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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
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