Dean Laurence Harris

Everolimus and Zoledronic Acid in Patients With Renal Cell Carcinoma With Bone Metastases: A Randomized First-Line Phase II Trial

BACKGROUNDnBone metastases from renal cell carcinoma (RCC) are a major cause of morbidity. Post hoc analysis has suggested that bone turnover markers can identify patients at risk of skeletal-related events (SREs) among those receiving zoledronic acid. This study sought to evaluate the effect on bone metastases of everolimus alone compared with everolimus plus zoledronic acid.nnnPATIENTS AND METHODSnThirty treatment-naive patients with RCC and ≥ 1 bone metastases were randomized 1:1 to everolimus (10 mg daily) versus everolimus plus zoledronic acid (4 mg intravenously 4-weekly). Bone-specific assessments were performed at baseline and at weeks 1, 4, 8, and 12. Treatment was continued on allocated arm until progression per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1). The primary outcome measure was urine N-telopeptide (uNTX) level, with secondary measures of plasma C-telopeptide (CTX), quality of life (Functional Assessment of Cancer Therapy-Bone Pain [FACT-BP], Brief Pain Inventory [BPI]), progression-free survival (PFS), SREs, and safety.nnnRESULTSnAfter 12 weeks, reduction in mean uNTX and CTX on everolimus plus zoledronic acid relative to everolimus was 68.4% (95% CI, 60.1%-74.9%; P < .0001) and 76.2% (95% CI, 67.3%-82.7%; P < .0001), respectively. There was no evidence of a difference for FACT-BP (P = .5), but evidence was favorable for BPI Severity (P = .05) and BPI Interference (P = .06). Median PFS was 7.5 months (95% CI, 3.4-11.2) on everolimus plus zoledronic acid and 5.4 months (95% CI, 3.2-6.3) on everolimus (P = .009). Median time to first SRE was 9.6 months (95% CI, 4.3-15.5) on everolimus plus zoledronic acid and 5.2 months (95% CI, 1.6-8.2) on everolimus (P = .03).nnnCONCLUSIONnIn this RCC population, the addition of zoledronic acid to everolimus significantly reduced bone resorption markers and may prolong tumor control.

Abstract A71: A Phase Ib study of demcizumab (DEM, anti-DLL4) plus pemetrexed and carboplatin in patients with first line stage IIIb/IV non-squamous non-small cell lung cancer.

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. DEM is a humanized IgG 2 anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Material and Methods: Patients received DEM (2.5, 5, or 7.5 mg/kg), pemetrexed 500 mg/m 2 , and carboplatin (AUC = 6) every 3 weeks followed by maintenance DEM (first 4 cohorts) or pemetrexed (7.5 mg/kg cohort) every 3 weeks until disease progression. Folic acid, vitamin B12 and dexamethasone were administered as pemetrexed pre-medication. The primary study objective was to determine the maximum tolerated dose of DEM. Other objectives included: safety, efficacy, immunogenicity, pharmacokinetic and biomarkers of Notch signaling. Results: Thirty patients have been enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg and 4 received 7.5 mg/kg of DEM once every 3 weeks. The median age was 63 years and 90% had stage IV disease. Related adverse events (all grades) in ≥10% of pts included: nausea (53%), fatigue (50%), hypertension (37%), vomiting (33%), neutropenia (27%), increased B-type natriuretic peptide (BNP) (23%), anemia (20%), peripheral edema (20%), increased ALT (20%), increased AST (17%), dyspnea, (17%), diarrhea (17%), decreased appetite (17%), pulmonary hypertension (13%), dysgeusia (13%), thrombocytopenia (13%), constipation (10%), and rash (10%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two patients receiving 5 mg/kg developed reversible pulmonary hypertension and heart failure on days 167 and 183, respectively. As a result, the duration of DEM was limited to 63 days in the 7.5 mg/kg dose cohort. The pharmacokinetics and immunogenicity specimens are being analyzed and these data will be presented. Nine of the 23 (39%) evaluable patients had a RECIST partial response and 11 had stable disease. The median progression free survival for the 5 mg/kg cohort was 5.3 months. Conclusion: DEM, pemetrexed and carboplatin was generally well tolerated with nausea, fatigue and hypertension being the most common drug related toxicities. The duration of demcizumab therapy is being limited to 63 days in subsequent cohorts due to cardiopulmonary toxicity which was observed following more prolonged administration. Encouraging early clinical activity has been observed. Enrollment is ongoing and updated results will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A71. Citation Format: Mark McKeage, Dusan Kotasek, Ben Markman, Michael Millward, Manuel Hildalgo, Michael Jameson, Dean Harris, Robert Stagg, Jakob Dupont, Brett Hughes. A Phase Ib study of demcizumab (DEM, anti-DLL4) plus pemetrexed and carboplatin in patients with first line stage IIIb/IV non-squamous non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A71.

RAD001 and zoledronic acid in patients with renal cell carcinoma with bone metastases (RAZOR): A randomized phase II trial.

402 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause morbidity, and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (Z) reduces skeletal-related-events (SREs) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving Z. We sought to evaluate the effect on BM of RAD001 (R) (everolimus) alone compared to R+Z in the first-line setting.nnnMETHODSn30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to R 10mg daily vs. R+Z 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl]). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates, or radiotherapy within 4 wks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, wks-1, 4, 8, and 12. Treatment was continued on allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12 wks. The primary endpoint was urine N-telopeptide (uNTX) level with secondary endpoints being plasma C-telopeptide (CTX), quality of life (FACT-BP, BPI), progression free survival (PFS), SREs, and safety.nnnRESULTSnHeng prognostic group poor, intermediate, and good risk was 20.0%, 46.7%, 33.3% in R+Z and 40.0%, 46.7%, 13.3% in R. Over first 12 wks, the reduction in mean: uNTX on R+Z relative to R was 68.4% (95% CI (60.1%, 74.9%); p<0.0001); CTX on R+Z relative to R was 77% (95% CI (68%, 83%); p<0.0001). For FACT-BP there was no evidence of a difference (p = 0.5) but addition of Z was favourable for BPI Severity -1.1 (-2.2, 0.23; p = 0.05) and BPI Interference -1.3 (-2.5, 0.03; p = 0.06). Median PFS was 7.5 mo (95% CI 3.4, 14.7) on R+Z and 4.6 mo (95% CI 3.2, 6.3) on R (p = 0.03). Median time to 1st SRE was 9.6 mo (95% CI 4.3, 15.5) on R+Z and 5.2 mo (95% CI 1.6-8.2) on R (p = 0.03).nnnCONCLUSIONSnAddition of Z to R significantly reduced bone resorption markers in this RCC population of pts with the adverse prognostic feature of BM. Pts receiving R+Z had prolonged time to 1st SRE and PFS; larger studies are required to further evaluate the addition of bone-specific to targeted therapies in this disease.nnnCLINICAL TRIAL INFORMATIONnACTRN12609000980235.

Phase IB Trial of the Anti-Cancer Stem Cell DLL4-Binding Agent Demcizumab with Pemetrexed and Carboplatin as First-Line Treatment of Metastatic Non-Squamous NSCLC

BackgroundDelta-like ligand 4-Notch (DLL4-Notch) signaling contributes to the maintenance of chemotherapy-resistant cancer stem cells and tumor vasculature.ObjectiveThis phase IB trial of demcizumab, an IgG2 humanized monoclonal antibody directed against DLL4, was undertaken to determine its maximum tolerated dose, safety, immunogenicity, preliminary efficacy, pharmacokinetics, and pharmacodynamics, combined with standard chemotherapy.Patients and MethodsForty-six treatment-naive patients with metastatic non-squamous non-small cell lung cancer (NSCLC) were enrolled in this open-label, dose-escalation study using a standard 6u2009+u20096 design. Demcizumab (2.5, 5.0, and 7.5xa0mg/kg) was given once every 3xa0weeks with standard doses of pemetrexed and carboplatin using a continuous (six cycles followed by demcizumab maintenance) or a truncated demcizumab regimen (four cycles followed by pemetrexed maintenance).ResultsInitially, continuous demcizumab was given until progression but two patients developed grade 3 pulmonary hypertension and congestive heart failure after eight or more infusions. Thereafter, 23 patients were treated with a truncated regimen of demcizumab, which was not associated with any grade 3 or greater cardiopulmonary toxicity. Common adverse events were hypertension, raised brain natriuretic peptide, and those expected from carboplatin and pemetrexed alone. Twenty of 40 evaluable patients (50%) had objective tumor responses. In peripheral blood, demcizumab treatment modulated the expression of genes regulating Notch signaling and angiogenesis, and achieved concentrations exceeding those saturating DLL4 binding.ConclusionsThis study has identified a truncated dosing regimen and recommended phase II dose of demcizumab (5xa0mg/kg q3-weekly ×4) for subsequent clinical evaluation in combination with standard carboplatin and pemetrexed chemotherapy. NCT01189968.

Long-term outcomes of hepatic resection for colorectal liver metastases at a New Zealand tertiary level public hospital.

Colorectal cancer is common with half of all patients developing metastases to the liver. The aim of this study was to document the survival for patients undergoing liver resection for colorectal cancer metastases.

1240PA PHASE 1B STUDY OF THE ANTI-CANCER STEM CELL AGENT DEMCIZUMAB (DEM), PEMETREXED (PEM) & CARBOPLATIN (CARBO) IN PTS WITH 1ST LINE NON-SQUAMOUS NSCLC

ABSTRACT Aim: Delta-like ligand 4 (DLL4) activates the Notch pathway and is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth, decrease CSC frequency & cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect in human tumor xenograft models. Methods: Pts received DEM (2.5 or 5u2003mg/kg), PEM 500u2003mg/m2 & CARBO (AUC = 6) every 3 wks X 6 cycles followed by maintenance DEM (cohorts 1-4) or truncated DEM (5 or 7.5u2003mg/kg), PEM 500u2003mg/m2 & CARBO (AUC = 6) every 3 wks X 4 cycles followed by maintenance PEM (cohorts 5 & 6). The objectives were to determine the MTD, safety, efficacy, immunogenicity, pharmacokinetics & biomarkers of Notch signaling. Results: Thirty-nine pts were enrolled; 6 received 2.5u2003mg/kg, 20 received 5u2003mg/kg, 6 received 7.5u2003mg/kg of truncated DEM & 7 received 5u2003mg/kg of truncated DEM. Related AEs in > 20% of pts were: nausea (49%), fatigue (44%), hypertension (41%), vomiting (31%), edema (26%), neutropenia (26%), & increased B-type natriuretic peptide (BNP) (23%). Increased BNP values are an early indicator of the cardiac effects of DEM & mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two pts receiving 5u2003mg/kg developed reversible pulmonary hypertension & heart failure on days 167 & 183, respectively. As a result, DEM treatment was limited to 63 days in cohorts 5 & 6. One of 32 (3%) evaluable pts had a RECIST CR, 13 (41%) had a PR and 14 had SD. The Kaplan Meier estimated median progression free survivals for the 2.5, 5, truncated 5 & truncated 7.5u2003mg/kg pts were 4.3, 5.3, not yet reached & 4.4 months, respectively. Five pts who discontinued the study for a reason other than progression (3 continued to receive CARBO & PEM off-study) were progression-free through Days 223 + , 243 + , 457 + , 497 + , 680+ and a sixth pt (who continued to receive CARBO & PEM off-study) progressed at Day 850. Conclusions: This therapy was generally well tolerated with nausea, fatigue & hypertension being the most common drug related toxicities. Encouraging early clinical activity has been observed. Additional data with truncated DEM will be presented. Disclosure: R. Stagg: I am an employee of OncoMed and I own stock in the company; J. Dupont: I work for OncoMed and own stock in the company. All other authors have declared no conflicts of interest.