Slide Title - Siematologia

Slide Title - Siematologia

OPTIMIZING ORAL BEXAROTENE THERAPY Madeleine Duvic, MD Professor of Medicine & Dermatology Deputy Chairman, Dept of Dermatology M.D. Anderson Cancer Center Houston, Texas Approved Therapies for CTCL Oral Corticosteroids - Beware of rebound Methotrexate for lymphoma Injectible mustargen lymphoma Photopheresis erythrodermic MF 1987 Denileukin diftitox - Ontak for CD25+ CTCL -1998 Bexarotene (Targretin) capsule and gel 1999 Vorinostat (Zolinza) refractory CTCL

Treatment Strategies Remove persistent antigen stimulus (staphylococcus, tinea, drug, chemicals) Select therapy for stage of disease Reverse the Th2 to Th1 shift, induce tumor cell apoptosis, raise CD8+ count Avoid immunosuppressive therapy Adjuvant antibiotics, anti-fungals, & topicals No indwelling catheters = oral agents Advantages of Oral Treatments More convenient for patients Less expensive administration

Long term constant dosing feasible Avoids line sepsis from staphylococcus leading to hospitalization, death Disadvantages? Less bioavailability? Drug-drug or food interactions Sharing drug with others Retinoid Receptor Biology RXR RAR Regulation of Cell Growth and Differentiation Regulation of

Apoptosis Tretinoin RAR RXR Alitretinoin Bexarotene Molecular Basis of Targretin Activity Receptors RXR RXR, RAR, PPAR, VDR, LXR ,TR Transcriptional Modulation of Cell Function

Inhibits Growth Modulates Differentiation Induces Apoptosis Ligand Bexarotene (Targretin) RXR selective Potential Gene Targets: Stats, RAR, INF, TNF- RAR Retinoids for MF The first biological response modifiers, but none approved prior to bexarotene 1999 Isotretinoin, etretinate, soriatane (?) with similar response rates as monotherapy >120 MF pts 58% overall RR and 19% CR Early lesions respond more than advanced PUVA/interferon (72%) vs RePUVA (73%) Claudy, Rouchouse et al. 1983; Kessler, Meyskens et al. 1983; Thomsen, Molin et al. 1984; Fitzpatrick and Mellette 1986; Kessler, Jones et al. 1987; Molin, Thomsen et al. 1987; Dreno, Claudy et al. Reviewed 1991

Isotretinoin & acitretin with IFN Knobler: 2 CR, 2 PR in 7 patients with interferon alfa and isotretinoin. Stadler - 42 stage I and II CTCL patients had a major response rate of 59.5% (38.1% CR, 21.4% PR) with acitretin. Tsimberidou et al. 6 responses in 18 patients with CTCL - interferon alfa and isotretinoin. IFN-alpha and etretrinate Zacharaie and Thestrup- 1 CR, 1 PR in 7 patients with etretinate and interferon Altomare - 7 CR, 3 PR in 13 patients Dreno - 28 of 45 patients (62%) responded by 12 months to either escalated doses of interferon alfa alone (17 patients) or interferon alfa and etretinate (11patients) RXR Retinoids Induce Apoptosis RXR agonists (bexarotene) induce apoptosis in HL-60 leukemia cells, SCC lines, and SS lines

Boehm, J Med Chem, 1995 & Zhang, Clin Cancer Res. 2002. RAR- blocks T- cell death but RAR- induces apoptosis (Tazarotene) Szondy. Cell Death Diff. 1998 Bexarotene is RXR selective with RAR at high concentrations Bexarotene Induces Apoptosis in CTCL Cells at 1-10 M Concentration at 72 Hrs Sub-G1 populations (%) Zhang Clin Cancer Res. 2002 MJ Hut78 30 45 60

40 25 50 35 20 30 48 hrs 20 10 15 10

5 10 72 hrs 20 96 hrs 0 0 0.1 1 30 10 5

0 24 hrs 40 25 15 0 0 MJ Annexin V cells (%) HH 0.1 1 0

10 35 25 30 45 40 35 25 20 30 24 hrs 20

25 48 hrs 15 20 72 hrs 15 10 10 HH Hut7 8 t

30 0.1 1 96 hrs 15 10 10 5 5 0 0 0 0.1

1 10 5 0 0 0.1 1 10 0 Concentration Bexarotene M 0.1 1

10 Phase I Clinical Trial LGD1069 Miller et al. J Clin Oncol. 1997 Feb;15(2):790-5 Dose Ranging Study 52 patients with advanced cancer Doses 5-500 mg/m2/day Responses in 2 CTCL patients 27 pts with pharmacologic levels DLTs: increased LFTs, leukopenia, hypertriglyceridemia, hypercalcemia Phase II Oral Bexarotene Monotherapy:

Response by Dose and Stage Dose EARLY Stage mg/m2/d (n=58) 6.5 300 >300 20% * 54% 67% LATE Stage (n=94) 45% 55% * 73% Cross-over RR Duvic et al. Archives Dermatol. 137:581-593, 2001

J Clinical Oncology, 19:2456-2471, 2001. Response Rate (With 95% Confidence Intervals) Targretin Capsules in Early CTCL (IB-IIA) Response Rates According to PGA, CA and PEC By Initial Dose Level (N = 58 Patients) 67% (10/15) 60% (9/15) 54% (15/28) 50% (14/28) 85% 47% (7/15)

72% 72% 69% 91% 36% (10/28) 54% 20% 20% (3/15) (3/15) 40% 40% 6.7% (1/15) 43%

35% 32% 35% 19% 18% 0% 0% 21% 0% PGA CA PEC 6.5 mg/m2/day PGA CA PEC 300 mg/m2/day

PGA CA PEC >300 mg/m2/day Time to Response by Initial Dose Group N = 58 Early Stage Patients 100% % Patients Who Respond 90% 80% 300 mg/m2/day N = 28 Patients Median 8.1 Weeks 70% >300 mg/m2/day N = 15 Patients Median 13.1 Weeks

60% 50% 40% 30% 6.5 mg/m2/day N = 15 Patients Median not reached 20% 10% 0% 0 20 40 60 80

100 120 140 160 180 200 220 240 260 Time to Response (Days) Targretin Capsules in EARLY STAGE CTCL Mean Overall Body Surface Area Involvement by Initial Dose Levels (N = 58 Patients) Mean Overall BSA Involvement 50% 40% 30% 300 mg/m2/day N = 28 Patients 20% >300 mg/m2/day N = 15 Patients 10% 6.5 mg/m2/day

N = 15 Patients 0% 0 5 10 15 20 25 30 Weeks on Study 35 40

45 50 Targretin Capsules in CTCL L1069-23 (014) Patient 1172 Baseline (6-98) 9 Months (3-99) Targretin Capsules in CTCL L1069-23 (014) Patient 1172 Skin Biopsies Baseline Week 8 Response Rate (With 95% Confidence Intervals)

Targretin Capsules in Advanced Stage CTCL Response Rates According to PGA, CA and PEC by Initial Dose Level (N = 94 Patients) PGA = Physicians Global Assessment CA = Composite Assessment PEC = Primary End Point Classification 48% 45% (27/56) 61% (25/56) 53% (20/38) 69% 47% (18/38) 55%

(21/38) 71% 63% 58% 27% (15/56) 38% 40% 37% 35% 32% 32% 15%

PGA CA PEC 2 300 mg/m /day PGA CA PEC >300 mg/m2/day Targretin Capsules in Advanced CTCL Time to Response According to PEC by Initial Dose Group (N = 94 Patients) % Patients Who Respond 100% 90% >300 g/m2/day N = 38 Pts

80% 70% 60% 300 mg/m2/day N = 56 Patients 50% 40% 30% 20% 10% 0% 0 50 100 150 200

250 300 Time to Response (Days) 350 400 Targretin Capsules in Advanced CTCL Duration of Disease Control According to PEC by Initial Dose (N = 46 Responding Patients) % Patients Who Relapse 0% 10% >300 mg/m2/day N = 21 Responding Patients

20% 30% 40% 50% 300 mg/m2/day N = 25 Responding Patients 60% 70% 80% 90% 100% 0 50 100 150

200 250 300 350 Time to Relapse (Days) 400 450 500 Targretin Capsules in CTCL Response Rates by TNM Staging According to PEC for 300 mg/m2/day Initial Dose (N = 84 Patients) 67% (2/3)

70% Response Rate 60% 50% 50% (2/4) 52% (11/21) 57% (13/23) 32% (6/19) 40% 44%

(4/9) 40% (2/5) 30% 20% 10% 0% IA IB IIA IIB TNM Clinical Stage III

IVA IVB Large Cell Transformation Treated With Bexarotene Week 4 Baseline Week 13 Prior Therapy With RAR Retinoids Does Not Preclude Response 30% (28 of 94) had prior Retinoids 5 of 28 pts (18%) had responded 53% (15 of 28 pts) with prior retinoid therapy had responses on bexarotene 14% CR and 39% PR Bexarotene Side Effects Hypertriglyceridemia >> cholesterol

Pancreatitis - TG are <1200 Central hypothyroidisms dose related, reversible, due to suppression of TSH mRNA: Low TSH & free Thyroxine T4 Headache transient, first dose ? depression Peeling of hands and feet Low WBC, Hbg, elevation of LFTs Decreases sensitivity to insulin hypoglycemia in diabetics Teratogenic, no I- Pledge Severity of the most Frequent (20%) Adverse events 300 mg/m2/day Initial Dose Group in Phase II-III (N = 84 Patients) Hyperlipemia Adverse Event Hypercholesteremia Headache

Mild Moderate Moderately Severe Severe Hypothyroidism Pruritus Asthenia 0 10 20 30 40 50 Incidence (%)

60 70 80 90 100 Optimizing Bexarotene Therapy for CTCL 70 CTCL pts. received bexarotene 54 had monotherapy RR 48% Four patients had CRs >4 yrs, 2-6 yrs in CR, taper bexarotene 16 combination Rx RR 69% ECP, IFN, PUVA 2 lipid lowering agents (Tricor 165 mg/day and

Lipitor to 80 mg/day) associated with higher RR, all started synthroid 25-50 g with bexarotene Talpur & Duvic. J Am Acad Dermatol. 2002. 47(5):672-84. BexCombination Therapies Bexarotene with PUVA Bexarotene with interferon Bexarotene with Ontak Bexarotene with photopheresis Bexartotene with photopheresis plus low dose interferon LLA Therapy Increases Response Bex Therapy Group Monotherapy Monotherapy w/o LLA

Monotherapy/1 LLA Monotherapy/2 LLA Combination Therapy Combotherapy/1 LLA Combotherapy/2 LLA No of Pts Overall RR 54 12 32 10 16 12 4 48% 25% 44% 90%

69% 66% 75% Initiation of Bexarotene Therapy Fasting TG & cholesterol, T4, TSH Start Tricor 140 mg day 7 Low Fat diet Start bexarotene 2 to 6 tablets with synthroid .025 -.050 mg on day 1 and increase gradually Check fasting TG & T4 weekly, q month Increase Synthroid to keep T4 >0.9, Add Lipitor, fish oil, niacin to keep TG <350-400 or cut back on bexarotene dose Phase II Trial of Oral Bexarotene Combined With Interferon Alfa-2b for CTCL

Bexarotene 300 mg/m2 for 8 wks If no CR start 3 5 mil u IFN- 3 x weekly 22 CTCL pts: IB (3), II (7), III (4), IV (8) 49 months (mean) from dx to enrollment All except one had failed prior treatment 4 had prior bexarotene therapy ASH Abstract # 2644 Abstract # 2644 Phase II Trial of Oral Bexarotene Combined With Interferon Alfa-2b for CTCL

17 pts completed 16 weeks 6 of 17 PRs, 1 CR by PEC, = 41% RR (95% CI 18-67%) 3 of 6 PRs with bex. only at 8 weeks Mean duration of response: 2.7 mos range 1-7.6 mos Abstract # 2644 Phase II Trial of Oral Bexarotene Combined With Interferon Alfa-2b for CTCL Grade 3 toxicity: hypercholesterol & triglyceridemia 5, neutropenia 3, lymphopenia 2, elevated AST 2 MonoBex response rate of 45% in advanced refractory CTCL patients Bexarotene plus interferon 41% Trial was stopped early for side effects Bottom line: cut the dose in combination

LONG TERM REMISSIONS WITH ORAL BEXAROTENE Long Term Bexarotene Responders Eighteen patients (about 10%) had long term responses 8 Females, 10 Males 1 IA, 5 IB, 2 IIA, 2 IIB, 8 IVA (4 SS) Median duration on bex 56 mos (R 20-96) Median dose 450 mg (225-600 mg) Median BSA Baseline = 44% and post 0.5 Median duration of PR 35.5 mos (R 12-86) Complete Responders 8/18 (44%) CRs maintained response for a median of 21 (9-69) mos. CD4/CD8 ratio pre 2.4 to post therapy 1.9 Three early stage (2 IB, 1 IIA) Five advanced stage (1 IIB, 4 IVA: 3 SS, 1 LN+)

Patient on Bexarotene 450 mg for 34 months maintained in PR for 26 months Baseline Week 20 79 y/o WM stage IB on bexarotene 600 mg for 72 months Maintained PR for 10 months, and CR for 60 months Pre Targretin Post Targretin Wk 12 Patient grew grew back hair with CR at 70 weeks, off Bexarotene in CR x 3 yrs Pre Targretin Wk 12 Wk 24

Wk 70 Near CR after having MF for 40 years ! Pre Targretin Post Targretin Stage IIB MF Radiation Plus Bexarotene Maintenance 11-99 12-99 1-00 Apisarnthanarax et al. Amer J Dermatol. 4 (6): 2003. Clinical Features of Szary Syndrome

Bexarotene Monotherapy: 44% Response Rate Treatment of Szary Syndrome Staph aureus dicloxicillin, bactroban, whirlpool, topical steroids/wet wraps No central lines sepsis w/o fever Itching: Doxepin 25-50 mg TID plus 50-100 mg at bedtime, Neurontin 300 mg TID Photopheresis q 2-4 wks with intron A (1-3 million units 3 x wk, bexarotene 1-3 caps) Response rate 69% Oral steroids make SS patients rebound!! MTX can result in LCT in nodes Bexarotene Induced T-cell Modulation and Response in CTCL 37 pts (33 MF, 1 ALCL, 3 PTCL) Dose 150-300 mg/m2/day x 13 m (4-18 m) 32/37 had high CD4:8 ratios at baseline, with increases in 27/32 after treatment

33/37 w/low CD8 abs (98, nl 150-1000) Normalization of CD8 counts in 26/33 in 6.5 weeks (range 3.5-12 wks) Porcu, Univ Ohio, ASH Abstract 744 Bexarotene Induced T-cell Modulation and Response in CTCL Physicians global response 64.8% (24/37) Responders vs non-responders: Higher CD8+ cells (975 vs 221 /mm3) (P=.002) Lower CD4:8 ratios (0.8 vs 2.5) (P=.005) Median duration of response is 9.5 months Decrease in CD8 preceded relapse 21 pts ASH Abstract 744 Complete Response after 9 yrs of Sezary Syndrome: ECP, bexarotene, and amoxicillin Pre- ECP

Pre- Targretin Post- Targretin PreTargretin PostTargretin Bexarotene: How Long to Treat ? Maximum tolerated dose until lesions clear. Not clear in 6-8 months? Add skin directed therapy gel or photopherapy, ECP If clear, slow taper of one alternate days over months. If relapse, raise dose and taper later. Seven years is longest duration of treatment in the last patient. Long lasting CRs on bexarotene. New pills on the horizon Vorinostat Zolinza, (aka SAHA) Small molecule inhibits Class I &II Histone

Deacetylases modulates 1% of gene expression TS, cell cycle , TFs Oral 400 mg daily dose, short half-life Response rate of 24-29% in heavily pretreated pts, refractory to bexarotene Side effects: GI N,V,Taste, fatigue, low platelets, decreases itching Combination with bexarotene in ongoing study Histone Deacetylation Results in Transcriptional Repression Open chromatin results Closed chromatin results in transcriptional activation in transcriptional repression HDAC HDAC Ac HDAC

Ac HDAC Ac Ac HDAC Ac Ac HDAC RAR RXR Ac=acetyl group; HDAC=histone deacetylase. Adapted from Johnstone RW. Nat Rev Drug Discov. 2002;1:287-299. Conclusions Bexarotene 300 mg/m2 is an effective oral

monotherapy for all stages of MF Long-term disease control and CRs are achievable Major side effects: hypertriglyceridemia and low TSH/T4 are reversible and controlled with oral meds. Higher doses and response rates with lipid control and thyroid supplement Combination with other effective therapy to achieve higher response and CRs. New Pills on the horizon BCX 1777 or Forodesine (Biocryst) Nucleoside analogue transition state inhibitor of PNP required for T-cells Causes changes in nucleotide pools apoptosis of T cells Oral bioavailability 28-50% In phase II clinical trials for CTCL and T cell leukemia DNA organized as nucleosomes of

146 bp DNA wrapped around 8 histones Mechanism of T-cell Inhibition by PNP Inhibitor Forodosine PNP dGuo Nucleotidase Kinase (dCK) Guanine + deoxyribose-1phosphate dGMP dGTP Imbalance in Deoxynucleotide Pools T-Cell Apoptosis BCX-1777 (forodesine-HCl) Transition State Inhibitor O N

N N N 1.77 A O O + + O O N O + H+ N O 3.0 A

O O - P O O PNP transition state BCX-1777 ASH Abstract # 2491 O N N O Schramm et al., 1998 Oral Chlorambucil & prednisone Mayo Clinic Winkelmann daily C-P for SS JAAD 10(6): 1000,1984

Pulse low dose chlorambucil & fluocortilone chlorambucil 10-12 mg day-1 for 3 days fluocortolone =first day 75 mg, second day 50 mg and third day 25 mg Pulse q 2wks, then increase duration between 7 CR, 6 PR, Mean DR 16.5 mos (median 12) long-term follow-up (mean 31.5, median 27 months) 6 CR, 3 PR, 4 deaths Coors, EA. Br J Dermatol. 2000 Jul;143(1):127-31 When to use oral low dose Methotrexate? Never? in Sezary Syndrome? In psoriasiform plaque MF? Doses of 25- 50 mg oral per week How does it work? Suppresses T cell activation and adhesion thru CLA Can lead to transformation

Retrospective Study of oral MTX 69 pts with up to 201 months observation 60 patch/plaque T2 MF, 20 (33%) responses 7 (12%) CRs and 13 (22%) PRs median TTF 15 months One of 7 tumor stage MF pts responded Kashani & Zackheim: JAAD Nov 49 (5): 873-878. Improvement in BSA BSA 70 Oral Targretin Ontak 18 ug/kg

60 Targretin gel 50 Interferon 3 x week 40 PUVA 3 X week 375 mg 30 525 mg 450 mg 20

10 L W k w 8 k 1 w 2 k1 w 5 k 1 w 8 k 2 w 1 k 2 w 4 k 2

w 9 k 3 w 3 k 37 w k4 w 2 k 4 w 6 k 5 w 0 k 5 w 4 k 5 w 8 k

6 w 4 k 7 w 0 k 7 w 4 k 78 w k8 w 2 k 8 w 8 k w 94 k 1 w 00 k

10 6 0 B % BSA 600 mg Weeks Patient Photos C A Bexarotene, Interferon, PUVA Almost CR x 3 years B

Post- ONTAK 4 -01 Resolution of Facial Plaques and tumors Puva/bex Maintenance 1-04 1-06 8-01 How to Choose? Skin directed topicals, UV, XRT Biological response modifiers: cytokines, interferons, retinoids Photopheresis erythroderma, blood Targeted Fusion Proteins & Monoclonal Antibodies avoid toxicity Purine Analogs & single chemotherapy Combination Chemotherapies Factors Related to Choice

Familiarity of the physician with MF Expected Response Rate and Durability of Response, Convenience for patient Distance to center or PUVA Cost and insurance coverage $$$ Quality of life palliation of itching or appearance What do we mean by progression? Tumor stage Epidermotropic Large cell (+/- large cell

Systemic Large Transformation (LN) Refractory Disease Spread to Blood (Sezary syndrome) ADVANCED, PROGRESSED, REFRACTORY MF New Advances in Treatment Options Topical Therapies for limited disease bexarotene gel, imiquimod, laser Biological response modifiers (BRM) and targeted therapies: interferons, Targretin (bexarotene), Ontak (denileukin diftitox), histone deacetylase inhibitors small molecules, antibodies Nucleoside analogues: gemcitibine,

deoxycorformycin, 2CDA, fludarabine Mini-Allo BMT Median time to response in advanced refractory CTCL Patients Median time to response was 25.7 weeks (range 14-169 days) at a dose of 300 mg/m2/day. Time to response was 8.4 weeks (range 22-169 days) at doses higher than 300 mg/ m2/day.

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