Prior Sorafenib Research Articles

Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040.

LBA101 Background: Overexpression of PD-L1 in HCC has a poor prognosis. Safety and preliminary antitumor efficacy of nivolumab, a fully human IgG4 monoclonal antibody PD-1 inhibitor, was evaluated in a multiple ascending-dose, phase I/II study in patients (pts) with HCC. Methods: Pts with histologically confirmed advanced HCC with Child-Pugh (CP) score ≤ B7 and progressive disease (PD) on, intolerant of, or refusing sorafenib were enrolled. Dose escalation occurred in parallel cohorts based on etiology: no active hepatitis virus infection or virus-infected HCC pts. Pts received nivolumab 0.1 – 10 mg/kg intravenously for up to two years. The primary endpoint was safety. Secondary endpoints included antitumor activity using mRECIST criteria, pharmacokinetics, and immunogenicity. Results: The study has enrolled 41 pts with a CP score of 5 (n = 35) or 6 (n = 6), ECOG score of 0 (n = 26) or 1 (n = 15), 73% with extrahepatic metastasis and/or portal vein invasion, and 77% with prior sorafenib use. Eighteen pts remain on study, and 23 discontinued treatment due to PD (n = 17), complete response (CR; n = 2), drug-related adverse events (AEs; n = 2) and non-drug–related AEs (n = 2). Drug-related AEs of any grade occurred in 29 pts (71%; 17% grade 3/4), with ≥ 10% of pts experiencing aspartate aminotransferase (AST) increase and rash (each 17%), alanine aminotransferase(ALT) and lipase increase (each 15%), and amylase increase (12%). Grade 3 and 4 AEs ≥ 5% were AST increase (12%), ALT increase (10%) and lipase increase (5%). A dose-limiting toxicity occurred in an uninfected pt at 10 mg/kg; no maximum tolerated dose was defined in any cohort. Response was evaluable in 39 pts: 2 CR (5%) and 7 partial responses (PR; 18%). Response duration was 14–17+ months for CR, < 1–8+ months for PR, and 1.5–17+ months for stable disease (SD). Overall survival (OS) rate at 6 months is 72%. Conclusions: Nivolumab has a manageable AE profile and produced durable responses across all dose levels and HCC cohorts, with a favorable 6-month OS rate. Updated safety, antitumor activity, and biomarker data will be presented. Clinical trial information: NCT01658878. [Table: see text]

Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): Analysis of REACH pts by Child-Pugh (CP) score.

4108 Background: REACH was a global, randomized, double-blind, phase III study evaluating the efficacy and safety of RAM as a single-agent treatment of pts with advanced HCC after prior sorafenib therapy. The primary outcome for the ITT population was presented at ESMO 2014. The overall survival (OS) HR for the ITT population (RAM 283; placebo [PBO] 282) was 0.866 (95% CI 0.717, 1.046; p = 0.1391). In pts with baseline alpha-fetoprotein (AFP) ≥ 400 ng/mL (RAM 119; PBO 131), OS HR was 0.67 (95% CI 0.51–0.90; p = 0.0059). Methods: Efficacy and safety of RAM based on CP score are presented for all pts enrolled in REACH inclusive of ITT (n = 565) and CP B (n = 78) population. Results: In REACH, pts with CP5 (N = 177 RAM, N = 180 PBO), CP6 (N = 108 RAM, N = 100 PBO), and CP7+8 (CPB) (N = 39 RAM, N = 39 PBO) were enrolled. Baseline pt characteristics were generally balanced between treatment arms by CP score. The table below shows OS, PFS, ORR and DCR according to CP score. The safety profile of RAM in pts with...

Phase 3 randomized, double-blind, controlled study of cabozantinib (XL184) versus placebo in subjects with hepatocellular carcinoma who have received prior sorafenib (CELESTIAL; NCT01908426).

TPS496 Background: Currently, there are no approved systemic therapies for patients with advanced hepatocellular carcinoma (HCC) who fail sorafenib. Cabozantinib is an oral receptor tyrosine kinase inhibitor (TKI) with activity against tyrosine kinases including MET, RET and VEGFRs. MET and VEGFR signaling have been implicated in tumor neo-angiogenesis and invasion. MET is overexpressed in HCC compared with non-tumor liver tissue, with higher MET expression linked to poor prognosis. Cabozantinib prolonged survival in a MET-driven transgenic mouse model of HCC, and has demonstrated clinical activity in multiple solid tumor types, including 41 subjects with advanced HCC treated in a phase 2 randomized discontinuation study. Methods: This phase 3, randomized, double-blind study evaluates the efficacy and safety of cabozantinib compared with placebo in subjects with advanced HCC previously treated with sorafenib and have progressed following 1-2 prior systemic treatments for HCC. Subjects must be ≥ 18 year old, have Child-Pugh Score of A and ECOG PS ≤ 1. Subjects are randomized 2:1 to receive either cabozantinib or placebo. Stratification factors are etiology of disease, geographic region and the presence of extrahepatic spread of disease and/or macrovascular invasion. The primary endpoint is overall survival. Secondary endpoints are progression-free survival and objective response rate by RECIST 1.1. Additional endpoints include safety, tolerability, circulating tumor cells, serum bone markers and plasma biomarkers, effects on bony disease assessed by bone scan and health-related quality of life (HRQoL) using the EuroQol Health questionnaire (EQ-5D-5L). Enrollment was initiated in September 2013. Target recruitment is 760 subjects. A total of 621 events planned with 2 interim analyses (at 311 and 466 events) would provide 90% power to detect a 31.6% increase in OS (HR=0.76). Clinical trial information: NCT01908426.

Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): Analysis of patients with elevated α-fetoprotein (AFP) from the randomized phase III REACH study.

232 Background: REACH was a global, multicenter, randomized, double-blind, phase 3 study evaluating the efficacy and safety of RAM as a single agent for the treatment of pts with advanced HCC after prior sorafenib therapy. The primary outcome for REACH was presented at ESMO 2014. The overall survival (OS) HR for the ITT population (RAM 283; placebo [PBO] 282) was 0.866 (95% CI 0.717, 1.046; p=0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. The pre-specified subgroup analysis of baseline AFP (cutoff 400 ng/mL) suggested AFP is a predictive marker for RAM survival benefit. Methods: Pre-specified subgroup analysis was performed based on baseline AFP with a cutoff of 400 ng/mL. Additional analyses were conducted using stratified/unstratified cox regression models and corresponding log rank test to evaluate the relationship between baseline AFP and RAM treatment effect. Results: In 250 pts with baseline AFP ≥400 ng/mL (RAM 119; PBO 131), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059). Median OS was 7.8m for RAM vs 4.2m for PBO. In 417 pts with a baseline AFP ≥1.5 × upper limit of normal (ULN; RAM 205; PBO 212), mOS was 8.6m for RAM vs 5.7m for PBO and the HR was 0.749 (95% CI: 0.603, 0.930) (p=0.0088). The interaction testing of baseline AFP and RAM treatment effect on OS using both cutoffs (400 ng/mL and 1.5 xULN) are significant (p-value = 0.0272 and 0.0372, respectively). The safety profile in these pt populations was similar to that observed in the overall safety population. Additional REACH analyses demonstrating the predictive value of baseline AFP for RAM treatment effect on OS will be presented. Conclusions: A clinically meaningful improvement in OS was observed in populations with a baseline AFP ≥400 ng/mL or ≥1.5 × ULN. Additional analyses demonstrated a consistent RAM OS benefit for the pt population with baseline AFP over a wide range of values above the normal range. Baseline AFP is a likely predictive marker for RAM OS benefit. Clinical trial information: NCT01140347.

Hepatocellular cancer (HCC) patients on phase I clinical trials in sorafenib era: Analysis of a single institution experience in last 10 years.

e15134 Background: Sorafenib is the only approved systemic therapy in HCC. Clinical trials in HCC often exclude patients with Child-Pugh Stage (CPS) B/C cirrhosis. Furthermore, limited information on outcomes specific to HCC population are reported from early clinical trials. We evaluated the efficacy and safety of early phase clinical trial agents in HCC. Methods: We analyzed 53 Phase I clinical trials that enrolled HCC patients at our institution between 2003–2013. Median progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves along with medians and groups were compared with the log rank test. The magnitude of association and survival was estimated with the hazard ratio (HR). Results: Median age 63 (33–84), males 75 %, ECOG PS 0–1 92%, CPS A 19%, B 71.7% and C 9.4%. 41.5% subjects were treated with prior Sorafenib. Class of agents used included cytotoxics such as microtubule inhibitors (26.4%), anti-folates (5.7%), alkylators (1.9%), topoisomerase inhibitors (...

Phase 3 randomized, double-blind, controlled study of cabozantinib (XL184) versus placebo in subjects with hepatocellular carcinoma who have received prior sorafenib (CELESTIAL; NCT01908426).

Phase 3 randomized, double-blind, controlled study of cabozantinib (XL184) versus placebo in subjects with hepatocellular carcinoma who have received prior sorafenib (CELESTIAL; NCT01908426).

Ramucirumab in metastatic renal cell carcinoma: The beginning or the end?

The current editorial focuses on a phase 2 study evaluating ramucirumab in patients with metastatic renal cell carcinoma (mRCC) who have received prior sunitinib and/or sorafenib therapy. The potential for further development is discussed in the context of the rapidly changing landscape of therapy for mRCC.

Collective analysis of efficacy and safety of patients with advanced hepatocellular carcinoma (HCC) enrolled into early-phase clinical trials.

320 Background: Sorafenib is the only approved systemic therapy in HCC. Clinical trials in HCC often exclude patients with Child-Pugh Stage (CPS) B/C cirrhosis. Furthermore, limited information on outcomes specific to HCC population are reported from early clinical trials. We evaluated the efficacy and safety of early phase clinical trial agents used to treat HCC. Methods: 42 consecutive patients with advanced HCC enrolled in one of the 53 phase I trials at our institution between 2003- 2013 were analyzed. Median progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves along with medians and groups were compared with the log rank test. The magnitude of association and survival was estimated with the hazard ratio (HR). Results: Median age 63 (33–84), males 75 %, ECOG PS 0–1 92%, CPS A 19%, B 71.7% and C 9.4%. 41.5% subjects were treated with prior Sorafenib. Class of agents used included cytotoxics such as microtubule inhibitors (26.4%), anti-folates (5.7%), alkylators (1.9%), topoisomerase inhibitors (5.7%), and non-cytotoxic agents such as pro-apoptotic therapies (15.1%), anti-VEGF (17%) mTOR/ EGFR/ IGFR (22.6%), and HDAC inhibitors (5.7%). When evaluating for efficacy for all patients, the mPFS (95% CI) =2.3 (1.9, 3.9) months and 12 month OS ± SEM = 59% ± 15%. The mPFS was 3.7 months versus 2.1 months for CPS A subjects and CPS B/C subjects respectively (HR 1.5, CI: 0.7- 3.5, p= 0.31). The 12-month OS was 80 ± 18% among pts with CPS A vs 74 ± 8% in CPS B. Grade 3-4 toxicity included hematologic (13.2%) and hepatic (20.8%), with no significant difference in toxicity between the two CPS groups. Finally, cytotoxic agents had a mPFS of 3.1 months (95% CI: 2.1- 4.4) vs 1.9 months (95% CI: 1.1- 2.3) for non-cytotoxic therapy (HR 1.56, 95% CI: 0.8–3.07, p = 0.19). The 12 month OS was 46% vs 50% between these two groups (HR 6.2, CI: 1.3–29.3, p = 0.009). Conclusions: Patients with advanced HCC have a modest survival that is compounded further by poor liver function. Our data suggests that there are no significant differences in efficacy and safety between HCC patients with varying liver dysfunction based on CPS status.

EVOLVE-1: Phase 3 study of everolimus for advanced HCC that progressed during or after sorafenib.

172 Background: No effective treatment options exist for advanced HCC following sorafenib failure. Preliminary data suggest everolimus may provide benefit after sorafenib. EVOLVE-1 (NCT01035229) assessed the efficacy and safety of everolimus for advanced HCC after sorafenib failure. Methods: Pts aged ≥18 y with BCLC stage B or C HCC and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were sorafenib intolerant were randomized 2:1 to everolimus 7.5 mg/d or placebo. All pts received best supportive care. Randomization was stratified by region (Asia v rest of world) and macrovascular invasion (yes v no). Study drug was given continuously until disease progression or intolerable toxicity. CT/MRI was performed every 6 wk. Primary endpoint was OS. Secondary endpoints were TTP, disease control rate (DCR; percentage of pts with best overall response of CR, PR, or SD per RECIST 1.0), and safety. Final analysis was performed when 454 deaths occurred. Results: 546 pts from 18 countries enrolled from Apr 2010 to Mar 2012 (everolimus = 362, placebo = 184). Baseline characteristics were balanced between arms; median age was 66.0 y, 84.8% of pts were male, 86.3% had BCLC stage C disease, 16.7% were from Asia, 32.8% had macrovascular invasion, and 74.0% had extrahepatic disease. Prior sorafenib was discontinued for disease progression in 80.8% of pts and intolerance in 19.0%. Median OS was 7.56 mo with everolimus and 7.33 mo with placebo (HR 1.05; 95% CI 0.86-1.27; P = .675). Median TTP was 2.96 mo and 2.60 mo, respectively (HR 0.93; 95% CI 0.75-1.15). DCR was 56.1% and 45.1%, respectively (P = .010). The most common grade 3/4 AEs with everolimus (v placebo) were anemia (7.8% v 3.3%), asthenia (7.8% v 5.5%), decreased appetite (6.1% v 0.5%), and hepatitis B viral load increase or reappearance (6.1% v 4.4%). No pts experienced HCV flare. HBV reactivation was experienced by 39 pts (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. Conclusions: Everolimus did not improve OS in pts with advanced HCC whose disease progressed on or after sorafenib or who were sorafenib intolerant. The safety profile was consistent with that previously observed with everolimus. Clinical trial information: NCT01035229.

A Phase I/II Trial of Combination of PKC412 and 5-azacytidine (AZA) for the Treatment of Patients with Refractory or Relapsed (R/R) Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Abstract Abstract 3587 Background: Midostaurin (PKC412) is a potent orally bioavailable FLT3 inhibitor with activity in acute myeloid leukemia (AML). 5-azacytidine (5-AZA) is a hypomethylating agent that plays an important role in the treatment of AML and MDS. We hypothesized that adding midostaurin to 5-AZA may improve the response rate with limited toxicity profile. Materials and Methods: Patients ≥18 years with MDS, chronic myelomonocytic leukemia (CMML) or AML, who failed prior therapies with performance status ≤ 2, adequate liver (bilirubin ≤ 2 × ULN, ALT ≤ 2.5× ULN) and renal (creatinine ≤2× ULN) functions were eligible. Patients were included in phase I regardless of FLT3 mutation status; only FLT3 mutated patients were included in phase II. Patients received 5-AZA 75 mg/m2 subcutaneously or intravenously for 7 days of each cycle (Days 1–7) and midostaurin at 25 mg (cohort 1) and 50 mg (cohort 2; target dose) orally twice daily for 14 days (Days 8–21) per cycle. Patients were planned to receive up to 12 cycles if benefit from treatment. Supportive care was standard. The study was approved by institutional IRB and conducted in accordance of the declaration of Helsinki. Results: 20 patients have been enrolled: 13 included in phase I (6 in cohort 1 and 7 in cohort 2) and 6 patients in phase II. One patient in cohort 1 was inevaluable for DLT (withdrawal before completing cycle #1). One patient in cohort 2 received midostaurin dose as per cohort 1 dose by patient error. Patients’ characteristics and responses are summarized in table 1 . Overall response rate (ORR) in phase I was 3/13 (21%) (2 CRi and 1 patient decreased BM blasts from 27% to 7% after 2 cycles and went to transplant). ORR in phase II was 2/6 (33%) (1 patient with AML achieved CRi, 1 patient with CMML {received prior sorafenib} achieved CR). In addition, 1 AML patient had bone marrow blasts improved form 77% to 10% after 1 cycle, completed 3 cycles of therapy and then refused further treatment, and 1 AML patient had bone marrow blasts improve from 34% to 7 % and was continued on treatment). A total of nine patients with FLT3-ITD mutations enrolled in the trial: four patients in phase I with a median allelic ratio of 0.44 (range, 0.219–0.726); 1/4 (25%) achieved CRi, 2 of the non-responders had received prior FLT3 inhibitors (1 had developed FLT3-D835). Five patients in phase II had FLT3-ITD (median allelic ratio 0.06, range 0.014–0.279; one with concomitant D835 mutation) and one patient had FLT3-D835 mutation only (allelic ratio 0.238). 4/6 patients in phase II had failed prior FLT 3 inhibitors. In total, the ORR among patients with FLT3-ITD mutations was 3/9 (33%). All toxicities were grade 1 and 2 with no difference between the 2 dose schedules of midostaurin. No DLT or deaths were identified. Conclusion: The combination of midostaurin/5-AZA is safe and well tolerated at the intended doses (midostaurin 50 mg PO twice daily). Good ORR in high risk patients with relapsed or primary refractory FLT3-ITD positive AML was observed. Schedule is being amended to allow uninterrupted midostaurin administration. Phase II study continues to enroll patients with FLT3 mutations and updated results will be presented at the meeting. Table 1: . Patients' characteristics and responses Number 19 Age, years (range) 62 (36–86) Gender, N (%) Male 13 (68) Female 6 (32) Median Hemoglobin g/dl (range) 9.7 (7.7–11.8) Median white blood cell count ×109/L (range) 5.6 (0.3–62.8) Median platelets ×103/mL (range) 24 (6–692) Median bone marrow blast % (range) 56 (4–96) AML history, N (%) de novo 7 (37) MDS related 8 (43) Therapy related AML 2 (10) AML arising from MPN 1 (5) CMML 1 (5) Cytogenetic risk group * , N (%) Intermediate 10 (53) Unfavorable 9 (47) FLT3-ITD status, N (%) Positive 9 (47) Negative 9 (47) ND 1 (5) Median allelic ratio (FLT3-ITD only, n=9) (range) 0.219 (0.014–0.726) Median number of prior therapies (range) 2 (1–6) Median number of cycles, (range) 3 (1–6) Overall response rate (phase I I Celgene: Research Funding; Ambit: Research Funding.

A phase II study of TR105 in patients with hepatocellular carcinoma (HCC) who have progressed on sorafenib.

e15177 Background: CD105, also known as endoglin, is an endothelial cell membrane receptor that is highly expressed on tumor vasculature, including HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Patients with HCC and compensated liver function (Childs Pugh A/B7), ECOG 0/1, were enrolled to a single arm phase II study of TRC105 15mg/kg IV every 2 weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal 2-stage design was employed with a 50% 4-month PFS target for progression to the second stage. Correlative biomarkers evaluated included: DCE-MRI; FDG-PET; color Doppler ultrasonography; circulating endothelial progenitor cells, plasma levels of angiogenic factors; soluble CD105 and tumor IHC for CD105. Immunogenicity studies were also performed. Results: 8 pts have been treated so far; M:F 6:2; Median age = 58 (range 24-67); 7 pts had progressed following sorafenib (N=1 intolerant). N=1 pt had fibrolammellar HCC. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N=3) and epistaxis (G1; N=4). One patient with a history of ischemic heart disease developed acute cardiac syndrome during the first infusion and was replaced. No patient was progression free at 4 months by RECIST criteria. Median time on study was 8 weeks (range 4-16 weeks). Median no. of doses administered was 4 (range 2-7). Preliminary evidence of biologic response was seen on DCE-MRI in 1pt (of 3 evaluable) with a reduction in kTrans and kep and 3pts (of 3 evaluable) who demonstrated reduction in intra-tumoral color flow on color Doppler. Conclusions: TRC105 is well tolerated in this HCC population post-sorafenib. Although there was biological evidence of antiangiogenic activity it is unlikely that the study will proceed to the second stage. Full clinical and correlative data for the first stage of the study will be presented. Future role of TRC105 in HCC will most likely be as combination therapy with sorafenib or other anti-VEGF therapy. Clinical trial information: NCT01375569.

Sequential Phase I and II Trials of Stereotactic Body Radiotherapy for Locally Advanced Hepatocellular Carcinoma

To describe outcomes of prospective trials of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC). Two trials of SBRT for patients with active HCC unsuitable for standard locoregional therapies were conducted from 2004 to 2010. All patients had Child-Turcotte-Pugh class A disease, with at least 700 mL of non-HCC liver. The SBRT dose range was 24 to 54 Gy in six fractions. Primary end points were toxicity and local control at 1 year (LC1y), defined as no progressive disease (PD) of irradiated HCC by RECIST (Response Evaluation Criteria in Solid Tumors). A total of 102 patients were evaluable (Trial 1, 2004 to 2007: n = 50; Trial 2, 2007 to 2010: n = 52). Underlying liver disease was hepatitis B in 38% of patients, hepatitis C in 38%, alcohol related in 25%, other in 14%, and none in 7%. Fifty-two percent received prior therapies (no prior sorafenib). TNM stage was III in 66%, and 61% had multiple lesions. Median gross tumor volume was 117.0 mL (range, 1.3 to 1,913.4 mL). Tumor vascular thrombosis (TVT) was present in 55%, and extrahepatic disease was present in 12%. LC1y was 87% (95% CI, 78% to 93%). SBRT dose (hazard ratio [HR] = 0.96; P = .02) and being in Trial 2 (HR = 0.38; P = .03) were associated with LC1y on univariate analysis. Toxicity ≥ grade 3 was seen in 30% of patients. In seven patients (two with TVT PD), death was possibly related to treatment (1.1 to 7.7 months after SBRT). Median overall survival was 17.0 months (95% CI, 10.4 to 21.3 months), for which only TVT (HR = 2.47; P = .01) and being in Trial 2 (HR = 0.49; P = .01) were significant on multivariate analysis. These results provide strong rationale for studying SBRT for HCC in a randomized trial.

Continuous-dose regorafenib (REG) in hepatocellular carcinoma (HCC): Phase I safety and pharmacokinetic (PK) study.

300 Background: REG is a novel oral inhibitor of multiple kinases involved in angiogenesis, oncogenesis, and tumor microenvironment. A multicenter, open-label, single-arm phase I dose-escalation study evaluated REG given with a continuous schedule and established 100 mg once daily as the maximum tolerated dose. This study explored the safety and PK of this dose in an expanded cohort of advanced HCC pts. Methods: Adults with advanced treatment-refractory HCC (Child Pugh [CP] A or B) received REG 100 mg daily until tumor progression, unacceptable toxicity, or pt/investigator decision to stop. Safety and PK were primary endpoints. Tumor response was a secondary endpoint. Results: The HCC expansion cohort included 20 pts: male/female ratio: 14/6; 10 Asian, 4 white, 4 Hispanic, 1 black, 1 other; mean age: 56.8 ± 13.5 years; 16 CP A, 4 CP B; 2 stage II, 3 stage IIIA, 1 stage IIIC, 13 stage IV; 14 pts had disease progression at entry; 11 pts had 2+ metastatic sites; 19 pts had received prior sorafenib. Median duration of treatment was 42 days (range 23–329); 2 pts were still on treatment at data cutoff. Two pts died during the study (both due to disease progression). Drug-related AEs were reported in 18 pts (90%). The most common grade 3+ drug-related AEs were hypertension (n=4, 20%), fatigue (n=2, 10%), hand-foot skin reaction (n=2, 10%), pain (n=1, 5%), and hemoglobin, ALT, AST, lipase, and other metabolic/laboratory abnormalities (n=1, 5% each). Nine pts required REG dose modifications, and 2 pts stopped treatment permanently because of drug-related AEs. No drug-related serious AEs were reported. Single-dose PK data (cycle 1, day 1) were available from 18 pts, but only 1 pt was evaluable for steady-state PK samples. Single-dose analysis did not indicate any effect of CP status on REG PK. One pt had a partial response and 6 pts had stable disease; median time to progression was 36 days (range 28-237). Conclusions: Continuous-dose REG 100 mg once daily was well tolerated in pts with advanced HCC that progressed on prior sorafenib. PK data obtained after a single 100 mg dose did not indicate any effect of CP status on the PK of REG or its primary metabolites. Disease control was achieved in 7 pts. Clinical trial information: NCT01117623.

A Phase I/II Trial of Combination of Midostaurin (PKC412) and 5-Azacytidine (5-AZA) for the Treatment of Patients with Refractory or Relapsed (R/R) Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

AbstractAbstract 3587 Background:Midostaurin (PKC412) is a potent orally bioavailable FLT3 inhibitor with activity in acute myeloid leukemia (AML). 5-azacytidine (5-AZA) is a hypomethylating agent that plays an important role in the treatment of AML and MDS. We hypothesized that adding midostaurin to 5-AZA may improve the response rate with limited toxicity profile. Materials and Methods:Patients ≥18 years with MDS, chronic myelomonocytic leukemia (CMML) or AML, who failed prior therapies with performance status ≤ 2, adequate liver (bilirubin ≤ 2 × ULN, ALT ≤ 2.5× ULN) and renal (creatinine ≤2× ULN) functions were eligible. Patients were included in phase I regardless of FLT3 mutation status; only FLT3 mutated patients were included in phase II. Patients received 5-AZA 75 mg/m2 subcutaneously or intravenously for 7 days of each cycle (Days 1–7) and midostaurin at 25 mg (cohort 1) and 50 mg (cohort 2; target dose) orally twice daily for 14 days (Days 8–21) per cycle. Patients were planned to receive up to 12 cycles if benefit from treatment. Supportive care was standard. The study was approved by institutional IRB and conducted in accordance of the declaration of Helsinki. Results:20 patients have been enrolled: 13 included in phase I (6 in cohort 1 and 7 in cohort 2) and 6 patients in phase II. One patient in cohort 1 was inevaluable for DLT (withdrawal before completing cycle #1). One patient in cohort 2 received midostaurin dose as per cohort 1 dose by patient error. Patients’ characteristics and responses are summarized in table 1. Overall response rate (ORR) in phase I was 3/13 (21%) (2 CRi and 1 patient decreased BM blasts from 27% to 7% after 2 cycles and went to transplant). ORR in phase II was 2/6 (33%) (1 patient with AML achieved CRi, 1 patient with CMML {received prior sorafenib} achieved CR). In addition, 1 AML patient had bone marrow blasts improved form 77% to 10% after 1 cycle, completed 3 cycles of therapy and then refused further treatment, and 1 AML patient had bone marrow blasts improve from 34% to 7 % and was continued on treatment). A total of nine patients with FLT3-ITD mutations enrolled in the trial: four patients in phase I with a median allelic ratio of 0.44 (range, 0.219–0.726); 1/4 (25%) achieved CRi, 2 of the non-responders had received prior FLT3 inhibitors (1 had developed FLT3-D835). Five patients in phase II had FLT3-ITD (median allelic ratio 0.06, range 0.014–0.279; one with concomitant D835 mutation) and one patient had FLT3-D835 mutation only (allelic ratio 0.238). 4/6 patients in phase II had failed prior FLT 3 inhibitors. In total, the ORR among patients with FLT3-ITD mutations was 3/9 (33%). All toxicities were grade 1 and 2 with no difference between the 2 dose schedules of midostaurin. No DLT or deaths were identified. Conclusion:The combination of midostaurin/5-AZA is safe and well tolerated at the intended doses (midostaurin 50 mg PO twice daily). Good ORR in high risk patients with relapsed or primary refractory FLT3-ITD positive AML was observed. Schedule is being amended to allow uninterrupted midostaurin administration. Phase II study continues to enroll patients with FLT3 mutations and updated results will be presented at the meeting.Table 1:Patients' characteristics and responsesNumber19Age, years (range)62 (36–86)Gender, N (%)Male13 (68)Female6 (32)Median Hemoglobin g/dl (range)9.7 (7.7–11.8)Median white blood cell count ×109/L (range)5.6 (0.3–62.8)Median platelets ×103/mL (range)24 (6–692)Median bone marrow blast % (range)56 (4–96)AML history, N (%)de novo7 (37)MDS related8 (43)Therapy related AML2 (10)AML arising from MPN1 (5)CMML1 (5)Cytogenetic risk group*, N (%)Intermediate10 (53)Unfavorable9 (47)FLT3-ITD status, N (%)Positive9 (47)Negative9 (47)ND1 (5)Median allelic ratio (FLT3-ITD only, n=9) (range)0.219 (0.014–0.726)Median number of prior therapies (range)2 (1–6)Median number of cycles, (range)3 (1–6)Overall response rate (phase I &II)5 (26)CR/CRi, N (%)4 (21)PR, N (%)1 (5)SD, N (%)8 (42)*Cytogenetic grouping according to MRC criteria, ND = not documented. CR = complete remission, CRi = complete remission with incomplete hematologic recovery, SD = stable disease. Disclosures:Off Label Use: 5-azacytidine in AML. Cortes:Novartis: Consultancy, Research Funding; Celgene: Research Funding; Ambit: Research Funding.

Activity of cabozantinib (XL184) in hepatocellular carcinoma: Results from a phase II randomized discontinuation trial (RDT).

4007 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. MET over-expression has been observed in advanced hepatocellular carcinoma (HCC). Anti-VEGF pathway agents have shown clinical benefit in pts w/ HCC. Simultaneous targeting of the MET and VEGF signaling pathways with cabo may therefore be a promising treatment strategy. Methods: Eligible HCC patients (pts) were required to have measurable disease per RECIST, ≤ 1 prior systemic regimen and Child-Pugh score of A. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized phase was progression free survival (PFS). The primary endpoint was overall response rate (RR) per mRECIST in the Lead-in stage. Results: Enrollment has been completed (n = 41); all pts are unblinded. Median age: 61 years (33 to 83). Males: 76%; Asian: 37%. HCC etiology: Hep B 24%; Hep C 22%; alcohol abuse 20%; other 38%. Extra-hepatic spread observed in 70%. Median number of prior systemic treatments was 1; prior sorafenib was 51%. Median baseline AFP was 368 ng/mL (3 – 259,298); 86% had elevated AFP at baseline. Median follow-up was 5.5 mos (0.8 -18.5). 29 pts (71%) completed the Lead-in stage. Median PFS from Study Day 1 was 4.2 mos. 2/36 pts evaluable for tumor assessment at 12 weeks achieved a confirmed PR (cPR) by original RECIST (RR 5%). One more pt randomized at Week 12 achieved a cPR at 18 weeks. 28/36 pts (78%) with ≥1 post-baseline scan had tumor regression (with no apparent relationship to prior sorafenib therapy). The overall disease control rate (DCR = PR+SD) at Week 12: was 68% (Asian subgroup: 73%). AFP responses (defined as reduction from baseline of >50% in pts with elevated AFP at baseline) in 26 pts with ≥1 post-baseline result: 10/26 (38%). Most common Gr 3/4 AEs: diarrhea (17%), palmar-plantar erythrodyesthesia (15%), and thrombocytopenia (10%). Conclusions: Cabo treatment exhibits activity in HCC pts regardless of prior sorafenib treatment. The safety profile was comparable to that of other VEGFR TKIs.

Clinical, pharmacodynamic (PD), and pharmacokinetic (PK) evaluation of cediranib in advanced hepatocellular carcinoma (HCC): A phase II study (CTEP 7147).

4112 Background: Sorafenib remains the only approved systemic therapy in HCC. We performed a phase II study of cediranib (AZD2171)—a more potent and selective pan-VEGF receptor inhibitor—in advanced HCC patients (pts). Methods: Eligibility criteria included unresectable or metastatic measurable HCC, ECOG PS ≤2, CLIP score ≤3, and adequate organ function. Patients received cediranib at 30 mg po qd continuously (4-wk cycle). The primary endpoint was progression free survival (PFS). We also assessed overall survival (OS) and response rates, steady-state PK of cediranib, and blood circulating biomarkers. Results: Since 6/16/09, we have enrolled the targeted 17 pts required for the first stage of the planned study: ECOG 0/1/2=5/11/1, CLIP 1/2/3=6/4/7, Child A/B=14/3, BCLC C=17. Nine pts had prior sorafenib. The best response was stable disease in five pts (29%). The median PFS was 5.3 months (95% CI: 3.5-9.7). The median OS was 11.7 months (95% CI: 7.5-13.6). Grade 3 toxicities included hypertension (29%), hyponatremia (12%), elevated SGOT (12%) and one pt each (6%) in SGPT, fatigue, hyperbilirubinemia, cardiac ischemia, and proteinuria. Grade 4 pulmonary embolism and brainstem hemorrhage occurred in 1 pt each. Steady-state PK parameters (mean±SD) were, Cmin, 22±21 ng/mL; Cmax, 55±33 ng/mL; AUCτ, 887±503 ng*h/mL. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 decreased significantly after cediranib treatment (p<0.05). PFS was inversely correlated with baseline levels of bFGF, sVEGFR2 and VEGF, and OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-alpha and CD34+CD133+ hematopoietic progenitor cells (p<0.05). Conclusions: Cediranib at 30 mg daily is associated with high frequency of grade 3 hypertension and shows preliminary evidence of antitumor activity in advanced HCC pts. Exploratory studies confirmed potential PD and response biomarkers of anti-VEGF therapy. Cediranib exhibits similar PK in HCC pts as in those with other tumor types and normal/near normal hepatic function. This study was stopped by AstraZeneca after discontinuation of cediranib development for unrelated factors.

I-131-lipiodol therapy in local disease control and survival in patients with advanced hepatocellular carcinoma: An observational study.

e14721 Background: In patients with Locally advanced/metastatic HCC, the median survival is 3 months. Most of these patients have altered liver functions which makes them unsuitable for any therapy. In this exploratory study we aim to test the effectiveness of I-131-lipiodol in prolonging survival in these patients. Methods: 15 patients with locally advanced HCC (unresectable) and metastatic HCC with altered liver functions (CHILDS B and C) were given I-131-lipiodol. Patients had received prior chemotherapy, prior TACE therapy, prior sorafenib and had treatment refractory progressive disease. We compared effects of I-131-Lipiodol in prolonging survival beyond three months in these patients. We performed a non parametric one sample kolmogorov Smirnov test comparing survival with I-131-lipiodol to an average 90 days survival reported in patients with advanced HCC. Results: Survival ranged from 46 to 417 days with a median survival of 144 days. However one sample test showed significant improvement in survival with I-131-lipiodol therapy compared to standard of care (z = 1.4, p = 0.04). Conclusions: I-131-lipiodol is a useful local therapy in management of patients with advanced HCC, randomized controlled trials are needed to validate its findings in adjuvant and palliative settings.

A phase I/II study of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR in advanced hepatocellular carcinoma (HCC).

4108 Background: Hepatocyte growth factor (HGF)/MET signalling plays a pivotal role in tumor cell proliferation, migration and invasion in HCC and circulating levels of HGF correlate with poor prognosis. This phase I/II trial (MET111645) evaluated foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR, as first-line therapy in Asian advanced-HCC patients. Methods: Asian patients with measurable, unresectable/metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG PS 0-1, adequate organ function and Child-Pugh grade A were recruited. The phase I was a standard 3+3 dose escalation design with a phase II cohort expansion. The primary endpoint was safety and tolerability at the maximum tolerated dose (MTD) and the secondary endpoints included antitumor activity (objective response rate [ORR], disease stabilization rate [DSR; confirmed CR/PR or SD for at least 12 weeks], and time to progression [TTP] evaluated by central review according to modified RECIST), and overall survival (OS) at the MTD, plus pharmacokinetics (PK). Results: Thirteen patients were enrolled in phase I. Two dose-limiting toxicities (DLT) (renal failure, proteinuria) were observed at 45 mg once daily (QD) but no DLTs were observed at 30 mg QD. Thus, the MTD was determined to be 30 mg QD. A further 32 patients were enrolled at the MTD, for a study total of 39 patients treated at 30 mg QD. The most common AEs, independent of causality,were hypertension (36%), decreased appetite (23%), and pyrexia (21%). The most common SAEs were hepatic encephalopathy (10%) and ascites (8%). Two patients discontinued foretinib due to AEs. No dose reductions were reported. Thirty-eight patients were evaluable for efficacy. The ORR was 24% (95% CI 11-40), DSR 79% (95% CI; 63-90), and the median TTP was 4.2 months (95% CI 2.7-7.5). Mature OS data will be presented. Mean steady-state exposures (AUC/Cmax) were comparable after administration of foretinib at 30 and 45 mg. Conclusions: Foretinib has an acceptable safety, tolerability, and PK profile in an Asian HCC population. It has demonstrated promising antitumor activity that warrants further testing in a randomized setting.

A phase II study of temsirolimus/sorafenib in patients with radioactive iodine (RAI)-refractory thyroid carcinoma.

5514 Background: Sorafenib is an oral tyrosine kinase inhibitor of multiple targets, including RAF, VEGFR1, and VEGFR2. Published response rates with sorafenib in RAI refractory thyroid cancer have ranged from 11-23%. Temsirolimus is an intravenous inhibitor of mTOR; mutations in the PI3K/mTOR/AKT pathway occur late in thyroid cancer and may be associated with aggressive disease. Methods: The study was a single institution, phase II design. Primary objective was response rate. Eligible patients (pts) had progressive, RAI-refractory/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-medullary, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 200 mg orally twice a day and temsirolimus at 25 mg intravenously weekly. 38 patients were enrolled; 37 were eligible and 36 patients started treatment between 12/18/09 – 10/20/11. Data cutoff date is 1/19/12. Fourteen pts are still actively on study. Results: Of the 37 eligible pts, demographics: female-46%; median age-64 years (30-81); histology-papillary (23)/follicular (1)/Hürthle (5)/poorly differentiated (6)/anaplastic (2); prior systemic treatment (21); prior sorafenib (6). Grade 4-5 adverse events at least possibly related to drug: grade 5 – sudden death, NOS (1 pt): grade 4 – colonic perforation (1 pt). Evaluation of best response: partial (PR) (8, including 3 with anaplastic/poorly differentiated); stable disease (SD) (21); progression (1); inevaluable (7). The partial response rate was 38% in the cohort that previously did not receive any systemic treatment. There was no correlation of response to either BRAF (10) or RAS (5) mutational status. Median time on treatment is 203 days (range 14-638 days) at the cutoff date. For the 21 pts with SD, the maximum percentage shrinkage by RECIST criteria ranged from -2% to -35% (one patient with unconfirmed PR) with a median time on treatment of 203 days (range 39-503 days). Conclusions: The combination of sorafenib and temsirolimus shows promising results in a heavily pretreated population. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc.

A multicenter, randomized, double-blind, phase III study of ramucirumab (IMC-1121B; RAM) and best supportive care (BSC) versus placebo (PBO) and BSC as second-line treatment in patients (pts) with hepatocellular carcinoma (HCC) following first-line therapy with sorafenib (SOR).

TPS4146 Background: Blockade of vascular endothelial growth factor (VEGF) signaling in HCC has been shown in preclinical models with monoclonal antibodies and small molecule multikinase inhibitors, and in clinical trials with SOR, to have anti-tumor activity and improve survival. RAM, a fully human monoclonal antibody, binds to the VEGF receptor-2 (VEGFR-2), potently blocks the binding of the VEGF ligand to VEGFR-2, inhibits VEGF-stimulated activation of VEGFR-2, and neutralizes VEGF-induced mitogenesis of human endothelial cells. In a single-arm, Phase 2 study of RAM as 1st-line monotherapy in 42 pts with advanced HCC (Zhu, ILCA 2010, abstr. O-033), preliminary results included median progression-free survival (PFS) of 4 months (m), time to progression (TTP) of 4.2 m, overall survival (OS) of 12 m and disease control rate of 70% (best overall response: 10% partial response, 60% stable disease). Methods: Pts with HCC with disease progression during or following 1st-line therapy with SOR (or who were intolerant to SOR) are randomized 1:1 to receive RAM (8 mg/kg) or PBO once every 2 weeks, with BSC, until disease progression or intolerable toxicity. Eligibility includes prior SOR as 1st-line systemic treatment for HCC, Child-Pugh A, B7 or 8 cirrhosis, ECOG PS 0-1, bilirubin < 3 mg/dL, transaminases ≤ 5 × upper limit of normal (ULN), creatinine ≤ 1.2 × ULN, and platelets ≥ 75×103/µL. The primary endpoint is OS. Secondary endpoints include PFS, best objective response rate, TTP, patient-reported outcome measures of disease-specific symptoms and health-related quality of life, safety, and RAM pharmacokinetics, pharmacodynamics, and immunogenicity. With 544 patients, this study is designed to detect an increase in OS (median 6 m with PBO to 8 m with RAM; 1-sided α= 2.5%, 85% power). As of 18 January 2012, approximately 52% of planned pts have been randomized. The IDMC reviewed this study on 21 June and 3 November 2011 and recommended the study to continue unmodified.