Phase 1 Trial Evaluating MRG-106, a Synthetic Inhibitor of microrna- 155, in Patients with CTCL

Transcription

1 EORTC CLTF 2017 meeting on Cutaneous Lymphomas: Insights & Therapeutic Progress Phase 1 Trial Evaluating MRG-106, a Synthetic Inhibitor of microrna- 155, in Patients with CTCL Christiane Querfeld, Francine Foss, Lauren Pinter-Brown, Pierluigi Porcu, Basem M. William, Theresa Pacheco, Bradley Haverkos, Youn Kim, Joan Guitart, Ahmad Halwani, Jennifer DeSimone, Anita G. Seto, Linda A. Pestano, Judy Ruckman, Michele Landry, Gilad S. Gordon, Paul Rubin, William S. Marshall

2 MicroRNA-155 Regulates Key Pathogenic Pathways in CTCL Epigenetic alterations have been implicated in the pathogenesis of CTCL mirna profiling and RT-PCR discriminate CTCL and non-malignant inflammation with a high accuracy mir-155 is overexpressed; mir-203 & mir-205 are decreased in CTCL skin JAK/STAT, PI3K, and RAS pathways are activated in CTCL and regulated by mir-155 that lead to uncontrolled clonal cell expansion Ralfkiaer et al. Blood 2011; Netchiporouk et al. Cell Cycle 2014; Van Kester et al. 2011; Maj et al. Br J Derm 2012; Kopp et al. APMIS 2013; Kopp et al. Cell Cycle 2013; Moyal et al. Exp Derm 2013; Moyal et al. Br J Derm 2017

3 n tre a te d a t d a y 1 Preclinical Data: mir-155 is Upregulated in MF Lesions and Inhibition Affects Cell Growth and Apoptosis H u T a p o to s is p a th w a y a c tiv a tio n C a s p a s e 3 /7 a c tiv ity n=10 n=13 n=21 n=13 In collaboration with Madeleine Duvic (MD Anderson) UntreatedU n a te d BexaroteneB e x a n e mir-155 M Inhibitor (MRG-106) 3

4 First-In-Human Phase 1 Study of MRG-106 in Patients with Mycosis Fungoides MRG-106 is an optimized oligonucleotide inhibitor of mir-155 formulated in saline Study objectives: Primary objective: Safety and tolerability Secondary objectives: PK profile, efficacy, recommended Phase 2 dose and route of administration Study Design: Subjects permitted to continue CTCL therapy if stable dose > 4 weeks prior to MRG-106 administration Part A: Activity of MRG-106 through intralesional injection Part B: Dose-escalation by systemic administration (subcutaneous or I.V.) Dose schedule for systemic administration: Three doses in the first week followed by weekly doses Five subjects were eligible for only 4 weeks of treatment due to original protocol version 4

5 Patient Characteristics: Parameter Part A Intralesional, N=6 Part B Systemic, N=23 Total N=29 Sex Female 1 ( 16.7%) 7 ( 30.4%) 8 ( 27.6%) Male 5 ( 83.3%) 16 ( 69.6%) 21 ( 72.4%) Age Median (range) 61 (50-64) 63 (21-85) 63 (21-85) Race Asian 0 ( 0.0%) 1 ( 4.3%) 1 ( 3.4%) African American 1 ( 16.7%) 1 ( 4.3%) 2 ( 6.9%) Not reported 1 ( 16.7%) 0 ( 0.0%) 1 ( 3.4%) Other 0 ( 0.0%) 1 ( 4.3%) 1 ( 3.4%) Caucasian 4 ( 66.7%) 20 ( 87.0%) 24 ( 82.8%) Disease Stage at Diagnosis Stage IA 0 ( 0.0%) 4 ( 17.4%) 4 ( 13.8%) Stage IB 1 ( 16.7%) 7 ( 30.4%) 8 ( 27.6%) Stage IIA 2 ( 33.3%) 2 ( 8.7%) 4 ( 13.8%) Stage IIB 3 ( 50.0%) 6 ( 26.1%) 9 ( 31.0%) Stage IIIA 0 ( 0.0%) 2 ( 8.7%) 2 ( 6.9%) Stage IIIB 0 ( 0.0%) 1 ( 4.3%) 1 ( 3.4%) Unknown 0 ( 0.0%) 1 ( 4.3%) 1 ( 3.4%) Baseline mswat N Median (range) 22.5 (3-96) 42.7 (2-180) 34.9 (2-180) Prior Systemic CTCL Therapies Median (range) 3 (1-4) 2 (0-9) 2 (0-9) Concomitant Systemic CTCL Therapies Median (range) 1 (0-2) 1 (0-3) 1 (0-3) Part A Intralesional, N=6 Part B Systemic, N=5 Total N=11 Mean mir-155 copy number from lesional skin biopsy (range) 744 (109,3154) 554 (NQ,912) 690 (NQ,3154) Normal skin mir-155 = Not Quantifiable (N/Q) 5

6 Improvement of CAILS with Intralesional Injection of MRG-106 (Part A) MRG-106 was well-tolerated with generally minor injection site reactions MRG-106 injected lesions Early termination = last injection day CAILS assessment day 6

7 22 of 23 Patients treated systemically with MRG-106 have mswat score improvement independent of treatment duration 19 subjects were eligible for > 1 month of treatment 13 subjects chose to continue with additional months of treatment 6 doses = initial cycle 4 doses in subsequent cycles 7

8 69% Patients treated for > 1 Month show 50% mswat Score Improvement bexarotene NONE bexarotene NONE Subject methotrexate narrow band UVB, intron A, interferon NONE bexarotene Subject ID bexarotene NONE prednisone, vorinostat NONE NONE Study Day SD = Stable Disease PR = Partial Response PD = Progressive Disease Drug Holiday Last Dose Ongoing Database Oct 11,

9 Case Example ( ): 300 mg IV Infusion Cohort Age: 51; Sex: Male Date of diagnosis: 2013 CTCL stage at screening: IB Baseline mswat: 180 Concomitant systemic therapy: Methotrexate (started June 2015) Has skin (mswat) PR lasting > 4 months Day 1 mswat: 180 Day 93 mswat: 68 (62% reduction) 9

10 Case Example ( ): 300 mg IV Infusion Cohort Age: 63; Sex: Male Date of diagnosis: 2015 CTCL stage at screening: IIB Concomitant systemic therapy: Bexarotene (started 2015) Has skin (mswat) PR lasting > 4 months Day 1 Day 29 Day 127 Day 182 CAILS: 12 CAILS: 9 CAILS: 3 CAILS: 0 10

11 MRG-106 Has a Favorable Safety Profile Most common coded Adverse Events: AEs by preferred term, N (%) Any grade Grade 3-4 Injection site pain (I.L. & S.Q.) 6 (21) 0 Fatigue 6 (21) 0 Nausea 4 (14) 0 Pruritus 4 (14) 1 Erythema 4 (14) 0 No SAEs attributed to MRG-106 No Grade 4 Adverse Events attributed to MRG-106 One Grade 3 worsening pruritus attributed to MRG-106 (Dose-Limiting Toxicity) Database Oct 11,

12 MRG-106 Has a Favorable Safety Profile All Grade 3 or 4 Adverse Events Database Oct 11, 2017 Part A (Intratumoral) 75mg (6) Part B (Subcutaneous) Part B (IV, 2 hr infusion) Part B (IV Bolus) System Organ Class Preferred Term 300mg (3) 600mg (3) 900mg (3) 300mg (3) 600mg (3) 900mg (3) 300mg (5) Total (29) Metabolism and nutrition disorders 1 ( 16.7%) 1 ( 33.3%) 3 ( 10.3%) Hypercalcemia 1 ( 16.7%) 1 ( 3.4%) Hyponatremia 1 ( 33.3%) 1 ( 3.4%) Hypophosphatemia 1 ( 33.3%) 1 ( 3.4%) Blood and lymphatic system disorders 1 ( 16.7%) 1 ( 33.3%) 1 ( 33.3%) 3 ( 10.3%) Leukopenia 1 ( 33.3%) 1 ( 3.4%) Neutropenia 1 ( 33.3%) 1 ( 33.3%) 2 ( 6.9%) Lymphopenia 1 ( 16.7%) 1 ( 3.4%) Laboratory findings 1 ( 16.7%) 1 ( 20.0%) 2 ( 6.9%) Blood creatine phosphokinase increased 1 ( 16.7%) 1 ( 3.4%) Uric acid increased 1 ( 20.0%) 1 ( 3.4%) Infections 1 ( 16.7%) 1 ( 3.4%) Cellulitis 1 ( 16.7%) 1 ( 3.4%) Skin and subcutaneous tissue disorders 1 ( 33.3%) 1 ( 3.4%) Pruritus 1 ( 33.3%) 1 ( 3.4%) Vascular disorders 1 ( 33.3%) 1 ( 3.4%) Hypertension 1 ( 33.3%) 1 ( 3.4%) 12

13 Conclusions MRG-106 is generally well-tolerated to date No SAEs or Grade 4 AEs deemed related to study drug One Grade 3 AE deemed potentially related to study drug: pruritus 9 of 13 (70%) patients treated for > 1 month have 50% mswat score reduction mswat improvement is durable in all patients, who continued on treatment Magnitude of mswat improvements appeared to correlate with time on MRG-106 treatment Efficacy appears similar across dose range tested ( mg/dose) Study in CTCL is on-going 13

14 MRG CTCL Investigators Jennifer DeSimone (Inova) Herbert Eradat (UCLA) Francine Foss (Yale) Joan Guitart (Northwestern) Ahmad Halwani (Huntsman) Youn Kim (Stanford) Theresa Pacheco (University of Colorado) Lauren Pinter-Brown (UC Irvine) Pierluigi Porcu (Thomas Jefferson) Christiane Querfeld (City of Hope) Basem William (The Ohio State University) 14