Standard Dose Escalation Research Articles

The Effect of a Slower than Standard Dose Escalation Scheme for Dipyridamole on Headaches in Secondary Prevention Therapy of Strokes: A Randomized, Open-Label Trial (DOSE)

Background: Combination therapy with acetylsalicylic acid and dipyridamole is first-line treatment in secondary prevention of strokes. Approximately 40% of patients report headache as a side effect of dipyridamole. Dose escalation of dipyridamole reduces this side effect. In practice, different dose escalation schemes are used. In theory, slower dose escalation than a standard scheme reduces headaches even more. This study aimed to find the best dose escalation scheme for prevention of headaches as a side effect of dipyridamole in the secondary prevention of strokes. Methods: In this randomized, open-label, 4-week trial, 114 patients who had an ischemic stroke or transient ischemic attack were randomized to receive either a standard or slow dose escalation scheme of dipyridamole. Participants were asked to report the four most common side effects of dipyridamole in a study diary on study days 1, 3, 5, 7, 14, 21 and 28. They were asked to score headache intensity on a visual analog scale (VAS). Participants were unaware that the trial was focused on headaches. Primary end point was to determine if a slow dose escalation scheme reduces the percentage of patients with headaches. Secondary objective was to determine the number of patients who discontinued treatment with dipyridamole because of headaches. Results: Overall 37 patients (38%) of the final population reported headache, 19 (39%) in the standard dose escalation group and 18 (37%) in the slow dose escalation group (p = 1.0). In the standard dose escalation group patients scored headaches (VAS >4) on an average of 3.3 days and patients in the slow dose escalation group on 3.6 days (p = 0.82). Mean VAS scores on study days 1, 3, 5, 7, 14 and 21 ranged from 1.4 to 3.7 in both groups. These scores did not differ significantly. However, on day 28 patients scored a significantly lower mean VAS score in the standard dose escalation group than in the slow dose escalation group (2.5 vs. 4.8; p = 0.05). In the standard dose escalation group 6 patients (11%) discontinued treatment because of side effects of dipyridamole and 3 patients (6%) in the slow dose escalation group (p = 0.49, Fisher's exact test). Conclusion: We showed that slower than standard dose escalation of dipyridamole in combination therapy with acetylsalicylic acid does not reduce headaches as a side effect. The use of such schemes should be discontinued in clinical practice. Slow dose escalation might, however, reduce the number of patients who discontinue treatment, but further research is needed to confirm this.

The Next Generation of Clinical Studies with Antidepressants in Bipolar Disorder

Antidepressants are still widely used in the treatment for bipolar disorder (BD), but evidence do not support their extensive use during depressive episodes. Recently, an important systematic review was published after an extensive literature search on the use of antidepressants in bipolar depression (1). Based on the conclusions, in spite of a considerable number of clinical studies (more than 37 so far) and meta-analyses currently available, the authors did not make broad statements endorsing antidepressant use in BD, but acknowledge that individual bipolar patients may benefit from these agents. Other studies showed similar results (2). These publications also call attention to a wide range of methodological issues and discrepancies as well as to heterogeneous statistical approaches and conclusions. Also, studies have emphasized other limitations (2) including small samples, co-treatments, lack of adequate controls, and varied design, and therefore, current clinical evidence seems still inconclusive. Thus, the first generation of studies has not provided consistent clinical answers to ensure more generalizable conclusions and guidelines for clinicians. They focused primarily in answering two simple questions: first, testing “yes or no” for the use of antidepressants regarding efficacy and safety (switch risk) in bipolar depression. This linear paradigm still does not help to guide clinicians’ therapeutic decision. The second question aimed to address what agent (or class) would be more effective and safer in bipolar depression. These two main aspects still remain not fully elucidated and additional questions have arisen, described next. Also, the role of BD diagnosis (bipolar I or II), family history and the risk of cycle acceleration, suicidality, mixed episodes/rapid cycling as associated outcomes did not provide yet consistent guidance. These variables were evaluated as secondary analyses and did not present standardized definitions (e.g., switch process and cycle acceleration). In the same perspective, even though it is clear that antidepressant monotherapy is contraindicated in bipolar depression, some large studies used this approach to compare with new agents (e.g., EMBOLDEN II). Thus, this is an area where future studies critically require translational approach for the next generation of clinical trials (3). Only few trials with antidepressants in bipolar depression have systematically evaluated the potential clinical usefulness of biomarkers that may predict antidepressant response in BD and even less have thoroughly assessed the potential biological basis of switch risk. Most of the studies also have limitations including small samples, co-treatments, lack of adequate controls, and varied design. The identification of neurobiological substrates able to minimize sample heterogeneity may also help to identify potential enriched samples for further confirmatory studies with different classes of antidepressants would be a critical step forward. This may also provide evidence to support the use of antidepressants in specific subgroups and guide clinical decision in the personalized treatment paradigm. At the same time, the development of standardized conceptual definitions is essential to perform neurobiological studies and may be added to the evaluation of diverse constructs and dimensions across neurobiological systems. In the same context, the next generation of proof of concept studies is also expected to provide information on which clinical and neurobiological variables are associated with a subgroup that will likely respond to a specific antidepressant and address key questions including optimal duration of antidepressant treatment and presence (or not) of a dose- and/or time-dependent regulation of mood elevation using adequate methodology (e.g., more frequent rating scales, standard dose escalation design). These approaches may also help to define the lowest effective dose for the shortest time necessary for sustained remission. Future studies would also benefit from dimensional approaches and evaluation of new targets such as the glutamatergic system. Finally, it is also critical to better understand this complex and non-linear interaction, the study of specific domains such as early improvement, short and long-term response, cognition, role of compliance, duration of use, and dosage/response curve. These are important variables to be considered integrated with biomarkers such as predictors of response and surrogate outcomes. The next generation of studies is also expected to evaluate a broader risk–benefit equation, integrating generalizable data to discoveries on personalized treatments for those who need it most.

Phase I clinical trial of the intraperitoneal (IP) administration of a novel nanoparticle formulation of paclitaxel (NTX).

2558 Background: IP therapy is an attractive option for patients with IP carcinomatosis as many of these malignancies remain confined IP. Agents whose plasma clearance rates substantially exceed their rates of uptake from the peritoneal cavity are especially suited for IP administration. Pre-clinical studies of a novel formulation of nanoparticulate paclitaxel in animal tumor models demonstrated superior activity and substantially reduced systemic toxicity. This allowed for significant IP doses and concentrations, yet yielded very low systemic concentrations of paclitaxel. We report here the results of a Phase I trial of IP administered NTX. Methods: Patients (ECOG≤2) had relapsed, treatment refractory solid IP tumors and adequate organ function. NTX was administered IP as a bolus injection after 500 ml saline followed by IP administration of up to 2 L of saline. We utilized an accelerated dose escalation scheme until one DLT occurred during cycle 1, followed by a standard dose escalation (3+3 design) based on CTCAE V3 toxicities. The pharmacokinetics of IP administered NTX were characterized in plasma and ascites fluid. Secondary objectives were to define the recommended phase 2 dose of NTX, and characterize preliminary activity and toxicity. Results: 20 patients were treated at dose levels from 50 – 275 mg/M2 q 28 days. Primary malignancy was ovarian cancer (74%). Treatment was well tolerated at all dose levels. Common toxicities potentially related to NTX were: gastrointestinal (68%), constitutional (42%), and pain (42%). Average number of cycles received was 2 (range 1 to 6). Best response was stable disease (4 patients, 21%). Median length of disease stability was 99 days (range 85 to 151 days); median time on study patients with stable disease was 313 days (range 142 to 740 days). All Cmax in plasma were less than 35 ng/mL, with ascites fluid Cmax generally greater than 1000 ng/mL. Conclusions: IP NTX is well tolerated. MTD has not yet been reached. Pharmacokinetic data demonstrate significant, persistent IP exposure to paclitaxel with minimal systemic exposure. Accrual at the 275 mg/M2 dose level continues; updated results will be presented. Further clinical development of NTX is indicated. Clinical trial information: NCT00666991.

Abstract LB-167: Phase I dose escalation study of abexinostat and doxorubicin in patients with metastatic sarcomas.

Abstract Intro/Objective: Several inhibitors of histone deacetylase have been shown to enhance chemotherapy induced apoptosis and reduce sarcoma tumor burden in preclinical models. We sought to determine the MTD, PK/PD, safety and toxicity of the histone deacetylase inhibitor (HDACi) abexinostat when administered with doxorubicin in patients with metastatic sarcomas. Methods: Participants were enrolled in a standard 3x3 dose escalation phase I study design. Abexinostat was administered on days 1-5 with 75 mg/m2 of doxorubicin administered on day 4 of every 21 day cycle until disease progression, drug intolerance, or a cumulative lifetime dose of 450 mg/m2 of doxorubicin was reached. GCSF support was provided at physician discretion on Arm A or provided to all participants in Arm B. 3-6 subjects were administered abexinostat at doses of 15, 30, 45, and 60 mg/m2 BID. All patients without progressive disease after receiving a cumulative lifetime dose of 450 mg/m2 of doxorubicin continued with abexinostat as a single agent until disease progression. Results: 22 participants (10 with prior doxorubicin therapy) were enrolled (6 in Arm A, 14 in Arm B), 20 were evaluable for DLT, and 17 were evaluable for radiologic response. In Arm A, participants were administered abexinostat at 30 or 15 mg/m2 BID. DLTs of grade 3 and 4 ANC were observed in two out of three participants dosed at 30 mg/m2 BID. Neither of these patients received GCSF prophylaxis. In Arm B, participants were administered abexinostat at 30, 45, or 60 mg/m2 BID, all with mandated GCSF support. Two DLTs were observed on the 60 mg/m2 BID dose (grade 3 infection and grade 4 thrombocytopenia). The pharmacokinetics of abexinostat was not affected by doxorubicin. HDAC activity, as measured by histone acetylation in PBMC, was maximally inhibited at 30mg/m2 BID. In the 17 participants evaluable for radiologic response there was 1 PR, 11 SD, and 5 PD as best response, with 7 participants completing 5 cycles or more. 3 of those participants remain in SD as their last disease status when this abstract was submitted. 4 participants who continued on monotherapy remained in SD for a median of 9.8 weeks after completing doxorubicin. The most common toxicities were fatigue, thrombocytopenia, and anemia (see Table 1). No study related deaths were observed. Conclusion: The MTD for abexinostat is 45 mg/m2 BID when administered on days 1-5 when doxorubicin is given at 75 mg/m2 on day 4 of a 3-week cycle and GCSF support is provided. Toxicities were manageable and tumor responses were seen. Additional studies are needed to further define the specific contributions of HDAC inhibition for patients receiving doxorubicin to treat metastatic sarcoma. Grade Type 1 2 3 4 Totals Fatigue 13 6 0 0 19 Platelets 10 3 1 2 16 Hemoglobin 11 4 1 0 16 Nausea 13 1 0 0 14 Neutrophils 4 1 4 3 12 Leukocytes 6 3 3 0 12 Diarrhea w/o prior colostomy 7 3 1 0 11 Hyperglycemia 7 1 1 0 9 QTc interval 7 2 0 0 9 Alopecia 1 5 1 0 7 Hypophosphatemia 3 4 0 0 7 Constipation 5 2 0 0 7 Extremity/limb pain 6 1 0 0 7 Anorexia 7 0 0 0 7 Lymphopenia 0 2 4 0 6 Pain: other 5 1 0 0 6 Hypomagnesemia 4 1 0 0 5 Hyponatremia 5 0 0 0 5 Taste disturbance 5 0 0 0 5 Citation Format: Edwin Choy, Sriram Balasubramanian, James Butrynski, Jeffrey Morgan, Mint Sirisawad, Chitra Mani, Suzanne George, Andrew Wagner, David Harmon, Yael Rubinstein, Zhenfeng Duan, Francis Hornicek, George Demetri. Phase I dose escalation study of abexinostat and doxorubicin in patients with metastatic sarcomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-167. doi:10.1158/1538-7445.AM2013-LB-167

A phase I study of ganetespib in advanced hepatocellular carcinoma (HCC).

259 Background: Ganetespib is an Hsp90 inhibitor that downregulates EGFR, VEGFR, HER2, MET, IGF-IR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This multicenter Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary activity of ganetespib in patients with advanced HCC. Methods: Thirteen patients with advanced HCC, Child-Pugh A or B cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at ganetespib doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2 IV given on days 1, 8, and 15 of a 28 day cycle. RECIST 1.1 response was evaluated by CT/MRI every 8 weeks. The primary objective was to determine the RP2D, and secondary objectives included assessments of safety, toxicity, pharmacokinetics, median time to progression (TTP), median progression-free survival (PFS), median overall survival (OS), and objective response rate (ORR). Results: Twelve of the 13 patients enrolled received study drug, and enrollment is ongoing for the 200 mg/m2 cohort. Of the 12 patients: male 66%; median age 57 years; median number of prior treatments 2; Asian 33%; HCC etiology (HBV 41.7%, HCV 41.7%, hemachromatosis 8.3%, unknown 16.7%); median baseline AFP 115.3 ng/mL. Median TTP for the 10 evaluable patients was 49 days (1.6 months). No responses were seen, but 2/10 (20.0%) patients had stable disease at 8 weeks. AFP response, defined as reduction from baseline of >50% in patients with an elevated baseline AFP, was seen in 0% of patients. Most common AEs: diarrhea (100%), AST elevation (58.3%), hyperglycemia (58.3%), and fatigue (58.3%). Most common Gr 3/4 AEs: hyperglycemia (25%), anemia (16.7%), lipasemia (16.7%), and ALKP elevation (16.7%). One (8.3%) patient had a fatal AE, septic shock, within 30 days of receiving the drug. One DLT was observed: Gr 3 lipasemia at the 100mg/m2 dose. Conclusions: Ganetespib had a manageable safety profile and demonstrated limited efficacy in patients with advanced HCC. Determination of the R2PD, further assessment of clinical efficacy, and analysis of molecular markers are still pending, and a follow-up Phase II study will be considered based on this data. Clinical trial information: NCT01665937.

Phase I/II study of lenvatinib (E7080), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC): Phase I results.

231 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFR-beta. Maximum tolerated dose (MTD) of lenvatinib for solid tumor pts was determined to be 25 mg once daily dosing (qd). The current study was planned to determined MTDs and pharmacokinetic profiles of lenvatinib in HCC pts with Child-Pugh grade (CP) A and B. Methods: Between Aug. 2009 and Nov. 2011, a total of 20 pts with advanced HCC were enrolled in phase I part (Ph I). Ph I consists of a standard dose escalation design in separate cohorts of CP-A (6 pts per cohort) and CP-B (3+3 pts). The initial dose level of lenvatinib for CP-A and for CP-B was 12 mg qd. Tumor response was assessed by RECIST 1.1. Results: Nine pts with CP-A and 11 pts with CP-B were enrolled and evaluable for safety and efficacy. Pt characteristics: median age: 63.5 years, Male: 85%, HBV: 35% / HCV: 45%. 1/6 pt in 12 mg qd and 2/3 pts in 16 mg qd experienced DLTs (fever/vomiting, hepatic encephalopathy and proteinuria) in the CP-A group. In the CP-B group 2/5 pts in 12 mg qd and 0/6 pt in 8 mg qd experienced DLTs (hepatic encephalopathy and AST increased/hyperbilirubinaemia/creatinine increased). The most common toxicities were hypertension (all grade (Gr):75%, Gr3:50%), diarrhea (all Gr:70%, Gr3:0%), anorexia (all Gr:65%, Gr3:0%), palmar-plantar erythrodysaesthesia syndrome (all Gr:65%, Gr3:5%), fatigue (all Gr:65%, Gr3:0%) and hyperbilirubinaemia (all Gr:50%, Gr3:15%). Confirmed partial responses were observed in 4 pts and stable disease were in 9 pts. Median time to progression was 3.7 mo. Following administration of 12 mg lenvatinib, trough plasma concentrations (Ctrough) of the CP-A (n=5), CP-B (n=2), and pts with other solid tumors were 49.7 ± 23.6 (mean ± standard deviation), 73.7 and 22.8 ± 9.8 ng/mL respectively. Conclusions: The MTD for lenvatinib in advanced HCC pts with CP-A and CP-B are 12 mg qd and 8 mg qd, respectively. Ctrough is substantially higher than in HCC pts than in pts with other solid tumors. Lenvatinib 12 mg qd in HCC pts with CP-A and 8 mg qd in HCC pts with CP-B were associated with manageable toxicity and preliminary evidence of antitumor activity. Clinical trial information: NCT00946153.

Phase1/2 Single Arm Study of Rigosertib (ON 01910.Na) in Patients (Pts) with Relapsed or Refractory Acute Leukemia or Transformed Myeloproliferative Neoplasms

Abstract 3606 Introduction:Rigosertib (ON01910.Na) is a non-ATP competitive multi-kinase inhibitor which differentially arrests tumor cells in G2-M stages and inhibits polo-like kinase and PI-3 kinase pathways with decreases of Cyclin-D1 and Akt phosphorylation. Earlier clinical studies in advanced solid tumors as well as in myelodysplastic syndrome (MDS) and acute leukemia reported a favorable toxicity profile and showed early evidence of clinical activity. Therefore, we initiated a study in acute myeloid leukemia (AML) investigating alternative schedules to determine the optimal dose and anti-leukemia efficacy. Methods:This phase 1/2 study enrolled pts > 18 years (yrs) of age with relapsed or refractory AML or transformed myeloproliferative neoplasms (MPN). Pts were given rigosertib by continuous IV infusions over 24 hours (hrs) with a fixed dose of 2400mg/day either for 72 hrs or 120 hrs every other week using a standard dose escalation scheme. A blood sample was withdrawn at 6 hrs after the start of infusion during cycle 1 and cycle 2 to assess the plasma concentration of rigosertib. The study was subsequently amended and, after 2 cycles of IV rigosertib (each cycle being 2 weeks) pts could receive rigosertib orally, 560mg twice a day continuously for 20 weeks. The objectives of phase 1 study were to define maximum tolerated dose (MTD), dose limiting toxicities (DLT), identify all toxicities and anti-leukemia activity. Phase 2 primary objective was to determine the clinical efficacy; secondary objectives were to assess time to response or progression, duration of response and overall survival at 6 months. Results:26 pts have been enrolled in study since September 2010; median age was 66 yrs (range: 32–83 yrs) and 15 of them were males. Twenty pts were on 72 hrs dose schedule. One of the 6 pts in the 120 hrs dose schedule eventually did not participate. The average plasma levels of rigosertib in pts on week 1 and 3 were 9.20 ± 5.05 and 9.81 ± 6.70 μM, respectively. Eight pts were enrolled in phase 2. Diagnosis included: 10 (38%) de novo AML, 11 (42%) MDS related AML, 3 (12%) treatment related AML and 2 (8%) transformed MPN. Pts had received a median of 3 prior therapies (range: 1 to 7). There are 7 (27%) pts with primary refractory AML and 19 (73 %) with relapsed AML. Seven of 26 (27%) pts had a prior allogeneic stem cell transplant and 50% had a complex karyotype. Pts received a median of 2 cycles (range, 1 to 4). Serious adverse events (SAE) seen were: altered mental status, confusion, delirium (8), febrile neutropenia (4), acute respiratory distress (4), leukocytosis (4), sepsis (3), pneumonia (2), urinary tract infection (2),multi organ failure (2), cardiomyopathy (2), fever (1), hypotension (1), hypertension (1), hypokalemia (1), elevated alanine amino transferase (1), pericarditis (1), intracranial hemorrhage (1) and pneumothorax (1). SAE incidence was not related to the duration of infusions (3 or 5 days) and occurred mainly during the first 28 days of treatment. The most common grade1 or 2 adverse events (AE) observed were: hypokalemia (4), thromboembolic events (3), hypotension (2), insomnia (2) and hemorrhoids (2). All the SAEs except altered mental status (AMS) were considered unlikely or not related to the drug. The MTD was determined to be 2400mg over 24 hrs for 3 days. DLT at 2400mg over 24 hrs for 5 days was grade 3 transient AMS (including confusion or delirium). Five pts on 120 hrs schedule developed AMS, 2(40%) of them were thought to be related to rigosertib. Three of 20 pts on 72 hrs schedule had transient AMS and 2 (10%) of them were considered to be possibly related to rigosertib. In terms of efficacy, after 2 cycles best response noted is stabilization of disease with > 50% absolute reduction of peripheral blasts in 2/25 (8%) pts, while in 4(16%) other pts peripheral blasts were maintained at +/−10% of pretreatment level. There was also transient hematologic response with improvement of platelets in another 4 (16%) pts. The most common reasons for treatment discontinuation were disease progression or death from disease related complications. For pts taken off study, the median days on study were 29 (range: 5–92 days). The median survival for all pts was 5 weeks. Phase 2 of the study has 6 active pts. Conclusions:Interim analysis of phase 1/2 study of rigosertib shows that it has an acceptable toxicity profile with the main AE being transient AMS. Rigosertib therapy results in stable disease in some pts. Study accrual continues. Disclosures:Off Label Use: Rigosertib is being used for relapsed or refractory AML in phase 1 clinical trial. Maniar:Onconova Therapeutics Inc: Employment, full employee of Onconova with stock options Other. Wilhelm:Onconova Therapeutics Inc: Employment, full employee of Onconova with stock options Other. Cortes:University of Texas, MD Anderson cancer center: Research Funding.

A phase I trial of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer

Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities. Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6-bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily. Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib. MTD was imatinib 400 mg plus full dose mFOLFOX-bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR.

A phase I/II trial of vandetanib for patients with recurrent malignant glioma

Vandetanib is a once-daily multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and the rearranged-during-transfection oncogene. A phase I trial was conducted to describe the pharmacokinetics of vandetanib in patients with recurrent glioma on enzyme-inducing anti-epileptic drugs (EIAEDs) and to identify the maximum tolerated dose (MTD) in this population. A phase II trial evaluated the efficacy of vandetanib in patients with recurrent malignant glioma not on EIAEDs as measured by 6-month progression-free survival (PFS6). In the phase I trial, 15 patients were treated with vandetanib at doses of 300, 400, and 500 mg/day, in a standard dose-escalation design. The MTD in patients on EIAEDs was 400 mg/day, and steady-state levels were similar to those measured in patients not on EIAEDs. Dose-limiting toxicities were prolonged QTc and thromboembolism. Thirty-two patients with recurrent glioblastoma multiforme (GBM) and 32 patients with recurrent anaplastic gliomas (AGs) were treated in the phase II trial, at a dosage of 300 mg/day on 28-day cycles. Six patients (4 GBM, 2 AG) had radiographic response. PFS6 was 6.5% in the GBM arm and 7.0% in the AG arm. Median overall survival was 6.3 months in the GBM arm and 7.6 months in the AG arm. Seizures were an unexpected toxicity of therapy. Vandetanib did not have significant activity in unselected patients with recurrent malignant glioma.

428P - Phase 1 Study of Veliparib With Concurrent Whole Brain Radiation Therapy (WBRT) in Patients (PTS) With Brain Metastases (METS)

ABSTRACT Background Veliparib, an oral PARP-1 and -2 inhibitor, potentiates the antitumor activity of DNA damaging agents including radiation therapy in vivo, and is shown to cross the blood-brain barrier. Updated data on safety and antitumor activity from an ongoing phase 1, dose-escalation study of veliparib with concurrent WBRT in pts with brain mets are presented here. Methods Pts with brain mets (including leptomeningeal) from primary non-CNS metastatic solid tumors (except germ cell cancer), adequate organ function, and Karnofsky performanace status (KPS) ≥70 were treated with WBRT (37.5 Gy in 15 fractions or 30 Gy in 10 fractions daily) and veliparib BID in escalating doses of 10–300 mg; the final WBRT fraction was followed by 1 extra day of veliparib. Safety and exploratory efficacy were assessed. Safety was evaluated in pts who received at least 1 dose of veliparib. Best brain tumor response (complete or partial per RECIST) rates were calculated for all pts who had at least 1 measureable lesion at baseline. Median survival time was estimated using Kaplan-Meier methodology for all dosed pts. Results To date, 66 pts (M/F, 23/43; median age 58 y) have been treated. Baseline KPS was 70, 80, 90, and 100 in 7.6, 31.8, 37.9, and 22.7% pts, respectively; primary tumor types were breast (n = 21), NSCLC (n = 23), melanoma (n = 10), colorectal (n = 3), renal (n = 1), and others (n = 8); 74.2% pts had multiple lesions, and 16.7% had prior brain stereotactic radiosurgery. Treatment-emergent dose-limiting toxicities were grade 3 hypokalemia and hyponatremia in 1 pt each at the 150 mg dose. Grade 3/4 treatment-emergent adverse events (≥4%) were fatigue (6.1%), dehydration (6.1%), anemia (4.5%), thrombocytopenia (4.5%), hyperglycemia (4.5%), and hyponatremia (4.5%). Best tumor response rate and median survival time were 36.8% and 6.6 months (m) for NSCLC, and 50% and 8.3 m for breast cancer. Conclusion Addition of veliparib up to 200 mg BID was well tolerated with concurrent standard WBRT and dose escalation is ongoing. These encouraging safety and preliminary efficacy data suggest that veliparib requires further evaluation as a radiosensitizer with WBRT in pts with NSCLC and brain mets in a randomized trial. Disclosure M.P. Mehta: Consultant: Abbott, BMS, Elekta, Merck, Novartis, Novocure, Tomotherapy, Vertex; Stock Options: Accuray, Pharmacyclics; DSMB: Apogenix; Protocol Data Review: Adnexus; Board of Directors: Pharmacyclics. W.J. Curran: Dr. Curran had served on the advisory board of Lilly, BMS, and Plexxikon. There are no conflicts. D. Wang: As a clinical investigator, and the principle investigator at Henry Ford Health System, I have conducted this clinical trial that is financially supported by Abbott Oncology. I have no other conflict of interest to be disclosed, otherwise. L. Kleinberg: I have received research funding from Abbott. J. Qian: Full-time Abbott employee and stockholder. T. Leahy: Full-time Abbott employee and stockholder. B. Desai: Full-time Abbott employee and stockholder. V.L. Giranda: Full-time Abbott employee and stockholder. All other authors have declared no conflicts of interest.

A phase I study of the androgen signaling inhibitor ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC).

4548 Background: ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. (Clegg et al., 2012) We conducted a phase I trial to assess safety, pharmacokinetics (PK), and determine the recommended phase II dose (RP2D). Methods: Eligible patients with mCRPC received ARN-509 orally on a continuous daily dosing schedule. Seven doses (30, 60, 90, 120, 180, 240, and 300 mg) were tested using standard 3x3 dose escalation criteria. Once drug concentrations were achieved that met or exceeded optimal levels predicted preclinically, an additional 2 dose levels were tested to further confirm the safety margin of ARN-509 (390 and 480 mg). Anti-tumor activity was assessed by PSA, radiographic responses, and FDHT-PET imaging. Results: Thirty patients were enrolled. The most common grades 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 treatment-related grade 3 adverse event (abdominal pain) at 300 mg, possibly related to a higher pill burden. PK was shown to be linear and dose-dependent. At 12 weeks, 42% of patients have had ≥ 50% PSA declines. Eleven (37%) patients have discontinued the study due to progression, with the longest patient still on study for more than 16 months. FDHT-PET imaging demonstrated AR blockade at 4 weeks across multiple dose levels. Conclusions: In this phase I study, ARN-509 was shown to be safe and well tolerated with linear PK. Based on promising activity across all dose levels and pharmacodynamic evidence of AR antagonism, an optimal biologic dose of 240 mg daily was selected for phase II investigation. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals.

A single-arm, open-label, multicenter phase I/II study of the combination of panobinostat (pan) and carfilzomib (cfz) in patients (pts) with relapsed/refractory multiple myeloma (RR MM).

TPS8115 Background: Despite novel therapies, MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM. Preclinical studies demonstrate synergistic anti-MM activity with histone deacetylase inhibitors (HDACi) and proteasome inhibitors (PI) through the dual inhibition of the proteasome and aggresome pathways. Pan is an oral pan-HDACi which has shown synergy with bortezomib in clinical studies. Cfz is a 2nd generation PI which has shown marked anti-MM activity with an improved safety profile. In this trial we evaluate the safety and efficacy of the combination of pan and cfz in pts with RR MM. Methods: This multi-center US study plans to enroll up to 52 adults with RR MM. The phase I study will determine the MTD of the combination of cfz and pan and follow a standard dose escalation design. Pan will be administered orally three times weekly during weeks 1 and 3 of each 28-day cycle (Days 1, 3, 5, 15, 17, 19) at a starting dose of 20 mg. Cfz will be administered intravenously on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cfz starting dose will be 20mg on days 1,2 of cycle 1 with escalation to the corresponding dose level beginning at 27 mg , if well tolerated. Dose modifications will not be permitted during cycle 1 unless a pt experiences a DLT. A maximum of four dose levels will be evaluated. Approximately 24 pts will be enrolled during the phase I portion to establish the MTD. In the phase II portion of this study, pts with RR MM will receive treatment with the optimal dose of pan and cfz established during phase I. Pts will be assessed for response to treatment after each cycle (4 weeks). Pts with objective response or stable disease will continue treatment until disease progression or unacceptable toxicity occurs. The primary endpoint is to establish the optimal doses of cfz and pan that can be administered to pts with RR MM (phase I) and to evaluate the overall response rate (phase II). Secondary endpoints include time-to-progression, progression-free survival, overall survival and safety. Approximately 25 pts are planned for the phase II portion. Current status: As of 1/27/12 3 patients have been enrolled.

A phase I study of EP-100, a luteinizing hormone releasing hormone (LHRH) ligand conjugated to a synthetic cytolytic peptide in patients with advanced refractory LHRH- receptor (R)-expressing tumors.

3060 Background: EP-100 is a synthetic 28 amino acid LHRH peptide conjugated to an 18 aa cytolytic peptide. Selective targeting in LHRH-R expressing cells occurs via direct binding to the extracellular membrane receptor followed by disruption of the membrane by the cytolytic peptide portion. A first in human, phase I study was performed. Methods: Eligible pts had adequate organ function and LHRH-R tumor expression, as determined by IHC. EP-100 was given IV (30-60 min) weekly x 3 for cohorts 1- 6 (n=20 at 0.6 - 5.2 mg/m2) and then twice weekly x 3 for cohorts 7- 11 (n=18 at 7.8 - 40 mg/m2) with a week break. The pharmacokinetic profile of EP-100 and antibody production against EP-100 was determined by a validated HPLC/MS and ELISA respectively. Potential activity of EP-100 on the pituitary gonadotropes was determined by plasma LH and FSH. Results: We screened 97 pts, archival tumor tissue obtained from 81 pts; 53 (65%) were positive for LHRH-R, of which 37 were enrolled (female 76%) and treated. The LHRH-R expression rate in breast was 81% (N=21) and in ovarian cancer 56% (n=18). Most pts had breast (n= 16, 42%) ovary (n=7,18%), colon (n=4, 11%) or uterine (n=3, 8%) cancer. Pts were treated in a 3 + 3 standard dose escalation scheme. Doses were escalated 100% in the absence of a grade 2 drug related toxicity. MTD was not reached at the highest dose level of 40 mg/m2. Only one DLT occurred, a grade 2 increase in ALT/AST. The only other drug-related toxicity was a self limited infusion-related skin reaction (grade 1-2) in 10 pts. EP-100 was rapidly cleared from circulation, mean half life ranged from 7.1 ± 3.8 min to 15.9 ± 3.6 min. Best response was stable disease for &gt;12 weeks in 5 pts. In 3 pts rapid, sustained decreases in LH/FSH levels were noted. Antibody production against EP-100 was absent in all pts. Conclusions: The study has completed accrual, the phase II dose is 30-40 mg/m2 twice a week x 3 weeks.EP-100is safe, well tolerated and not antigenic/immunogenic. Preclinical studies indicated synergy with paclitaxel and doxorubicin. A phase II study of EP-100 plus paclitaxel in ovarian cancer is planned.

Phase I/II safety and pharmacokinetic (PK) study of ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase I results of a Prostate Cancer Clinical Trials Consortium study.

43 Background: In CRPC, androgen receptor (AR) overexpression is associated with resistance to first-generation anti-androgen therapy such as bicalutamide. ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data shows that ARN-509 binds AR with 5-fold greater affinity than bicalutamide, and induces tumor regression in hormone-sensitive and CRPC xenograft models. Methods: In this open-label, Phase 1/2 study, mCRPC patients received ARN-509 orally on a continuous daily dosing schedule. In Phase 1 , 7 doses (30, 60, 90, 120, 180, 240, 300 mg) were tested using standard 3x3 dose escalation criteria to assess safety, PK, and determine the recommended Phase 2 dose (RP2D). Preliminary anti-tumor activity was assessed by PSA kinetics, radiographic responses, circulating tumor cells (CTCs), and FDHT-PET imaging. Results: Twenty-four patients (median age 68 yrs, Gleason Score 8; prior docetaxel 13%) were enrolled. The most common Grade 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 treatment-related Grade 3 adverse event (abdominal pain) at 300 mg, possibly related to a higher pill burden, which led to an additional 3 patients being enrolled at the highest dose with no further dose limiting toxicities. PK was shown to be linear and dose-dependent. Twelve patients (55%) had ≥ 50% PSA declines. To date, 7 patients have discontinued the study due to progression, with the longest patient still on study for more than 1 year. FDHT-PET imaging demonstrated AR blockade at 4 weeks across multiple dose levels. Based on preclinical assessment of maximum efficacious dose, PK, and promising activity across all doses, 240 mg was selected as the RP2D. Conclusions: In this Phase 1 study, ARN-509 was shown to be safe and well tolerated, with promising preliminary activity based on PSA and pharmacodynamic evidence of AR antagonism. The Phase 2 portion of the study will enroll up to 90 patients with treatment-naïve non-metastatic and mCRPC.

Evaluation of Clostridium novyi–NT spores in dogs with naturally occurring tumors

To establish the maximum tolerated dose of Clostridium novyi-NT spores in tumor-bearing dogs and evaluate spore germination within tumors and tumor response. 6 client-owned dogs. A standard dose-escalation study was planned, with maximum tolerated dose defined as the highest dose at which 0 or 1 of 6 dogs had dose-limiting toxicoses (DLT). Dogs received 1 dose of C. novyi-NT spores i.v.. Toxicoses were graded and interventions performed according to specific guidelines. Grade 3 or higher toxicosis or any toxicosis combination that substantially affected patient status was considered DLT. Clinical response was measured by use of response evaluation criteria in solid tumors at 28 days. The first 2 dogs had DLT. The dose was decreased. Two of the next 4 dogs had DLT; therefore, dose administration was stopped because the study endpoint had been reached. The most common toxicosis was fever (n = 6 dogs). Two dogs developed abscesses (1 within a nasal carcinoma and 1 splenic abscess) attributable to C. novyi-NT infection; both required surgical intervention. Clostridium novyi-NT was cultured from 1 of 6 tumors. Five dogs were available for response assessment (4 had stable disease; 1 had progressive disease). Results indicated that C. novyi-NT can germinate within tumors of dogs. Toxicosis, although common and sometimes severe, was manageable with treatment. Further studies in dogs with superficial tumors may allow for continued dose escalation and provide information for use in clinical trials in veterinary and human oncology.

Predicting Hydroxyurea Responses in Children with Sickle Cell Anemia

Abstract▪2131▪This icon denotes a clinically relevant abstract Background:Over the past 15 years, numerous prospective and cross-sectional clinical trials have demonstrated that hydroxyurea has both laboratory and clinical efficacy for pediatric patients with sickle cell anemia (SCA). In infants, toddlers, children, and adolescents, hydroxyurea administered at maximum tolerated dose (MTD) leads to significant increases in hemoglobin (Hb) concentration, MCV, and %HbF along with simultaneous decreases in neutrophils, reticulocytes, total bilirubin, and serum lactate dehydrogenase. Clinical benefits include reduction in acute vaso-occlusive events (pain and acute chest syndrome), and emerging data suggest protection against chronic organ damage with a low risk of genotoxicity. For individual patients, however, the %HbF response to hydroxyurea and the MTD dose itself are highly variable. Currently there are no accurate predictors of the final %HbF or the MTD dose. Methods:To address the phenotypic variability, the Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175) was designed to capture prospectively first-dose (20 mg/kg) pharmacokinetics (PK) of hydroxyurea including maximum serum concentration (Cmax), area under the concentration curve (AUC), apparent oral clearance (CL/F), half-life (t1/2), and apparent volume of distribution (V/F). A consistent dose escalation schedule was then used to achieve a stable MTD, at which time PK studies were repeated and hydroxyurea responses (%HbF and MTD dose) were recorded along with other pharmacodynamics parameters. Results:After written informed consent, a total of 98 pediatric patients commenced hydroxyurea, 65 of whom reached MTD with complete paired PK information. In the majority of patients (39 of 65), a ‘fast/slow' absorption phenotype identified at first-dose PK analysis was retained at MTD, supporting the concept of a genetic basis for this variation. Inter-individual PK variability was substantially greater than intra-individual variability; for example, the coefficient of variation (%CV) for CL/F was 44.4% on day 1 and 42.3% at MTD among all subjects, but averaged only 12.8% within the same subject. The CL/F was partly dependent on the rate of absorption but was most strongly influenced by subject weight and serum creatinine. At MTD, the average AUC was 114 ± 22.3 mg·h/mL, and the %CV of AUC was reduced from 24.8% on first-dose PK to 19.5% at MTD, likely reflecting dose titration toward a common degree of myelosuppression. In an attempt to predict the MTD dose toward this target AUC using data available at baseline, ‘best-fit' equations were developed such as the following with or without PK data:Predicted MTD (mg/kg/day) = 31.9 - [17.1*Baseline Creatinine] - [0.14*Baseline BMI] + [0.0036*Baseline ARC]Predicted MTD (mg/kg/day) = 32.6 - [15.1*Baseline Creatinine] - [0.16*Baseline BMI] - [0.56*First-dose half-life] + [0.0034*Baseline ARC] - [0.48*PK phenotype (fast=0, slow=1)]A simpler equation for predicting MTD dose using only baseline creatinine and weight was then developed: Predicted MTD (mg) = 400 - [1000*Baseline Creatinine] + [21*weight] Conclusions:The relatively small intra-individual PK variability at hydroxyurea MTD compared to baseline PK studies, coupled with a similar degree of drug exposure when patients achieve a stable MTD, supports future investigation to predict the optimal hydroxyurea dose prior to the first dosing. Prediction equations of the MTD should be tested prospectively against standard dose-escalation schedules. Disclosures:Off Label Use: Hydroxyurea for children with sickle cell disease.

A first-in-human, open-label, phase I/II safety, pharmacokinetic, and proof-of-concept study of ARN-509 in patients with progressive advanced castration-resistant prostate cancer (CRPC).

TPS190 Background: The results of molecular profiling studies show that androgen receptor (AR) overexpression is associated with resistance to conventional anti-androgens such as bicalutamide (Nat Med 10:33-39, 2004). ARN-509 is a novel small molecule AR antagonist that lacks the partial agonist activity seen with bicalutamide in the context of AR overexpression, an in vitro mimic of castration resistance. In addition, ARN-509 reduces the efficiency of nuclear translocation, and impairs AR binding to DNA and AR target gene modulation, thereby inhibiting tumor growth and promoting apoptosis. A phase I/II clinical trial of continuous oral ARN-509 in patients with progressive CRPC with and without prior chemotherapy began in July 2010. Methods: The study is designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor effects of ARN-509 in patients with progressive CRPC. In the dose escalation phase, patients are assigned using standard 3x3 dose escalation criteria to receive oral ARN509 at the following dose levels: 30, 60, 90, 120, 180, 240, and 300 mg. The primary objective is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of ARN-509 that leads to a DLT in a maximum of 30% of patients. Pharmacokinetic (PK) analysis is performed after a single dose of ARN509 in week-1. Correlative studies include circulating tumor cells, optional FDG and FDHT PET imaging, and optional tumor biopsies. Following completion of the dose escalation phase, three expansion cohorts will be enrolled at the RP2D to provide an initial signal of anti-tumor activity with a time to PSA progression endpoint. The three expansion cohorts include: 1) non-metastatic CRPC docetaxel (doc) and abiraterone (abi)-naive (50 patients); 2) mCRPC doc and abi-naive (20 patients); and 3) mCRPC abi pre-treated (10-20 patients). The effect of food on the PK of ARN-509 and the effect of ARN-509 on ventricular repolarization will be evaluated in the expansion phase. The escalation phase is ongoing; enrollment to cohort 4 (120 mg) began in January 2011.DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals. NCT01171898.

Evaluation of an intervention to improve communication about phase I/II trials.

6028 Background: Communicating well with patients and families about early phase cancer trials presents many challenges. Studies examining the informed consent process show deficiencies including failure to check understanding about prognosis, a lack of clarity about the experimental nature of trials and inadequate discussion of palliative care options (Jenkins et al, JCO, 2010). We evaluated a one-day facilitator led, modular program combining DVD review and group discussion with exercises and evidence-based didactic presentations. DVDs were based on real scenarios with breast, melanoma, colorectal and lung cancer patients and were presented as 4 modules dealing with standard chemotherapy plus novel agents, monoclonal antibodies, standard dose escalation studies and phase II targeted treatment trials. Methods: Objective and subjective assessments were made pre (T1) and post (T2) workshop. We tape-recorded 47 participants conducting Phase I/II trial interviews with simulated patients. Coders blinded to time-point rated tapes for inclusion and omission of key areas. Patient simulators at T1 and T2 rated presence and comprehensiveness of communication needed to elicit informed consent. Finally participants completed assessments of self-confidence. Results: Significant improvements in communication behaviours were found post course. Objective analysis comparing taped interviews at T1 and T2 showed positive shifts in issues such as:- establishing knowledge of prognosis (p=0.005), discussing symptomatic care options (p=0.002), and the experimental nature of trials (p=0.009). Patient simulator ratings showed overall improvements in key areas including awareness of palliative/symptom control options (p=0.004), voluntariness of participation (p=0.004), opportunity to ask questions (p=0.044) and time to consider participation (p=0.009). Participants own self confidence increased significantly in all 13 areas probed (p≤0.008). Conclusions: This short, but intensive, educational workshop changed the communication skills and self efficacy of healthcare professionals in ways likely to promote better understanding and valid, ethically informed consent from patients contemplating early phase trial entry.

A prospective clinical trial of lenalidomide with topotecan in women with advanced epithelial ovarian carcinoma

Lenalidomide is an anti-angiogenic IMiD(®) immunomodulatory drug. The objective of this study was to determine the maximum tolerated dose (MTD), overall safety profile, and activity of oral lenalidomide in combination with topotecan in women with advanced epithelial ovarian or primary peritoneal carcinoma. In this Phase I/II open-label, dose-escalation study, patients with histologically or cytologically confirmed advanced ovarian or primary peritoneal carcinoma with disease progression or recurrence following first-line therapy with a platinum agent and paclitaxel were eligible. The Phase I trial utilized a standard dose-escalation design to define the MTD and evaluate the safety profile of lenalidomide and topotecan. The starting doses were lenalidomide 5 mg, days 1-14, and intravenous topotecan 1.25 mg/m(2), days 1-5 of a 21-day cycle. Only the lenalidomide dose was escalated, in 5-mg increments up to 25 mg. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The Phase II portion was designed to evaluate the antitumor activity based on objective response rate of lenalidomide and topotecan. Five women with advanced epithelial ovarian carcinoma were enrolled, each receiving 5 mg oral lenalidomide and 1.25 mg/m(2) topotecan. Four patients discontinued because of dose-limiting toxicity, most commonly grade 4 neutropenia (n = 3). One patient discontinued because of lack of therapeutic effect. The study was terminated early for reasons of toxicity. The addition of lenalidomide to topotecan is not a feasible drug combination in women with advanced epithelial ovarian carcinoma because of dose-limiting toxicity.

Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas

Purpose Inhibition of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways may result in synergistic antitumour activity. We designed a phase I study to evaluate the combination of vandetanib, an investigational agent with activity against EGF receptor and VEGF receptor 2, and bevacizumab, a monoclonal antibody against VEGF. Experimental design Patients with advanced solid tumours and lymphomas were enrolled. Objectives were to determine the safety and maximum tolerated dose of the combination, characterise pharmacokinetics, measure angiogenic marker changes in blood, and assess tumour blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Vandetanib was given orally once daily and bevacizumab intravenously once in every 3 weeks in 21-day cycles utilising a standard dose-escalation design. Results Fifteen patients were enrolled, and a total of 94 cycles of therapy were administered. No protocol-defined dose-limiting toxicities were observed; due to toxicities associated with chronic dosing, hypertension, proteinuria, diarrhoea and anorexia, dose escalation was stopped at the second dose level. We observed one partial response and one minor response; 9 patients experienced stable disease. There were significant changes in plasma VEGF and placental-derived growth factor levels, and decreases in K trans and k ep were observed by DCE-MRI. Conclusion In this trial, we safely combined two targeted agents that cause dual blockade of the VEGF pathway, demonstrated preliminary evidence of clinical activity, and conducted correlative studies demonstrating anti-angiogenic effect. The recommended phase II dose was established as vandetanib 200 mg daily and bevacizumab 7.5 mg/kg every 3 weeks.