Clinical trials updates: current and future cholangiocarcinoma trials

Transcription

1 U C L C A N C E R I N S T I T U T E Clinical trials updates: current and future cholangiocarcinoma trials John Bridgewater UCL Cancer Institute AMMF Information Day Imperial College, 10 May 2016

2 U C L C A N C E R I N S T I T U T E ABC-studies in context Eckel and Schmid Br J Cancer 2007;96:

3 U C L C A N C E R I N S T I T U T E Fail to start chemotherapy rate following randomisation into adjuvant studies Trial Surgery % (did not start/ randomised to receive) BILCAP Biliary resection Pancreatoduodenectomy Extended hepatectomy 0.7 (1/137) YCHOU Hepatectomy 4.7 (15/321) CONKO 1 Pancreatoduodenectomy 13.4 (25/186) ESPAC1 Pancreatoduodenectomy 17 (25/147) ESPAC3 Pancreatoduodenectomy 11.3 (124/1088) ESPAC3 (V2) Pancreatoduodenectomy 15.4 (32/207)

4 U C L C A N C E R I N S T I T U T E

5 U C L C A N C E R I N S T I T U T E ABC-02 - schema Eligible patients (n=400*) + QoL Randomized 1:1 (stratified by centre, primary site, PS, prior therapy and locally advanced vs. metastatic) Arm A Gem 1000 mg/m 2 D1,8,15 q 28d Arm B Cisplatin 25 mg/m 2 + Gem 1000 mg/m 2 D1,8 q 21d 24 weeks (6 cycles) 24 weeks (8 cycles) Primary endpoint OS

6 U C L C A N C E R I N S T I T U T E BILCAP

7 U C L C A N C E R I N S T I T U T E BILCAP Data mature end 2016

8 BILCAP stratification factors IDMC open report November 2015

9 BILCAP IDMC report November 2015

10 ACTICCA-01 design (AIO Arnold) gemcitabine + cisplatin for 24 weeks gemcitabine 1000 mg/m2 (day 1, 8) qd 22 cisplatin 25 mg/m2 (d 1, 8) qd 22 curative intent resection of intrahepatic, hilar or extrahepatic CCA n=280 R stratification criteria intrahepatic vs. hilary/extrahepatic CCA lymphnode positivity vs. negativity + observation assessment every third month (CT/MRI and CA 19-9) observation assessment every third month (CT/MRI and CA 19-9) N=73+ in Europe CRUK CTAAC funding Mar 2013 Slow to open in UK because of BILCAP Trial modified to include GB May require modification if BILCAP or PRODIGE12 +ve

11 ACTICCA-01 design (AIO Arnold) gemcitabine + cisplatin for 24 weeks gemcitabine 1000 mg/m2 (day 1, 8) qd 22 cisplatin 25 mg/m2 (d 1, 8) qd 22 curative intent resection of intrahepatic, hilar or extrahepatic CCA n=280 R stratification criteria intrahepatic vs. hilary/extrahepatic CCA lymphnode positivity vs. negativity + observation assessment every third month (CT/MRI and CA 19-9) observation assessment every third month (CT/MRI and CA 19-9) Capecitabine

12 Study description Study size Outcome Date ABC-01 ABC-02 ABC-03 Randomised phase 2 Phase 3 Randomised phase Published Published Published ABC-04 Phase 1b 13 Published ABC-06 ABC-07 ABC-08 Adjuvant BILCAP ACTICCA-01* Photodynamic Therapy Photostent-02 Phase 3 Phase 2 Phase 1b Accruing Accruing Accruing Phase 3 Phase Completed Accruing Phase 3 98 Submitted for publication Phase In set-up 2015 Advanced disease Neoadjuvant BBC-01

13 ABC-06 Eligible patients (162) Randomise (stratified for PS and locally advanced vs. metastatic) Arm A (81) Arm B (81) mfolfox + BSC BSC 0S Valle CI recruiting n=83

14 ABC-07 The 1-year PFS for locally advanced pts ABC-02: 104 pts 24% In ABC-02 68/78 (87%) had PR+SD after 8 cycles of chemo. In the cisplatin-gemcitabine arm 39/44 (88%) had PR+SD. This group could potentially benefit of addition local therapy. Hawkins recruiting n=1

15 ABC-08 Phase 1b Cisplatin Acelarin n=12-8 (McNamara) Patients will be randomized to one of the following two arms: Arm Agent(s) Dose Route Schedule 1 2 Acelarin mg/m2 IV Cisplatin 25 mg/m2 IV Gemcitabine 1000 mg/m2 Cisplatin To inform BI.2 study 25 mg/m2 IV IV Duration Until D1 and D8 disease of 3 wk progression cycle or toxicity

16 BI.2 CisGem vs Cis-Acelarin n=642 NCIC Canada (Nucana, Knox) Arm 1 Patients with locally advanced or metastatic adenocarcinoma of the intra or extrahepatic bile ducts, gallbladder cancer or ampullary cancer R A N D O M I Z A T O N Acelarin mg/m2 D1 + D8 of 3wk cycle Cisplatin 25 mg/m2 D1 + D8 of 3wk cycle Arm 2 Gemcitabine 1000 mg/m2 D1 + D8 of 3wk cycle + Cisplatin 25 mg/m2 D1 + D8 of 3wk cycle Continue Treatment Until PD

17 UCL Cancer Institute JSBF study evaluating VEGF and cmet targeting N= 300 Patients R 2:1 Sponsor Lilly Valle R 2:1 Ramucirumab + IV placebo + Merestinib + Oral placebo + Gemcitabine + Cisplatin Gemcitabine + Cisplatin Gemcitabine + Cisplatin Gemcitabine + Cisplatin Ramucirumab 8mg/kg IV D1&8 3qw Cisplatin 25mg/m2 IV D1 & 8 3qw Gemcitabine 1g/m2 IV D1 & 8 Arm A1 N=100 3qw IV placebo IV D1&8 3qw Cisplatin 25mg/m2 IV D1 & 8 3qw Gemcitabine 1g/m2 IV D1 & 8 3qw Merestinib 80mg oral, daily Cisplatin 25mg/m2 IV D1 & 8 3qw Gemcitabine 1g/m2 IV D1 & 8 3qw Oral placebo Daily Cisplatin 25mg/m2 IV D1 & 8 3qw Gemcitabine 1g/m2 IV D1 & 8 3qw Arm A2 N=50 Stratification factors Locally-advanced or metastatic BTC First line treatment ECOG PS 0/1 1:1 randomisation Double-blind Primary tumour site Geographic region Metastatic status Gall bladder IH-CC EH-CC Ampulla of Vater Europe or North America Rest of the world Yes/No Arm B1 N=100 Arm B2 N=50 CisGem treatment will be 8 cycles No cap of Ramucirumab/Merestinib/placebo Crossover is not permitted Appropriate best supportive care will be offered to all Interim safety analysis after n=75 patients complete Cycle 1

18 Proof-of-concept study of AZD4547 in patients with FGFR dysregulated tumours RMH/AstraZeneca (Turner) 3 independent tumour cohorts (OG, Chondrosarcoma, cholangiocarcinoma): 9-17 evaluable patients per arm

19 PRODIGE-38 FFCD (Malka) Optimum biliary drainage if necessary Arm A Bilirubin < 1.5 N R Arm B N=188 phase 2. 60/89 or more patients 6m PFS then expand No ampullaries Laurent-Puig translational They think about 50% of all BTC CISGEM: At D1 and D8 of each cycle (every 21 days for 6 months) Cisplatin: 25 mg/m² IV over 1 hour Gemcitabine: 1000 mg/m² IV over 30 minutes mfolfirinox: At D1 of each cycle (every 15 days for 6 months) Oxaliplatin: 85 mg/m² IV over 20 minutes Irinotecan: 180 mg/m² IV over 90 minutes 5FU continuous infusion: 2400 mg/m² over 46 hours Folinic acid: 400 mg/m² over 2 hour

20 EORTC-1560-GITCG (Synergy 1, Moehler, Mainz) N=75 (2:1 randomization to Pembrolizumab arm) Primary endpoint: PFS at 6 months Secondary endpoints: Response rate (RECIST v1.1) Immune related Progression Free Survival (irpfs) Overall Survival (OS) Toxicity (CTCAE v4.03) Quality of life (QoL) (EORTC QoL C30 and BIL 21) Exploratory end-points: Assessment of immunological response Pathological and clinical predictive factors for response/toxicity

21 Eligible patients with unresectable intrahepatic cholangiocarcinoma (ICC) SIRCCA Study Primary Endpoint: Survival at 18 months (Arm B > Arm A by at least 15 %) Stratify: Co-CI s: Bruix J & Wasan HS Extra-hepatic disease Cirrhosis Unilobar vs. bi-lobar intended treatment Albumin <35g/L vs. 35g/L ECOG Status Randomise S 1:1 N = 180 Systemic chemotherapy CIS + GEM (A) SIR-Spheres followed by systemic chemotherapy CIS + GEM (B)

22 The 100,000 Genomes Project 100,000 whole genome sequences in NHS patients with rare inherited disease, cancers and pathogens from the NHS in England Whole Genome Sequencing Generate health and wealth Legacy of infrastructure, human capacity and capability

23 Tumour type Allocation Breast Cancer 2,000 Colorectal Cancer 2,000 Ovarian cancer Lung Cancer Prostate Cancer Childhood solid 2,000 2,000 2, Renal Sarcoma Unknown Primary UGI

24 UCL Cancer Institute Added value from GeCIP Further omics Concurrent clinical trial information Education Infrastructure BUT Fresh biopsies Infrastructure to harvest material and collect data Modest funding

25 Conclusion Expanding portfolio (chemotherapy, immunotherapy and targeted therapy) but little surgery and modest radiation All lines of therapy Promising translational input 6 first line studies 2 second + line ABC ABC BILCAP 2017

26 Thanks to Helen and the AMMF Juan Valle Harpreet Wasan John Primrose ABC TMG (CRUK UCL trials unit) NCRI UGI CSG Hepatobiliary subgroup International Biliary Tract Cancer Collaboration (IBTCC)

27 U C L C a n c e r I n s t i t u t e International Biliary Tract Cancer Collaborators