Abstract: Multiple factors critical to the effectiveness of academic phase I cancer programs were assessed among 16 academic centers in the U.S. Successful cancer centers were defined as having broad phase I and I/II clinical trial portfolios, multiple investigator-initiated studies, and correlative science. The most significant elements were institutional philanthropic support, experienced clinical research managers, robust institutional basic research, institutional administrative efforts to reduce bureaucratic regulatory delays, phase I navigators to inform patients and physicians of new studies, and a large cancer center patient base. New programs may benefit from a separate stand-alone operation, but mature phase I programs work well when many of the activities are transferred to disease-oriented teams. The metrics may be useful as a rubric for new and established academic phase I programs.

Abstract: Patients with persistent/chronic immune thrombocytopenia (cITP) have low platelet counts, increased risk of bleeding and bruising, and often suffer from reduced health‐related quality of life (HRQoL). cITP treatments may either improve HRQoL by increasing platelet counts or decrease it because of side effects. The open‐label EXTEND study (June 2006 to July 2015) evaluated long‐term safety, tolerability, and efficacy of eltrombopag (an oral thrombopoietin‐receptor‐agonist) in adults with cITP who completed a previous eltrombopag ITP trial. The final results of EXTEND were published and used to assess changes in patient‐reported HRQoL over time and association between HRQoL and platelet response. Four validated HRQoL instruments were administered: SF‐36v2 including physical component summary (PCS) and Mental Component Summary; Motivation and Energy Inventory Short Form (MEI‐SF); Fatigue Subscale of FACIT (FACIT‐Fatigue); and FACT‐Thrombocytopenia Subscale Six‐Item Extract (FACT‐Th6). For the 302 patients enrolled, median duration of eltrombopag treatment was 2.37 years. All 4 HRQoL instruments demonstrated positive mean changes from baseline over time adjusted for patient baseline characteristics and rescue therapy use, and had positive association with platelet response (platelet count ≥30 × 10 9 /L; ≥50 × 10 9 /L; and ≥50 × 10 9 /L and 〉 2 times baseline). Improvements from baseline started within 3 months and persisted through 5 years of treatment for FACIT‐Fatigue and FACT‐Th6 ( P 〈 .05 for nearly all time points); through 2.5 years for SF‐36v2 PCS and less consistently for the MEI‐SF. In conclusion, in addition to eltrombopag increasing platelet counts and reducing bleeding/bruising, it also alleviated fatigue, concerns about bleeding and bruising, and improved physical function in many patients, especially responders.

Abstract: LBA3501 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

Abstract: LBA3501 Background: Perifosine (P) is an oral, synthetic alkylphospholipid that inhibits or modifies signal transduction pathways including AKT, NFkB and JNK. A randomized phase II study examined P-CAP vs. CAP in pts with 2nd or 3rd line mCRC. This study showed improvement in mTTP (HR 0.254 [0.117, 0.555]) and mOS (HR 0.370 [0.180,0.763] ). Based on these results, a randomized phase III study of P-CAP vs. CAP with a primary endpoint of overall survival (OS) in pts with refractory mCRC was initiated. Methods: The study was a prospective, randomized, double-blind, placebo-controlled randomized phase III trial. Eligible pts had mCRC which was refractory to all standard therapies. Pts randomized 1:1 to Arm A = P-CAP (P 50 mg PO QD + CAP 1000 mg/m 2 PO BID d1-14) or Arm B = CAP (placebo + CAP 1000 mg/m2 PO BID d 1-14). Cycles were 21 days. Baseline tumor block collection and a biomarker cohort of pts with pre- and on-treatment tumor and blood samples were performed. Results: Between 3/31/10 and 8/12/11, 468 pts were randomized, 234 pts were in each arm. Baseline demographics were balanced between the arms: age 〈 65y (A: 65%, B: 58.5%), male (A: 57.7%, B: 53.0%), ECOG PS 0 (A: 39.7%, B: 39.7%), K-ras mutant (A: 50.4%, B: 51.3%), and median number of prior therapies (A: 4, B: 4). As of 3/19/12, median follow up was 6.6 months. Median overall survival: Arm A = 6.4 mo, Arm B = 6.8 mo, HR 1.111 [0.905,1.365], p = 0.315. Median overall survival for K-ras WT pts: Arm A = 6.6 mo, Arm B = 6.8 mo, HR 1.020 [0.763,1.365] , p = 0.894; K-ras mutant pts: Arm A = 5.4 mo, Arm B = 6.9 mo HR 1.192 [0.890,1.596], p = 0.238. Conclusions: Despite promising randomized phase II data, this phase III study shows no benefit in overall survival adding perifosine to capecitabine in the refractory colorectal cancer setting. Response rate, progression free survival, and safety data will be presented. Biomarker analysis is pending to see if subgroups of patients may have potential benefit.

Abstract: To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel. Patients and Methods Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m 2 intravenously for 3 weeks of a 4-week cycle combined with either 45 μg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later. Results Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%). Conclusion This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.

Abstract: T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53 -wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53 -wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

Abstract: Background EPAG, an oral thrombopoietin receptor agonist approved for cITP, increased platelets (plts) and reduced bleeding in 6 wk and 6 m placebo-controlled trials in previously treated cITP patients. EXTEND is an ongoing, open-label extension study, begun in Jun 2006, to assess the safety and efficacy of long-term treatment with EPAG in cITP patients who completed a previous EPAG study. Long-term safety and efficacy data up to Feb 2013 are presented. Methods EPAG was started at 50 mg and titrated to 25-75 mg/d or less often, based on plt counts. Patients who received ≥2 y of EPAG and transitioned off due to commercial availability of EPAG were considered to have completed EXTEND, whether or not they continued treatment with commercial EPAG. Results Of 302 patients enrolled, 43% (129) completed, 48% (146) withdrew, and 9% (27) remain on study. The most common reasons for withdrawal were adverse events (AEs; 15%), patient decision (13%), lack of efficacy (11%), and stable plts ≥6 m following interruption of EPAG (3%). The Table shows baseline patient characteristics and treatment duration. Doses of 75, 25, and 25 mg QOD were required by 62%, 51%, and 20% of patients, respectively, at some time during the study; 5% remained on 50 mg throughout the study (overall median duration of exposure, 122 wk; average dose, 50.8 mg/d). Overall, 85% (258/302) of patients achieved plts ≥50,000/µL in the absence of rescue therapy, and 61% achieved plts ≥50,000/µL for ≥50% of on-treatment assessments. Median plts increased to ≥50,000/µL by Wk 2, remaining consistently ≥50,000/µL throughout the treatment period. Nine of 10 patients who withdrew due to stable plts for ≥6 m following interruption of EPAG maintained plts ≥100,000/µL for ≥6 m without any ITP therapy. Incidence of bleeding symptoms (WHO grades 1-4) decreased from baseline to 1 y and thereafter (Figure). Of 101 patients receiving concomitant ITP treatment at baseline, 40 had a sustained reduction or permanently stopped ≥1 concomitant ITP treatment without ever receiving rescue therapy. The most frequently discontinued/reduced ITP medications were corticosteroids (35/40; 88%) and danazol and azathioprine (4/40 each; 10%). In 92% (277) of patients, AEs occurred. Serious AEs (SAEs) occurred in 31% (94) of patients, and 22 patients had 33 SAEs considered possibly drug related. Drug-related SAEs occurring in ≥2 patients were cataracts (7), alanine aminotransferase (ALT) (4) or aspartate aminotransferase (2) increased, deep vein thrombosis (DVT; 4), bilirubin increased (3), myocardial infarction (MI; 2), and pulmonary embolism (PE; 2). AEs leading to withdrawal occurred in 44 patients (15%), 29 (10%) of whom experienced SAEs. The most frequent AEs leading to withdrawal were increased ALT (7), increased bilirubin (5), cataracts (4), and DVT (4). In 19 patients (6%), 26 thromboembolic events (TEEs) were reported (incidence rate, 2.53/100 patient y; 95% CI, 1.52-3.95). Observed TEEs were DVT (11), central nervous system ischemic events (7), MI (5), and PE (3). No association with elevated plt counts was observed, as only 3/19 patients experienced the TEE at or shortly after achieving their maximum plt count. Hepatobiliary laboratory abnormalities (HBLAs) were reported in 37 patients (12%), and 8 were withdrawn because of HBLAs. No HBLAs were associated with signs of liver impairment; most resolved on treatment or after discontinuation. An independent central pathology review of bone marrow (BM) biopsies stained for reticulin from 115 patients treated with EPAG for ≤5.5 y found no clinically relevant increase in reticulin deposition. Two patients (2%) had maximum reticulin marrow fibrosis (MF) grade of ≥2 after 〉 24 m on treatment; neither experienced any AE or hematologic parameter abnormality potentially related to impaired BM function. Conclusions Sustained plt increases and reduced bleeding symptoms were observed in EPAG-treated cITP patients throughout the study. Sustained increases in plt counts were maintained in a few patients after discontinuing EPAG. Concomitant ITP medications were reduced without requiring rescue medications. Eltrombopag was well tolerated with exposures ≤6.5 y. Rates of TEEs and HBLAs did not increase with longer treatment duration, and BM biopsies showed no clinically significant increase in MF grade. No new safety signals were observed. Long-term safety and efficacy continue to be assessed in this ongoing study. Disclosures: Bussel: Symphogen: Membership on an entity’s Board of Directors or advisory committees; Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Eisai Inc.: Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wong:GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau. Burgess:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Chan:GlaxoSmithKline: Employment. Bailey:GlaxoSmithKline: Employment, Equity Ownership.

Abstract: Abstract 622 Background: Veltuzumab is a 2nd-generation humanized anti-CD20 monoclonal antibody with structure-function differences from rituximab, and evidence of higher potency preclinically (Goldenberg et al., Blood. 113(5):1062–70, 2008). In non-Hodgkin lymphoma (NHL), subcutaneous (SC) injections of low-dose veltuzumab were well-tolerated and demonstrated high activity (Negrea et al., Haematologica. 96:567–73, 2011), comparable to that achieved by intravenous infusions (Morschhauser et al., J Clin Oncol. 2009;27:3346–53). As such, we postulated that low-dose SC veltuzumab also may be effective and particularly convenient for treating autoimmune diseases, especially since a high-concentration formulation was developed. Hence, a multicenter, phase I/II study was undertaken to evaluate SC veltuzumab as a monotherapy administered in immune thrombocytopenia (ITP). Methods: Adults with primary ITP who failed ≥1 standard therapy were eligible if platelets were ≤30 K/μL without major bleeding. In Cohort 1, 80, 160, or 320 mg SC veltuzumab was given twice 2 weeks apart (total dose 160, 320, 640 mg, respectively). In Cohort 2, 320 mg veltuzumab was given weekly for 4 doses (total dose 1280 mg). Steroids or other premedications were not required. Best platelet response to treatment (on at least 2 occasions, one week apart) was classified as complete (CR, 〉 150K/μL), partial (PR, 50–150K/μL), or minor (MR, 30–50K/μL). For responders, time to relapse was measured from first injection to relapse with platelets below 30K/μL, initiation of subsequent treatment, or lost to follow-up. Adverse events (AEs) and safety laboratories were evaluated by NCI CTC v3 toxicity grades. Other evaluations included circulating B-cell levels (CD19), veltuzumab serum levels, and human anti-veltuzumab antibody (HAHA) titers. Results: A total of 45 patients (28 female/17 male, median 54-years old, 8 post splenectomy) were enrolled in Cohorts 1 (N=34) and 2 (N=11). They were a median of 2 years from diagnosis of ITP; 12 patients had newly-diagnosed or persistent disease (ITP ≤ 1 year) treated with corticosteroids and/or immunoglobulins, and 33 patients had chronic disease (ITP 〉 1 year) and also had received azathioprine or danazol (N=14), thrombopoietin-receptor agonists (N=8), rituximab (n=6), platelets (N=6) or chemotherapy (N=4). SC veltuzumab was well tolerated with a limited number of AEs (all Grade 1–2 transient injection reactions) and no other safety issues. At all doses, B cells were depleted rapidly after the first administration of veltuzumab, with recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with each injection, achieving mean Cmax values of 11.7, 19.3 and 40.6 μg/mL at dose levels of 80, 160, and 320 mg, respectively, in Cohort 1, and 67.0 μg/mL at 320 mg in Cohort 2. HAHA titers were positive in 7 patients; interestingly, 6 had objective responses (OR: CR+PR+MR), including 3 CRs. Five patients were inevaluable for treatment response (3 given rescue medication for rapidly decreasing platelets at study entry, 2 still continuing treatment). Of the 40 evaluable patients, 27 (68%) had ORs, including 7(18%) CRs, 14 (35%) PRs, and 6 (15%) MRs. Follow-up data is mature for Cohort 1, with median time to relapse for 23 responders increasing by response category (MR: 2.1, PR: 5.7, CR: 14.2 months) and 8 (35%) responding 〉 1 year (2 ≥ 3 years). Ignoring the generally short-lived MRs, CR and CR+PR rates are tabulated below. Results for all evaluable patients (as well as only those with potentially more refractory chronic disease) show no evidence of dose-dependence, with meaningful activity (including CRs) already achieved at the lowest dose level. Conclusions: Low-dose SC veltuzumab was convenient, well-tolerated, with good B-cell depletion and promising activity in relapsed ITP. As a single agent, SC veltuzumab appears potent across a variety of dose levels and dosing schedules even in more heavily treated patients with chronic disease. These results support further studies in ITP combining SC veltuzumab with other agents or given as a maintenance regimen. Disclosures: Horne: Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

Abstract: BACKGROUND: Veltuzumab (hA20), a humanized MAb with significant structurefunction differences from rituximab, has shown clinical activity at low doses in non- Hodgkin’s lymphoma. Since anti-CD20 immunotherapy has demonstrated activity in ITP with standard doses of rituximab, we hypothesized that low-dose veltuzumab would be effective in this disorder, thus also justifying subcutaneous injections. The goal of this first study in ITP is to evaluate the safety and tolerability of veltuzumab administered at low doses either intravenously or by subcutaneous injection, to obtain information on efficacy, pharmacodynamics, pharmacokinetics, and immunogenicity, and to determine feasible doses for further studies. METHODS: A multicenter, phase I/II study was initiated in adult ITP patients with platelets 〈 30K/μL, and a prior history of platelets 〈 150K/μL for 〉 6 months, who had failed ≥1 standard therapy. Patients were administered 2 doses of veltuzumab 2 weeks apart and evaluated for efficacy over 12 weeks, with responding patients continuing evaluation in long-term follow-up. Efficacy was assessed by platelet level responses with increases confirmed at least 1 week apart classified as complete (CR, 〉 150K/μL), partial (PR, 50–150K/μL), or minor (MR, 30–50K/μL) responses. Adverse events and safety laboratories were evaluated by NCI CTC v3 toxicity grades. Pharmacodynamics were evaluated by B-cell levels (CD19), while pharmacokinetics and immunogenicity were evaluated by serum veltuzumab levels and human anti-veltuzumab antibody (HAHA) titers, respectively, using an ELISA assay performed by the Sponsor. RESULTS: Seven patients (5F/2M, median age 41, 2 splenectomized) have now received intravenous veltuzumab at doses of 80 mg (N=3), 120 mg (N=3) or 200 mg (N=1). They had ITP for 0.5 – 12 years, had received prior steroids (N=7), IVIG and/or WinRho (N=6), or chemotherapy (N=3), and had 6–27 K platelets/μL and Grade 0–1 bleeding scores at study entry. One patient withdrew after receiving 100 mg and experiencing a Grade 3 infusion reaction, subsequently undergoing splenectomy. Otherwise, the treatment was well tolerated with all infusions completed within 60 – 90 minutes. Of the 6 evaluable patients, all 4 non-splenectomized patients responded to treatment with at least a doubling of their baseline platelet levels, achieving 2 CRs, 1 PR, and 1 MR. At present, both CRs are still continuing with 〉 100 K platelets/μL at 16 and 24 weeks after treatment. The patient with a PR, who was treated at 80 mg, had platelets decreased 〈 30K/μL at 11 weeks, but then achieved a second PR after retreatment at 120 mg, which is now ongoing 6 weeks later. The patient with MR still has platelets at least double the baseline levels at 12 weeks. Although neither of the 2 splenectomized patients responded, one had spontaneously increased platelets 〉 30 K/μL just prior to 1st infusion and has continued to maintain these levels now 12 weeks after treatment, while the other has since been treated with cyclosporine, also without response. Veltuzumab quickly depleted B cells after the first dose, with decreases sustained 〉 12 weeks. Even at these low doses, veltuzumab achieved expected serum levels (mean Cmax, 20.3 and 46.0 μg/mL at 80 and 120 mg, respectively) and remained in circulation without evidence of rapid clearance or sequestration (mean post-treatment half-life ~1 week). Two patients developed low-level positive HAHA results of uncertain clinical significance after treatment. CONCLUSIONS: These initial results indicate that doses of 80 or 120 mg veltuzumab have acceptable safety and demonstrate promising activity for ITP, including durable complete responses. Based on these findings, the study is proceeding, with patients now being recruited for therapy with low-dose veltuzumab administered by subcutaneous injection.

Abstract: Background: ARQ 092 is an oral allosteric, potent and selective AKT inhibitor with in vitro and in vivo activity in solid and hematological tumors. ARQ 092-101, the first clinical trial of ARQ 092, has enrolled more than 100 subjects with advanced solid tumors or recurrent malignant lymphoma. As reported previously, the dose escalation portion of the study has been completed and two dosing schedules (intermittent and weekly), are recommended for phase 2 studies. The recommended phase 2 dose (RP2D) for the intermittent dosing schedule is 200 mg once daily (QD) (one week on, one week off) and for the weekly dosing schedule is 300 mg twice daily (BID) (one day on, six days off). [1, 2] Enrollment in an expansion cohort at RP2Ds is ongoing. Here we report the results from 11 subjects with lymphoma/CLL. Material and Methods: Subjects with lymphoma/CLL have been enrolled and treated in the dose escalation and expansion cohorts with intermittent or weekly dosing schedule at the RP2Ds. Tumor responses for subjects with lymphoma were evaluated based on the Revised Response Criteria for Malignant Lymphoma. Adverse events were evaluated based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Blood samples were collected for PK analysis. Archival or biopsy tumor tissue samples were collected for genetic analysis. Results: As of 15 Jun 2015, 11 subjects with lymphoma/CLL (73% male; median age 78 years; 5 follicular, 3 mantle cell, 2 diffuse large B cell, 1 CLL; 4 in dose escalation cohorts, 7 in expansion cohort) have been enrolled and treated at initial doses of 120 to 270 mg QD intermittently (n=7) or 300 mg BID weekly (n=4). All subjects have received at least one prior systemic therapy (median 2, range 1-6). Median duration on study treatment for all 11 subjects was 8 weeks (range 1 to 30 weeks). One subject with CLL and two with follicular lymphoma experienced durable partial responses, respectively with times to response of 8, 8 and 24 weeks and response durations of 16, 8+, and 2+ weeks. The two follicular PR subjects, one of whom had an AKT1 (E17K) mutation, remain on study treatment. In addition, one subject with follicular and one with mantle cell lymphoma experienced stable diseases. Four subjects experienced progressive diseases and two were not evaluable for tumor responses due to early consent withdrawal and clinical disease progression. Table 1. Common drug-related adverse events (≥10%) included macula-papular rash 45%, hyperglycemia 36%, mucosal inflammation 18% and stomatitis 18%. Response Follicular N=5 CLL N=1 Mantle cell N=3 Diffuse large B cell N=2 Total N=11 PR 2 1 3 SD 1 1 2 PD 1 2 1 4 NE 1 1 2 ORR 40% 100% 0% 0% 27% DCR 60% 100% 33% 0% 45% Conclusions: The safety profile of lymphoma subjects is consistent with subjects with solid tumors enrolled in this study. Preliminary signs of single agent activity have been documented with 3 PRs in heavily pretreated lymphoma/CLL including one with AKT1 (E17K) mutation. [1] First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. M. Saleh et al., Abstract LB-197, AACR 104th Annual Meeting, 6-10 Apr 2013. Washington, D.C. U.S. [2] First-in-human study with ARQ 092, a novel pan AKT-inhibitor, in subjects with advanced solid tumors or recurrent malignant lymphoma. M. Saleh et al., Abstract 320, EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics , 18-21 Nov 2014, Barcelona, Spain Disclosures Harb: Onyx Pharmaceuticals: Consultancy. Chai:ArQule, Inc.: Employment. Larmar:ArQule, Inc.: Employment. Abbadessa:ArQule, Inc.: Employment. Schwartz:ArQule, Inc.: Employment.