Future Strategies For Refractory Myeloma. Marc S. Raab

Transcription

1 Future Strategies For Refractory Myeloma Marc S. Raab

2 Multiple Myeloma Clonal proliferation of malignant plasma cells. excess bone marrow plasma cells monoclonal protein osteolytic bone lesions renal disease genetically heterogeneous Punched Out Lesions Still an incurable disease 2 nd most frequent hematologic malignancy Germany: ~6000 new patients/year, 2% of all cancer deaths Raab et al., Lancet, 2009

3 New challenges refractory MM Current therapy: - Chemotherapy incl. stem cell transplantation - Proteasome inhibitors ( PI ; Borte-/ Carfil-/ Ixazomib) - Thalidomide-derivatives ( IMiD ; Lena-/ Pomalidomide) Myeloma Overall Survival Newly diagnosed Former therapy PI + IMiD 60 mos Relapsed / Refractory to PI + IMiD <9 mos months Kumar SK et al., 2008 & 2012 refractory MM has the most urgent medical need

4 Novel and novel-novel Proteasome Inhibitors Bortezomib Carfilzomib Ixazomib Immunomodulators Thalidomide, Lenalidomide Pomalidomide Antibodies Elotuzumab Daratumumab MOR202, SAR Others Panobinostat, ABBV838, ACY-241, ABT199, ARRY520, CRM1, EDO-S101, PIM447, Ibrutinib, Afuresertib, Trametinib, Dabrafenib

5 Blocking the aggresome pathway

6 HDAC-6 specific inhibition: ACY-1215 ACE-MM-102: Combination of Ricolinostat with Pom/Dex Over 80 refractory relapse patients in Phase 2, closing to accrual Nov As of August 3, 2015, 46 patients were safety evaluable and 36 were efficacy evaluable with median follow-up of 4 months - ORR ( PR) was 50%, regardless of refractory status to Len, Bort, or cytogeneic risk (t4;14 +/- del 17p) - Pom/Dex historically had a 16% ORR at 4.2 mo in similar patient population Ricolinostat remains a tolerable and safe oral agent - Common toxicities are predominantly low grade, including fatigue, diarrhea, neutropenia, anemia, thrombocytopenia and constipation - No evidence of ricolinostat accumulation or drug-drug interaction with Pom PK of ricolinostat is similar to that observed in combination with Btz and Len.

7 HDAC-6 specific inhibition: ACY-241 ACY-241: Structure and Potency ACY-1215 ACY-241 Compound HDAC1 (nm) HDAC2 (nm) HDAC3 (nm) HDAC6 (nm) Solubility ACY ~ 10 µg/ml ACY µg/ml Structurally similar to ACY 1215 Potency and selectivity similar to ACY 1215 Enhanced aqueous solubility allows tablet form Similar single agent cytotoxicity New chemical entity

8 ACY-241 / Pom / Dex ACE-MM-200 Trial Outline: ACY-241/Pom/Dex 1a: ACY-241 monotherapy 1b: combination ACY Pom + Dex * Continue dose escalation in 1a even if MTD reached in 1b

9 KPT inhibition - Selinexor Novel small molecule selective inhibitors of nuclear export (SINE) compounds that target CRM1 exportins: Induce cell death, by the forced nuclear retention of tumor-suppressors, transcriptional factors that are otherwise inactive in these cells due to aberrant CRM1 transport into the cytoplasm

10 Selinexor single agent Phase I/II study in hematologic malignancies 3+3 design Broad Range of doses: 3 mg/m 2 to 80 mg/m 2 Varying regimens: does/cycle Varying Histology: MM, WM, NHL, CLL

11 Selinexor - Adverse events

12 Selinexor single agent limited activity All 35 pts dosed: ORR (1/35) patients 3%, CBR (6/35) 17%

13 Selinexor and Dexamethasone Preclinical Data support synergy between steroids and Selinexor

14 Selinexor and Dexamethasone Persistent G1/2 Nausea Fatigue/Asthenia Improved GI 20% Emesis/Diarrhea Thrombocytopenia Intent to Treat Analysis: all 10 pts: ORR 60%, CBR 80%

15 Selinexor and the future Trial in Quad refractory patients: Selinexor + Dex Single arm phase II for accelerated approval Combination Studies are ongoing/planned Bortezomib Pomalidomide Carfilzomib Lenalidomide Moffit: Selinexor + Pegylated Doxorubicin Preclinical rationale to novel-novel combinations BRDi + Selinexor Melphalan?

16 ARRY-520, Filanesib Kinesin Spindle Protein (KSP, eg5) is a microtubule motor protein required for mitosis and separation of spindle pole KSP inhibition prevents formation of bipolar spindle, leading to cell death (*Mol Cancer Ther : )

17 ARRAY : Phase 2 Study Design ARRY mg/m 2 q 2 weeks Cohort 1: ARRY-520 Single Agent G-CSF 2-stage, single-arm cohort (N=32) G-CSF Cohort 2: ARRY Dexamethasone Combination ARRY mg/m 2 q 2 weeks G-CSF Dexamethasone 40 mg weekly G-CSF Dexamethasone 40 mg weekly 1 st stage with 18 evaluable patients (21 treated) of 2-stage, single-arm cohort (N=48)

18 ARRY : inclusion criteria Cohort 1: Phase 2 ARRY-520 single agent 2 prior treatment regimens, including BTZ and an IMiD Disease should have progressed during or after last regimen Cohort 2: Phase 2 ARRY Dexamethasone 2 prior treatment regimens Refractory (progression during or w/in 60 days) to last regimen 2 consecutive cycles of prior treatment that included Len and BTZ Refractory to Len, BTZ, and dex (40 mg per week) Patients intolerant to Len or BTZ not included Adequate prior alkylator therapy

19 ARRY : Prior therapies ARRY-520 ARRY dex N = 32 N = 55 Median Prior Regimens 6 8 Prior Proteasome Inhibitor 29 (91%) 55 (100%) Prior BTZ 29 (91%) 55 (100%) BTZ-refractory 17 (53%) 54 (98%) Prior IMiD 32 (100%) 55 (100%) Prior Len 31 (97%) 55 (100%) Len-refractory 24 (75%) 55 (100%) Prior Corticosteroid 32 (100%) 55 (100%) Triple-Refractory (Len, BTZ, Dex) 13 (41%) 53 (96%) Prior Alkylator 32 (100%) 55 (100%) Prior Anthracycline 16 (50%) 38 (69%) Prior Transplant 26 (81%) 49 (89%)

20 1-acid glycoprotein (AAG) is a potential selection marker for filanesib Background 1-acid glycoprotein (AAG) is an acute-phase serum protein used to diagnose and monitor inflammatory disorders AAG binds to ARRY-520 Increasing [AAG] results in increased IC 50 for ARRY-520 in vitro No correlation between [AAG] and common MM prognostic markers Hypothesis: Patients with elevated serum AAG may have sub-therapeutic exposure due to lower available ARRY-520 High pre-dose [AAG] correlates with lack of ORR and shorter time on study for patients treated with ARRY-520

21 ARRY : AAG and response ARRY-520 Single Agent All Pts 1 AAG- High AAG- Low All Pts 2 ARRY dex AAG- High AAG- Low n ORR ( PR) 5 (16%) 0 (0%) 5 (24%) 8 (15%) 0 (0%) 7 (19%) CBR ( MR) 6 (19%) 0 (0%) 6 (29%) 11 (20%) 0 (0%) 10 (28%) Duration of Response (months) Time to Next Treatment (Months) OS (months)

22 ARRY : ongoing trials 1. Randomized Phase II study of Carfilzomib +/- Filanesib N=75 2. Single arm phase II Filanesib + dexamethasone registration enabling study Pts Prior Len + BZ and refractory to CFZ or Pom 3. Bortezomib- Filanesib Combination ongoing 4. Pomalidomide-Filanesib Combination

23 ABT-199, Venetoclax 1 An Increase in BCL-2 Expression Allows the Cancer Cell to Survive 2 Venetoclax Binds to and Inhibits Overexpressed BCL-2 Venetoclax 3 Apoptosis is Initiated Active Caspase Apoptosome Pro-apoptotic Proteins (BAX, BAK) Anti-apoptotic Proteins (BCL-2) BH3-only APAF-1 Cytochrome c Procaspase BAK BAX BCL-2 BCL-2 Mitochondria Mitochondria Mitochondria BH3-only family member proteins include BIM, BAD, PUMA, and NOXA

24 ABT-199 : background The anti-apoptotic protein BCL-2 is highly expressed in a subset of myeloma cells and has been implicated in mediating the survival of myeloma cells 1 Venetoclax is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor 2 Venetoclax induces cell death in multiple myeloma cell lines and primary samples in vitro Multiple myeloma cells harboring the t(11;14) chromosomal translocation have a high level of BCL-2 and low level of MCL-1, which increases sensitivity to single-agent venetoclax treatment

25 ABT-199: study design Patients > 1 prior therapy were treated on a 21-day cycle with daily venetoclax (3+3 design): Patients received prophylaxis for tumor lysis syndrome and were monitored at first dose and dose increases Patients who progressed during treatment were permitted to add dexamethasone

26 ABT-199: patient disposition Characteristics N = 29 Age, median [range] 66 [42 79] Male gender, n (%) 16 (55) White race, n (%) 24 (92) ISS stage III, n (%) a 6 (22) Cytogenetic abnormalities, n (%) a t(11;14) 11 / 27 (41) t(4;14) 2 / 26 (8) del17p 4 / 26 (15) del13q 14 / 26 (54) Prior therapies Median [range] lines of therapy 6 [1 13] Stem cell transplant, n (%) 19 (66) Bortezomib / Refractory, n (%) b 26 (90) / 15 (52) Bortezomib and lenalidomide / Refractory, n (%) b 24 (83) / 10 (34) Lenalidomide / Refractory, n (%) b 27 (93) / 12 (41) Creatinine clearance ml/min, n (%) 6 (21)

27 ABT-199: adverse events Event, n (%) N=29 AEs, any grade 29 (100) Common all-grade AEs (in 20% patients) Diarrhea 12 (41) Nausea 12 (41) Fatigue 7 (24) Asthenia 6 (21) Neutropenia 6 (21) Vomiting 6 (21) AEs, grade 3 or 4 17 (59) Common grade 3 or 4 AE (in 10% patients) Thrombocytopenia 7 (24) Neutropenia 4 (14) Anemia 3 (10) Event, n (%) N=29 Any serious AE a 10 (35) Common SAEs (in 5% patients) Cough 2 (7) Malignant neoplasm progression 2 (7) Pyrexia 2 (7) a 1 SAE of upper abdominal pain was assessed as possibly related to venetoclax 2 patients had DLTs at 600 mg: o o Upper abdominal pain Nausea with abdominal pain MTD was not reached; RPTD of 1200 mg was determined from safety and efficacy data in each cohort No patients developed tumor lysis syndrome

28 Median best percent change in M-protein Decrease of 15.6% in patients with t(11;14); increase of 10.6% in non-t(11;14) ABT-199: response Best Response, n (%) All Patients n=29 t(11;14) n=11 non-t(11;14) a n=18 Overall Response 2 (7) 2 (18) 0 Complete response 2 (7) 2 (18) 0 Partial response Minimal response 1(3) 1 (9) 0 Stable disease 15 (52) 3 (27) 12 (67) Disease progression 11 (38) 5 (46) 6 (33) Time on study 2.6 [ ] 5.1 [ ] 2.2 [ ] Time to progression 2.0 [ ] 3.9 [ ] 1.9 [ ] Duration of stable disease 2.6 [ ] 3.5 [ ] 1.3 [ ] Stable disease > 2 months, n (%) b 8/15 3/3 5/12

29 ABT-199: summary Venetoclax monotherapy was well tolerated in heavily-pretreated R/R multiple myeloma patients Preliminary efficacy data, including complete responses, are supportive of single agent activity of venetoclax in this population, particularly in t(11;14) patients Venetoclax exposure was dose proportional at almost all assessed dose levels, based on limited pharmacokinetic data Recommended phase 2 dose was achieved; the study is currently enrolling in the safety expansion cohort at 1200 mg

30 MEK inhibition in Multiple Myeloma: early clinical data Retrospective evaluation 58 refractory MM with RAS / BRAF mutations Median of 5 prior lines 22 pts received monotherapy 4/22 achieved PR Most significant AEs: Rash Diarrhea Cardiac toxicity (lower LV-function) MEK inhibition with partial responses in subsets of rmm Heuck et al., Leukemia 2015

31 Cut down the tree or trim the branches? Personalizing therapy based on rmm biology