Phase Ib Dose-escalation Study Research Articles

Maintenance Lenalidomide for Adults Aged 18-65 Years with AML in First Complete Remission after Intensive Chemotherapy: A Phase Ib Dose-Escalation Study of the Australasian Leukemia and Lymphoma Group (ALLG)

Relapse risk in the first 12 months after achieving complete remission (CR) is approximately 40% in the adult acute myeloid leukemia (AML) population (Bradstock, Blood 2005; Burnett, JCO 2013). In this phase 1b study conducted by the ALLG, patients with AML in first CR or CR with incomplete count recovery (CRi) after intensive chemotherapy were allocated to escalating dose cohorts of lenalidomide maintenance; 10 mg (n=8), 20 mg (n=9), 30 mg (n=9) or 40 mg (n=4) administered daily for two continuous 28-day cycles, followed by lenalidomide 10 mg daily for a total lenalidomide duration of 12 months. To date, 28 patients have been enrolled from 8 centers. The median age is 54 (range 18-65) years, ECOG performance status was 0 in 82% and 1 in 18%. Preceding chemotherapy for patients 18-55 years was HiDAC-3 induction (cytarabine 3 g/m2 bd D1, 3, 5, 7 + idarubicin 12 mg/m2 D1-3) and IcE (idarubicin 12 mg/m2 D1-2, cytarabine 100 mg/m2 D1-5 and etoposide 75 mg/m2 D1-5) consolidation. Patients aged 56-65 years received 7+3 induction (cytarabine 100 mg/m2 CIVI D1-7 + idarubicin 12 mg/m2 D1-3) and IDAC-2 (intermediate dose cytarabine 1 g/m2 bd D1, 3, 5 + idarubicin 12 mg/m2 D1-2) consolidation. Patients with core binding factor subtypes were consolidated with 3-4 cycles of HiDAC (cytarabine 3g/m2 bd D1,3,5). Patients received either one (3%), two (79%) or three-four (18%) cycles of consolidation chemotherapy prior to study entry. Cytogenetic risk at diagnosis was favorable (29%), intermediate (67%) or adverse (4%) by MRC criteria (Grimwade, Blood 2010). Molecular features included FLT3-ITD in 33% and NPMc mutation in 26%. During cycles 1-2 the frequency of grade 3-4 neutropenia/thrombocytopenia for each lenalidomide cohort was: 10 mg (13/13%), 20 mg (11/0%), 30 mg (50/12%), 40 mg (75/25%). Four patients have developed grade 3 skin rash on study. Two patients experienced grade 3 febrile neutropenia but there were no treatment-related deaths. The maximum tolerated dose has not been reached and recruitment is continuing at the 50mg dose level. With a median follow-up of 23 months, actuarial incidence of relapse in the first 12 months after commencing lenalidomide was 18% and 26% in the second year (Figure 1A). Overall survival (OS) after starting lenalidomide maintenance was 97% at 12 and 91% at 24 months (Figure 1B). Relapse-free survival (RFS) 24 months after starting lenalidomide maintenance according to cytogenetic or molecular factors was 78% (favorable karyotype), 48% (intermediate karyotype), 75% (NPMc mutation), 31% (FLT3-ITD) and 53% (FLT3-ITD and NPMc double negative). In conclusion, lenalidomide maintenance in an adult AML population has acceptable tolerance, even after prior HiDAC. Relapse risk in the first year during lenalidomide maintenance is lower than historically observed, but later relapses continue to be seen suggesting that future studies could investigate extended duration schedules of lenalidomide maintenance. [Display omitted] [Display omitted] DisclosuresWei:Celgene: Consultancy, Honoraria, Research Funding. Off Label Use: Lenalidomide as maintenance therapy for AML. Hertzberg:Celgene: Consultancy, Honoraria. Seymour:Celgene: advisory board Other, Consultancy, Honoraria.

Abstract CT328: Clinical results of a phase Ib dose-escalation study of the Mek inhibitor cobimetinib (GDC-0973) and the Akt inhibitor ipatasertib (GDC-0068) in patients (pts) with solid tumors

Abstract Introduction: Co-activation of Mek and Akt signaling pathways is common in solid tumors; in preclinical studies, combined Mek and Akt inhibition improves efficacy in models with dual activation. Cobimetinib is a potent, selective, allosteric Mek1/2 inhibitor (single-agent maximum tolerated dose [MTD] 60 mg once daily [QD] for 21-days-on/7-days-off [21/7]); ipatasertib is a potent, selective, ATP-competitive pan-Akt inhibitor (MTD 600 mg QD 21/7). Methods: This Phase Ib enrolled pts with advanced solid tumors in 3+3 dose-escalation to evaluate safety and pharmacokinetics (PK) of ipatasertib + cobimetinib on 2 dosing schedules: in Arm A, increasing doses of ipatasertib QD 21/7 + cobimetinib QD 21/7; in Arm B, increasing doses of ipatasertib QD 21/7 + cobimetinib QD on Days 1, 4, 8, 11, 15, 18 every 28 days (intermittent schedule). PK samples were collected on Cycle 1, Days 1 and 15, and archival tumors were collected for KRAS mutations (mut) by allele-specific PCR and PTEN status by immunohistochemistry. Results: 47 pts enrolled in dose-escalation (Arm A: 17, Arm B: 30). No dose-limiting toxicities (DLTs) occurred, but several pts had AEs that did not meet protocol-defined DLTs. Based on cumulative safety, combination MTD in Arm A was ipatasertib 200 mg QD 21/7 + cobimetinib 60 mg QD 21/7; in Arm B was ipatasertib 300 mg QD 21/7 + cobimetinib 150 mg intermittent. As of 29 July 2013, adverse events (AEs) of any grade (G) in ≥ 20% of pts, assessed by investigators as related to cobimetinib and/or ipatasertib (Table 1): Table 1.All Study Drug-Related AEs ≥ 20% of PtsAEArm AArm BAll GG ≥ 3All GG ≥ 3Diarrhea94%35%87%20%Nausea71%0%57%7%Vomiting65%0%67%7%Fatigue53%6%47%0%Blood CPK increased35%0%--Dehydration29%6%--Dermatitis acneiform29%0%63%3%Mucosal inflammation29%6%--Anemia24%0%--Decreased appetite24%0%23%0%Edema peripheral24%0%--Rash maculo-papular--30%7%Dysgeusia--27%0% There were 5 study drug-related serious AEs: Arm A (G3 diarrhea, G3 dehydration), Arm B (G3 nausea, G3 vomiting, G3 pneumonitis). Preliminary PK of cobimetinib + ipatasertib were not altered significantly. Partial responses by RECIST were seen in 3 pts with diagnostic-positive (Dx+) tumors: Arm A (KRAS-mut, PTEN-low ovarian), Arm B (KRAS-mut mesonephric cervical; KRAS-mut, PTEN-null endometrial cancer). Prolonged stable disease > 6 months (mo) was seen in both arms in 4 pts, including PTEN-null endometrial cancer (16.6 mo+). Conclusions: Cobimetinib and ipatasertib can be tolerated at combination MTDs, and early signs of anti-tumor activity occurred in pts with Dx+ tumors. Enrollment is ongoing on Arm B schedule in two PTEN-low expansion cohorts: endometrial and triple-negative breast cancer. Citation Format: Johanna C. Bendell, Patricia LoRusso, Daniel C. Cho, Luna Musib, Yibing Yan, Ilsung Chang, Premal Patel, Iris T. Chang, Raymond D. Meng, Geoffrey I. Shapiro. Clinical results of a phase Ib dose-escalation study of the Mek inhibitor cobimetinib (GDC-0973) and the Akt inhibitor ipatasertib (GDC-0068) in patients (pts) with solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT328. doi:10.1158/1538-7445.AM2014-CT328

A Phase Ib Dose-Escalation Study of the Hsp90 Inhibitor Snx-5422 and Erlotinib in Patients with Egfr-Mutant Lung Cancer and Acquired Resistance to Egfr Tyrosine Kinase Inhibitors

ABSTRACT Aim: SNX-5422 is a pro-drug of SNX-2112, a highly potent, non-geldanamycin analogue, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumour models including models of acquired resistance (AR) in EGFR-mutant lung cancer. To prevent disease flare after stopping EGFR tyrosine kinase inhibitors (TKIs) in patients (pts) with EGFR mutant lung cancer, erlotinib (E) is often continued with subsequent lines of treatment for AR. This phase IB study will determine the maximally tolerated dose (MTD) of SNX-5422 and E for pts with mutated EGFR and RECIST progression on EGFR TKIs. Methods: All pts had EGFR mutant lung cancer, with development of AR (per Jackman, JCO 2010) after treatment with an EGFR TKI. Pts underwent repeat tumour biopsies after development of AR and prior to study entry. Pts received SNX-5422 qod, 3 wks on/1 wk off, and E 150mg daily P.O. in 28-day cycles, with dose escalation using a standard 3 + 3 design. Safety and tolerability were evaluated also to determine the MTD and blood samples were obtained for pharmacokinetics. Results: Since May 2013, 17 pts were enrolled. No dose-limiting toxicities (DLTs) were reported in the first cohort (SNX-5422 50 mg/m2 + E), but DLTs (diarrhoea) were reported by 2 pts in the second cohort (SNX-5422 75 mg/m2 + E). Adverse events possibly related to the combination in ≥ 4 of 17 pts in were diarrhoea, nausea, fatigue, dry eyes, paronychia, and rash, all graded 1 or 2; except for 2 cases of grade 3 diarrhoea. No cardiovascular, renal or hepatic toxicities have been observed. 1 Pt reported mild, reversible nictalopia at the DLT level of SNX-5422 75 mg/m2 + E. Pts received a median of two cycles (range 1-6), and 3 remain on study. No partial responses have been seen in 15 evaluable pts; 1 ongoing pt had an 18% decrease from baseline in target lesions in Cycle 4. Stable disease was the best response in 4 pts at 8 wks, 3 pts at 16 weeks and 1 pt at 24 weeks. Conclusions: SNX-5422 and E is a well-tolerated combination at dose levels up to SNX-5422 50 mg/m2 qod + E 150 mg. The MTD was declared SNX-5422 50 mg/m2 + E. Disclosure: J. Hinson: I am employed by Esanex, Inc who is marketing and developing the drug in this study; E. Orlemons: I am employed by Esanex Inc who is developing the agent studied in this trial. I have financial interests including stock ownership. All other authors have declared no conflicts of interest.

Neurocognitive functioning and quality of life in patients with recurrent malignant gliomas treated on a phase Ib trial evaluating topotecan by convection-enhanced delivery.

Malignant gliomas are highly proliferative, invasive tumors that are resistant to conventional treatment, and disease progression is often accompanied by physical and mental debilitation. Neurocognitive functioning (NCF) and quality of life (QoL) were evaluated as part of a prospective phase Ib dose-escalation study of topotecan by convection-enhanced delivery (CED) for adult patients with recurrent malignant gliomas. Sixteen patients were enrolled, and NCF and QoL were evaluated using the Cognitive Stability Index and SF-36 at baseline and monthly for 4 months post treatment. Descriptive analyses included the reliable change index for serial evaluations and correlations for associations between outcome variables and age, tumor volume, total topotecan dose, and treatment effect. Individual classifications of response to treatment indicated that a majority of patients reported stable scores over the follow-up period. Demographic and treatment-related variables were not associated with outcomes. Baseline processing speed scores were invalid for 6 subjects. Higher rates of valid scores were observed on subsequent administrations. As the first study to use CED of any kind to evaluate the impact of CED on NCF or QoL, there was no evidence of severe detriment to either outcome. Long-term evaluation is necessary to track changes in NCF and QoL related to disease progression. Invalid scores suggest that computer-based assessments may not be suitable for all patients with malignant gliomas, especially those with cognitive deficits secondary to their disease. Future trials should include a wider range of sensitive measures to assess the impact of CED on patient NCF and QoL.

Phase IB study to evaluate efficacy and tolerability of olaparib (AZD2281) plus gefitinib in patients (P) with epidermal growth factor receptor (EGFR) mutation positive advanced non-small cell lung cancer (NSCLC) (NCT=1513174/GECP-GOAL).

8079 Background: Progression-free survival (PFS) and response rate (RR) to EGFR tyrosine kinase inhibitors (TKIs) vary in P with NSCLC driven by EGFR mutations, suggesting that other genetic alterations may influence oncogene addiction. High BRCA1 mRNA expression negatively influenced PFS among EGFR mutant P treated with erlotinib. We hypothesized that since olaparib can attenuate and/or prevent BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these P. Methods: This is a Phase IB dose escalation study (standard 3+3 design) to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK), and clinical activity of orally administered olaparib in combination with gefitinib in EGFR mutant advanced NSCLC. P were treated with gefitinib 250mg once daily plus olaparib at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: Twenty-two P were included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg ...

A phase Ib dose-escalation study of everolimus combined with cisplatin and etoposide as first-line therapy in patients with extensive-stage small-cell lung cancer

This phase Ib study aimed to establish the feasible everolimus dose given with standard-dose etoposide plus cisplatin (EP) for extensive-stage small-cell lung cancer (SCLC). An adaptive Bayesian dose-escalation model and investigator opinion were used to identify feasible daily or weekly everolimus doses given with EP in adults with treatment-naive extensive-stage SCLC. A protocol amendment mandated prophylactic granulocyte colony-stimulating factor (G-CSF). Primary end point was cycle 1 dose-limiting toxicity (DLT) rate. Secondary end points included safety, relative EP dose intensity, pharmacokinetics, and tumor response. Patients received everolimus 2.5 or 5 mg/day without G-CSF (n=10; cohort A), 20 or 30 mg/week without G-CSF (n=18; cohort B), or 2.5 or 5 mg/day with G-CSF (n=12; cohort C); all received EP. Cycle 1 DLT rates were 50.0%, 22.2%, and 16.7% in cohorts A, B, and C, respectively. Cycle 1 DLTs were neutropenia (cohorts A and B), febrile neutropenia (all cohorts), and thrombocytopenia (cohorts A and C). The most common grade 3/4 adverse events were hematologic. Best overall response was partial response (40.0%, 61.1%, and 58.3% in cohorts A, B, and C, respectively). Everolimus 2.5 mg/day plus G-CSF was the only feasible dose given with standard-dose EP in untreated extensive-stage SCLC.

Phase IB study of olaparib (AZD2281) plus gefitinib in EGFR-mutant patients (p) with advanced non-small-cell lung cancer (NSCLC) (NCT01513174/GECP-GOAL).

2581 Background: Progression-free survival (PFS) and response to EGFR tyrosine kinase inhibitors (TKIs) vary in p with NSCLC driven by EGFR mutations. In our experience, high BRCA1 mRNA expression was associated with shorter PFS in EGFR-mutant p treated with erlotinib. We hypothesized that since olaparib downregulates BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these p. Methods: This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics, and clinical activity of orally administered olaparib in combination with gefitinib in EGFR-mutant advanced NSCLC p. In a standard 3+3 design, p were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: 18 p have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (3) and 250mg TDS (6). Median age, 69; male, 4; PS 0, 17; EGFR TKI treatment-naïve, 10. Toxicities: anemia (66.6%), leucopenia (33.3%), nausea (33.3%), diarrhea (33.3%), asthenia (27.7%), rash (22.2%) vomiting (11%), decreased appetite (16%), and hyperlipasemia (5.5%). Most toxicities were G1-2; G3 drug-related events included leucopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 1 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions were needed. 1 p died due to pulmonary embolism unrelated to treatment. Partial responses (PR) were observed in 7 p (41.1%), all EGFR TKI-naïve; stable disease (SD) in 7 (41.1%), most previously treated; progressive disease (PD) in 3 (17.6%), all previously treated. Durable PR and SD were observed in EGFR TKI-naïve and previously treated p. 8 patients are still on treatment. Enrollment to dose level 4 will be completed in February 2013. Conclusions: This phase IB trial of gefitinib plus olaparib, has confirmed the activity and tolerability of the combination. The final recommended dose of olaparib is expected to be between 200 and 250 mg TDS. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC will be opened in 2013. Clinical trial information: NCT0151317.

Phase Ib dose escalation study of oral quisinostat, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma.

8530 Background: Aggresome formation is a mechanism of resistance to agents (e.g., bortezomib) which block proteasome activity. HDACi (e.g., quisinostat) prevents aggresome formation by deacetylation of tubulin that allows the transport of unfolded proteins to lysosomes for degradation. Methods: Patients received quisinostat (Q) at escalated doses (6, 8, 10 and 12 mg) on days 1, 3, and 5 weekly, subcutaneous VELCADE (V) at 1.3 mg/m2on days 1, 4, 8, and 11 of a 3-week cycle, and oral dexamethasone (D) at 20 mg on the day of and the day after VELCADE dosing. The primary endpoint was the maximum tolerated dose (MTD) of Q in the combination (Q+V+D). The secondary endpoints included safety, overall response rate, and pharmacodynamic biomarkers. Results: Eighteen patients (3, 3, 6, and 6 in increasing Q doses) were enrolled: 56% male; median age = 69 (range 50-82) years; multiple myeloma stage: IA = 11% and IIIA = 89%; prior lines of therapy: 1 = 100%, 2 = 55.6%, and 3 = 11.1%; prior VELCADE treatment = 50%. At the highest dose (12 mg) 2 patients had dose-limiting toxicity, 1 with QTc prolongation and 1 with atrial fibrillation. The MTD was established at the 10 mg Q for the Q+V+D regimen. The most common adverse events (≥ 10% of patients) were diarrhea (39%), asthenia (33%), peripheral oedema (22%), nausea (17%), thrombocytopenia (17%), alopecia (11%), constipation (11%), and vomiting (11%); most were grade 2 or lower in toxicity. To date, 13 patients have discontinued treatment, of which 5 completed 11 cycles of treatment. The overall response rate was 87.5% (14/16, 95% CI: 61.7% to 98.5%), including 1 complete response, 2 very good partial response, and 11 partial responses. Most patients (9/11) showed a decrease in number of circulating multiple myeloma cells after 1 cycle. Two of 5 patients showed an increase in acetylated histone 3 from baseline as measured in peripheral blood mononuclear cells. Conclusions: The MTD is 10 mg quisinostat in combination with VELCADE and dexamethasone. The combination is active in the treatment of relapsed multiple myeloma and has an acceptable safety profile. Clinical trial information: NCT01464112.

BEZ235 in combination with everolimus for advanced solid malignancies: Preliminary results of a phase Ib dose-escalation study.

e13518 Background: The mammalian target of rapamycin (mTOR) is a critical signaling pathway in many tumors including cancers of the breast and colon, glioblastoma multiforme, and hepatocellular carcinoma (HCC). Preclinical studies demonstrated the combination of BEZ235, a competitive dual phosphatidylinositide 3-kinase (PI3K)/mTOR inhibitor, and the mTOR inhibitor, everolimus led to greater regression of a carcinogen-induced HCC than treatment with higher doses of either drug alone. Based on this, we initiated a study of BEZ235 combined with everolimus in patients with advanced solid tumors. Methods: A single institution phase Ib dose-escalation study. Patients with advanced solid malignancies, no available standard of care treatment option, and ECOG performance status 0-2 were eligible. Prior treatment with PI3K inhibitors was not allowed. Sequential cohorts of 3-6 patients were treated. The starting dose was everolimus 2.5 mg and BEZ235 200 mg daily in an oral sachet formulation. Cohort 2 received everolimus 2.5 mg and BEZ235 400 mg daily. Pharmacokinetic and pharmacodynamic studies were performed during the first cycle. The phosphorylation of specific downstream effectors of the mTOR pathway was assessed in peripheral blood mononuclear cells (PBMC). Results: Eleven patients, median age 58 (36-73 years) were treated. Tumors included non-small cell lung cancer, colon cancer, and glioblastoma, hepatocellular carcinoma, pancreatic cancer, esophageal cancer, adenoid cystic carcinoma of the larynx, and appendiceal carcinoma. Four patients were treated on cohort 1. None experienced dose-limiting toxicity. Seven patients were treated on the second dose cohort. One patient withdrew necessitating replacement and another developed grade 3 stomatitis from herpes virus requiring cohort expansion. The most common adverse events were thrombocytopenia, lymphopenia, transaminitis, diarrhea, nausea and fatigue. No tumor responses were noted. PBMC showed a decrease in 4E-BP1S65 phosphorylation on day 28 in 2 of 3 patients in cohort 1. Conclusions: The combination of BEZ235 and everolimus was well tolerated at these doses. The trial remains open to accrual. Clinical trial information: NCT01508104.

A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with bevacizumab (BEV) for advanced solid tumors.

3059 Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, PK and preliminary efficacy of TRC105 in combination with BEV. Methods: Pts with advanced solid tumors, ECOG PS 0-1, and normal organ function were treated with escalating doses of IV TRC105 (3, 6, 8 or 10 mg/kg/wk) plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk. Results: Thirty one pts (median age = 62; M:F 14:17; median 4 prior regimens; primarily metastatic colorectal or ovarian cancer) were treated with TRC105 wkly + BEV. TRC105 3 mg/kg wkly + 15 mg/kg q3wk BEV was well tolerated. Concurrent administration of TRC105 6 mg/kg wkly + 15 mg/kg BEV q3wk resulted in headaches in 4 of 5 pts on cycle 1 day 1 (two grade 3). Dose escalation to the recommended single-agent phase II dose of 10 mg/kg TRC105 weekly + BEV (10 mg/kg q2wk) was tolerated when the initial TRC105 dose was introduced one week after BEV dosing and administered over 2 days. Headache was the only serious adverse drug reaction observed. Adverse events characteristic of each individual drug were not increased in frequency or severity. Target TRC105 serum concentrations were achieved at 6 mg/kg. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed beginning at 6 mg/kg and was dose proportional. Five of 19 heavily pretreated, BEV or VEGF receptor tyrosine kinase inhibitor (TKI) refractory pts with colorectal and ovarian cancer, each with marked tumor burden, experienced radiographic reductions in tumor volume (10-17%). Three of these patients remained on study longer than the prior VEGF inhibitor treatment and two are ongoing. Seven ongoing patients have been treated for 2-8 months. Conclusions: TRC105 10 mg/kg wkly was well tolerated with BEV 10 mg/kg q2wk. The combination demonstrated activity in BEV and VEGF TKI refractory pts. Randomized phase II trials of BEV +/- TRC105 have commenced in renal cell cancer and glioblastoma. Clinical trial information: NCT01332721.

A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with capecitabine for advanced solid tumors (including patients with progressive or recurrent HER2-negative metastatic breast cancer).

3057 Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody being studied in phase II trials that potentiates chemotherapy in preclinical models. Methods: Pts with advanced solid tumors (for purposes of dose escalation) or pts with metastatic HER2-negative breast cancer (following completion of dose escalation), ECOG PS 0-1, and normal organ function were treated with intravenously administered TRC105 wkly plus capecitabine at 1,000 mg/m2 BID for 14 of every 21 days, and assessed for safety, PK, and response. Results: Fourteen patients (median age = 52; M:F 4:10; median of 3 prior regimens; 10 with breast and 4 with colorectal cancer) were enrolled. Dose escalation proceeded from 7.5 mg/kg TRC105 to the recommended single agent phase II dose of 10 mg/kg of TRC105 in combination with capecitabine, without development of dose limiting toxicity. Fourteen pts were treated at 7.5 mg/kg (n=4) or 10 mg/kg (n=10) TRC105 wkly + 1,000 mg/m2 BID/14d capecitabine of repeating 21 day cycles. Patients experienced expected TRC105 related adverse events of grade 1 or grade 2 infusion reaction, epistaxis, gingival bleeding, telangiectasia, headache, rash, and fatigue. Grade 3 headache and grade 3 vomiting were each seen in one patient. Adverse events characteristic of each individual drug were not increased in frequency or severity when the two drugs were administered together. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed at both dose levels. A heavily pretreated male breast cancer patient remained on study for 9 months with a RECIST-defined partial response. Stable disease beyond 9 weeks was observed in three patients. Conclusions: The recommended single agent phase II dose of 10 mg/kg TRC105 wkly was well tolerated in combination with capecitabine. The combination treatment could be advanced in HER2-negative breast or colorectal cancer. Clinical trial information: NCT01326481.

Phase Ib dose-escalation study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, administered by intravenous (IV) infusions in patients with metastatic colorectal carcinoma (mCRC).

3608^ Background: Pexa-Vec is an EGFR-targeted vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity (Nat Rev Cancer 2009). Dose-dependent IV Pexa-Vec delivery was defined previously (Nature2011). This study was designed to assess the safety, maximal tolerated dose and anti-tumor activity of Pexa-Vec administered IV in patients with mCRC after failure of standard therapies. Methods: Nine patients were treated at 1 of 3 dose levels (106, 107 or 3x107pfu/kg IV every 2 weeks x 4) in a standard 3+3 dose-escalation design; 6 additional patients were enrolled at the MFD. Anti-tumor activity according to RECIST was determined using serial CT scans. Pharmacokinetic studies were also performed. Data summarized prior to database lock. Results: 15 patients with mCRC refractory to irinotecan, oxaliplatin, and 5-FU were treated (median lines of therapy 5; range 2-7); 13 of 15 received prior anti-angiogenic agents, and 11 of 12 KRAS WT tumors failed cetuximab. Adverse events were generally grade 1/2 and included: fever (93%), chills (93%), headache (60%), nausea (60%), and hypotension (40%). No dose-limiting toxicities or grade 3/4 events were reported. Only patients treated at high-dose (Cohort 3 & Expansion) exhibited a pustular rash (n=9; 78%). Pexa-Vec genomes detected in blood acutely were above the dose threshold for systemic delivery. Notably, clearance was not more rapid with repeated IV treatments despite the induction of humoral immunity. Furthermore, patients at the top dose level exhibited increased disease stabilization at Week 4 (89% high-dose (n= 9) versus 33% low-dose (n=6)). A trend (p=0.16) towards increased overall survival at high vs low-dose Pexa-Vec was observed with 78% high-dose patients still alive between 5 and 13 mos. Conclusions: Repeat IV Pexa-Vec was well-tolerated with transient flu-like symptoms. Dose-dependent safety, pharmacokinetics and anti-tumor activity were described in treatment-refractory mCRC patients. Clinical trial information: NCT01380600.

358P - Pharmacokinetics of Eribulin Mesilate in Combination With Capecitabine in Patients With Advanced/Metastatic Cancer: Results From a Phase Ib Dose-Escalation Study

ABSTRACT Background Eribulin is a microtubule dynamics inhibitor EMA approved for certain patients (pts) with locally advanced (LA)/metastatic breast cancer (MBC) who have received ≥2 prior chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and taxane. This Phase Ib, open-label dose-escalation study assessed maximum tolerated dose (MTD), safety and pharmacokinetics (PK) of eribulin in combination with capecitabine in pts with advanced/metastatic cancer. Methods Pts received eribulin mesilate (2–5-min IV) by Schedule 1 (1.2, 1.6 or 2.0 mg/m2 on Day [D] 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m2 on D1 and D8) in combination with twice-daily oral capecitabine 1000 mg/m2 on D1–14 every 21 days. To assess PK and drug-drug interaction of eribulin, capecitabine and capecitabine metabolites in Cycle 1 and 2, samples were taken on D1 (pre-, 0, 0.25, 0.5, 1–4, 6 and 8 h post-dose), any time on D2–3 and D4–6, and D8 (Schedule 1: pre-, 0.5, 1–4 and 6 h post-capecitabine; Schedule 2: pre-dose). PK was examined by non-compartmental analysis, and cardiac repolarization by 12-lead ECGs at screening, D1 (pre- and 4 h post-dose), D2–3, D8 and D15. Correlation of eribulin and capecitabine plasma concentrations with change from baseline (Δ) QTc was explored. Results Schedule 1 (n = 19) and Schedule 2 (n = 15) MTDs were 1.6 and 1.4 mg/m2 eribulin mesilate, respectively. Dose-limiting toxicities (all n = 1) were: Grade (G) 4 neutropenia, G3 febrile neutropenia, G3 fatigue, G3 lethargy (Schedule 1); G4 neutropenic sepsis, G3 neutropenia (Schedule 2). There were no unexpected toxicities. Eribulin PK was independent of schedule and had dose-related increases in exposure. No accumulation occurred upon multiple dosing; at each dose, eribulin PK was comparable in Cycles 1 and 2. Exposure to capecitabine and metabolites was variable and independent of schedule. Co-administration had no effect on ΔQTc. Conclusions No drug-drug interaction of eribulin and capecitabine was observed. From these results, the combination appears to be tolerated without effect on cardiac repolarization. A Phase II LA/MBC study evaluating Schedule 2 MTD is ongoing. Disclosure C.J. Twelves: The author declares the following conflicts of interest: consultant/advisory role (Eisai) and honoraria/speakers bureau (Eisai). C. Savulsky: The author declares the following conflicts of interest: employee (Eisai Ltd). C. Johnston: The author declares the following conflicts of interest: employee (Eisai Ltd). L. Reyderman: The author declares the following conflicts of interest: employee (Eisai Inc.). J. Wanders: The author declares the following conflicts of interest: employee at the time of study (Eisai Ltd). R. Plummer: The author declares the following conflicts of interest: research funding (Eisai Ltd). T.R..J. Evans: The author declares the following conflicts of interest: research funding (Eisai Ltd). All other authors have declared no conflicts of interest.

454P - Phase IB Dose-Escalation Study of BEZ235 or BKM120 in Combination with Paclitaxel (PTX) in Patients With Advanced Solid Tumors

ABSTRACT Background The pan-PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235 have demonstrated preclinical and clinical antitumor activity as single agents and in combination with other drugs. Here, we report interim results of BKM120 or BEZ235 + PTX in pts with advanced solid tumors. Methods In the first 2 arms of this 4-arm Phase Ib dose-escalation study, pts with metastatic or locally advanced solid tumors received once-daily oral BKM120 or BEZ235 + wkly IV PTX. Dose-escalation was guided by a Bayesian logistic regression model with overdose control. The primary objective was to determine the MTD of BKM120 or BEZ235 + PTX. Results 33 pts were treated with BKM120 (mg/d) + PTX (mg/m2) at 6 dosing levels: 40/70 (1 pt); 40/80 (5 pts); 60/80 (3 pts); 80/80 (4 pts); 100/80 (16 pts); and 120/80 (4 pts). DLTs were observed in 4 pts (1/16 at 100/80 and 3/4 at 120/80), including asthenia, hyperglycemia, and depression. The MTD of BKM120/PTX was declared as 100/80. Most common G3/4-suspected study treatment-related AEs (>5%) were neutropenia, hyperglycemia, and anemia. For the BEZ235 arm, 29 pts were treated with BEZ235 (mg/d) + PTX (mg/m2) at 4 dosing levels: 400/70 (2 pts); 400/80 (3 pts); 600/80 (4 pts); and 800/80 (20 pts). DLTs were observed in 4 pts (3/20 at 800/80 and 1/4 at 600/80), including GI events, peripheral neuropathy, and febrile neutropenia. The MTD of BEZ235/PTX was declared as 800/80. Most common G3/4-suspected study treatment-related AEs (>10%) were fatigue, diarrhea, and anemia. As of Feb 29, 29 pts were evaluable for response in each arm. In the BKM120/PTX arm, 1 CR (penile carcinoma [Ca]), 4 PRs (breast and ovarian Ca pts, each with multiple lines of prior therapy [12 and 3] and progression on prior PTX; cervical and vulvar Ca), and 11 SDs were observed. In the BEZ235/PTX arm, 1 PR (large-cell Ca of the lung, taxane-naive), and 9 SDs were observed. Conclusion BKM120 or BEZ235 + PTX were generally well tolerated and showed preliminary signs of efficacy. The MTDs of both BKM120/PTX and BEZ235/PTX were reached. For BKM120, the MTD in combination with PTX was the same as the single-agent MTD. Arms 3 and 4 will determine the MTD of BEZ235 or BKM120 + PTX and trastuzumab in pts with advanced HER2+ breast Ca. Disclosure M. Schuler: Martin Schuler is an advisor for Novartis, and receives research funding from Novartis. J. Machiels: Jean-Pascal Machiels is on an advisory board for Boehringer, and receives a research grant from Sanofi. D. Hess: Dagmar Hess owns N. Steeghs: Neeltje Steeghs receives research funding from Novartis. L. Paz-Ares: Luis Paz-Ares has been an advisor for Lilly, Bayer, Roche and Pfizer. He has also received honoraria from all of the above. R. von Moos: Roger von Moos is a participant of advisory boards for Amgen, Novartis, Roche, BMS, and MSD, and receives unrestricted research grants and speaker honoraria from Amgen and Roche. B. Rabault: Bertrand Rabault is a employee of Novartis Pharma AG and owns stock in novartis pharma. All other authors have declared no conflicts of interest.

450PD - A Phase IB Combination Study of RO4929097 (RO), A Gamma-Secretase Inhibitor, and Temsirolimus (TEM) in Patients (PTS) with Advanced Solid Tumors

ABSTRACT Background The notch signalling pathway has a critical role in regulating cellular differentiation, proliferation, and apoptosis. RO is a potent and selective gamma-secretase inhibitor with antitumor activity in animal models. Pre-clinical experiments indicate that the PI3K/AKT/mTOR pathway may mediate resistance to gamma secretase inhibitors, providing a rationale for combination therapy with RO and TEM. Methods A phase Ib dose-escalation study with a 3 + 3 design was conducted. Three dose levels (DLs) were planned. Objectives were to determine the recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the combination. Eligible pts received once daily oral RO on a 3 day on/4 day off schedule every week (QW), and intravenous QW TEM. Initial doses were 10 mg RO and 25 mg TEM. Cycles were every 21 days, except for cycle 1, which was 28 days. Treatment-related dose-limiting toxicities (DLTs) were evaluated during cycle 1. Results 17 pts (data cut-off 26-Apr-2012) have been treated on three DLs. Number of pts, DLTs and schedule are shown in Table 1. Demographics: M:F 6:11; median age: 60 yrs (range 28-84); ECOG 0/1:4/13. Pts received a median of 3 cycles (range 1-12). The most common adverse events (AEs) related to the study drug combination included: fatigue (82%; G3 6%), mucositis, (71%; G3 6%), neutropenia (59%; G3 12%), anemia (59%; G3 0%), and hypertriglyceridemia (59%, G3 0%).Two DLTs (G3 rash, G3 mucositis) were observed in the same patient in DL1 prompting dose expansion. No additional DLTs were observed. Of 15 patients evaluable for response, no objective responses were observed. 11 pts (73%) had stable disease (SD) as their best response; with 3 pts (sarcoma, neuroendocrine, non-small cell lung cancer) on therapy for ≥6 cycles. Conclusions RO can be safely combined with TEM. The RP2D was established as RO at 20 mg combined with 37.5 mg of TEM. PK and circulating angiogenic factors analyses will be presented. Dose Level RO Dose (mg) TEM Dose (mg) No. of pts treated No. of pts with DLT DLT 1 † 10 25 8 1 G3 rash, G3 mucositis 2 20 25 3 0 3 ∧ 20 37.5 6 0 † 2 pts were not evaluable for DLT ∧ DL3 (RP2D) was expanded to 6 pts Disclosure All authors have declared no conflicts of interest.

A phase Ib dose escalation study of JX-594 (TK-vaccinia virus expressing GM-CSF) administered by biweekly intravenous infusion in patients with metastatic, refractory colorectal carcinoma.

e13044 Background: JX-594 is a recombinant vaccinia virus engineered to selectively replicate in and destroy cancer cells while stimulating a systemic anti-tumor immune response and inducing a reduction in tumor blood perfusion. Preclinical data has demonstrated JX-594 activity is enhanced in cells with up regulation of the EGFR pathway. JX-594 anti-tumor activity in multiple advanced solid tumors has been observed in early stage clinical studies. This study was designed to assess the safety, MTD/MFD, and initial anti-tumor activity of JX-594 administered IV every other week x 4 total treatments in patients with metastatic CRC after failure of standard chemotherapy. Methods: A standard 3+3 dose escalation design was used to enroll patients into three dose levels (106, 107 or 3x107pfu/kg) of JX-594 administered IV every 2 weeks x4. Safety was assessed using CTCAEv3.0. Anti-tumor activity was determined based on serial CT scans and CEA measurements. Patient samples were collected for pharmacokinetics and pharmacodynamics. Results: Enrollment is ongoing with 8 patients treated at total doses ranging from 5x107 to 2x109 pfu. Adverse events have generally been limited to grade 1/2, transient flu-like symptoms (fever, chills, headache). No DLT was reported. Three patients in the top two dose levels demonstrated SD on week 4 CT scan with one maintained at week 8. In these same 3 patients, CEA declined by 50% in a single patient while the other 2 had no significant change in CEA. Conclusions: Preliminary data for this dose escalation trial demonstrates JX-594 is well tolerated after 4 IV treatments administered every other week. CEA and CT scan assessment suggest possible efficacy. Enrollment continues and an expansion cohort at the MTD is planned. Updated data is expected at the time of presentation.

A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors.

2566 Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In preclinical models, concurrent administration of GDC‑0973, a potent, selective, MEK1/2 inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved efficacy compared to either agent alone dosed continuously or intermittently. Methods: A phase Ib dose-escalation study with 3+3 design was initiated in patients (pts) with advanced solid tumors to evaluate the safety and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941. Pts received: concurrent GDC-0973 + GDC-0941 once daily (qd) on a 21 day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 qd on a 21/7 schedule (MEK int); or GDC-0973 + GDC-0941 qd on a 7 day on /7 day off schedule (7/7). Starting doses were 20 mg GDC-0973 + 80 mg GDC-0941 (21/7), 100 mg GDC-0973 + 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 + 130 mg GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n=1), G4 CPK elevation (n=1). Compared to the 21/7 MTD of 40 mg GDC-0973 + 100 mg GDC-0941, higher doses of GDC-0973 + GDC-0941 were tolerated on the MEK int schedule. Overall, adverse events related to the study drug combination in ≥ 20% pts were diarrhea, rash, nausea, fatigue, vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary analysis indicated PK of GDC-0973 and GDC-0941 are not altered when dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial metabolic response (≥ 20% decrease in mean SUVmax from baseline) at ≥1 time points. Partial responses were observed in 3 pts (mBRAF melanoma, mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease ≥ 5 months. Conclusions: Combination dosing of GDC‑0973 and GDC-0941 is generally well tolerated, with toxicities similar to those observed in single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules continues and updated data will be presented.

Phase Ib dose-escalation study of a phase II randomized trial to assess the safety and tolerability of tigatuzumab (CS-1008) in combination with sorafenib in patients (pts) with advanced hepatocellular carcinoma (HCC).

e14617 Background: Tigatuzumab (T), a humanized monoclonal antibody that acts as a DR5 agonist and exerts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-like activity, is currently undergoing a phase Ib/II study in advanced HCC. Preclinical studies showed that sorafenib (S) can overcome TRAIL resistance in HCC cells and enhances T-induced apoptosis. In this phase Ib dose-escalation portion of a phase 2 study, safety/tolerability of T + S was evaluated in advanced HCC pts. Methods: Adult pts (≥ 18 years) with advanced HCC and measurable disease (RECIST v1.1), ECOG=0/1, and Child-Pugh A, were administered sequentially-escalating doses of T (2, 4, 6 mg/kg/week IV) in combination with S (400 mg PO BID) over 4 weeks (n = 3/cohort). If no pt had a dose-limiting toxicity (DLT), dose escalation proceeded. If 1/3 pts had DLT, the cohort was to be expanded to 6; if 2/3 or 2/6 pts had DLT, the cohort was to be expanded to 9. Dose escalation was to be stopped when ≥ 3 pts experienced DLTs in a cohort with the prior dose designated as the maximum tolerated dose (MTD). Pts received treatment until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent. Results: Nine pts (3 at each dose level of T + S) were treated in this phase Ib portion. Grade 3/4 treatment-emergent AEs (> 20% incidence) were increased AST, blood amylase, and lipase and hand-foot syndrome. Serious AEs were reported in 5 pts (upper GI hemorrhage, esophageal varices hemorrhage [EVH], tumor progression, increased serum amylase, fever, and lumbar spine compression), which were considered unrelated to study medication except for EVH (T + S), increased serum amylase (T + S), and fever (S). No DLTs were observed and the MTD of T was not reached. 2 pts had a partial response, and 4 pts had disease stabilization. The trial is ongoing. Conclusions: Phase Ib data show that T in combination with S was safely administered with no DLT and demonstrated clinical activity in advanced HCC pts. T and S constitute a promising rational combination treatment for HCC.

A phase Ib dose-escalation study of TRC105 in combination with bevacizumab for advanced solid tumors.

3034 Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is a human/mouse chimeric anti-CD105 monoclonal antibody that completed phase I testing and is being studied in multiple phase II trials. Methods: Pts with advanced solid tumors (non-CNS), ECOG PS 0-1, and normal organ function were treated with escalating doses of intravenously administered TRC105 plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk and assessed for safety, PK, and response. Results: Twelve pts were treated (3 with TRC105 at 3 mg/kg q1wk + BEV at 15 mg/kg q3wk, 5 with TRC105 at 6 mg/kg q1wk + BEV at 15 mg/kg q3wk, and 4 with TRC105 at 6 mg/kg q1wk + BEV at 10 mg/kg q2wk), and 10 have completed the DLT evaluation period. TRC105 at 6 mg/kg q1wk + BEV at 15 mg/kg q3wk resulted in grade 1-3 headaches with sinus congestion following the cycle 1 day 1 (C1D1) dose in 5 of 5 pts that improved with continued dosing. Treatment with BEV 10 mg/kg q2wk and sequential dosing with Bev starting on C1D1 and TRC105 on C1D8 resulted in decreased frequency and severity of headaches, allowing dose escalation to continue. TRC105 serum concentrations that saturate CD105 binding sites (>200 ng/mL) were achieved continuously at 6 mg/kg q1wk. At 3 mg/kg q1wk TRC105 + 15 mg/kg q3wk BEV, one pt with BEV-resistant ovarian cancer had stable disease for 6 cycles and one pt with refractory hepatocellular cancer who failed sorafenib and sunitinib had an AFP decrease from 1578 at baseline to 179 at the end of cycle 3. Two of three evaluable pts at 6 mg/kg q1wk TRC105 + 15 mg/kg q3wk BEV with VEGF-refractory tumors (HCC and CRC) are ongoing in C4 with stable disease. Dose escalation continues and TRC105 dose levels of 8 and 10 mg/kg are planned. Conclusions: The combination of TRC105 and BEV was tolerated with early evidence of activity in VEGF-refractory pts by sequential administration during initial dosing in C1.

A phase Ib dose-escalation study of eribulin mesylate in combination with capecitabine in patients with advanced/metastatic cancer.

2552 Background: Eribulin mesylate is a microtubule dynamics inhibitor approved by FDA for patients (pts) with metastatic breast cancer after treatment with at least two prior chemotherapeutic regimens. This Phase Ib, open-label dose-escalation study determined the maximum tolerated dose (MTD) of eribulin in combination with capecitabine. Methods: Pts with advanced solid malignancies refractory to standard therapies, adequate organ function and ECOG performance status ≤2 received eribulin mesylate (2–5-min IV) by Schedule 1 (1.2, 1.6 or 2.0 mg/m2 on Day 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m2 on Days 1 and 8), in combination with twice-daily oral capecitabine 1000 mg/m2 Days 1-14 every 21 days. The MTD was defined as the highest dose in each schedule where ≤1/6 pts experienced dose-limiting toxicity (DLT). Safety and pharmacokinetics (PK) were assessed. Results: Of the 34 pts recruited, 19 (53% male; median age 62 years; 42% ECOG 0, 58% ECOG 1) and 15 (33% male; median age 61 years; 33% ECOG 0, 60% ECOG 1, 7% ECOG 2) were enrolled in Schedules 1 and 2, respectively. Most common tumor types were large intestine (20.6%), lung/bronchus (17.7%) and breast (14.7%). DLTs are shown in the table; there were no unexpected toxicities with the combination. The MTD for eribulin mesylate was 1.6 and 1.4 mg/m2 for Schedules 1 and 2, respectively, in combination with capecitabine 1000 mg/m2 twice-daily. Eribulin PK were dose proportional and independent of schedule or capecitabine co-administration. Combination with eribulin had no effect on the disposition of capecitabine and its metabolites. Although sample size was small, preliminary signs of efficacy were observed. Conclusions: The combination of eribulin and capecitabine was well tolerated with no unexpected safety findings. Schedule 2 MTD (1.4 mg/m2 Days 1 and 8) delivered a higher dose intensity of eribulin than Schedule 1 and was selected for evaluation in an ongoing Phase II breast cancer study. [Table: see text]