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Sviluppi futuri di nab -Paclitaxel nel carcinoma metastatico del pancreas

Sviluppi futuri di nab -Paclitaxel nel carcinoma metastatico del pancreas. Michele Milella Istituto Nazionale Tumori Regina Elena Roma. It’s not just the cancer cell: interaction with the (micro)environment in PDAC. Hh inhibitors: targeting tumor-stroma interactions in PDAC.

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Sviluppi futuri di nab -Paclitaxel nel carcinoma metastatico del pancreas

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  1. Sviluppi futuri di nab-Paclitaxel nel carcinoma metastatico del pancreas Michele Milella Istituto Nazionale Tumori Regina Elena Roma

  2. It’s not just the cancer cell: interaction with the (micro)environment in PDAC

  3. Hh inhibitors: targeting tumor-stroma interactions in PDAC

  4. Meccanismo d’azione nab-paclitaxelè la prima nano-chemioterapia target1 Dissociazione in singoli complessi di paclitaxel albumina Legame recettoriale attivo e mirato tra paclitaxel albumina e recettori gp60, con attivazione di caveolina-1 1 2 Incremento della transcitosi attraverso le membrane cellulari endoteliali Incremento dell’accumulo a livello tumorale di paclitaxel albumina attraverso il legame con la proteina SPARC 3 4

  5. A Phase II Trial of nab‐Paclitaxel in Patients With Advanced Pancreatic Cancer Who Have Progressed on Gemcitabine‐Based Therapy Paclitaxel albumin in patients with gemcitabine-refractory advanced pancreatic cancer: Study Design/Eligibility Criteria • Age > 18 • Locally advanced, unresectable or metastatic pancreatic ductal carcinoma • ECOG PS 0-2 • Good organ function • Progressed within 6 months of gemcitabine Endpoints • 6-month overall survival rate • Response rate by RECIST criteria / Progression-free survival • Safety and tolerability • CA19-9 at baseline and every 2 cycles /SPARC immunohistochemistry (IHC) on available pre-treatment tumor specimens performed at a reference lab Single-institution phase II open-label trial Treatment: nab-P 100 mg/m2 IV over 30 minutes on days 1, 8 and 15 of a 28-day cycle Contrast CT at baseline and every 2 cycles Hosein et al. Presented at ASCO Annual Meeting, 2010; Abstract #4120

  6. Paclitaxel albumin in patients with gemcitabine-refractory advanced pancreatic cancer: safety Hosein, et al. ASCO 2010 (abstract 4120) Paclitaxel albumin was well tolerated in this group of patients

  7. Paclitaxel albumin in patients with gemcitabine-refractory advanced pancreatic cancer: efficacy Hosein, et al. ASCO 2010 (abstract 4120) 37% of patients derived clinical benefit and 21% remained on therapy for 6 months, suggesting paclitaxel albumin is active in this setting

  8. nab-Paclitaxel has single-agent activity in advanced PDAC: a clinical case • D.C., 60 yr-old female, with locally advanced, inoperable PDAC • Pretreated with single-agent Gem, Gem/Ox, Folfox (with very poor tolerance) and RF ablation of the pancreatic lesion • Subsequent therapy with Folfiri for peritoneal progression • April 2011, further peritoneal and hepatic progression, symptomatic ascites, ECOG PS 2, CA19.9: 1742  off-label nab-Paclitaxel started (100 mg/m2 weekly 3/4) • After 2 administrations: G4 neutropenia, with worsening of the ascites and PS 3, hospitalization required; CA19.9: 1280  supportive care and restarted on nab-Paclitaxel (dose -reduced to 75%) w G-CSF support • July 2011: CT scan shows SD, PS improved to 1, no signs of ascites, CA19.9: 880  continue nab-Paclitaxel w G-CSF support • As of today, the patient has completed 5 cycles of nab-Paclitaxel with good tolerance, her ECOG PS has returned to 0, she has gone back to work; clinically there are no signs of ascites, CA19.9 has decreased to 278, CT scan is stable.

  9. Paclitaxel albumin + vandetanib in patients with advanced pancreatic cancer • Treatment • Cohort A: paclitaxel albumin 100 mg/m2 QW 3/4 + V 100, 200 or 300 mg po QD • Cohort B: paclitaxel albumin 260 mg/m2 Q3W + V 100, 200 or 300 mg po QD • Results • MTD of V was the maximum planned dose in each cohort (300 mg QD) • DLTs • Cohort A: 3 DLTs (1 at each dose level) • 2 patients with grade 3 rash and 1 patient with grade 4 neutropenia, grade 3 mucositis, prolonged QTc • Cohort B: No DLTs at any dose level • Preliminary efficacy results of all evaluable patients (n=22) • PR: 6 (27%), SD: 10 (45%), PD: 6 (27%) • Median PFS: 5.3 months (95% CI 3.7- 7.3) • Median OS: 8.2 months (95% CI: 6.2-11.5) • Conclusions • Both schedules were well tolerated with promising preliminary efficacy indicated El-Khoueiry et al. ASCO 2011 (abstract 4124)

  10. Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: Phase I/II study design Open label phase I/II study in chemotherapy-naive patients with metastatic adenocarcinoma of the pancreas Phase I: Gemcitabine 1000 mg/m2 QW 3/4 + Dose escalation of paclitaxel albumin according to a standard 3+3 design Phase II: Accrual expanded to 42 patients Treatment at the MTD • Study objective: To evaluate the safety and efficacy of paclitaxel albumin + gemcitabine and the correlation of clinical response with tumoural SPARC and serum CA19-9 levels in patients with metastatic pancreatic cancer • Study endpoints • Safety: MTD and DLTs (Phase I); safety (incidence of treatment-related AEs and SAEs) • Efficacy: RR, PFS, OS, PET scan response, CA 19-9 and SPARC levels in relation to efficacy Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  11. Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: eligibility criteria Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  12. Dose Finding Scheme Gemcitabine 1000 mg/m2 i.v. Dose Levels nab-Paclitaxel 100 mg/m2 i.v. 125 mg/m2 i.v. 150 mg/m2 i.v. Days 15 1 8 22 28 Week 3 Week 4 Week 1 Week 2 28 dayscycle Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  13. MTD and DLT nab-Paclitaxel Dose Levels First 6 pts: 2 pts d8 dose held for neutropenia (G3) and thrombocytopenia (G2) 3 responders 100 mg/m2 i.v. Protocol amendment to allow 20 pts 125 mg/m2 i.v. MTD 150 mg/m2 i.v. 44 pts recruited 1 pt died due to neutropenia (biliary stent) cycle 1 2 pts reversible Grade 3 Aes (Fatigue, Neutropenia) Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  14. Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: baseline demographics Von Hoff et al. J Clin Oncol 2011. Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd) * cut-off for normal range: <37 u/mL

  15. Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: prior therapy *data are for 1 patient Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  16. Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: safety Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  17. Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: Treatment exposure Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  18. Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: efficacy * Median, months (95% CI) Von Hoff et al. J Clin Oncol 2011. Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  19. Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: survival 100 75 50 25 0 Paclitaxel albumin 125 mg/m2 (n=44) 12.2 months Probability of survival (%) 0 3 6 9 12 15 18 21 24 27 30 Time (months) Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  20. Paclitaxel albumin + gemcitabine in metastatic pancreatic cancer: rapid response on PET scans 6 weeks Baseline Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  21. Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: FDG PET Incomplete metabolic responses (n=38) Complete metabolic responses (n=17) 100 75 50 25 0 p=0.01 20.1 months Probability of survival (%) 10.2 months Complete Censored 0 3 6 9 12 15 18 21 24 27 30 Time (months) • FDG PET scans were available for 55 patients • Median decrease in metabolic activity at 12 weeks: • 79% (all patients) • Patients with a metabolic response (defined by EORTC as absence of FDG uptake) had a significantly improved OS: • Median OS: 20.1 vs 10.3 mo, p=0.01 Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)

  22. Rapid CA19-9 decreases after treatment initiation CA19-9 decrease ≥50% was observed in (78%) of patients with available CA19-9 levels Median max % change in 54 patients was 91% Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: CA19-9 CA19-9 levels strongly correlated with RR, PFS, OS D. von Hoff et al. ASCO 2009 (Poster 4525).

  23. Paclitaxel albumin + gemcitabine in patients with metastatic pancreatic cancer: SPARC 100 75 50 25 0 Average z score ≥0,high SPARC (n=19) Average z score <0,low SPARC (n=17) p=0.0431 17.8 months Probability of survival (%) 8.1 months 0 3 6 9 12 15 18 21 24 27 30 Time (months) • SPARC status was evaluated in 36 patients • A significantly longer OS was reported in the high SPARC vs low SPARC group • Median OS: 17.8 vs 8.1 mo, p=0.0431 • SPARC level remained a significant predictor for OS after adjusting for clinical covariates (eg age, sex, race, baseline CA 19-9) (p=0.041) • Stromal SPARC correlated with OS (p=0.013) but SPARC in tumour cells did not (p=0.15) Von Hoff et al. J Clin Oncol 2011.

  24. Companion Preclinical Studies Aggregate tumor regression response in individual xenografts 22 of 90 (24%) 34 of 95 (36%) 53 of 96 (55%)

  25. Effects in Tumor Stroma Collagen Type I Immuno-staining Treatmentgroup Profuse Desmoplastic Stroma Control Persisting Stroma Gemcitabine Desmoplastic Stroma Depletion nab-Paclitaxel GEM + nab-Ptx Dilated blood vessels x3 increase in Nestin

  26. Intratumor concentration of GEM 7500 2.8 fold increase 5000 Mean Gem concentration (ng/g) 2500 nab-Paclitaxel + Gemcitabine Gemcitabine alone 0

  27. Ongoing studies with nab-Paclitaxel in pancreatic cancer

  28. Randomized Phase III Study of Weekly nab-Paclitaxel plus Gemcitabine versus Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas (CA046) • Primary Objective • To evaluate efficacy of the combination of nab-paclitaxel and gemcitabine versus gemcitabine alone in improving overall survivalin patients with metastatic adenocarcinoma of the pancreas • Secondary Objectives • To evaluate the following: • Objective tumor response and progression-free survival (PFS) according to RECIST criteria • Safety and tolerability • Functional tumor response according to EORTC criteria • Change in serum CA19-9 and plasma SPARC levels • SPARC in tumor tissue and peripheral blood and determine its possible correlation with efficacy outcomes

  29. Study Design RANDOMIZE nab-Paclitaxel 125 mg/m2(No Premedication)+Gemcitabine 1000 mg/m2Weekly, 3 of 4 Weeks Gemcitabine 1000 mg/m2Weekly, 7 of 8 Weeks (Cycle 1) thenWeekly, 3 of 4 Weeks (Cycle 2 Onward) (1:1) Planned accrual N = 842 Intent-To-Treat (ITT) Patients

  30. We left here just one year ago… Sperduti, ASCO 2010

  31. …and we got here in just one year!!!!

  32. …with great hope for a bright future!!!

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