Individualised therapies Individualisierte Tumortherapie heute: Fakten
und klinische Herausforderungen
Prof. Dr. Monika EngelhardtHematology & Oncology department, University of Freiburg
DACH Symposium 7.3.2016
The long wayfrom an initial medication idea to clinical trials
From a medication idea to its testing and clinical practice: the main steps
10.000 agents being tested
1 achieving to be FDA/EMA approved
Duration of average12 years and more
from initial medication development to reach the pt
Benefits Potential challenges
Access to innovative therapies Sufficient time and patience
Generation of novel clinicalinsights -> medical progress generation
Unknown side effects
Helping others + medical sciencePhase I: dose titration + in lower doses: potentially lesser clinicalefficacy
More intensive control/medical care
Closer physician-patient relationship
Patient benefits of participation in clinical trials
Efforts to providetargeting therapies
c-MET inhibitor(small molecule -
INC280) ATLANTIC
(MEDI4736 - PD-L1 Ab) BRAF
Pre-Screening 19 8 28
Pt-inclusion 1 1 0
• Not enough buzz for research• Most trials end up having to double their original timelines to meet
enrollment goals, ~50% of sites under-enroll and ~ 10% fail to enroll• Lack of time and effort for effective communication (especially w elderly pts)• Non-eligibility (in- and exclusion criteria) 65% of those who don‘t qualify
for a study don‘t search for another!• Fear of participation (due to...... side effects, risks to overall health,
receiving placebo)• Long waiting period until start of therapy
(due to central lab confirmations)• Short availability of e.g. phase I CT-slots
Excludes ptsw urgent therapy needs!
Challenges in patient recruitment for CTs
Stensland et al. J Nat Cancer Inst 2014Djulbegovic et al. Plos one 2013
Highly important: CTs have to be carefully selected PSRB
• 85% of CTs are unnecessary• Jobs, funds and academic title are awarded on quantity, not
quality (at the expense of content)• Industry: marketing of drugs and medical devices• Journals: printing for cash• Wrong formulation of questions, ineligible study design,
incorrect data evaluation, no or little access to results
„More quality of clinical trails, less trash“
Süddeutsche Zeitung, #5; 1/2014Jürgensmeier et al. Clin Cancer Res 20;4425-35, 2014http://ashclinicalnews.org/a-few-of-my-favorite-things/
Trial discussion and acceptance modus
Adequate pt # at UKF? eTBD search
Competitive, activetrials?
Regulatory and financial aspects?
Protocol Study Review Board (PSRB)(Head of the department; Attending physicians; PIs; CCR-Group)
Harmonized, democratic decision on trial acceptance
Relevant scientifictrial question(s)?
1. PSRB meeting Med 1: 2004PSRB-#s 1/2004 - 2/2016: 82
Ongoing and recruiting CTs 2010-2015University Medical Center Freiburg
2010 2011 2012 2013 2014 2015Ongoing 206 247 297 307 331 360Recruiting 176 203 217 207 238 252
+154
+76
European hematology association roadmap for research: a consensus document
The EHA Roadmap for Hematology Research
1. European research groups have been instrumental in setting up extensivetrials to test important new products
2. Nevertheless, over the past years, number of clinical trials in Europedecreased
3. New regulations have the potential of making future trials in Europe tooexpensive and complex, especially for academic research and thereforemay cause a further decrease in clinical trials
4. A drop in number of trials and participants would harm the interest ofEuropean patients and cause damage to Europe's knowledge infrastructureand future economy
Haematologica - Opinion ArticleEHA Roadmap for European Hematology Research: a consensus documentThe European Hematology Association Roadmap for European Hematology Research: a consensus documentAndreas Engert, Carlo Balduini, Anneke Brand, Bertrand Coiffier, Catherine Cordonnier, Hartmut Döhner, Thom Duyvené de Wit, Sabine Eichinger, Willem Fibbe, Tony Green, Fleur de Haas, Achille Iolascon, Thierry Jaffredo, Francesco Rodeghiero, Gilles Salles, Jan Jacob Schuringa. Haematologica February 2016;101:115-208
# of CTs # of pts pts/CT
Total # of CTs 108 933 8.6
… of these: recruiting CTs 55 560 10.2
… of these: still ongoing CTs 53 373 7.0
… of these: upcoming CTs 39 - -
Current CT activities Med I 2016
1. Interdisciplinary tumorboards (attendance of ECTU-physicians in 11 boards); molecular TB (Wednesdays at 7:30 a.m.)
2. Daily clinical routine conferences of attending physicians3. “Monday-OTM-Training” (weekly study training & education of Med 1 team)4. “Tuesday-ECTU-Training” (weekly for members of ECTU and once/month
with Clinical Trials Center)5. PSRB meetings for new and current CTs6. Quick Queck® (electronic patient-individualized study search)7. CT sites: Intra- and Internet and trimestral newsletters8. Cross-link with CTx-management
Recruiting options for clinical trials: Med I/CCCF
QuickQueck idea & implementation: Lena Illert, Justus Duyster, EDV Med 1 & ECTU Team
®
Clinical trials MM, UKFIndi-cation Title Description/content of clinical trial # pts
First-line DSMM XIV Ph II, <65 J, R1: VRD vs. RAD -> R2: arm A-D 36
DSMM XIII Ph III, 60-75 J, Rd -> PD vs. RD+2xTx R-maint 17PD-1 - Rd Ph III Elderly, non-SCT eligible pts 3/16
Re-lapse CD38 Ab MOR03087 Ph I/IIa-dose escalation, >2 prior therapies:
ab+dex (8c), ab+Rd (7e) + ab-Pom/Dex (7d) open 3
EMN09-Study Ph I done; now: Ph II, dose escalation, >2 prior lines: 8x Cfz - Benda - Dex maintenance 7
PD-1 - Pom-dex Ph III, > 2 priot therapies 3/16Elotuzumab Pom-dex Ph II, > 2 prior therapies: lena + proteosome inhibitor 4/16
Pom-Vd vs. Vd Ph III, at least 1 + <4 MM-regimes, prior len-therapyrequired, Ø Vd-refractory (MM-007) 1
BRF117019: Dabrafenib+Trametinib Ph II >2 prior therapies, currently progressing prescreen:6
UKFpathol: 10Re-gister Assessment MM-TB Pt./referring physicians/participants-questionnaire
+ -satisfaction100 / 30 /
55
rFCI Prognostic factors, prevention of toxicity, treatmentplanning >800
Latencies to diagnosis Retro- & prospective analysis + pts survey 108 / 200
Conditional Survival Analysis of prognostic factors 816
MM-outpts clinic + outpts clinic of studiesMM-center: Profs. Drs. Engelhardt, Wäsch, Waldschmidt, Kiote-Schmidt, Zober, Miething, Schönheimer-physiciansStudy nurses: D. Jakobs, C. Messner, I. SurlanLymphoma/MM-center: Bürk, Büsch, Tel. 0761 270 71580 od. -71520MM-tumorboard: each Monday, 16h, kl. Hörsaal pt registration through TOS
Current CTs in Early Clinical Trial Unit (ECTU)Novel / clinical trial agent Tumor indicationPD-L1 Inhibitor (MPDL 3280A) R/R DLBCL; R/R Foll. lymphomaPD-L1 Inhibitor (MPDL 3280A) NSCLC, cCRC, MelanomBCL-2 Inhibitor (GDC-0199/ ABT-199) R/R CLLBCL-2 Inhibitor (BCL201/Idelalisib) R/R Foll. Lymphom + MCLanti-CD38 AK (MOR03087) R/R Multiple MyelomaProteasome Inhibitor (Carfilzomib) R/R Multiple MyelomaPLK-1 Inhibitor (Volasertib) untreated MDSHDAC Inhibitor (Givinostat) Jak2 positive PVPD-L1 Inhibitor (MEDI 4736) NSCLCPD-L1 Inhibitor (MSB0010718C) Solid tumors: Gastric, Melanoma, Ovar, NSCLCPD-L1 Inhibitor ACC, Mesothelioma, UrothelialNilotinib/Ruxolitinib BCR-ABL pos. ALL/BML BCTCP AMLPalbociclib MLL pos. AMLRuxolitinib/Pomalidomid Myelofibrosis
Contacts: Med 1: Drs. L.Illert, A.Krohn, C.Kiote-Schmidt, B.Rister, H.Schäfer, I.Surlan
Current CTs in Early Clinical Trial Unit (ECTU)Novel / clinical trial agent Tumor indicationPD-L1 Inhibitor (MPDL 3280A) R/R DLBCL; R/R Foll. lymphomaPD-L1 Inhibitor (MPDL 3280A) NSCLC, cCRC, MelanomBCL-2 Inhibitor (GDC-0199/ ABT-199) R/R CLLBCL-2 Inhibitor (BCL201/Idelalisib) R/R Foll. Lymphom + MCLanti-CD38 AK (MOR03087) R/R Multiple MyelomaProteasome Inhibitor (Carfilzomib) R/R Multiple MyelomaPLK-1 Inhibitor (Volasertib) untreated MDSHDAC Inhibitor (Givinostat) Jak2 positive PVPD-L1 Inhibitor (MEDI 4736) NSCLCPD-L1 Inhibitor (MSB0010718C) Solid tumors: Gastric, Melanoma, Ovar, NSCLCPD-L1 Inhibitor ACC, Mesothelioma, UrothelialNilotinib/Ruxolitinib BCR-ABL pos. ALL/BML BCTCP AMLPalbociclib MLL pos. AMLRuxolitinib/Pomalidomid Myelofibrosis
1
Contacts: Med 1: Drs. L.Illert, A.Krohn, C.Kiote-Schmidt, B.Rister, H.Schäfer, I.Surlan
• 69 year old male• NSCLC, Adenocarcinoma EGFR + ALK wild-type; ID 12/2015 • Arm A: Tremelimumab 1mg/kg (CTLA4-Ab), MEDI 4736 20mg/kg (PD-L1-Ab)
19.01.2016: Informed consent for study MYSTIC study participation
20.01.2016: c1d117.02.2016: c2d1
Staging after c2: PR
Side effects: exanthemaBenefits: 1. response, 2. monthly medication, 3. QoL less impaired
MYSTIC (MEDI 4736): case study1
A: Tremelimumab + MEDI4736B: MEDI4736 monotherapyC: Platinum-based CTx
ID NSCLCImproved responses a) CTLA4+PD-L1 Abb) vs. PD-L1 or CTx?c) side effects profile as 1.-line?
Immuncheckpoint Inhibitors: anti-PD-1/PD-L1 Ab (phase I/II)
Monocloncal Ab: Elotuzumab (phase III)
Targeted Therapies
2
3
Modified from Maus, Grupp, Porter and June ASH 2014
PD-1/PD-L1 Elotuzumab
Therapeutic aproaches to overcomeimmuntolerance to tumors
PD1/ PD-1 ligand binding leads to T-cell exhaustion
T-Cell
Tumor-Cell
Modified from Freeman G J PNAS 2008;105:10275-10276
Modified from Freeman G J PNAS 2008;105:10275-10276
T-Cell
Tumor-Cell
MPDL3280AMSB0010718C
PD1/ PD-1 ligand binding leads to T-cell exhaustion
Modified from Freeman G J PNAS 2008;105:10275-10276
T-Cell
Tumor-Cell
MPDL3280AMSB0010718C
PembrolizumabNivolumab
PD1/ PD-1 ligand binding leads to T-cell exhaustion
Phase III study of Lenalidomide +Dexamethasone ± Pembrolizumab in
Newly Diagnosed MM
Phase III study of Pomalidomide + Dexamethasone ± Pembrolizumab in
rrMM
Upcoming studies with PD-1 blocking Ab UKF
Immun-Checkpoint-Inhibitors Treatment-related AEs
Side effects of PD-1/PD-L1� Vitiligo (3 %) � Pneumonitis (3 %)� Colitis (11 %)� Thyreoiditis (3 %) � Fatigue (24 %)� Anorexia (8 %) � Anemia (1 %)� Nausea (8 %)
Docetaxel Atezolizumab (MPDL3280A-PD L1 Ab)
IL-6R (CD126) – tocilizumab
Antibodies: Will they contribute to further progress?
Adapted from Hideshima T, Anderson KC. Nat Rev Cancer 2002;2:927–37; Hideshima T, et al. Blood 2004;104:607–18.
IL-6 – siltuximab (CNTO-328)
BT062BB-4
Elotuzumab
DaratumumabSAR650984 Dacetuzumab
Rituximab
Samalizumab(ALXN6000) Lorvotuzumab
Cetuximab
IPH2101
Milatuzumab
SLAMF7
Latest developments of antibody-therapy designPD-1/PD-L1 Elotuzumab
• Humanized monoclonal IgG1 anitbody• Target: Cell Surface 1 (CS1)• CS1 taget is uniformly and highly expressed in >95% of primary MM• Elotuzumab significantly enhances anti-tumor activity of Len & Bortezomib
Eloquent-2: 3-year safety and efficacy update
Rd + Placebo until PD (n=325)
ERd: E: 10mg/kg IV weekly until PD (n=321)RRMM1-3 prior therapies
Not Len-refr.n=646
1-y 2-y 3-y
68%
57%41%
27%26%
18% ERdRd
PFS
(%)
OS
(%)
1-y 2-y 3-y
PFS (months)OS (months)0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
0
0.2
0.4
0.6
0.8
1.0
0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
PFS/OS ERd Rd HR p-valueMedian PFS (ms) 19.4 (16.6-22.2) 14.9 (12.1-17.2) 0.73 (0.6-0.89) 0.0014Median OS (ms) 43.7 (40.3-NR) 39.6 (33.3-NR) 0.77 (0.61-0.97) 0.0257
• Elotuzumab approved as mAb due to relevant improvement of treatment efficacy w minimal added toxicity
• Novel approach of treating RRMMM.Dimopoulos. Blood (Suppl) 28; 2015 [S.Lonial. NEJM 2015]
A.Palumbo. Blood (Suppl) 2015: Elo-VD vs. VD; n=152 pts: median PFS: 9.9 vs. 6.8 ms; HRPFS: 0.75
Open Label, Randomized Ph 2 Trial of Pomalidomide/ Dexa ± Elotuzumabin rrMM
Upcoming study UKF (4/2016)
Clinical challenge
• Despite major advances in tumor treatment, including MM, median OS: 5-8y-> Relapse occurs in almost all pts
• Combination-therapies are more effective than mono-therapies• New agents with novel modes of action, such as immune therapies, are
urgently needed
Efficacy
Low cost & tox High cost & tox
1 drug2 drug
3 drug
4 drug
4 -> IITs
VBDD - Studiendesign
Einschlusskriterien• >18 Jahre• Patienten mit RRMM• Messbare Erkrankung• KPS ≥ 60%• PB: ANC ≥500/µl, PLT ≥25 Tsd/µ, Hb ≥7g/dl• Leber: AST/ALT ≤ 2.5x ONW, Bili ≤ 1.5x ONW• Niere: eGFR ≥ 20ml/min
Offene, einarmige, Monocenter Phase I/II Studie mit konsekutivem 3+3-Design
Primärer Endpunkt: MTD
Sekundärer Endpunkt: safety, IMWG responses, PFS/OS, QoL, comorbidity and HDAC-activity in PBMNCs/BM
Wdh
. d28
, max
. 6 Z
ykle
n
Dimopulos M et al Lancet Onol. 2013;14(11):1129-40Weber DM et al Clin Lymphoma Myeloma Leuk. 2012;12(5):319-24
ECTU Early clinical Trail Unit CCCF
ECTU - Early clinical Trail Unit CCCF
• seit Januar 2013 in der Medizinische Klinik I etabliert• 3 ambulante / 3 stationäre Betten auf St. Holthusen
ECTU - Early clinical Trail Unit CCCF
• seit Januar 2013 in der Medizinische Klinik I etabliert• 3 ambulante / 3 stationäre Betten auf St. Holthusen• 10 Studienasistentinnen / 5 Studienärzte
Pts' feed-back on ECTU CCCF 2015 (n=42)
0%
20%
40%
60%
80%
100%
Anteil Patienten, die diesen Punkt mit "Sehr gut" oder "gut" bewertet haben
Patientencharakteristika VBDD IITVariables n (%) Median (range)
# of pts 33Age (years; range) 63 (47-78)Karnofsky index (%) 90 (70-100)m : f 19 (58%) : 14 (42%)Type of MM
IgG / IgA 18 (55%) / 11 (33%)Light chain only MM 4 (12%)Light chain (kappa/lambda) 24 (73%) / 9 (27%)
Durie & Salmon stage I / II / III 0 / 2 (6%) / 31 (94%)A / B 29 (88%) / 4 (12%)
ISS stageI vs. II/III 6 (18%) / 27 (82%)
BM-infiltration rate (%) 50 (5-90)Cytogenetics (CG via iFISH)
Favorable CGs 19 (58%)Unfavorable CGs 14 (42%)
Prior therapies 3 (1-9)SCT 31 (94%)Bortezomib 29 (88%)IMIDs 14 (42%)
Anzahl komplettierter VBDD - Therapiezyklen
0 1 2 3 4 5 61
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
33
Anzahl komplettierter Therapiezyklen (max. 6)
Patie
nten
Serologisches VBDD - Ansprechen
Serologisches VBDD - Ansprechen
HDAC-Aktivität im peripheren Blut:vor Zyklus 1 VBDD-Therapie und am d8 Zyklus 2
VBDD führt zu substantieller HDAC-Inhibition in PB MC mit - medianer Aktivität von 52% der pre-treatment Levels (p=0.113) und
- abs. Verminderung bei 11/16 Pat.
-> Korrelation mit Tiefe und Dauer des VBDD-Ansprechens: ongoing
Keller K Dissertationsschrift UKF 2014Hackanson B et al Leuk Res. 2012;36(8):1055-62
QoL- und Komorbiditätsanalysen vor und nach VBDD-Therapie
Karnofsky PS = Karnofsky Performance Scale, CI =-Comorbidity Index, SF-12 = 12-Item Short Form Health Survey
Stewart AK et al N Engl J Med 2015;372(2):142-52Kleber M et al. Blood Cancer J 2011, e35
Kleber M et al. Clin Lymphoma Myeloma Leuk. 2013, 13(5):541-51Engelhardt et al. Haematologica 2014;99(2);232.42
Zober, Dold,.....Engelhardt. Poster presentation DGHO 2015 (P776)
Goals UKF
12 Top oncology centers Germany
Freiburg
Clinical trials: importance understood? Why clinical trial recruitment is so hard
To protect you from untested
drugs
If we don't know which drugs are safe and most effective, why
don't they just let us into more clinical trials?
Conclusions: guiding priniciples for advanced research
1. Right research questions must be defined2. Well-grounded design and realization of CTs3. Giving access to all data results4. Authoring and publishing of undistorted and useful research reports
„CTs are essential for medical improvement & considering guidingprinciples, maximum benefit will be obtained for pts.“
ECTU Team UKF / CCCFContact: [email protected]@[email protected]
Special acknowledgement:Prof. Dr. Justus Duyster
Rainer Bredenkamp
