Pancreatic Ductal Adenocarcinoma (PDAC)crukcambridgecentre.org.uk/sites/default/files/Teaching...

Pancreatic Ductal Adenocarcinoma (PDAC) The Clinical Problem and Current Drug Treatment

Duncan Jodrell

Professor of Cancer Therapeutics

CRUK Cambridge Institute

Li Ka Shing Centre,

University of Cambridge

The clinical problem

• The 10th most common cancer, but the 4th most common killer

• Using current trends in outcome, PDAC is projected to become the 2nd most common cancer killer by 2030

• Why?

– Presents late:

• Non specific symptoms; weight loss, epigastric pain

• only 10-20% of patients suitable for operation at presentation (usually those presenting with obstructive jaundice)

– Considered to be relatively resistant to chemotherapy (average survival

< 12 months, following a diagnosis of metastatic disease)

– Debilitating effects often preclude aggressive treatment:

• Pain, anorexia, biliary obstruction, duodenal obstruction, cachexia

7/1

1/1

3

17

/01

/14

Patients present “late”, often with extensive metastatic and rapidly progressing disease

~ 2 month interval between scans

Summary overview of survival and resection percentages of different groups of patients with pancreatic cancer.

Gillen S, Schuster T, Meyer zum Büschenfelde C, Friess H, et al. (2010) Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages. PLoS Med 7(4): e1000267. doi:10.1371/journal.pmed.1000267 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000267

http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000267

Established treatments for advanced disease

• Gemcitabine (Burris et al, JCO, 1997)

– Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU treated patients (P = .0022)

– The median survival durations were 5.65 and 4.41 months for gemcitabine treated and 5-FU treated patients, respectively (P = .0025).

– The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients.

• Gemcitabine plus erlotinib • Gemcitabine plus capecitabine • Gemcitabine plus nab-paclitaxel (2013)

• Not to mention multiple, negative GEM plus X Phase III trials!

• FOLFIRINOX (2013)

Gemcitabine plus erlotinib

(Moore et al, 2007)

569 patients HR was 0.82 for survival (p=0.038) This translates into a median survival advantage of 0.33 months Q: can molecular phenotyping or genotyping identify the small number of patients who benefit from erlotinib? e.g. “EGF addicted” tumours

Gemcitabine plus capecitabine

(Cunningham et al, 2009) 533 patients HR (survival) = 0.86 (p=0.08) compared to gemcitabine alone 935 patients were included in a meta-analysis of 3 studies, confirming the HR of 0.86 (p=0.02) On this basis, GEMCAP became the standard of care in the UK

The positive outcome of the Phase III (MPACT) study was presented at ASCO 2013 861 patients HR was 0.72, leading to an improvement in overall survival of 1.8 months

Gemcitabine/nab-paclitaxel (AbraxaneTM)

(Von Hoff et al, 2013)

FOLFIRINOX

(Conroy et al, 2013)

342 patients HR of 0.57, leading to a survival advantage of 4.3 months 2 weekly regimen: Oxaliplatin (85 mg m-2) Irinotecan (180 mg m-2) Folinic acid (400 mg m-2) Bolus 5FU (400 mg m-2) Infusional 5FU (2400 mg m-2 over 46 hours) ….. plus G-CSF (filgastrim) s.c. in 43%

Gemcitabine Control Experimental Arm

GEM CAP

Response: 12%

Median PFS: 3.9 months

OS: 6.2 months

Response: 19%


OS: 7.1 months

FOLFIRINOX

Response: 9%


OS: 6.8 months

Response: 32%


OS: 11.1 months

GEM/nab-paclitaxel

Response: 7%


OS: 6.7 months

Response: 23%


OS: 8.5 months

Is FOLFIRINOX just too toxic? mFOLFIRINOX 2 weekly regimen: Oxaliplatin (85 mg m-2) Irinotecan (135 mg m-2) Folinic acid (400 mg m-2) Omit Bolus 5FU (400 mg m-2) Infusional 5FU (2400 mg m-2

over 46 hours) ….. plus G-CSF prophylactically

FOLFIRINOX or gemcitabine/nab-paclitaxel? What will the community decide?

According to clinicaltrials.gov (2014):

FOLIRINOX plus x 3 studies

Gem/nab-p plus x 12 studies

Removal of:

the distal half of the stomach (antrectomy),

the gall bladder and its cystic duct (cholecystectomy),

the common bile duct (choledochectomy),

the head of the pancreas,

the duodenum,

the proximal jejunum, and

the regional lymph nodes.

Reconstruction consists of:

attaching the pancreas to the jejunum (pancreaticojejunostomy)

to allow digestive juices to flow into the gastrointestinal tract

attaching the hepatic duct to the jejunum (hepaticojejunostomy)

to allow bile respectively to flow into the gastrointestinal tract

attaching the stomach to the jejunum (gastrojejunostomy)

to allow food to pass through.

Whipple’s Procedure

http://en.wikipedia.org/w/index.php?title=Antrectomy&action=edit&redlink=1

http://en.wikipedia.org/wiki/Cholecystectomy

http://en.wikipedia.org/wiki/Jejunum

http://en.wikipedia.org/wiki/Lymph_node

http://en.wikipedia.org/wiki/Pancreaticojejunostomy

http://en.wikipedia.org/wiki/Gastric_juice

http://en.wikipedia.org/w/index.php?title=Hepaticojejunostomy&action=edit&redlink=1

http://en.wikipedia.org/wiki/Bile

http://en.wikipedia.org/w/index.php?title=Gastrojejunostomy&action=edit&redlink=1

Adjuvant chemotherapy studies:

• ESPAC-1: demonstrated that bolus 5FU/folinic acid (FUFA) is active adjuvant therapy

– The 5-year survival rate was 21% among patients who received chemotherapy and 8% among patients who did not receive chemotherapy (P=0.009). (Neoptolemos et al, NEJM, 2004).

• ESPAC-3: demonstrated that gemcitabine and FUFA are equivalent as adjuvant therapy

• ESPAC-4 (ongoing (in ampullary, completed recruitment in adeno) NIHR trial)

– GEMCAP vs GEM as adjuvant therapy

– In advanced disease, GEMCAP is associated with an increased response rate (19% vs 12%) and survival (HR 0.86)

• APACT: Gem/nab-paclitaxel versus Gem alone (Celgene sponsored study) – Andrew Biankin = translational lead, Jeff Evans = UK clinical lead

• What about FOLFIRINOX or mFOLFIRINOX? Is anyone asking the question? – Krankenhaus Nordwest – Neoadjuvant/adjuvant FOLFIRINOX versus adjuvant gemcitabine (SoC)

APACT Gem vs GemNab-P

mFOLFIRINOX or Gem

± chemoRT

mFOLFIRINOX SIEGE trial

Gem

2nd Line Clinical Trials Capecitabine

PRICKLE if borderline

(GemNab-P) mFOLFIRINOX


How does nanoparticle albumin–bound (nab)-paclitaxel potentiate gemcitabine activity?

PDAC is a stromal-rich tumour and it expresses high levels of secreted protein acidic and rich in cysteine (SPARC)

One hypothesis was that SPARC may act as an albumin-binding protein, sequestering the nab-paclitaxel, to concentrate the drug intra-tumourally

SPARC expression was therefore suggested to be a potential predictive biomarker for nab-paclitaxel activity (Von Hoff, J. Clin Oncol. 2011)

… but subsequently, review of the MPACT Phase III data discounted this (Hidalgo, World GI, 2014)markers

Gemcitabine metabolism

dFdU

Gemcitabine (dFdC) dFdCTP

Inactive

Active

- Incorporated

into DNA

CDA = Cytidine deaminase

dCK = deoxycytidine kinase

UMP-CMPK = cytidine monophosphate kinase

dCK, UMP-CMPK1,2

CDA

Variability in CDA activity and CDA polymorphisms have both been associated with variability in response and toxicity following gemcitabine administration

Reverse translation: We use the KPC model of pancreatic

ductal adenocarcinoma in many of our studies

KPC

KrasLSL.G12D

p53LSL·R172H

* R172H

II III IV V VI VII VIII IX XI X I

STOP

AUG

p53

PdxCre Pdx Pro. Cre

tg

II III IVa I

STOP

IVb

* Kras

G12D

Hingorani et al, Cancer Cell. 2005; 7(5):469-83.

Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets Agnieszka K. Witkiewicz, et al. Nature Communications 6, 6744 doi:10.1038/ncomms7744

KRAS (92%) and TP53 (50%) are the most common mutations in the TCGA database

KPC mice develop pre-malignant (PanIN) and malignant (adenocarcinoma) lesions identical to human PDAC

Human Mouse Human Mouse

Pan

IN1

a P

anIN

2

PD

A

Pan

IN1

b

Pan

IN3

M

et

Nab-paclitaxel plus gemcitabine was more active than either single agent alone in the KPC model

Frese et al. Cancer Discovery, 2012

Typical chromatograms

RT: 0.00 - 15.00

0 2 4 6 8 10 12 14

Time (min)

0

20

40

60

80

100

0

20

40

60

80

100

0

20

40

60

80

100

Relativ

e Abun

dance

0

20

40

60

80

100

0

20

40

60

80

1007.63

14.58

11.39

7.96 9.28 10.73 12.55 14.49

6.08

5.49 6.50

5.16

5.37

5.02 6.09 6.97

4.50

4.632.11 2.940.43

4.34

4.574.242.511.04

NL: 2.23E4

TIC F: + c ESI SRM ms2 264.030 [111.040-113.040] MS gemstability_S1

NL: 1.60E3

TIC F: - c ESI SRM ms2 263.000 [220.030-220.230] MS gemstability_S1

NL: 2.43E3

TIC F: - c ESI SRM ms2 245.000 [202.010-202.210] MS gemstability_S1

NL: 2.45E3


NL: 5.57E4


dFdC

dFUR (IS)

dFdU

13C, 15N CTP (IS)

dFdCTP

Bapiro et al., (2011). Cancer Chemother. Pharmacol. 68 (5): 1243-53

Limits of quantification: Gemcitabine (dFdC) 0.2 ng/mg tissue dFdCTP 0.2 ng/mg tissue

Our sensitive LC-MS assay for gemcitabine and its metabolites

Validated using

10 mg tissue

Nab-paclitaxel increases gemcitabine and dFdCTP concentration in the tumour

G nP+G0.00

0.05

0.10

0.15

0.20

0.25

pla

sm

a d

Fd

C:d

Fd

U r

ati

o

p = 0.057

G nP+G0.0

0.2

0.4

0.6

0.8

1.0

tum

ou

r d

Fd

C:d

Fd

U r

ati

o

p = 0.014

nP nP+G0

20

40

60

ng

PT

X /

mg

tis

su

e

p = 0.397

Plasma and tumour dFdC/dFdU ratios were also increased

G nP+G0

2

4

6

8

10

ng

dF

dC

TP

/ m

g t

iss

ue

p = 0.036

dFdCTP

No increase in nab-paclitaxel

delivery

Frese et al. Cancer Discovery, 2012

Gemcitabine nab-PTX + Gem Vehicle nab-PTX

Nab-paclitaxel decreases protein levels of cytidine deaminase (CDA)

CDA by Western Blot

Vehicle nab-PTX Gemcitabine nab-PTX+Gem

control PTX

Cda

actin

MG132

Further studies were undertaken to demonstrate that this was related to paclitaxel-induced ROS production and also suggested that scheduling of nab-paclitaxel 24 hours prior to gemcitabine might be beneficial

CDA IHC

Effect reversed by proteasome inhibition

Frese et al. Cancer Discovery, 2012, Albrecht Neese (personal communication)

END POINTS

Primary: Progression free survival Secondary : Safety Response Overall survival Quality of life Health economics Predictive markers Prognostic markers

Pippa Corrie (CI), (Cambridge Clinical Trials Unit - Cancer Theme)

RANDOMISATION

Concomitant NP/GEM

IV Abraxane, 125 mg/m2

Days 1, 8 & 15 IMMEDIATELY FOLLOWED BY IV Gemcitabine, 1000 mg/m2

Days 1, 8 & 15 4-weekly for 6 cycles N=60

Sequential NP/GEM

IV Abraxane, 125 mg/m2

Days 1, 8 & 15 FOLLOWED AFTER 24 HRS BY IV Gemcitabine, 1000 mg/m2

Days 2, 9 & 16 4-weekly for 6 cycles N=60

End of Treatment Visit 30 days from date of last dose of trial treatment

“supported”

Ist line chemotherapy for PDAC

Serial research sample collection, focussing on CDA (activity and expression), stroma and apoptosis

Screening/Pre-Randomisation

Blood Sample

Tumour Sample

CDA activity

CDA expression, SPARC, stroma

Disease Progression

CDA expression, SPARC, stroma, apoptosis

Blood Sample

Tumour Sample at Progression

CDA activity

Treatment

Blood Sample

Post Treatment Tumour Sample

CDA activity

CDA expression, SPARC, stroma, apoptosis

Cycle 1 D1, D8, D15 D2, D9, D16 (sequential arm only)

Cycle 2-6 D1

End of Treatment

D30 from date of last dose

Cycle 3 D1 ± 7 d

ctDNA (Nitzan Rosenfeld), CDA expression (Hayley Whitaker), CDA activity (Donna Smith); all CRUK CI (then!)

What about immunotherapy?

Immune checkpoint inhibitors: CTLA-4 and PD-1

Anti PD-1 antibody therapy

• Nivolumab (anti PD-1) acts as an immunomodulator, by blocking ligand activation of the programmed cell death 1 (PD-1) receptor on activated T cells.

• Common adverse events with nivolumab included fatigue, rash, diarrhea, decreased appetite, nausea, and pruritus.

• Grade 3-4 toxicity occurred in 41 of 296 patients (14%), with 3 deaths attributed to treatment-related pneumonitis.

• Multiple phase III clinical trials are being performed (e.g. kidney, lung and melanoma)

ASCO 2013

A combination of a CTLA-4-blocking antibody (ipilimumab) and the PD-1–blocking antibody (nivolumab) appears to provide deep, rapid, and durable tumor responses in patients with advanced melanoma ….

….. according to results of a phase I study (17 patients).

Presented by Jedd D. Wolchok, MD, PhD, at a Clinical Science Symposium at the American Society of Clinical Oncology (ASCO) meeting in 2013

Royal RE, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828-33.

“Single agent Ipilimumab, is ineffective for the treatment of advanced pancreas cancer.“

Failure of immune checkpoint antagonists in pancreatic ductal adenocarcinoma

Cancer Patients Responders Melanoma 52 9 Renal-cell 17 2 NSCLC 49 5 Ovarian 17 1 Colorectal 75 0 Pancreatic 14 0

Why does immune surveillance fail in pancreatic ductal adenocarcinoma? The role of FAP+ stromal cells

Doug Fearon, CRUK CI

p53 (LOH) Cytokeratin FAP Pancreatic ductal adenocarcinoma

Murine PDAC (KPC) is resistant to checkpoint antagonists

Anti CTLA4 and anti PD-L1 are ineffective in the KPC model

Is this related to the presence of local immunosuppression mediated by FAP+ cells in the stroma?

PDA growth curves (ultrasound)

Doug Fearon, Cambridge Feig et al, PNAS 2013

A B

C

Blocking the CXCR4/CXCL12 interaction, using the small molecule CXCR4 inhibitor AMD3100, leads to sensitivity to aPD-L1

Feig et al, PNAS 2013

Single agent Phase I trial: CXCR4 antagonism with AMD3100 (plerixafor,

MobizilTM), administered to patients with histologically confirmed, incurable

PDAC and other cancers.

Started trial #1 in Q3 2015. 8 patients treated to date.

Combination Phase I trial: AMD3100 administered in combination with anti-

PD1 or anti-PD-L1 antibody in the same population

The studies will assess safety, as well as aiming to demonstrate the proof of

mechanism in patients by documenting alterations in T-cell tumour distribution,

ideally associated with tumour cell killing (loss of p53 positive tumour cells) and

reduction in FDG-PET uptake.

Tissue 1 Tissue 2

Escalating doses of AMD3100

18FDG PET 18FDG PET, PD, ctDNA

Consent then Screening

Days 1 to 8 Days -28 to 0

CT scan, ctDNA

PKPD baseline CT scan, PD, ctDNA

Outpatient observation

Days 9-28

Safety assessment

PK, PD, ctDNA

Patients shown to be benefiting on day 28, will have the option of repeat treatment, if a repeat scan on day 56 confirms a partial response.

CAMPLEX trial schematic

Bristi Basu, Lisa Bax, Martin Smoragiewicz, James Thaventhiran

Am I going too fast?

No animals were harmed in the making of this slide

Personalised medicine

Precision medicine

Individualised therapy

Founding members of

PRECISION-PANC

3 CRUK Major Centres

2 CRUK Centres focussing on PDAC

NCRI Studies Group

CRUK

Major Pharma

BOTH laboratory research

and clinical trials

Putative actionable molecular phenotypes/genotypes of pancreatic cancer Based on an analysis of data from the International Cancer Genome Consortium (ICGC) contributions (100 whole genomes/240 whole exomes) (Andrew Biankin et al.) up to 45% of cases of PDAC may have actionable phenotypes

PARPi, BRCA 1,2 and pancreatic cancer Eileen O’Reilly et al, ASCO 2014

• Phase I trial of gemcitabine, cisplatin plus escalating dosage of veliparib (PARPi)

• Entry criteria included patients, previously untreated for advanced pancreatic cancer

• Treatment Plan: cisplatin 25mg/m2 iv, gemcitabine 600mg/m2 iv and velaparib po b.d.

• 9 patients with germline BRCAmut: 5 (56%) partial response (PR)

4 (44%) stable disease

• Conclusions:

– The RP2D of veliparib is 80 mg PO BID day 1-12 q 3 weeks with GemCis days 1&8

– Main grade 3-4 toxicities are hematologic and fatigue.

The combination of cisplatin, gemcitabine + veliparib showed

high activity in BRCA mutated pancreatic cancer

Biomarker Discovery Gemcitabine/ nab-paclitaxel FOLFOX-A Gemcitabine

Cisplatin PARPi

PDDG

Frances Richards

Tashinga Bapiro

Jo Bramhall

Jenny Harrington

Aarthi Gopinathan

Siang Boon Koh

Séverine Mollard

Graham Mills

Tobias Janowitz

Yann Wallez

James Thaventhiran

(Immunology, CIMR)

Dave Tuveson

Natalie Cook

Kris Freese

Albrecht Neesse

Christine Feig

Doug Fearon

James Jones

Matt Kraman

Richard Wells

Derek Chan

Claire Connell

Thomas Flint

Cambridge Pancreatic Cancer Centre, Clinical and Research staff: Raaj Praseedom, Pippa Corrie, Bristi Basu, Neville Jamieson, Asif Jah, Simon Harper, Emmanuel

Huguet, Nicholas Carroll, Rebecca Brais, Martina Lofthouse, Debbie Pitfield, Joanna Calder, Lisa Bax,

Katy Dalchau, Burcu Babaoglan, Alkida Bucaj

CRUK Cambridge Institute

Core Facilities

PK/Bioanalysis: Donna-Michelle

BRU and TMC

Microscopy

Histopathology

Genomics

….. and our patient volunteers.

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