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. ...
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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, 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 + 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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