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The Combination of Gemcitabine/Nab-Paclitaxel with An The combination of gemcitabine/nab-paclitaxel with an anti-DLL4 monoclonal antibody demcizumab produces synergistic growth inhibition, delays tumor recurrence and reduces tumorigenicity of tumor initiating cells in pancreatic cancer Wan-Ching Yen, Marcus Fischer, John Lewicki, Austin Gurney, and Timothy Hoey. OncoMed Pharmaceuticals, Inc. Redwood City, CA ABSTRACT RESULTS Establishment of Xenograft from Phase 1b Patient (Dem+Gem) Duration on Study and Median Progression Free Survival Clinical management of pancreatic cancer is challenging and this disease remains the fourth mAb+/- most common cause of cancer-related death. Conventional chemotherapeutic agents, Gem/nab-Pac Gem/nab-Pac only No treatment (day 1-31) (day 32-83) (day 84-136) 54 Days Post Gem/nab-Pac Termination including gemcitabine, commonly used in the treatment of pancreatic cancer, have low 2000 200 response rates and limited effects on improving patient survival. A recent phase III clinical 3 Control mAb 3 ® 1500 Gem/nab-Pac trial has demonstrated that nab-paclitaxel (Abraxane , a protein-bound paclitaxel) in PD (1/8) Anti-DLL4+ 150 combination with gemcitabine significantly improved the response rate and overall survival Gem/nab-Pac 1000 compared to patients receiving gemcitabine alone. We previously demonstrated that 100 targeting Notch signaling by anti-DLL4 (demcizumab) inhibits tumor growth, reduces tumor 500 initiating cell frequency and induces differentiation in patient-derived pancreatic xenograft 50 Tumor Volume, mm Volume, Tumor SD (1/8) tumors. To further explore the utility of demcizumab in the setting of pancreatic cancer, we mm Volume, Tumor 0 evaluated anti-DLL4 combination with gemcitabine/nab-paclitaxel in a panel of pancreatic 0 50 100 0 xenograft models. We found that anti-DLL4 in combination with gemcitabine plus nab- Days Post Treatment CR (6/8) paclitaxel resulted in striking tumor regression, whereas tumors treated with OMP-PN42 Xenograft Tumors chemotherapeutic agents grew continuously. The effect of the triple combination in some tumors was quite durable and persisted after both antibody and chemotherapeutic treatments Control mAb Gem/nab-Pac Combination-PD Combination-SD were discontinued. The significant growth inhibitory effect by the combination of anti-DLL4 with gemcitabine/nab-paclitaxel was associated with a decrease in cancer stem cell frequency and an increase in apoptosis and tumor cell differentiation. The triple combination of anti-DLL4, gemcitabine and nab-paclitaxel was generally more efficacious compared with anti-DLL4 plus gemcitabine alone. Notably, in a xenograft established from a patient that The blue bars represent the time on study. The green bars represent patients who discontinued the study without progression and have remained progression-free off study. previously did not respond to demcizumab plus gemcitabine, the triple combination was The patient with the green bar received demcizumab and gemcitabine through day on study 21 and then received additional gemcitabine off-study highly effective. We are currently evaluating demcizumab in combination with Alcian Blue Gem/nab-Pac Gem/nab-Pac gemcitabine/nab-paclitaxel in a phase 1b clinical trial in pancreatic cancer. +/-mAb only No Treatment Control mAb (day 1-29) (day 30-49) (day 50-84) 1500 800 Gemcitabine Gem+nab-Pac 3 3 BACKGROUND Anti-DLL4+ Gem Anti-DLL4+Gem+nab-Pac 600 1000 • Pancreatic cancer is the fourth leading cause of cancer death in the United States with 5- 400 Ki67 year survival rate of only 3% and a median survival of less than 6 months. Conventional 500 chemotherapeutic agents, including gemcitabine, commonly used in the treatment of 200 Tumor Volume, mm Volume, Tumor pancreatic cancer, have low response rates and limited effects on improving patient survival. mm Volume, Tumor • Recently, clinical data has shown that nab-paclitaxel (Abraxane®), an albumin-stabilized 0 0 0 10 20 30 40 0 20 40 60 80 paclitaxel, is effective in combination with gemcitabine for the treatment of pancreatic ductal Figure 1. Top: Anti-DLL4 (20 mg/kg every other week) in combination with weekly gemcitabine (10 mg/kg) plus nab-paclitaxel (30 Days Post Treatment Days Post Treatment adenocarcinoma (Von Hoff DD, et al. N Engl J Med 2013; 369(18):1691-1703). mg/kg) resulted in striking tumor regression in OMP-PN8 xenograft tumors. The effect was durable and persisted after discontinued both antibody and chemotherapeutic treatments. Bottom: Histologic analysis of control and treated tumors at the conclusion of the Figure 4. Left: OMP-PN42 was insensitive to anti-DLL4 (20 mg/kg every other week) in combination with weekly • Evidence has accumulated suggesting that tumors may arise and grow as a result of the study. The combination induced differentiation (Alcian blue) and a decreased proliferation (ki67) in the responsive tumor. Images gemcitabine (20 mg/kg), consistent with the response seen in the patient treated with this combination. Right: Triple formation of a subset of cells termed cancer stem cells (CSC) or tumor initiating cells; this were taken at 20x. combination with anti-DLL4 (20 mg/kg) and weekly gemcitabine (10 mg/kg) plus nab-paclitaxel (30 mg/kg) delayed OMP- PN42 tumor growth, whereas tumors treated with chemotherapeutic agents alone grew continuously. OMP-PN42 was cell population may also be involved in tumor recurrence and resistance to radiation and obtained through a collaboration with Dr. Manuel Hidalgo at START Madrid. chemotherapy. Reduction in Tumor Volume • The Notch signaling pathways play an important role in controlling cell fate, self-renewal Chemo+/-mAb Chemo only CSC Frequency and cell proliferation and differentiation. (day 1-26) (day 27-61) RECIST Best Overall Response (n=30) • Delta-like 4 ligand (DLL4) is an important component of Notch-mediated stem cell self- 1200 Control mAb 3 1000 Gemcitabine 0.07 Control mAb renewal and vascular development. DLL4 over-expression is found in tumor vasculature and Dose Level – mg/kg DEM DEM DEM Total DEM/GEM 2.5 DEM/GEM/ Gem+nab-Pac 0.06 Gem+nab-Pac in tumor cells to activate Notch signaling in cancer stem cells. 800 2.5 2.5 5 (Evaluable = 16) nab-Pac Anti-DLL4+Gem/nab-Pac • The objective of this study is to evaluate the effect of an anti-DLL4 monoclonal antibody in 0.05 Anti-DLL4+Gem/nab-Pac every 2 weeks every 4 weeks every 4 weeks (Evaluable = 6) 600 combination with gemcitabine/nab-paclitaxel in patient-derived pancreatic xenograft models. 0.04 400 • Isolate tumors post-treatment • Transplant 30, 90, 270 cells (n=10) 0.03 Partial Response 1 1 2 4 (25%) 3 (50%) • Grow 89 days without treatment 200 • Calculate CSC Frequency based 0.02 Tumor Volume, mm Volume, Tumor MATERIALS and METHODS on tumor take rate CSC Frequency Stable Disease 4 2 1 7 (44%) 2 (33%) 0 0.01 0 20 40 60 0.00 Days Post Treatment 1/44 1/22 1/554 Clinical Benefit Rate 5 3 3 11 (69%) 5 (83%) The anti-DLL4 antibodies were generated at OncoMed Pharmaceuticals, Inc. (PR + SD) • The pancreatic tumors OMP-PN8 and OMP-PN13 were obtained from University of Figure 2. The combination of anti-DLL4 (20 mg/kg every other week) with weekly gemcitabine (10 mg/kg)/nab-paclitaxel (30 mg/kg) Progressive Disease - 3 2 5 (31%) 1 (17%) Michigan. OMP-PN42 was obtained from a patient that failed to respond to demcizumab plus resulted in tumor regression and decreased cancer stem cell frequency in OMP-PN13 xenograft tumors. gemcitabine from Phase 1b trial and generated at OncoMed Pharmaceuticals, Inc. Tumors Not Evaluable 3 2 3 8 - were passaged subcutaneously in NOD/SCID mice up to 4 passages. • For efficacy studies, treatments were initiated when tumors reached 100 mm3. Animals were treated with gemcitabine or gemcitabine plus nab-paclitaxel with or without anti-DLL4 CONCLUSIONS antibody. 1500 Control mAb • Histologic analysis used formalin-fixed, paraffin-embedded sections. Slides were scanned 3 Gemcitabine • Anti-DLL4 in combination with gemcitabine/nab-paclitaxel was efficacious against nab-Pac pancreatic xenograft tumor growth. using Imagescope (ScanScope AT, Aperio) . 1000 Gem/nab-Pac • For Limiting Dose Dilution (LDD) study, single cell suspensions from control and treated Anti-DLL4+ Gem • The significant growth inhibitory effect by the triple combination was associated with a tumors were diluted to appropriate cell doses and injected subcutaneously in NOD/SCID Anti-DLL4+nab-Pac decrease in cancer stem cell frequency and an increase in apoptosis and tumor cell 500 mice. Mice were followed up for up to 3 months and sacrificed before tumor volumes reached Anti-DLL4+Gem/nab-Pac differentiation. 2,000 mm3. Cancer stem cell frequency was determined using L-Calc Version 1.1 software program (StemCell Technologies, Inc., Vancouver, Canada). mm Volume, Tumor 0 • The triple combination was highly effective against tumor growth in a xenograft derived from • Data are expressed as mean±S.E.M. Differences of p<0.05 are considered significantly 0 10 20 30 40 a patient that previously did not respond to demcizumab plus gemcitabine. different. Days Post Treatment • An ongoing Phase 1b dose escalation study of demcizumab plus gemcitabine with or • Three of the 6 (50%) evaluable patients who received DEM/GEM/nab-paclitaxel had a st without nab-paclitaxel evaluates in 1 line pancreatic cancer patients. Figure 3. Triple combination of anti-DLL4 (20 mg/kg every other week) with weekly gemcitabine (25 mg/kg)/nab-paclitaxel (15 mg/kg) RECIST partial response and 2 had stable disease resulting in a clinical benefit rate of was more efficacious compared to anti-DLL4 plus either gemcitabine (40 mg/kg) or nab-paclitaxel (30 mg/kg) in OMP-PN13 xenograft 83%. The Kaplan-Meier estimated median progression free survival for this cohort has not tumors. been reached. • A randomized Phase 2 trial in 1st line pancreatic cancer is planned for 2014..
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