Erlichman, Charles

6587 Background: Recently the Patient-Reported Outcomes version of the CTCAE was developed to augment clinically graded adverse events with information reported directly by patients on clinical trials (Basch, 2009). The validation and potential application of PRO-CTCAE in phase I clinical trials are of great interest as toxicity is the primary endpoint. Methods: Selected PRO-CTCAE items (21 items measuring 12 symptomatic adverse events) corresponding to the major adverse events required to be graded clinically were collected in an ongoing phase I clinical trial of weekly cilengitide and paclitaxel in patients with advanced solid malignancies (NCT01276496). PRO-CTCAE was administered in a paper booklet by a clinical research associate prior to treatment on days 1, 8 and 15 of their regular visits. These PRO-CTCAE items were summarized descriptively in comparison to clinician-assessed CTCAE ver 4.0 (NCI, 2009) during the first cycle. As a pilot study to assess feasibility of PRO-CTCAE in phase I trials, PRO-CTCAE was not intended for determination of dose-limiting toxicity. Results: Twelve patients were accrued to two separate doses of cilengitide and paclitaxel. The median age was 56 (range 36—67) and half of patients were female. All patients had an ECOG performance score <= 1. Over 90% of patients had received prior surgery and chemotherapy. All but one patient completed weekly PRO-CTCAE during the first cycle, the only patient refused to complete weeks 2 and 3 did not give a reason. PRO-CTCAE captured most of the symptomatic adverse events reflected in clinician-assessed CTCAE. Some symptomatic adverse events were not reported clinically by CTCAE but were reported by patients by PRO-CTCAE. Overall, PRO-CTCAE items indicated slightly more severe degree of symptoms experienced by patients than those reported in CTCAE. Conclusions: This is the first study that PRO-CTCAE items were integrated within regular study visits in a phase I trial. The administration of PRO-CTCAE has been proved feasible and fruitful, providing consistent and enhanced symptomatic toxicity from the patient point of view. The addition of PRO-CTCAE did not significantly increase patient burden. Clinical trial information: NCT01276496.

4032 Background: PNET has long had few effective therapies other than chemotherapy. Placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/PDGF receptor inhibitor sunitinib noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are still <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co primary endpoints were RR and 6-month PFS. Planned enrollment was 50 patients, with interim analysis for futility after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed. Results: 55 pts were eligible for response assessment. Confirmed PR was documented in 20 of 55 patients (37%). 44 of 55 (80%) patients were progression-free at 6 months. Of 49 pts evaluable for this endpoint, 12 month PFS is 49%. 15 patients remain on therapy. For evaluable patients, the most common grade 3-4 adverse events attributed to therapy were hypertension (18%), hyperglycemia (13%), fatigue (11%). leukopenia (9%), headache (9%), proteinuria (7%), and hypokalemia (7%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 37%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Phase III trials of combined VEGF/mTOR inhibition in PNET should be pursued. Clinical trial information: NCT01010126.

2562 Background: Empiric chemotherapy (taxane/platinum) is standard for CUP. Because prognosis is poor, novel approaches are needed. The PI3K/mTOR pathway is frequently dysregulated in cancer. Everolimus (E), an mTOR inhibitor, is approved for multiple malignancies. We performed a phase II study of Pac + Carb + E as first-line therapy in metastatic CUP patients (pts). We additionally determined if a gene expression profiling (GEP) test that identifies tissue of origin (Pathwork Tissue of Origin) could identify responsive pts. (NCT00936702) Methods: Newly diagnosed, untreated CUP pts were eligible. Central pathology review confirmed CUP prior to registration; GEP was performed on formalin fixed tumor tissue. Pac (200 mg/m2), Carb (AUC=6) and E (30 mg once weekly) were delivered every 3 wks until progression or intolerable adverse events (AEs). The primary endpoint was confirmed response, with ≥11 of 50 responses (22%) needed for trial success. Secondary endpoints were OS, progression-free survival (PFS) and AEs. Results: 46 pts (median age 61) received a median 4 cycles (range: 1-33). 39 (85%), 21 (46%) and 1 (2%) experienced ≥1 grade (gr) 3+, 4+, or 5 (sepsis) AE, with gr 3+ hematologic AE most common (74%). Of 44 evaluable pts, 15 had a confirmed response (RR 34%, 95% CI: 21-50%), with a median PFS and OS of 4.1 and 10.1 mos, respectively. Adequate tissue for GEP was available in 36 pts and predicted 10 different sites of origin. In pts with a predicted tissue of origin in which taxane/platinum is standardly used, higher RR and significantly longer PFS and OS were observed compared with pts whose GEP identified a malignancy where taxane/platinum is not standard (Table). Conclusions: In pts with untreated CUP, Carb +Pac +E demonstrated promising antitumor activity. The GEP test identified patients clinically responsive to Carb/Pac/E therapy, and may be useful to select CUP pts for specific antitumor regimens. Clinical trial information: NCT00936702. [Table: see text]

2551 Background: Protein kinase C iota (PKCi) is overexpressed in non-small cell lung (NSCLC), ovarian and pancreatic cancers and promotes tumorigenesis. The gold compound aurothiomalate (ATM) inhibits downstream activation of Rac1 by PKCi. We sought to determine the maximum tolerated dose (MTD) of ATM. Methods: We conducted a phase I dose escalation trial of ATM in patients with NSCLC, ovarian or pancreatic cancer. In the dose escalation cohort patients received ATM IM weekly for three cycles (cycle duration 4 weeks) at 25 mg, 50 mg or 75 mg in a 3+3 design. The dose was not escalated for individual patients. Up to 9 subjects were allowed to enroll in the expansion cohort at the MTD. Blood samples were analyzed for elemental gold levels. Patients were evaluated for response every eight weeks with computed tomography using modified response evaluation criteria in solid tumors. Results: Fifteen patients, all pretreated, enrolled in this study. There were ten patients with NSCLC, four with ovarian cancer and one with pancreatic cancer. Six patients were treated at the 25 mg dose, 6 patients at 50 mg, and 2 at 75 mg. There was 1 dose limiting toxicity (DLT) at 25 mg (hypokalemia), 1 DLT at 50 mg (urinary tract infection), and none at 75 mg. There were 3 grade 3 hematologic toxicities in the dose escalation cohort. The recommended MTD of ATM is 50 mg, and 1 subject was treated in the expansion cohort at 50 mg. Patients received treatment for a median of 2 cycles (range 1-3). The best response observed was stable disease in 2 subjects. There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold with concentrations exceeding 20 µM after one month of therapy with 75 mg of ATM and after 2 months of therapy with 50 mg of ATM, consistent with linear pharmacokinetics. Conclusions: In summary, this phase I study was successful in identifying ATM 50 mg IM weekly as the MTD. In this heavily pre-treated group of patients in who we observed at best stable disease, it remains unclear whether future investigations that target PKCi should focus on single agent ATM, combination therapy with ATM, or other PKCi inhibitors that are currently in development. Clinical trial information: NCT00575393.

8013 Background: Obatoclax mesylate (GX15-070MS) is a BH3 mimetic that inhibits Bcl-2 protein family members including MCL-1, a dominant target in myeloma (MM). Obatoclax (OBX) inhibited viability of 14 MM cell lines (mean IC50 215 nM) and primary MM samples while exhibiting pre clinical synergy with bortezomib (BTZ). Sensitivity correlated with basal levels of Mcl-1 and Bcl-XL, but not Bcl2, Bim, Bax or Bak expression. Methods: We report a phase I trial of OBX in combination with BTZ. Eligibility required measureable disease, > 1 prior MM therapy, ≤10 cycles of prior BTZ and did not progress on prior BTZ therapy, creatinine ≤2 ULN. Starting dose level 1 was OBX 14 mg/m2 24-hour continuous iv. infusion days 1, 8, 15 of a 21-day cycle. BTZ given at 1.3mg/m2 iv. days 1, 4, 8 and 11. After protocol amendment OBX level 1 dosing was 30 mg/m2, level 2 was 40 mg/m2 IV both by continuous 3 hour infusion days 1, 8 and 15 on a 21 day schedule. Pre med. with famotidine was required. Results: Eleven patients were accrued, median age 62 (range: 46-77), median time from diagnosis was 4.7 years. Median of 2.5 cycles (range: 1-10). Median follow-up for patients still alive is 11.6 months (range: 0.9-35.5). At dose level 1, there were 2 DLTs. After amendment 8 patients were accrued (3 hour infusion): 4 at amended dose level 1 and 4 at dose level 2. All patients are now off treatment. 10 patients are evaluable for response: 2 patients at original dose level 1 (2 PR), 3 patients at dose level 1 (2 PR, 1 MR), no patients at dose level 2 responded: overall PR of 40%, clinical benefit response in 50% (95% CI: 19-81%). 6 patients had disease progression and 2 patients died. 4 DLTs were seen: at original dose level 1 grade 4 thrombocytopenia and delay of therapy > 15 days. At dose level 2, 1 patient had grade 3 somnolence, a 2nd patient grade 3 euphoria and grade 4 thrombocytopenia. No DLTs were seen at amended dose level 1. Common adverse events of any grade included GI, hematologic and neurologic e.g. euphoria, decreased level of consciousness, psychosis, speech. Conclusions: In summary MTD is OBX 30mg/m2 by 3 hour iv infusion once weekly, BTZ 1.3 mg/m2 days 1,4,8, and 11. Major toxicities were central neurologic and hematologic. This P2C consortium study was supported by NCI N01-CM62205.

5544 Background: Pazopanib, an orally bioavailable multitargeted inhibitor of kinases including VEGF-R, demonstrated impressive activity in metastatic differentiated thyroid cancer (49% durable RECIST PRs) and promising preclinical activity in anaplastic thyroid cancer (ATC) models, prompting its evaluation also as a candidate therapeutic in advanced ATC. Methods: A multicenter single arm phase II trial of 800 mg pazopanib daily was undertaken with the primary endpoint of RECIST response rate. The trial was designed such that there would be a 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true tumor response rate is >5%. A pre-specified stopping rule designated that enrollment would cease unless 1 or more RECIST PRs+CRs were observed in the first 14 of 33 potential patients. Eligibility required informed consent, >18 years of age, performance status ECOG 0-2, systolic blood pressure (BP) <140 mm Hg and diastolic BP <90 mm Hg at entry, QTc interval <480 msecs, and measurable disease by RECIST criteria. Anatomical imaging and toxicity evaluations were required every 4 weeks. Results: Sixteen patients were enrolled. One patient withdrew prior to therapy, leaving 15 evaluable patients – 33.3% were male, with a median age of 66 years (range 45-77); 11 of 15 patients had progressed through prior systemic therapy. Four patients required 1-2 dose reductions, with the most common severe toxicities (CTC-AE version 3.0 grades 3-5) hypertension (13%) and pharyngolaryngeal pain (13%). Reasons for treatment discontinuation included: disease progression (12 pts), death on study due to a vascular event possibly related to treatment (1 pt.), and intolerability (radiation recall tracheitis – 1 pt, and uncontrolled hypertension – 1 pt). Although transient disease regression was observed in several patients, there were no confirmed RECIST tumor responses, triggering study closure at time of interim analysis. Two patients are alive with disease 9.9 months and 2.9 years post-registration; the remaining 13 died of disease. The median time to progression was 62 days and the median survival time was 111 days. Conclusions: Pazopanib has poor single agent activity in advanced anaplastic thyroid cancer.

5020 Background: V+C was well tolerated in a phase I trial and responses and prolonged disease stabilization were observed in BRCA + patients (pts).To assess the relative contribution of the PARP inhibitor to the efficacy observed for the combination, we conducted a randomized multicenter trial comparing the response rate (RR) of V and C to the RR of C alone in patients with deleterious BRCA mutations and recurrent ovarian, or primary peritoneal, fallopian tube or high-grade serous ovarian cancer. Methods: Pts were ≥ 18 yrs, KPS ≥ 70%, had adequate organ function, prior therapy with PARP inhibitors was allowed.Both drugs were administered orally qd; C 50 mg, V 60 mg; 21 day cycles. Pts were randomized to receive either C alone or V+C. At disease progression, pts on C alone were allowed to cross over to the combination. Radiologic imaging was performed at baseline and q 3 cycles for assessment of response. Dose reduction of V was allowed to 40 mg for gr 3 non-hematologic or gr 4 hematologic toxicities. The study design had an 88% power to detect the difference between a 15% RR for C alone versus 35% for V+C, early closure if fewer responses were observed on the combination arm in the first 65 pts enrolled (half of the total projected accrual). Results: Total of 74 pts were enrolled (36 pts C, 38 pts V+C), median age 58 (37-79 yrs), # of prior therapies: median 4 (1-9), 2 pts had prior PARP therapy. Treatment was well tolerated, Gr ≥ 2 toxicities per arm for initial regimen (# of pts): C alone: lymphopenia (2), mucositis (1); V+C: lymphopenia (4), anemia (2), leucopenia (2), neutropenia (2). Of the 74 pts evaluable for response at the interim analysis, 3 PRs observed in 36 pts on V+C and 5 PRs of 38 pts on C alone arm; thus accrual was stopped. PAR levels assessed by validated ELISA were inhibited (>80%) in PBMCs in 9/10 pts 4 hours post V, no inhibition with C alone. Conclusions: Addition of V, a PARP inhibitor, to C did not improve RR versus C alone. Exomic sequencing, gene expression studies, and Fanconi Anemia triple stain immunofluorescence (FATSI) assay for FancD2 nuclear foci formation using archival tissue are ongoing.

4047 Background: PNET has long had few effective therapies other than chemotherapy. Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are still <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50 patients, with interim analysis for futility after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed. Results: Confirmed PR was documented in 13 of the first 25 (52%) evaluable patients. 21 of 25 (84%) patients were progression-free at 6 months. Both endpoints exceeded the protocol-defined criteria to continue enrollment. For 36 evaluable patients, the most common grade 3-4 adverse events attributed to therapy were hypertension (14%), leukopenia (11%), lymphopenia (11%), hyperglycemia (11%), mucositis (8%), hypokalemia (8%), and fatigue (8%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 52%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 84% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing.

3001 Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.

e13052 Background: The combination of GEM and CDDP has shown activity in a variety of cancers, including biliary tract/gallbladder. Preclinical testing shows a potential benefit to the addition of EV. Methods: Using a standard 3+3 design, the MTDs of GEM + EV (Cohort I) and GEM + CDDP + EV (Cohort II) were determined as shown in the table. The MTD was defined as the dose level below the lowest dose that induces a DLT in at least one-third of pts. At the MTD of Cohort II, 10 patients were enrolled with biliary tract/gallbladder cancer (Cohort III). A weekly CBC was obtained. Assessments occurred every 3 weeks and imaging for response at every other cycle. Results: In Cohort I (N=12), no DLT occurred at dose level 0, and in dose level 1, grade 3 thrombocytopenia was found in 2 of 6 pts. The MTD for Cohort I was determined to be dose level 0. Responses were seen in 3 pts: 2 CRs (primary peritoneal, pancreatic) and 1 PR (breast). In Cohort II (N=15) DLTs at dose level 0 were neutropenia and thrombocytopenia in 2 of 3 pts and at dose level -1, thrombocytopenia in 2 of 6 pts. At dose level -2, 1 of 6 pts experienced a DLT (grade 3 thrombocytopenia), establishing this dose level as the MTD. Responses were seen in 2 pts, both PRs (ampullary, pheochromocytoma). All 10 pts have been enrolled in Cohort III with 2 DLTs (neutropenia and thrombocytopenia). Stable disease seen in 5 of 7 evaluable pts. Conclusions: Gem + EV was well tolerated at dose level 0, though dose escalation was limited by thrombocytopenia. GEM + CDDP + EV had DLTs of neutropenia and thrombocytopenia leading to the MTD of dose level of -2. Cohort III is fully accrued and the 2 DLTs are hematologic. [Table: see text]