novel therapies in cutaneous t-cell lymphoma...novel therapies in cutaneous t-cell lymphoma august...

Novel Therapies in Cutaneous T-Cell Lymphoma

August 13, 2016

Lubomir Sokol, M.D, Ph.D.

Department of Malignant Hematology

Moffitt Cancer Center

Tampa, Florida

6th CUTANEOUS LYMPHOMA SYMPOSIUM

Disclosures Advisory Boards: Spectrum, Seattle Genetics

Off Label Use: Brentuximab vedotin, Mogamulizumab, Pembrolizumab, Plitidepsin, Resimmune, Darinaparsin, MRG-106, Chidamide, Fenretinide, CPI-613

Cutaneous T-Cell Lymphoma Outline

Classification

Prognostic System

Established Therapy

Novel Agents in Clinical Trials

Conclusions

2016 Revision of WHO Classification of Lymphoid Neoplasms

1) Mycosis Fungoides

2) Sezary Syndrome

3) Lymphomatoid papulosis

4) Primary cutaneous anaplastic large cell lymphoma

5) Primary cutaneous g/d T-cell lymphoma

6) Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma

7) Primary cutaneous acral CD8+ T-cell lymphoma

8) Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder

9) Subcutaneous panniculitis-like T-cell lymphoma

10) Hydroa vacciniforme-like lymphoproliferative disorder

Biological Behavior of CTCL INDOLENT INTERMEDIATE AGGRESSIVE

Mycosis Fungoides

Sezary Syndrome Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma

Lymphomatoid Papulosis Subcutaneous Panniculitis-Like T-Cell Lymphoma (HLH)

Primary cutaneous g/d T-cell lymphoma

Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary Cutaneous CD4+ small/medium Pleomorphic T-Cell Lymphoproliferative Disorder

Hydroa Vacciniforme-Like T-Cell Lymphoproliferative Disorder

Primary cutaneous acral CD8+ T-cell lymphoma

Disease-specific survival (MF/SS).

Sean Whittaker et al. Blood 2016;127:3142-3153

©2016 by American Society of Hematology

Factors Associated with MF Progression

A) increasing age

B) male gender

C) folliculotropism

D) plaques

E) lymphadenopathy

F) large cell transformation

G) low CD8+ counts

H) blood eosinophilia

I) elevated serum lactate dehydrogenase levels

van Doorn R et al. Arch Dermatol 2000 Kim YH et al. Arch Dermatol 2003

CLIPI

Early Disease (St. IA-IIA)

Male gender

Age>60

Plaques

Folliculotropic disease

Node stage NX/N1

Benton EC et al. Eur J Cancer. 2013 Sep;49(13):2859-68

CLIPI

Advanced Disease (St. IIB-IVB)

Male gender

Age>60

Blood stage B1/B2

Visceral involvement

Node stage N2/3

Benton EC et al. Eur J Cancer. 2013 Sep;49(13):2859-68

CLIPI Early Disease (IA-IIA) Advanced Disease (IIB-IVB)

Risk group Score 10 year OS (%)

Risk group Score 10-year OS (%)

Low 0-1 90.3 Low 0-1 53.2

Intermediate 2 76.2 Intermediate 2 19.8

High 3-5 48.9 High 3-5 15

Benton EC et al. Eur J Cancer. 2013 Sep;49(13):2859-68

FDA Approved Drugs for CTCL and PTCL

1999 - Denileukin Diftitox (Ontak) CTCL

2000 - Bexarotene (Targretin) CTCL

2006 - Vorinostat (Zolinza) CTCL

2009 - Romidepsin (Istodax) CTCL (PTCL)

2009 - Pralatrexate (Folotyn) PTCL (CTCL)

2011 - Brentuximab vedotin (Adcetris) ALCL (CTCL)

2014 - Belinostat (Beleodaq) PTCL

CD25 Denileukin Diftitox

CD30 Brentuximab vedotin

CD52 Alemtuzumab

Molecular Targets for Therapy of CTCL

Mogamulizumab CCR4

RFC Pralatrexate

HDAC

PNP RXR

Vorinostat Romidepsin

Bexarotene Forodesine

Pembrolizumab PD-1

Siplizumab CD2

CD4 Zanolimumab

Modern Therapy in CTCL

Currently in Use/Testing In CTCL Discontinued/Not Developed

Bexarotene Denileukin Diftitox

Vorinostat Siplizumab

Romidepsine Zanolimumab

Pralatrexate Forodesin

Alemtuzumab

Brentuximab vedotin

Results of Studies with HDAC Inhibitors Outcome Vorinostat Romidepsin Panobinostat Belinostat

Phase II (Olsen et al.) II (Whittaker et al.)

II (Duvic et al.) II (Foss et al.)

N 74 96 95 16

ORR (%) 29.7% 34% 20% 25%

CR (%) 1 6 4 4

PR (%) 21 27 11 12

DoR 6.1 mos. 15 mos. NA NA

TTP 9.8 mos. 8 mos. NA NA

Approval 2 prior systemic therapy

1 prior systemic therapy

Multiple myeloma

PTCL

Mechanism of action of brentuximab vedotin

Deng C et al. Clin Cancer Res 2013;19:22-27

©2013 by American Association for Cancer Research

A Phase 3 Trial of Brentuximab Vedotin (SGN-35) Versus Physician's Choice (Methotrexate or

Bexarotene) in Patients With CD30-Positive Cutaneous T-Cell Lymphoma

NCT01578499

CD30+ Cutaneous T cell Lymphoma previously treated with systemic therapy or radiation therapy.

Planed enrollment: 132 pts

ORR 56.3% vs. 12.5% (p<0.0001)

Secondary points: CR, PFS, Symptoms, also statistical significant improvement in favor of BV

Brentuximab vedotin 1.8 mg/kg every 3 weeks for to 8 cycles. Optional extension up to 8 cycles in responders.

E N R O L

Phase II R/R MF/SS Stage Ib-IV N=32 Median age: 59 (20-88) Median# of prior therapies: 4 (1-13) 28/32 Stage IIB or greater Primary objective: Overall response rate, correlation with CD30 expression

Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level:

A Multi-Institution Collaborative Project.

A S S E S S

ORR 70% (21/30) 1 CR Median TTR 6.6 wks (range 3–27). PFS at 12 months 54%

Dose Schedule

Kim YH et al. JCO 2015

AE: Peripheral neuropathy (78%), fatigue (61%), decreased appetite (28%), and nausea (22%). Time to development of neuropathy was median 14 weeks (range: 6–39) and the median time to resolution or improvement in neuropathy (from onset of neuropathy) was 24 weeks (range 6–46+).

Brentuximab vedotin 1.8 mg/kg every 3 weeks for to 8 cycles. CR: 2 more cycles and then stop. SD, PR: alternative systemic therapy

E N R O L

Phase II, open label, single arm R/R LyP, PC-ALCL, CD30+MF N=48 Median age: 59.5 (31-82-86) Primary objective: safety and activity. Secondary objective: correlation of CD30 level with response.

Results of a Phase II Trial of Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and Lymphomatoid

Papulosis

A S S E S S

ORR 73% (35/48) CR: 35% (17/48) ORR LyP and pc-ALCL: 100% ORR MF: 50% (28/56) MF/TTR: 12 wks (range 3-39) DOR: 32 wks (range 3-93 )

Dose Schedule

Duvic et al. JCO 2015

AE: Peripheral neuropathy (PN) 29/48 (60%): resolved in 14/29 (48%) and ongoing in 15/29 (52%) with 5 grade 2 and 10 grade one. .

Mogamulizumab KW-0761

Defucosylated humanized anti-CCR4 Antibody

CCR4 – chemokine receptor expressed on T-helper cells and Tregs

Expressed on T-cell lymphomas/leukemias

Defucosylated Fc region enhance ADCC

Ishida & Ueada 2006

Kw-0761 0.1, 0.3, 1.0 mg/kg IV once weekly x4 followed by 2 weeks of observation No DLT, No MTD observed

E N R O L

Open-label, multi-center, two-part trial Phase I/II MF/SS Stage IB-IVB Median Prior Tx : 5 Median age: 67 years (N=42) Primary Objectives: safety, tolerability, pharmacokinetics., MTD

Phase I/II –Mogamulizumab in Patients with CTCL

A S S E S S

ORR 37% (SS 47%) CR 8% PR 29% ORR (IIT global) 33% TTR 1 mo. PFS 11.4 mos. DoR 10.4 mos.

Dose Schedule

AE: nausea, H/A, chills

Madeleine Duvic et al. Blood 2015;125:1883-1889

Response in blood to mogamulizumab in Sézary syndrome.

Madeleine Duvic et al. Blood 2015;125:1883-1889

©2015 by American Society of Hematology

Kaplan-Meier curves of estimated progression-free survival.

Madeleine Duvic et al. Blood 2015;125:1883-1889

©2015 by American Society of Hematology

Randomized Phase 3 study Mogamulizumab vs. Vorinostat

KW-0761 Overall

Randomized Subjects 372

1/3 of patients still continue on the study Expected data analysis: end of 2016 or 2017 Ishida & Ueada 2006

Pembrolizumab (Keytruda) 2 mg/kg IV q3wk until disease progression or unacceptable toxicity Infuse IV over 30.

E N R O L

Phase II R/R after at least one systemic Tx (median 4 prior therapies) MF/SS Stage IIB-IVB N=24 Median age: 67 yr Primary objective: Overall response rate (ORR) Secondary objectives: TTR, DOR, PFS, EFS, OS, incidence of AEs

A Phase 2 Study of MK-3475 (Pembrolizumab) for the Treatment of Relapsed/Refractory Mycosis

Fungoides/Sézary Syndrome

A S S E S S

ORR 9/24 (38%) 1 CR, 8 PR SD 9/24 (38%) TTR 11 wk 89% responses ongoing

Dose Schedule NCT02243579

Withold if: Grade 2 pneumonitis Grade 2 or 3 colitis Symptomatic hypophysitis Grade 2 nephritis Grade 3 hyperthyroidism AST or ALT >3 and up to 5 x ULN or total bilirubin >1.5 and up to 3 x ULN

Cancer Immunotherapy Trials Network

Novel Agents In Clinical Trials in T-Cell Lymphoma

Immunotoxin A-dmDT390-bisFv (UCHT1) (Resimmune)

Truncated diphtheria toxin to residue 390 at the N-terminus followed by anti-human VL and VH domains of anti-CD3epsilon single-chain antibody (UCHT1) linked by a (G(4)S)(3) spacer (sFv)

Fusion protein produced in Pichia pastoris

Depletes CD3+ cells to 3 logs (normal T-cells repopulated by day 20 days

Thompson J et al. 2001

8 dose levels between 2.5 and 11.25 µg/kg per dose

E N R O L

Phase I R/R CTCL N=25 Primary objective: Safety and efficacy

A S S E S S

ORR 36% CR 16% Subgroup analysis: N=9 No Lfnd involvement, < stage III, mSWAT <50 ORR 89% CR 50% 4 pts with DFS 2-6 years

Dose Schedule

A Phase I/II Study of A-dmDT390-bisFv (UCHT1) Fusion Protein in Patients With Cutaneous T Cell Lymphoma

Phase II Stage IB-IIB mSWAT <50 LFND No Objectives: ORR >49% CR >20%

CHIDAMIDE Benzamide class

Inhibitor: HDAC 1, 2, 3, and 10.

Phase II Study – registration study in China

83 pts enrolled

79 pts assessments of efficacy

PTCL not otherwise specified (34%), anaplastic large-cell lymphoma (22%), extranodal natural killer (NK)/T-cell lymphoma, nasal type (20%), or angioimmunoblastic T-cell lymphoma (AITL, 13%).

30 mg orally twice per week.

ORR was 28% (22/79) CR/CRu 14% (11 of 79)

Shi Y Ann Oncol 2015

CHIDAMIDE PFS and OS 2.1 and 21.4 months, respectively.

AITL ORR (50%) and CR/CRu rate (40%)

Most adverse events (AEs) were grade 1 or 2, and AEs ≥grade 3 that occurred in ≥10% patients thrombocytopenia (22%), leukopenia (13%) and neutropenia (11%), respectively.

Shi Y Ann Oncol 2015

DARINAPARSIN

Darinaparsin (S-dimethylarsino-glutathione)

Darinaparsin (N-[S-(dimethylarsino)-N-L-gamma-glutamyl-L-cysteinyl]-gly- cine; S-dimethylarsino-glutathione, ZIO-101, ZinaparTM)

Novel organic arsenic molecule=dimethylated arsenic conjugated to glutathione

Hypoxic cytotoxin and radiosensitizer

MAPK-mediated and SHP1-dependent cell death

DARINAPARSIN

Phase II trial in r/r Hodgkin (HL) and non-Hodgkin lymphoma (NHL)

300 mg/m2 intravenously daily for 5 days, on a 28-day cycle.

The primary endpoint: ORR

29 pts with lymphoma (22 with NHL and 7 with HL)

ORR 17% (95% confidence interval (CI) 6–36%)

7 PTCL pts: 1 CR, 1CRu and 2 prolong SD The most common AE: fatigue, nausea, diarrhea, and

anemia.

PLITIDEPSIN Cyclic depsipeptide from marine invertebrate

Rac1/JNK pathway activation resulting in cell cycle arrest and apoptosis

Phase II clinical

Primary objectives: Efficacy, safety and pharmacokinetics

Plitidepsin 3.2 mg/m2 administered as a 1-hour intravenous infusion weekly on days 1, 8 and 15 every 4 weeks

67 pts with r/r aggressive non-Hodgkin’s lymphoma (PTCL n=34 and other lymphoma n=33)

ORR 20.7% (6/29) (CI 8-39.7% ) non-cutaneous peripheral T-cell lymphoma

Ribrag V et al. Haematologica. 2013

Fenretinide (4-hydroxy(phenyl)retinamide; 4-HPR)

Synthetic retinoid, studied in breast cancer prevention studies and in insulin resistance

FENRETINIDE

Phase I study in patients with hematologic malignancies (n=25) CIVI x 120 hrs q 21 days

4/11 (36%) ORR in T-cell lymphoma MTD 1280 mg/m2/day x5 days

Responses in T cell lymphoma observed with doses ranging 905-1810 mg/m2/day

IV Emulsion: 6-7 fold higher 4-HPR levels compare to oral administration

Mohrbacher A et al. J Clin Oncol 30, 2012 (suppl; abstr 8073)

FENRETINIDE

Phase II Clinical Trial of Intravenous Fenretinide Emulsion n Patients with R/R PTCL

NCT02495415.

LNA-based antimiR-155 MRG-106 A locked nucleic acid (LNA)-based oligonucleotide inhibitor of microRNA (miRNA) 155 (miR-155). MRG-106 binds and inhibits prooncogenic miRNA-155

MRG-106 MRG-106 is an inhibitor of non-coding small RNA miR-

155 that is found at high levels in the malignant T-cells of mycosis fungoides

Phase 1, Safety, Tolerability and Pharmacokinetic Study of MRG-106 in Patients With Cutaneous T Cell Lymphoma (CTCL), MF Subtype

NCT02580552

The primary objective: safety and tolerability MRG-106 in CTCL

Part A: injection directly into CTCL lesions in the skin.

Part B: subcutaneous injection

CPI-613

CPI-613 is an E1α pyruvate dehydrogenase (PDH) modulator that prevents cancer cells from metabolizing glucose for energy.

CPI-613 has been granted orphan drug status by the US FDA for pancreatic cancer.

Previously studied in solid tumors and myeloid malignancies

CPI-613

Phase I Trial of CPI-613 and Bendamustine Hydrochloride in Treating Patients With Relapsed or Refractory T-Cell Non-Hodgkin Lymphoma or Hodgkin Lymphoma

Objectives: safety and tolerability and finding the best dose of CPI-613 when given together with bendamustine hydrochloride

Conclusions Significant progress was made in therapy of CTCL within past 14 year

Mycosis fungoides is heterogeneous disease clinically and at molecular level

Currently available multidisciplinary therapeutic approaches can prolong survival

Biological agents have moderate activity with less toxicity in comparison to chemotherapy

Combinations of agents are not superior to sequential monotherapy

ORR 25-50% with CR rate of 10%

Modern Immunotherapy shows promising results

Personalized/Precision Medicine Approach will be Necessary to Improve ORR and Outcomes of Patients with Advanced Stage Disease