Clinical Trials for Patients with
Malignant Pleural Mesothelioma
Malignant Pleural Mesothelioma
Lee M. Krug, M.D.
Memorial Sloan-Kettering Cancer Center New York, New York
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
Challenges in MPM Clinical Trials
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Mesothelioma is a rare disease, and
as a result…..
• Large trials take a long time to
complete
• Less research funding available so
fewer investigators interested
• Less interest by pharma companies
due to low profitability
International Symposium on Malignant Mesothelioma 2011 -- curemeso.orgBut there is a need…
• MPM has an extremely high rate of
y
g
relapse after surgical resection
• Pemetrexed + cisplatin is the only
FDA-approved chemotherapy regimen for
advanced disease
– Improves median survival by 3 months
– Disease ultimately progresses after treatment
V
li it d d t
th
ffi
f
• Very limited data on the efficacy of
second-line therapy
International Symposium on Malignant Mesothelioma 2011 -- curemeso.orgApproaches for Development of
N
l MPM Th
i
Novel MPM Therapies
• Adjuvant: After surgery or combined
Adjuvant: After surgery or combined
modality therapy
• First-line:
– Add new agent in combination with
pemetrexed / cisplatin
– Develop new regimen
• Maintenance: After treatment with
t
d / i
l ti t
i t i
pemetrexed / cisplatin to maintain
response
Second line: At progression after 1
stline
• Second-line: At progression after 1
stline
therapy
International Symposium on Malignant Mesothelioma 2011 -- curemeso.orgOngoing (or Recently Completed)
Large Clinical Trials in Advanced MPM
Large Clinical Trials in Advanced MPM
Drug Line Phase Sponsor
Drug Line Phase Sponsor
Bevacizumab 1st with pem/cis II/III French Intergroup
CBP 501 1st with pem/cis RP II CanBas
Cediranib 1st with pem/cis I/II SWOG
Everolimus 2nd or 3rd II SWOG
MORAb 009 1st ith / i II M h t k
MORAb‐009 1st with pem/cis II Morphotek
NGR‐hTNF Maintenance RP II MolMed
Thalidomide Maintenance III Netherlands Cancer Thalidomide Maintenance III Netherlands Cancer
Institute Vorinostat 2nd or 3rd III Merck
WT‐1 vaccine Adjuvant RP II MSKCC
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
WT1 Peptide Vaccine
Background: Why target WT-1?
Background: Why target WT-1?
1. The WT-1 gene encodes a protein that is a zinc
transcription factor in tissue development cell transcription factor in tissue development, cell proliferation, differentiation and apoptosis.
2 WT 1 h li it d i i l ti b t h
2. WT-1 has limited expression in normal tissues, but has
high expression in many hematologic malignancies and solid tumors, particularly mesothelioma.
3. WT-1 is processed and presented to the immune
system.
4. Peptide vaccines can induce CTL recognition and killing of WT-1 expressing malignant cells.
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
Development of WT1 Peptide Vaccine
n Native WT-1 has low immunogenic due to poor processing or
presentation of the peptide and poor complex stability in the surface HLA
We designed new “heteroclitic” peptides by substituting specific amino acids in the anchor residues amino acids in the anchor residues using a bioinformatic model system (BIMAS).
P tid h b d th i
Peptides were chosen based on their predicted binding affinities to HLA class I molecules
The stability of the HLA-peptide complex was tested using the T2 stabilization assay
Test for in vitro activity of stimulated T cells (IFN-γ ELISPOT and Cr51 release)
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
WT1 Peptide Vaccine
Background: WT-1 Vaccine
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- We created synthetic peptides derived from WT1 proteins
Th 4 tid b l t ith ti t i
WT1 HLA
WT1 HLA--class I peptide class I peptide (HLA(HLA--A0201)A0201)
- The 4 peptides below cross react with native proteins
WT1 HLA
WT1 HLA class II peptidesclass II peptides (HLA(HLA DRB1)DRB1)
WT1
WT1--A1A1:: YYMFPNAPYLMFPNAPYL 9 9 aaaa (126
(126--134)134)
WT1 HLA
WT1 HLA--class II peptides class II peptides (HLA(HLA--DRB1)DRB1)
427 long:
427 long:: : RSDELVRHHNMHQRNMTKLRSDELVRHHNMHQRNMTKL 19 aa19 aa (427
(427 --445) 445)
331 long:
331 long::: PGCPGCNKRYFKLSHLQMHSRNKRYFKLSHLQMHSRKHTGKHTG 22 aa22 aa
331 long:
331 long:: : PGCPGCNKRYFKLSHLQMHSRNKRYFKLSHLQMHSRKHTGKHTG 22 aa22 aa (331
(331--352)352)
122A1 long
122A1 long: SG: SGQAQAYYMFPNAPYLMFPNAPYLPSCLPSCLESES 19 19 aaaa (122
(122--140)140)
Pinilla JI Leukemia 20: 2025, 2006 May R Clin. Cancer Res 13: 4547, 2007
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
WT1 Peptide Vaccine
Pilot Trial Design
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Primary Objective:
To test the safety and immunogenicity (CD4 and CD8 response) of the WT1 vaccine
of the WT1 vaccine Eligibility:
Mesothelioma (< 1 prior chemotherapy regimen)
NSCLC (stage III or IV after completion of initial therapy NSCLC (stage III or IV after completion of initial therapy
WT1-positive by immunohistochemistry Treatment:
Vaccine given weeks 0 4 6 8 10 12 Vaccine given weeks 0, 4, 6, 8, 10, 12 Montanide (1:1 volume) adjuvant
GM-CSF 70 mcg on day -2 and 0
If positive response and no disease progression, patients can continue up to 12 vaccinations
continue up to 12 vaccinations Monitoring:
Immune response (after 3, 6, 9 and 12 vaccinations) DTH skin test
– DTH skin test
– T cell response (proliferation, IFN- ELISPOT)
CT scans every 3 months International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
WT1 Peptide Vaccine
Patient Characteristics
Patient Characteristics
Mesothelioma (N=9) Mesothelioma (N=9) Mesothelioma (N=9) Mesothelioma (N=9)–– Ages 47 Ages 47 –– 86, 8 men and 3 women86, 8 men and 3 women
–– All epithelioid histologyAll epithelioid histology
–– 5 relapsed after multi5 relapsed after multi--modality therapymodality therapy
–– 4 unresectable with relapse after 4 unresectable with relapse after chemotherapy
chemotherapy chemotherapy chemotherapy NSCLC (N=2)
– Ages 57 and 53, 1 woman and 1 man – Both adenocarcinoma
– Both with stage III disease and treated with
combined modality combined modality International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
WT1 Peptide Vaccine
Immune Response Summary
Immune Response Summary
DTH Response DTH Response
–– 3 out of 8 pts had a DTH response3 out of 8 pts had a DTH response CD4 Response
CD4 Response CD4 Response CD4 Response
–– 6 patients out of 9 had CD4 response. 6 patients out of 9 had CD4 response. CD8
CD8 ResponseResponse CD8
CD8 Response Response
–– 5 out of 6 patients 5 out of 6 patients tested had CD8 responsetested had CD8 response
–– NOTE: Only patients with HLANOTE: Only patients with HLA--0201 were 0201 were t t d f CD8 lif ti
t t d f CD8 lif ti
tested for CD8 proliferation. tested for CD8 proliferation.
Krug et al, Cancer Immunol Immunother, 2010
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
Vaccination induces CD4 T-Cell Proliferation
Krug et al, Cancer Immunol Immunother, 2010
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
Analog peptide WT1-A1 induces IFN-secretion by CD3 T-cells that cross react with native peptide CD3 T cells that cross react with native peptide
Krug et al, Cancer Immunol Immunother, 2010
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
WT1 Peptide Vaccine
P ti
t O t
P ti
t O t
Patient Outcomes
Patient Outcomes
M th li (N 9) Mesothelioma (N=9) 5 patients completed at least 6 vaccines
8 patients developed progression of disease8 patients developed progression of disease 1 patient completed all 12 vaccines and
remains without progression 36 months later Median survival 13 months
Median survival 13 months
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
WT-1 Peptide Vaccine
Adjuvant Study Design
Adjuvant Study Design
R
• Malig Pleural Meso • WT-1 positive • 4 12 weeks since R A N Specific Immunotherapy: WT-1 vaccine / Montanide GM CSF • 4-12 weeks since completion of multi-modality treatment D O M + GM-CSF treatment including surgery • PS > 70% M I Z E Non-specific Immunotherapy: Montanide + GM-CSF E
Primary endpoint: 1-year PFS
Ai t i f 50% t 70%
Aim to increase from 50% to 70% N=78 patients (39 per arm)
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
CBP501 - Background
Malignant cells preferentially repair Malignant cells preferentially repair
damaged DNA at the G2 checkpoint, because of loss of the G1 checkpoint.
CBP501, a synthetic duodecapeptide,
inhibits several kinases involved in G2 arrest and thereby affects DNA repair
l ti l i li t ll selectively in malignant cells.
CBP501 enhances DNA damage by
cisplatin by reinforcing the double cisplatin by reinforcing the double-strand breaks and increasing the number of platinum-DNA adducts
Hypothetical structural model for the yp CBP501-hCHK1 complex International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
CBP501 enhances the effect of cisplatin on the cell cycle distribution of mesothelioma cell lines
%G2/M MSTO y H226 %G2/M %G2/M 2 fold 4 fold H28 H2452 /M G2/M H2452 4 fold 4 fold %G2 / % G 17
Yamamoto et al., AACR annual meeting, 2009 FACS analysis on mesothelioma lines (simultaneous)
Day 1: CBP501/CDDP 3hr treat, Day 3: FACS
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
CBP501 suppresses mesothelioma tumor
xenograft growth in combination with cisplatin
4.90 Relative tumor volume change of Scid micebearing NCI-H226 mesothelioma
xenograft growth in combination with cisplatin
18 3.90 4.40 me CBP501 7.5mg/kg Cisplatin 9mg/kg Vehicle 2.90 3.40 ti ve t u m o r vo lu Cisplatin CBP501 1 40 1.90 2.40 re la t CBP501+Ci pl ti Cisplatin 0.90 1.40 1 3 5 7 9 11 13 15 17 19 21 23 CBP501+Cisplatin
days after first treatment
Yamamoto et al., AACR annual meeting, 2009
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
CBP501 Randomized Phase II Trial In MPM
Trial Design
Trial Design
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Arm A
Arm A (42 patients)(42 patients) - CBP501: 25mg/m2 IV
First patient enrolled: Oct 2008
Expected last patient: Nov 2011 g
- Cisplatin: 75 mg/m2 IV
- Pemetrexed: 500 mg/m2 IV
every 3 weeks
Stratify:
Expected last patient: Nov 2011
MPM - Unresectable MPM - Unresectable Stratify: P.S: 0-1 vs 2 Histology: Epithelioid vs Other - Unresectable - No prior chemotherapy - Unresectable
- No prior chemotherapy Randomization
Ratio 2:1 (Arm A:B)
Arm B
Arm B (21 patients)(21 patients)
- Cisplatin: 75 mg/m2 IV
- Pemetrexed: 500 mg/m2 IV
every 3 weeks
If ≥ 50% of the patients in Arm A remain
progression-free for more than 4 months, every 3 weeks
p g ,
the combination will be considered suitable for further study in MPM.
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
Histone Deacetylase Inhibitors:
Mechanism of Action
Mechanism of Action
HDAC=histone deacetylase; HDACi=histone deacetylase inhibitor; HAT=histone acetyltransferase; STAT‐1=signal transducer and activator of transcription 1; NFB=nuclear factor kappa B; VEGF=vascular endothelial growth factor
and activator of transcription‐1; NFB=nuclear factor‐kappa B; VEGF=vascular endothelial growth factor Paik et al. J Thorac Oncol. 2010;5(2);275‐279 International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
Suberoylanilide Hydroxamic Acid
(SAHA V i
t t)
(SAHA, Vorinostat)
H N O N O N H OH Oral inhibitor of HDAC1, 2, 3, and 6 and other proteins that regulate gene transcription
Approved for treatment of CTCL.
In a phase I trial of oral SAHA, 13 patients with p , p malignant pleural mesothelioma enrolled with two unconfirmed partial responses and four patients with stable disease
patients with stable disease.
Krug et al, Clin Lung Cancer, 2005
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
Possible Mechanisms of Antineoplastic
Activity of Vorinostat in MPM
Activity of Vorinostat in MPM
I d ti f i f 21/WAF1
• Induction of expression of p21/WAF1 • Downregulation of thymidylate synthase • Inhibition of proteasome function
• Inhibition of proteasome function
• Reduced expression of HIF-1alpha and VEGF leading to reduced angiogenesisg g g
• Degradation of Akt via acetylation of Hsp90 • Downregulation of antiapoptotic proteins
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
Vorinostat Phase III Trial in MPM
Study Design
R Vorinostat 300 mg PO BIDStudy Design
A N D O Vorinostat 300 mg PO BID 3 of 7 d in a 3-week cycle Stratification • Performance status • Histology N=330 M I Z E gy (epithelial vs other)• No. prior therapies (1 vs 2) Placebo PO BID
3 of 7 d in a 3-week cycle N=330
• Global, multicenter, phase III, randomized, double-blind,
l b t ll d t d
placebo- controlled study
• Patients receive oral vorinostat 300 mg (or matching placebo) BID for 3 days each week of a 21-day cycle
BID=twice daily; PO=by mouth
placebo) BID for 3 days each week of a 21 day cycle
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
Vorinostat Phase III Trial in MPM
Study Timeline
Study Timeline
July, 2005 July, 2006 May, 2008 December, 2009 February, 2011 July, 2011First 1st Interim 2nd interim 3rd interim Complete Final First patient in 1st Interim analysis 2nd interim analysis 3rd interim analysis Complete enrollment Final analysis N=50 + 18 wk N220 135 events N400 270 events N=660 540 events + 18 wk F/U 135 events 270 events Enrollment suspended until Continue enrolling Continue enrolling until February 12, 2007 International Symposium on Malignant Mesothelioma 2011 -- curemeso.org
Conclusions
• Despite many hurdles, several novel agents
b i
t di d i
li i l t i l f
MPM
are being studied in clinical trials for MPM
• Efforts to develop therapies with targets
ifi ll
l
t t MPM h ld
ti
specifically relevant to MPM should continue
• Collaborations across institutions is necessary
to complete large studies
to complete large studies
• Support from patients and foundations will
increase the chance of success
increase the chance of success
International Symposium on Malignant Mesothelioma 2011 -- curemeso.org