Individualised tumor therapies today: facts and challenges

Individualised tumor therapies today:
facts and challenges
Monika Engelhardt
Hematology & Oncology department, University of Freiburg
Head: Prof. Dr. Justus Duyster
30.11.2015
The long way
from an initial medication idea to clinical trials
From a medication idea to its
testing and clinical practice:
the main steps
1 achieving to be FDA/EMA approved
Duration of average
12 years and more
10.000 agents being tested
from initial medication
development
to reach the pt
Patient benefits of participation in clinical trials
Benefits
Potential challenges
Access to innovative therapies
Sufficient time and patience
Generation of novel clinical
insights -> medical progress
generation
Unknown side effects
Helping others + medical science
Phase I: dose titration + in lower
doses: potentially lesser clinical
efficacy
More intensive control/medical
care
Closer physician-patient
relationship
Challenges in patient recruitment for CTs
•
•
•
•
•
•
•
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
Excludes pts
(due to central lab confirmations)
w urgent therapy needs!
Short availability of e.g. phase I CT-slots
c-MET inhibitor
Efforts to provide
targeting therapies (small molecule INC280)
ATLANTIC
(MEDI4736 - PD-L1 Ab)
BRAF
Pre-Screening
19
7
20
Pt-inclusion
1
0
0
Stensland et al. J Nat Cancer Inst 2014
Djulbegovic et al. Plos one 2013
„More quality of clinical trails, less trash“
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
Süddeutsche Zeitung, #5; 1/2014
Jürgensmeier et al. Clin Cancer Res 20;4425-35, 2014
http://ashclinicalnews.org/a-few-of-my-favorite-things/
Trial discussion and acceptance modus
Relevant scientific
trial question(s)?
Adequate pt # at UKF?
 eTBD search
Competitive, active
trials?
Regulatory and
financial aspects?
Protocol Study Review Board (PSRB)
(Head of the department; Attending physicians; PIs; CCR-Group)
Harmonized, democratic decision on trial acceptance
1. PSRB meeting Med 1: 2004
PSRB-#s 1/2004 - 11/2015: 80
Ongoing and recruiting CTs 2010-2014
University Medical Center Freiburg
+120
2010
2011
2012
2013
2014
Ongoing
206
247
296
303
325
Recruiting
176
203
219
200
225
+50
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 extensive
trials to test important new products
2. Nevertheless, over the past years, number of clinical trials in Europe
deceased
3. New regulations have the potential of making future trials in Europe too
expensive and complex, especially for academic research and therefore
may cause a further decrease in clinical trials
4. A drop in number of trials and participants would harm the interest of
European patients and cause damage to Europe's knowledge infrastructure
and future economy
Engert A. et al. Haematologica 2015 (in press)
Current CT activities Med I 2014
# of CTs
# of pts
pts/CT
Total # of CTs
129
1178
9.1
… of these: recruiting CTs
58
651
11.2
… of these: still ongoing CTs
54
527
9.8
… of these: upcoming CTs
17
-
-
Recruiting options for clinical trials: Med I/CCCF
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 physicians
3. “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 CTs
6. Quick Queck® (electronic patient-individualized study search)
7. CT sites: Intra- and Internet and trimestral newsletters
8. Cross-link with CTx-management
®
QuickQueck idea & implementation: Lena Illert, Justus Duyster, EDV Med 1 & ECTU Team
Selected CTs in Early Clinical Trial Unit (ECTU)
Novel / clinical trial agent
Tumor indication
PD-L1 Inhibitor (MPDL 3280A)
R/R DLBCL; R/R Foll. lymphoma
BCL-2 Inhibitor (GDC-0199/ ABT-199) R/R CLL
BCL-2 Inhibitor (BCL201/Idelalisib)
R/R Foll. Lymphom + MCL
anti-CD38 AK (MOR03087)
R/R Multiple Myeloma
Proteasome Inhibitor (Carfilzomib)
R/R Multiple Myeloma
PLK-1 Inhibitor (Volasertib)
untreated MDS
HDAC Inhibitor (Givinostat)
Jak2 positive PV
c-MET inhibitor (INC280)
NSCLC (EGFR+)
PD-L1 Inhibitor (MSB0010718C)
Solid tumors: Gastric, Melanoma, Ovar, NSCLC
PD-L1 Inhibitor
ACC, Mesothelioma, Urothelial
Nilotinib/Ruxolitinib
BCR-ABL pos. ALL/BML BC
TCP
AML
Palbociclib
MLL pos. AML
Ruxolitinib/Pomalidomid
Myelofibrosis
Contacts:
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 indication
PD-L1 Inhibitor (MPDL 3280A)
R/R DLBCL; R/R Foll. lymphoma
BCL-2 Inhibitor (GDC-0199/ ABT-199) R/R CLL
BCL-2 Inhibitor (BCL201/Idelalisib)
R/R Foll. Lymphom + MCL
anti-CD38 AK (MOR03087)
R/R Multiple Myeloma
Proteasome Inhibitor (Carfilzomib)
R/R Multiple Myeloma
PLK-1 Inhibitor (Volasertib)
untreated MDS
HDAC Inhibitor (Givinostat)
Jak2 positive PV
c-MET inhibitor (INC280)
1 NSCLC (EGFR+)
PD-L1 Inhibitor (MSB0010718C)
Solid tumors: Gastric, Melanoma, Ovar, NSCLC
PD-L1 Inhibitor
ACC, Mesothelioma, Urothelial
Nilotinib/Ruxolitinib
BCR-ABL pos. ALL/BML BC
TCP
AML
Palbociclib
MLL pos. AML
Ruxolitinib/Pomalidomid
Myelofibrosis
Contacts:
Drs. L.Illert, A.Krohn, C.Kiote-Schmidt, B.Rister, H.Schäfer, I.Surlan
1
•
•
•
C-MET inhibitor (INC280): case study
59 year old male
Metastastic NSCLC, ID 7/2012 (cerebral metastases )
3 prior therapies:
1. TKI: Gefitinib (Iressa®) 250mg  PR
2. Afatinib (Giotrif®) 40 mg  SD
3. Carboplatin 670mg + Pemetrexed 500mg/m2  PR
 03.09.2015: Informed consent for study INC280 study participation
14.09.2015: c1d1
09.11.2015: Staging after c2: PR
Side effects: nausea
Benefits: response, daily oral medication (QoL less impaired, due to selfemployed intake
requirement: treatment adherence)
Targeted Therapies
2
Immuncheckpoint Inhibitors: anti-PD-1/PD-L1 Ab (phase I/II)
3
Monocloncal Ab: Elotuzumab (phase III)
Therapeutic aproaches to overcome
immuntolerance to tumors
PD-1/PD-L1
Elotuzumab
Modified from Maus, Grupp, Porter and June ASH 2014
PD1/ PD-1 ligand binding leads to T-cell exhaustion
T-Cell
Tumor-Cell
Modified from Freeman G J PNAS 2008;105:10275-10276
PD1/ PD-1 ligand binding leads to T-cell exhaustion
T-Cell
MPDL3280A
MSB0010718C
Tumor-Cell
Modified from Freeman G J PNAS 2008;105:10275-10276
PD1/ PD-1 ligand binding leads to T-cell exhaustion
T-Cell
Pembrolizumab
Nivolumab
MPDL3280A
MSB0010718C
Tumor-Cell
Modified from Freeman G J PNAS 2008;105:10275-10276
Upcoming studies with PD-1 blocking Ab UKF
Phase III study of Lenalidomide +
Dexamethasone ± Pembrolizumab in
Newly Diagnosed MM
Phase III study of Pomalidomide +
Dexamethasone ± Pembrolizumab in
rrMM
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)
Antibodies:
Will they contribute to further progress?
Daratumumab
SAR650984
Samalizumab
(ALXN6000)
Dacetuzumab
Rituximab
Elotuzumab
Lorvotuzumab
Cetuximab
BT062
BB-4
IL-6R (CD126) – tocilizumab
SLAMF7
IPH2101
IL-6 – siltuximab (CNTO-328)
Milatuzumab
Adapted from Hideshima T, Anderson KC. Nat Rev Cancer 2002;2:927–37; Hideshima T, et al. Blood 2004;104:607–18.
Latest developments of antibody-therapy design
PD-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
Elotuzumab Therapy for rrMM
Median age: 66 (37-91)
Median pior therapy regimens: 2 (1-4)
ORR: 79% vs. 66%
AEs: lymphocytopenia, neutropenia, fatigue, pneumonia
Progression free survival
Elotuzumab-Rd
Control: Rd alone
Lonial et al. Multicenter, N Engl J Med 2015; 373:621-31
Upcoming study UKF
Open Label, Randomized Ph 2 Trial of Pomalidomide/ Dexa ± Elotuzumab
in rrMM
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
4 drug
Efficacy
3 drug
2 drug
1 drug
Low cost & tox High cost & tox
• New agents with novel modes of action, such as immune therapies, are
urgently needed
4
-> IITs
VBDD - Studiendesign
Wdh. d28, max. 6 Zyklen
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
Dimopulos M et al Lancet Onol. 2013;14(11):1129-40
Weber DM et al Clin Lymphoma Myeloma Leuk. 2012;12(5):319-24
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
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
9 Studienasistentinnen / 4 Studienärzte
Pts' feed-back on ECTU CCCF Q3/2015 (n=42)
Patientencharakteristika
Variables
# of pts
Age (years; range)
Karnofsky index (%)
m:f
Type of MM
IgG / IgA
Light chain only MM
Light chain (kappa/lambda)
Durie & Salmon stage
I / II / III
A/B
ISS stage
I vs. II/III
BM-infiltration rate (%)
Cytogenetics (CG via iFISH)
Favorable CGs
Unfavorable CGs
Prior therapies
SCT
Bortezomib
IMIDs
n (%)
33
Median (range)
63 (47-78)
90 (70-100)
19 (58%) : 14 (42%)
18 (55%) / 11 (33%)
4 (12%)
24 (73%) / 9 (27%)
0 / 2 (6%) / 31 (94%)
29 (88%) / 4 (12%)
6 (18%) / 27 (82%)
50 (5-90)
19 (58%)
14 (42%)
3 (1-9)
31 (94%)
29 (88%)
14 (42%)
Anzahl komplettierter VBDD - Therapiezyklen
33
31
29
27
25
Patienten
23
21
19
17
15
13
11
9
7
5
3
1
0
1
2
3
4
5
Anzahl komplettierter Therapiezyklen (max. 6)
6
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 2014
Hackanson B et al Leuk Res. 2012;36(8):1055-62
QoL- und Komorbiditätsanalysen vor und nach VBDDTherapie
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):142-52
Kleber M et al. Blood Cancer J 2011, e35
Kleber M et al. Clin Lymphoma Myeloma Leuk. 2013, 13(5):541-51
Engelhardt 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
If we don't know
which drugs are
safe and most
effective, why
don't they just let
us into more
clinical trials?
To protect you
from untested
drugs
Conclusions:
guiding priniciples for advanced research
1. Right research questions must be defined
2. Well-grounded design and realization of CTs
3. Giving access to all data results
4. Authoring and publishing of undistorted and useful research
reports
„CTs are essential for medical improvement & considering
guiding principles, maximum benefit will be obtained for pts.“
ECTU Team UKF / CCCF
Contact:
[email protected]
[email protected]
[email protected]
Special acknowledgement:
Prof. Dr. Justus Duyster
Rainer Bredenkamp
VBDD - Studienrationale
•
BDD: etabliertes und effektives MM-Protokoll für Rezidiv-Patienten1,2
•
Postulierte Synergismen zwischen Vorinostat
a) + Doxorubicin  Cathepsin B↑  Apoptose↑3
b) + Bortezomib  Blockade der Aggresomenformation (EscapeMechanismus)  Apoptose↑4
1 Ludwig H et al J Clin Oncol 2010;28:4635-41
2 Sonneveld P et al Cancer 2008;112:1529-37
3 Cheriyath V et al Br J Cancer 2011;104:957-67
4 Hideshima T et al Mol Cancer Ther 2011;10:2034-42
MM - clinical trials UKF
Indication Title
First- DSMM XIV
line
DSMM XIII
PD-1 - Rd
Relapse CD38 Ab MOR03087
EMN09-Study
PD-1 - Pom-dex
Pom-Vd vs. Vd
Description/content of clinical trial
Ph II, <65 J, R1: VRD vs. RAD -> R2: arm A-D
35
Ph III, 60-75 J, Rd -> PD vs. RD+2xTx  R-maint
Elderly, non-SCT eligible pts
Ph I/IIa-dose escalation, >2 prior therapies:
ab+dex (8c), ab+Rd (7e) + ab-Pom/Dex (7d) open
Ph I done; now: Ph II, dose escalation, >2 prior
lines: 8x Cfz - Benda - Dex  maintenance
Ph II
Ph III, at least 1 + <4 MM-regimes, prior lentherapy required, Ø Vd-refractory (MM-007)
16
BRF117019:
Dabrafenib+Trametinib Ph II >2 prior therapies, currently progressing
Register
Latencies to diagnosis
Pt./referring physicians/participants-questionnaire
+ -satisfaction
Prognostic factors, prevention of toxicity, treatment
planning
retro- & prospective analysis + pts survey
Conditional Survival
Analysis of prognostic factors
Assessment MM-TB
rFCI
# pts
MM-outpts clinic + outpts clinic of studies
MM-center: Profs. Drs. Engelhardt, Wäsch, Waldschmidt, Kiote-Schmidt, Zober, Miething, Schönheimer-physicians
Study nurses: D. Jakobs, C. Messner, I. Surlan
Lymphoma/MM-center: Bürk, Büsch, Tel. 0761 270 71580 od. -71520
MM-tumorboard: each Monday, 16h, kl. Hörsaal  pt registration through TOS
Q4/15
3
3
Q4/15
open since
10/15
screen:1
prescreen:5
UKFpathol: 10
100 / 30 /
55
>800
108 / 200
816

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