Clinical Trials for Patients with

(1)

Clinical Trials for Patients with

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

(2)

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

(3)

But 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

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ffi

f

• Very limited data on the efficacy of

second-line therapy

(4)

Approaches for Development of

N

l MPM Th

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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

st

_line

• Second-line: At progression after 1

st

_line

therapy

(5)

Ongoing (or Recently Completed)

Large Clinical Trials in Advanced MPM

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

(6)

WT1 Peptide Vaccine

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.

(7)

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)

(8)

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

(9)

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

(10)

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

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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

(12)

Vaccination induces CD4 T-Cell Proliferation

(13)

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

(14)

P ti

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P ti

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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

(15)

WT-1 Peptide Vaccine

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)

(16)

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

(17)

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

(18)

CBP501 suppresses mesothelioma tumor

xenograft growth in combination with cisplatin

4.90 Relative tumor volume change of Scid mice_{bearing 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

(19)

CBP501 Randomized Phase II Trial In MPM

Trial Design

g

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.

(20)

Histone Deacetylase Inhibitors:

Mechanism of Action

HDAC=histone deacetylase; HDACi=histone deacetylase inhibitor; HAT=histone acetyltransferase; STAT‐1=signal transducer and activator of transcription 1; NFB=nuclear factor kappa B; VEGF=vascular endothelial growth factor

and activator of transcription‐1; NFB=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

(21)

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

(22)

Possible Mechanisms of Antineoplastic

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

(23)

Vorinostat Phase III Trial in MPM

Study Design

R _{Vorinostat 300 mg PO BID}

Study 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

(24)

Vorinostat Phase III Trial in MPM

Study Timeline

July, 2005 July, 2006 May, 2008 December, 2009 February, 2011 July, 2011

First 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 N220 135 events N400 270 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