Pancreas Cancer Update Systemic Treatments

Transcription

1 Pancreas Cancer Update Systemic Treatments Carlos R Becerra. Baylor University Medical Center Stage Distribution for Pancreas Cancer in the US (24-21) Axis Title Localized Re gional Distant Unknown Sta ge at Diagno sis Survival by Clinical Stage % surviving Months Resectable Locally Advanced Metastatic

2 Comparative One-Year Survival 1 % 9% 8% 74% 7% 66% 6% 5% 51% 4% 3% 24% 25% 28% 2% 14% 1% % Pan cr eat ic Gastric/GEJ Lung Blad der Co lore ct al Br eas t Pr ostat e SEER data March 216 Localized Pancreas Cancer Recent progress in pancreatic cancer CA: A Cancer Journal for Clinicians Volume 63, Issue 5, pages , 15 JUL 213 DOI: /caac

3 CONKO-1 Study Design Resected pancreatic cancer 368 patients (7/98 to 12/4) Stratification: R; T; N Gemcitabine for 6 months Observation for 6 months Primary Endpoint: DFS Follow up every 8 weeks 368 pts to detect improved DFS of 6 months, a.5 and power 9%. Oettle et.al. JAMA 213 CONKO-1 Kaplan Meier Disease Free Survival 1% 75% Chemotherapy with gemcitabine (12.86; 15.57) 41 % patients censored (+) Observation (8.; 8.11) 22 % patients censored (+) 5% Log Rank: p<.1 25% % months Oettle et.al. JAMA 213 CONKO-1 Kaplan Meier Survival 1% 75% Chemotherapy with gemcitabine 53 % patients censored (+) Observation 45 % patients censored (+) 5% cumulative survival 25% % months Oettle et.al. JAMA 213

4 Slide 1 Presented By John Neoptolemos at 216 ASCO Annual Meeting Slide 7 Presented By John Neoptolemos at 216 ASCO Annual Meeting Tumour Pathology Presented By John Neoptolemos at 216 ASCO Annual Meeting

5 Slide 16 Presented By John Neoptolemos at 216 ASCO Annual Meeting Survival by Treatment Presented By John Neoptolemos at 216 ASCO Annual Meeting Treatment Effect by R-Status Presented By John Neoptolemos at 216 ASCO Annual Meeting

6 Ongoing studies in the adjuvant setting for pancreas cancer Pancreas cancer RO or R1 resection (846 patients) Gemcitabine x 6 cycles Gemcitabine and abraxane x 6 cycles Histologically confirmed resectable or borderline resectable pancreas cancer (31 patients) Resection followed by Gemcitabine x 6 cycles FOLFIRINOX x 6: Resection:FOLFIRINOX x 6 Locally Advanced Pancreas Gemcitabine Alone Versus Gemcitabine Plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial (E421) Gemcitabine Locally Advanced and Unresectable Pancreas Cancer (316 patients) Gemcitabine and XRT (initial XRT) Loehrer et. al. JCO 211

7 E421 Results Loehrer et. al. JCO 211 Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib Hammel et.al. JAMA 216 Overall survival by Random 2 status

8 PFS by Random 2 status Tolerance, Random 2 Chemotherapy Chemoradiotherapy (n= 136) (n= 133) Adverse Events - n (%) Grade 3/4 n (%) Grade 3/4 n (%) P Hematologic Neutrophils 8 (7) 3 (3.1).2 Platelets 3 (2.6) ().2 Hemoglobin 1 (.9) 1 (1) 1 Febrile neutropenia () () Gastrointestinal Nausea () 6 (5.9).9 Vomiting () 3 (2.9).1 Diarrhea 1 (.9) 5 (4.9).1 Mucositis () () Pulmonary Coughing 3 (2.6) ().6 Dyspnea 3 (2.6) ().6 Toxic death 1 (not related to RT) Neoadjuvant Therapy ChemoXRT GEMCITABINE 5FU Chemotherapy FOLFIRINOX GEM/ABRAXANE AGAP Trial

9 Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer: A Propensity Score Matched Analysis Mokdad et.al. JCO Feb 217 Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer: A Propensity Score Matched Analysis Mokdad et.al. JCO Feb 217 Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer: A Propensity Score Matched Analysis Mokdad et.al. JCO Feb 217

10 Pilot Study with Anakinra,Gemcitabine, Abraxane and Cisplatin in Patients with Localized and Locally Advanced Pancreas Cancer (the AGAP trial) Baylor only study Preclinical model developed by Baylor basic scientist Multidisciplinary approach Unique target Clinical benefit beyond tumor control Prior study at Baylor in metastatic pancreas cancer safe and prolonged survival Myeloid cells express IL-1β in pancreatic cancer tumors Cytokeratin/IL-1b/DAPI Connie Xu IL1R antagonist (Anakinra) prevents tumor growth in vivo Anakinra/PBS daily Anti-TSLPR Connie Xu

11 Effect of IL1 inhibition in combination with gemcitabine in a xenograft model of pancreas cancer Zhuang et.al. Clinical Cancer Research 216 Zhuang et.al. Clinical Cancer Research 216 Results AGAP Trial Enrolled 16/16 patients in 1 year (1 year ahead of schedule). Main Toxicity has been neutropenia that is reversible and managed with growth factor support Twelve patients had tumors resected, all with margins One patient died from post operative complications One patient declined further treatment and died while on hospice 13 patients remain alive (6 without recurrence). Three patients had unresectable tumors and received XRT followed by additional chemotherapy. No patient developed tumor progression while on treatment Exploratory biomarkers in collaboration with our basic scientists at Baylor and our collaborators at TGEN

12 Toxicities with AGAP in 16 patients that signed an informed consent and underwent treatment Adverse events Grade 1/2 Grade 3/4 Grade 5 Neutropenia 3 (19%) 8 (5%) Febrile Neutropenia 1 (6%) Anemia 2 (12%) 4 (25%) Thrombocytopenia 2 (12%) 1 (6%) Diarrhea 5 (31%) 3 (19%) Hypomagnesemia 5 (31%) Alopecia 9 (56%) 5 (31%) Nausea 11 (69%) 1 (6%) Fatigue 1 (62%) Redness at injection site 11 (69%) 1 (6%) Constipation 7 (44%) Syncope/Near Syncope 1 (6%) 1 (6%) Death 2 (12%) Pathology for PK Kaplan-Meier Analysis of the AGAP Trial % Survival Months

13 Metastatic Pancreas Cancer Study Design Planned N = 342 FOLFIRINOX Stage IV No prior treatment for metastatic disease Karnofsky PS 7 Measurable disease Total bilirubin ULN Gemcitabine Conroy T, et,al. NEJM 211 Kaplan Meier Estimates of Overall Survival and Progression-free Survival, According to Treatment Group. Conroy T et al. N Engl J Med 211;364:

14 Study Design Planned N = 842 Stage IV No prior treatment for metastatic disease KPS 7 Measurable disease Total bilirubin ULN Primary Endpoint: OS Secondary Endpoints: PFS and ORR by Independent Review (RECIST) Safety and Tolerability by NCI CTCAE v3. nab-paclitaxel 125 mg/m 2 IV qw 3/4 weeks + Gemcitabine 1 mg/m 2 IV qw 3/4 weeks 1:1, stratified by KPS, region, liver metastasis Gemcitabine 1 mg/m 2 IV qw for 7/8 weeks then qw 3/4 weeks With 68 events, 9% power to detect OS HR =.769 (2 sided α =.49) 1 interim analysis for futility Treat until progression CT scans every 8 weeks Von Hoff et al., ASCO GI 213 LBA148 PFS by Independent Review Proportion of Progression-free Survival nab-p + Gem Gem Events/N (%) PFS, months Median (95% CI) 75 th Percentile 277/431 (64) 5.5 ( ) /43 (62) 3.7 ( ) 5.9 HR =.69 95% CI ( ) P = Pts at Risk Months nab-p + Gem: Gem: PFS Rate at nab-p + Gem Gem % Increase 6 months 44% 25% 76% 12 months 16% 9% 78% Von Hoff et al., LBA Overall Survival Proportion of Survival nab-p + Gem Gem Events/N (%) OS, months Median (95% CI) 75 th Percentile 333/431 (77) 8.5 ( ) /43 (83) 6.7 ( ) 11.4 HR =.72 95% CI ( ) P = Pts at Risk Months nab-p + Gem: Gem: Von Hoff et al., ASCO GI 213 LBA148

15 Protocol # A Feasibility and Safety Study of PSCA- Specific Chimeric Antigen Receptor Engineered T Cells (BPX-61) In Subjects with Non-Resectable Pancreatic Cancer Take Control of Life Chimeric Antigen Receptor T Cells

16 PSCA (Prostate Stem Cell Antigen) Overexpressed in pancreatic, prostate, bladder, and ovarian cancers. Low expression in normal epithelial cells of prostate, urinary bladder, kidney, skin, esophagus, stomach, and placenta. Anti-PSCA antibodies (AGS-1C4D4 or AGS-PSCA) have been administered in clinical trials to approximately 2 subjects for the treatment of advanced pancreatic cancer (Wolpin 215) and prostate cancer (Antonarakis 211; Morris212). PSCA antibody treatment showed low toxicity at high antibody doses (up to 48 mg/kg) Rimiducid In Vivo Tumor Killing by BPX-61 T Cells Elimination of HPAC tumors in NSG mice with 1x1 7 BPX-61 T cells Potent initial CAR activity with and without CID

17 Persistence of BPX-61 Cells with and without Rimiducid (Rationale for Timing of Rimiducid Dose) (no CID) (no CID) (no CID) (CID started on day 14) (CID started on day 1) intermediate 1.25M BPX-61 without rimiducid slowed tumor growth for 14 days. rimiducid on day 14, increased tumor control with a reduction in tumor size. sufficient numbers of BPX-61 cells present at day effective antitumor response upon activation by rimiducid. BPX-61 cells persist in the presence of tumor antigen without rimiducid and control tumor growth when rimiducid is administered. Dosing: Escalation / De-escalation Phase I, single center, open-label, non-randomized, feasibility, safety and dose-finding study in patients with non-resectable pancreatic adenocarcinoma. The maximum tolerated dose (MTD) design consists of 5 cohorts consisting of 3-6 subjects per cohort who will be treated following a 3+3 dose escalation/de-escalation schema. Phase I Cohorts BPX-61 Dose 1.3 x1 6 (±2%) cells/kg x1 6 (±2%) cells/kg 3 (starting dose) 1.25 x1 6 (±2%) cells/kg x1 6 (±2%) cells/kg 5 5 x1 6 (±2%) cells/kg BP-12 Study Timeline CONFIDENTIAL 51

18 Completed studies at Baylor FOLFIRINOX standard of care for patients with metastatic pancreas cancer IL1 is part of the inflammatory milieu that enhances cancer cell proliferation and survival Anakinra is a potent IL1 inhibitor FDA approved for rheumatoid arthritis and neonatal onset multisystem inflammatory disease Pilot study of FOLFIRINOX in combination with anakinra Results FOLFIRINOX +Anakinra 16/16 patients consented for the study 12 patients completed all doses per protocol. 3/15 patients did not complete treatment due to toxicity (2) or clinical progression (1). 1 patient was ineligible for the study. 1 patient had a progression after 18 months and was rechallenged with FOLFIRINOX and anakinra (compassionate use IRB approved) with a partial response. However developed brain metastasis as site of tumor progression and was taken off treatment. Toxicities with FOLFIRINOX + Anakinra in 16 patients that signed an informed consent Adverse events Grade 1/2 Grade 3 Grade 4 Grade 5 Chills 5 (33%) Constipation 4 (27%) Diarrhea 7 (47%) 2 (13%) Fatigue 1 (67%) Hypokalemia 4 (27%) Nausea/vomiting 11 (73%) 1 (7%) Neuropathy 4 (27%) Neutropenia 4 (27%) 2 (13%) Pain/discomfort 7 (47%) Redness/pain at injection site 8 (53%) Swelling 3 (2%) Biliary obstruction 1 (7%) Gastric outlet obstruction 1 (7%) Syncope 1 (7%) Pulmonary embolism 1 (7%)

19 1 Kaplan-Meier Survival Analysis 8 FOLFIRINOX + ANA FOLFIRINOX % Survival 6 Median survival 11.1 months 4 Median survival 17.4 months 5/12 patients with survival > 25 months Months Results In the comparison of these two groups of patients receiving FOLFIRINOX treatment, several major differences should be noted: First, there were 171 patients who received the standard FOLFIRNOX treatment, while there were only 12 in the group that received all doses of modified FOLFIRINOX and anakinra. Patients in the FOLFIRINOX group were evaluated every 3 months, while those in the FOLFIRNOX + Anakinra group were evaluated every 2 months. The dose of FOLFIRINOX utilized was a modified version of the original regimen (deleted bolus 5 FU and leucovorin due to increased marrow and GI toxicity) Patients received growth factor support after every cycle of treatment on the FOLFIRINOX and anakinra study. Even with the small study numbers, there was still a significant difference between the two groups (P=.165). However confidence intervals are wide and overlap. This difference is even more impressive given the fact patients self administered anakinra in combination with chemotherapy for only two months. We observed no major adverse events with the addition of anakinra (except for local site reactions). Noted a decrease in narcotic utilization while patients received anakinra. Many thanks to the brave patients that decided to participate on clinical trials, to the wonderful multidisciplinary research and clinical team, to the research staff and to the Baylor Foundation for providing the seed money for some of the studies!