Design’and’conduct of’early2phase’radiotherapy’trials’ … · 2019-04-10 · targe6ng’signaling’pathways’in’radiotherapy’ Anatomical site Number of trials Molecular

Design and conduct of early-‐phase radiotherapy trials

with targeted therapeu6cs

Anne Hansen Ree Professor, MD PhD Clinical Oncologist

Akershus University Hospital

University of Oslo Oslo, Norway

Bonner et al., N Engl J Med 2006

Søvik et al., Int J Radiat Oncol Biol Phys

2009

modern radia6on oncology – high-‐precision radiotherapy protocols

biological op6miza6on of radia6on effects

next-‐genera)on therapy trials

ac6onable tumor targets for

pa6ent stra6fica6on

tumor response and

normal 6ssue toxicity

targe6ng signaling pathways in radiotherapy Anatomical

site Number of trials

Molecular drug target(s)

Central nervous system 20 VEGF

thalidomide targets EGFR RAS mTOR multitargeted agents

Head/neck 16 EGFR EGFR and VEGF (two agents) EGFR and COX-2 (two agents) EGFR and proteasome (two agents) VEGF multitargeted agent

Thorax/mediastinum 21 EGFR VEGF EGFR and VEGF (two agents) ERBB2 mTOR

Abdomen 7 EGFR VEGF thalidomide targets

Pelvis 26 HDAC EGFR VEGF COX-2

Skin 2 HDAC EGFR

Multiple 3 VEGF multitargeted agent PI3K/AKT

early-‐phase clinical trials combining radiotherapy and targeted therapeu6cs (by January 2013) – trial design no more advanced than non-‐randomized phase 2 – excluding trials using stereotac6c radia6on techniques or par6cle therapy

from Meniscus Limited

prolifera)on angiogenesis metastasis

ac)onable tumor signaling pathways

Ree & Hollywood, Radiother Oncol 2013

targe6ng signaling pathways in radiotherapy Anatomical

site Number of trials








Skin 2 HDAC EGFR


early-‐phase clinical trials combining radiotherapy and targeted therapeu6cs (by January 2013) – trial design no more advanced than non-‐randomized phase 2 – excluding trials using stereotac6c radia6on techniques or par6cle therapy


study endpoints – tolerability – safety – efficacy study outcomes – DLT and MTD – tolerable toxici6es – significant toxici6es – no addi6onal response – addi6onal response – unexpected early disease progression

HDAC (histone deacetylase)

inhibitors

Ac Ac Ac

HAT HDAC

histone acetyla6on – HDAC inhibi6on

– redistribu6on of the cell cycle – inhibi6on of DNA repair – inhibi6on of angiogenesis – promo6on of apoptosis – suppression of hypoxia-‐induced

HIF-‐1α ac6va6on

HDAC inhibitors in radiotherapy

experimental in vitro radiosensi6za6on

Flatmark et al., Radiat Oncol 2006

Ree et al., Nat Genet 2008

0 1 2 3 4 5 0.01

0.1

1

IR dose (Gy)

surv

ivin

g fra

ctio

n

¡ – SAHA n + SAHA (0.50 μM) p + SAHA (1.0 μM)

¡ – TSA ¯ + TSA (30 nM) £ + TSA (100 nM)

RKO

TSA

HCT116

SAHA

HCT116 SW620

n untreated ¯ SAHA p  IR � IR 3 hours aêr SAHA ¡ IR 12 hours aêr SAHA

Folkvord et al., Int J Radiat Oncol Biol Phys 2009

experimental in vivo radiosensi6za6on

experimental radiosensi6za6on under hypoxia

Saelen et al., Radiat Oncol 2012

in vitro in vivo

inves6ga6onal drug – preclinical tumor models – assessment of biological mechanisms of radiosensi6za6on – assessment of possible toxicity profiles

targe6ng signaling pathways in radiotherapy preclinical proof-‐of-‐concept

Mangoni et al., Br J Cancer 2012

— treatment toxicity — biological ac6vity of the inves6ga6onal agent — treatment response

targe6ng signaling pathways in radiotherapy clinical study endpoints

Phase 1 Study on Suberoylanilide Hydroxamic Acid (Vorinostat), a Histone Deacetylase Inhibitor, in Pallia6ve Radiotherapy

for Advanced Pelvic Tumors — Safety Profile, Biological Ac6vity, and Metabolic Signatures

Pelvic Radia6on and Vorinostat

ClinicalTrials NCT00455351

PRAVO

Pelvic Radia6on and Vorinostat

pelvic carcinoma – pallia6ve radiotherapy – vorinostat (SAHA)

ClinicalTrials NCT00455351

PRAVO

PRAVO — eligibility criterion – study mechanics

— histologically confirmed carcinoma scheduled to receive pelvic pallia6ve radia6on (to 30 Gy in 3-‐Gy frac6ons)

— sequen6al escala6on in dose levels of vorinostat: (100 mg – 200 mg – 300 mg – 400 mg)

— daily vorinostat → daily radiotherapy frac6on 3 hours

— magne6c resonance imaging tumor volumetry and diffusion — tumor biopsy sampling tumor histone acetyla6on — sampling of peripheral blood mononuclear cells new biomarkers of vorinostat ac6on

PRAVO — study mechanics

PRAVO — demographics – toxicity

— median age 66 years (range 45–87 years)

— mainly rectal (59%) and colon (35%) primaries

— indica6ons for radiotherapy were local pain (82%)* local bleeding (24%)* * a pa6ent might be included in more than one category

— common grade 1 and 2 adverse events were diarrhea (88%), anorexia (81%), and fa6gue (75%)

— treatment-‐related grade 3 adverse events (DLTs) were diarrhea, anorexia, and fa6gue (each event reported by 2 of 16 pa6ents) at treatment comple6on or immediately aêrwards Ree et al.,

Lancet Oncol 2010

PRAVO – Pelvic Radia6on and Vorinostat ClinicalTrial NCT00455351

conclusions: – vorinostat can be safely combined with short-‐term pelvic radiotherapy – the MTD of vorinostat in this sehng is 300 mg once daily – the inves6ga6onal agent reached the radia6on target – radiologic treatment responses were observed


PRAVO — gastrointes6nal toxicity

conclusions: – vorinostat can be safely combined with short-‐term pelvic radiotherapy – the MTD of vorinostat in this seVng is 300 mg once daily

Ree et al., Lancet Oncol 2010

Age (years) Gender

GTV (ccm)

ITV (ccm)

SBV (ccm)

V6 (%)

V12 (%)

V18 (%)

V24 (%)

V30 (%)

Vorinostat dose (mg)

DLT grade 3 adverse events

87 female 2845 648 823.8 79 74 70 67 40 300 anorexia, fatigue 81 female 72.2 380 990.9 63 41 22 18 0 300 66 female 171 483 2292 45 37 19 15 3 200 49 female 89.5 323 1291 43 38 33 25 11 200 47 female 198 414 2440 42 37 34 30 14 300 83 female 197 549 1114 41 29 24 19 3 400 diarrhea, anorexia, hyponatremia 55 male 87.7 867 1811 34 23 18 16 6 400 75 female 36.7 277 1516 31 14 11 8 0 400 diarrhea, fatigue, hypokalemia 62 male 114 324 2180 19 5 3 2 0 400 77 male 153 650 1972 18 7 3 3 1 300 45 female 58.1 175 2163 16 7 5 4 0 400 82 male 75.5 330 2946 15 4 1 1 0 300 77 female 164 625 1901 5 2 1 0 0 100 85 female 60.1 180 1256 4 2 2 1 0 400

Bratland et al., Radiat Oncol 2011

– at the 300 mg dose level: an adverse radia)on dose-‐volume effect rather than a toxic effect of vorinostat

PRAVO (Pelvic Radia)on and Vorinostat) ClinicalTrials NCT00455351

Anatomical site

Number of trials








Skin 2 HDAC EGFR


toxicity in combined-‐modality therapy

early-‐phase clinical trials combining radiotherapy and targeted therapeu6cs

radia6on delivery – target volume and dose varia6ons within normal 6ssues of interest

Assessment of radiation dose-volume effects

1 study (of 21)

1 study (of 7)

1 study (of 26)


Anatomical site

Number of trials








Skin 2 HDAC EGFR


radia6on sites – tumor manifesta6on(s) within a restricted anatomical loca6on study pa6ents – not candidates for cura6ve radiotherapy protocols – with a cura6ve therapeu6c intent but historically poor treatment outcome

Curative intent

Significant toxicities

definitive in 5 studies 1 study

definitive in 1 study 1 study preoperative in 2 studies

preoperative in 1 study 1 study

definitive in 2 studies 1 study preoperative in 21 studies 7 studies

definitive in 1 study

preoperative in 1 study

early-‐phase clinical trials combining radiotherapy and targeted therapeu6cs

95 34 11 Ree & Hollywood,

Radiother Oncol 2013

toxicity in combined-‐modality therapy


conclusions: – vorinostat can be safely combined with short-‐term pelvic radiotherapy – the MTD of vorinostat in this sehng is 300 mg once daily – the inves6ga6onal agent reached the radia6on target – radiologic treatment responses were observed

PRAVO — biological ac6vity of vorinostat

vorinostat dose 100 mg 200 mg 300 mg 400 mg tumor biopsy B T B T B T B T [B=baseline T=on-‐treatment]


study endpoint – op6mum biological dose: PD biomarker(s) reflec6ng mechanism of drug ac6on

radia6on delivery – 6ming of drug administra6on rela6ve to applica6on of radia6on in frac6onated radiotherapy

PRAVO — radiologic treatment response


study endpoint – treatment efficacy (surrogate response biomarker)

— tumor biopsy sampling tumor histone acetyla6on — sampling of peripheral blood mononuclear cells biomarkers of vorinostat ac6on that are not simultaneously manifes6ng molecular perturba6ons elicited by the radia6on itself

PRAVO — new biomarkers of vorinostat ac6on

drug-‐exposed, non-‐irradiated (surrogate) 6ssue

PRAVO — study mechanics

Ree et al., submimed 2013

Vorinostat dose (mg)

Age (years) Gender DLT grade 3

adverse events Comment

100 77 female

200 49 female 200 64 female 200 66 female

300 47 female PBMC not available 300 66 female 300 77 male 300 81 female 300 82 male 300 87 female anorexia, fatigue PBMC not available

400 45 female 400 55 male 400 75 female diarrhea, fatigue, hypokalemia 400 62 male 400 85 female 400 83 female diarrhea, anorexia, hyponatremia

PRAVO — biomarkers of vorinostat ac6on

Ree et al., Kalanxhi et al., unpublished

Ree et al., Kalanxhi et al., unpublished

biomarkers – vorinostat radiosensi6zing ac6on and toxicity

– gene regula6on (transcrip6on, RNA processing) – cell cycle progression (including the DNA damage response) – chroma6n biology – biomarkers in frac)onated RT

– overrepresented in PBMC from study pa6ents at the dose level of vorinostat (400 mg) causing DLTs – biomarkers of vorinostat toxicity

– biological principles in trial design and conduct — targe6ng of tumor signaling ac6vity implicated in prolifera6on, angiogenesis, and metastasis – an evolving paradigm in trial design and conduct — HDAC inhibi6on as targeted approach to (hypoxic) tumor radiosensi6za6on – a research program in trial design and conduct — PRAVO study design – biological ac6vity of vorinostat – tumor response to combined-‐modality treatment – tolerability to combined-‐modality treatment – biomarkers of vorinostat radiosensi6zing ac6on – biomarkers of vorinostat toxicity

targeted therapeu6cs – radia6on

mul6disciplinary research Akershus University Hospital – Norwegian Radium Hospital

Principal Inves)gators Anne Hansen Ree – Kjers6 Flatmark Division of Medicine Division of Cancer Medicine & Surgery & Laboratory Sciences – AUH – NRH—Oslo University Hospital Monica Chahal-‐Kummen Torveig Weum Abrahamsen Helga Helseth Hektoen Åse Bratland Chris6n Johansen Svein Dueland Erta Kalanxhi Kjers6 Flatmark Anne Hansen Ree Øystein Fodstad Karianne Risberg Sigurd Folkvord Kathrine Røe Marianne Johansen Janne Sølvernes Anneme Torgunrud Kristensen Division of Diagnos)cs Marie Grøn Sælen & Interven)on – NRH Knut H. Hole – Therese Seierstad

supported by – European Commission Seventh Framework Programme – South-‐Eastern Norway Regional Health Authority – Akershus University Hospital – Norwegian Cancer Society

Documents

Design’and’conduct of’early2phase’radiotherapy’trials’ … · 2019-04-10 · targe6ng’signaling’pathways’in’radiotherapy’ Anatomical site Number of trials Molecular