2011). These data may serve to better inform the medical community of the unmet need of pts who are not successfully treated with first-line MDS therapies, underscoring the need for optimization of care and the need for additional agents beyond those currently available. | Treatment | Metric | Moving Annual Total | | --------- | ------------------------------------------------------------------------------------ | -------------------------------- | -------------------------------- | | 2010 | 2011 | 2012 | | Dacogen | Median number of cycles 4-day admin schedule 5-day admin schedule | 3.00 14.7% 64.0% | 4.00 11.4% 67.6% | 3.00 12.6% 66.2% | | Vidaza | Median number of cycles 5-day admin schedule 7+ day admin schedule | 4.00 47% 20% | 4.00 49% 20% | 4.00 46% 20% | Table HMA Cycle and Administration Metrics per Line of Therapy Disclosures Demakos: Onconova Therapeutics, Inc: Consultancy. Silverman: Onconova Therapeutics, Inc: Consultancy. Lawrence: Onconova Therapeutics, Inc. : Employment. McKearn: Onconova Therapeutics, Inc. : Employment. Megaffin: Onconova Therapeutics, Inc. : Employment. Percy: Onconova Therapeutics, Inc. : Employment. Petrone: Onconova Therapeutics, Inc. : Employment, Stock Options Other.

5148 Background: First-line chemotherapy trials have reported that pain predicts OS in CRPC. We report relationships between OS and baseline pain –a major component of CRPC patient reported outcomes (PRO) –and pain at progression, for docetaxel pre-treated patients in a second-line chemotherapy trial in CRPC. Methods: Docetaxel pre-treated pts (N = 488) were analyzed from the multi-national, randomized, double-blind SPARC trial, comparing second-line satraplatin + prednisone vs placebo + prednisone in 950 metastatic CRPC pts. Daily pain intensity and narcotic analgesic use were recorded as a PRO from one week prior to randomization until end-of-study. Pain was measured by the 6-point Present Pain Intensity (PPI) component of the McGill-Melzack Pain Questionnaire. After randomization, weekly PPI scores were calculated as the mean of the daily PPI scores (using ≥3 daily measurements/week). Baseline pain was the mean of ≥5 daily PPI scores recorded during 7 days preceding randomization. An independent blinded review committee (IRC) determined pain progression (defined as an increase in weekly PPI score ≥1 point from baseline or ≥2 points from nadir, or a >25% increase from baseline in weekly average analgesic score for ≥2 consecutive weeks). To examine the effects of pain on OS, pts were categorized as “no pain” (PPI ≤1) or pain (PPI ≥2) by baseline assessment; and, as either pain progressors or pain non-progressors. Results: Shortened OS was observed in pts with baseline pain; median survival of 178 pts with pain was 44 weeks vs 72 weeks for 287 pts without pain (Strat. Log-rank p < 0.0001, Strat. HR 0.59; 95% CI: 0.48–0.74). IRC found disease progression in 414 (84.4%) of the docetaxel pre-treated pts with 196 of these pts showing pain progression. Pain progression was strongly linked to OS with 196 pain progressors having median OS of 47 weeks compared to 71 weeks for 292 pain non-progressors (Strat. Log-Rank p = 0.0022; Strat. HR 0.71; 95% CI: 0.57–0.87). Conclusions: Both pain at baseline and pain at progression are important prognostic indicators of OS in metastatic CRPC pts failing first-line docetaxel. [Table: see text]

Background: Lymphomas are increasing in frequency and represent the fifth most common cancer diagnosis in the United States. 1D09C3 is a fully human anti-HLA-DR monoclonal antibody (mAb) derived from a human combinatorial antibody library (HuCAL®) that has consistently demonstrated activity against various lymphoid tumors, both in vitro and in vivo (Nat Med2002;8:801–7). Therefore 1D09C3 may offer a novel therapy to patients with B-cell lymphoma who have failed therapy. Two phase I studies are ongoing to determine i) the maximum tolerated dose (MTD) and phase II recommended dose (RD), ii) the pharmacodynamic (pd)- and pharmacokinetic (pk)-profile and iii) the immunogenicity of 1D09C3 given within a bi-weekly and weekly schedule in this patient population. Material and methods: Patients with relapsed/refractory B-cell lymphoproliferative diseases are included in the two studies. 1D09C3 dose escalation is performed using modified Fibonacci increments with a minimum of 3 patients (pts) per dose level. It is administered once every week or every other week by a 2-hour intravenous (iv) infusion at escalating dose levels of 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 10 mg/kg/day for either 4 or 8 weeks. All toxicities are assessed according to the NCI CTC version 3.0. Blood samples are collected at different times in the study to determine pd- and pk- parameters and to assess immunogenicity of 1D09C3. Results: 19 pts have been enrolled into both protocols to date (13M/6F), median age 58 (range 30–76), pts with Hodgkin’s lymphoma (5), non-Hodgkin’s lymphoma (8) and chronic lymphocytic leukemia (6). The 4th dose level (2.0mg/kg/day) has been completed within the bi-weekly dosing scheme and accrual is ongoing until the MTD and thus the phase II RD will be determined. The safety profile was positive, with only few and mild treatment-related side-effects such as fatigue noted, although one dose limiting toxicity (DLT) was seen at the bi-weekly dose level 0.5 mg/kg/day. Pk analysis of intravenous 1D09C3 indicated the drug to be cleared rapidly from blood circulation. 2 pts have been tested positive for human anti-1D09C3 antibodies (HAHA) at the 2nd and 3rd dose level, respectively; no allergic reactions were noticed. Clinical benefit was observed in 3 out of 14 evaluable pts who experienced partial response (PR), whereas 8 had no changes (NC) and 3 progressive disease (PD). After study completion an independent response evaluation team (RET) will review the information provided and determine individual treatment responses for the overall study. Conclusion: Two phase I dose escalation studies of the anti-HLA-DR mAb 1D09C3 are currently open in three sites for accrual of pts with relapsed/refractory B-cell lymphoproliferative diseases to determine the MTD and phase II RD for a weekly and bi-weekly schedule. Preliminary data suggest that 1D09C3 is well tolerated within this heavily pre-treated patient population. Pd- and pk-data, development of HAHA and clinical responses will continue to be evaluated.

2045 Background: Satraplatin (S) is a third-generation oral platinum analog that has demonstrated activity in the treatment of patients with platinum-sensitive malignancies. A worldwide double-blind, placebo controlled randomized phase III trial evaluating S as 2nd line therapy for HRPC has recently completed enrollment. The current study was designed to determine the effect of hepatic impairment on S pharmacokinetics in patients with refractory cancer, as well as treatment efficacy and toxicity. Methods: S was administered orally at a dose of 80mg/m2/day (d) on d1–5 every 35 days. Study groups (cohorts) were defined at 4 levels of hepatic impairment - Group 1 (G1) = control; G2 = Child-Pugh Class A; G3 = Child-Pugh Class B; and Group 4 = Child-Pugh Class C. Results: 19 pts have been enrolled to date (11 M/ 8 F); median age is 57 (range 44–80). Pts with prostate (2), pancreas (4), colorectal (3), adenocystic (2), and 1 each neuroendocrine, hepatocellular, melanoma, breast, ovarian, SCLC, and anal cancers were enrolled. 8 pts were in G1, 3 pts in G2, 4 pts in G3, and 5 pts in G4. Accrual is ongoing in this study with a total of 8 pts planned for each group. The median number of prior regimens was 5 (range 2–8). A total of 35 cycles of S have been given: median 2/pt (range 1–4). 9 pts have completed 2 cycles of S. Hematologic toxicities during the first 2 cycles included grade (G) 3/4 thrombocytopenia in 15 %. There were no cases of G 3/4 neutropenia or anemia. One case of G3 hypokalemia, was reported. Two patients developed acute renal failure; one of which was due to uncontrolled nausea (N) and vomiting (V) and the other was associated with rapid disease progression in the liver. Both were G4 patients. Otherwise, N, V, and diarrhea were mild to moderate, and controlled with oral therapy. Conclusions: S is, in general, well tolerated in patients with mild or moderate liver impairment. Severe thrombocytopenia is the most common side-effect. Of the patients enrolled to date 15% did not have progression of disease. PK data will also be presented. [Table: see text]

12014 Background: Satraplatin (S) is a novel oral platinum analog that has demonstrated preliminary activity in hormone refractory prostate cancer (HRPC). A large (950 pts) worldwide, randomized phase III trial evaluating S as 2nd line therapy for HRPC recently completed enrollment. The current study was designed to determine the PKs of S under fasted and fed conditions, as well as treatment efficacy and toxicity. Methods: S was administered orally at 80 mg/m2/day (d) on d1–5 q 35 days, with prophylactic antiemetics. For the 1st cycle, pts were randomized to receive d1 and d5 doses of S in either the fed or fasted state when PK sampling was performed. The fed/fasted state was reversed for the 2nd cycle. Subsequent doses of S were given in the fasted state. Results: 17 pts were enrolled (9M/8F), median age 62 (range 33–78) and tumor types: HRPC (7), breast (3), 1 each with anal, parotid, leiomyosarcoma, Merkel cell, ovarian, mesothelioma, and neuroendocrine tumor. The median no. of prior regimens was 3 (range 1–8). A total of 58 cycles of S were given. Grade 3–4 hematologic toxicities (1st 2 cycles) included: neutropenia (11%), thrombocytopenia (24%) and anemia (24%). The hematologic nadir occurred during week 4. There was no grade 3–4 nausea, vomiting or diarrhea. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The peak plasma concentration (Cmax) for platinum in plasma ultrafiltrate (PUF) was decreased by 20% when S was administered following a high fat meal compared to the fasting condition. There was no effect of food on AUC0–24 hr. The time of Cmax (Tmax) was delayed in the fed state. Table shows PK parameters. One PR (HRPC) and 4 SD ≥ 5 months (breast, ovarian, parotid and HRPC) were confirmed. Conclusions: There is an effect of food on the Cmax, however the clinical implications are unknown at this time. For this reason, it is recommended that S be administered to pts in the fasting state. At the dose of 80 mg/m2/day, S was well tolerated in this group of heavily pretreated patients. [Table: see text] [Table: see text]

4802 Background: There is no chemotherapeutic agent specifically approved for second-line treatment for hormone-refractory prostate cancer (HRPC). Satraplatin (S) is a third-generation oral platinu...