Objective Responses Achieved in Patients with MYC-Altered Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Treated with the Dual PI3K and HDAC Inhibitor CUDC-907

#1555 DJ Landsburg ,
1 R Ramchandren ,
2 Y Oki ,
3 JM Pagel ,
4 PJ Lugtenburg ,
5 RB Gharavi ,
6 A Ma ,
6 A Hafeez ,
6 SK Barta 7
1 AbramsonCancer Center, Philadelphia, PA; 22Karmanos Cancer Institute, Wayne State University, Detroit, MI; 3Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas
ASH MD Anderson Cancer Center, Houston, TX; 4Swedish Cancer Institute, Seattle, WA; 5Erasmus MC Cancer Institute, Department of Hematology, Rotterdam, Netherlands on behalf of the Lunenburg
Dec 9, 2017 Lymphoma Phase I/II Consortium – HOVON /LLPC; 6Curis, Lexington, MA; 7Fox Chase Cancer Center, Philadelphia, PA

Introduction Phase 2 - Safety Results • Swimmer plot of MYC-altered by IHC patients best response and duration on treatment (days) is
provided below.
• The prognosis for patients with relapsed and/or refractory (RR) MYC-altered diffuse large B-cell • A summary of the most frequently reported treatment-emergent AEs (>13%) is provided below.
lymphoma (DLBCL) is dismal as they are often ineligible for or progress following autologous stem cell Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Total
transplantation and respond poorly to subsequent therapies (Blood. 2012 May 17;119(20):4619-24. AE Term transplant
n (%)
and Haematologica. 2013 Oct;98(10):1554-62; J Clin Oncol. 2017 Jan;35(1):24-31; Cancer. 2017 Nov Diarrhea 22 (32) 13 (19) 12 (18) 0 0 47 (69)
15;123(22):4411-4418). Nausea 23 (34) 9 (13) 0 0 0 32 (47)
• CUDC-907, a first-in-class oral dual inhibitor of HDAC (class I and II) and PI3K (class Iα, β, and δ) Thrombocytopenia 5 (7) 5 (7) 14 (21) 3 (4) 0 27 (40)
enzymes, has demonstrated downregulation of MYC mRNA and protein levels in MYC-altered DLBCL Hypokalemia 8 (12) 4 (6) 8 (12) 0 0 20 (29)
cell lines, as well as anti-tumor activity in multiple MYC-driven animal cancer models (Mol Cancer Fatigue 14 (21) 5 (7) 0 0 0 19 (28)
Ther. 2017 Feb;16(2):285-299). CR (n=4)
Anorexia 11 (16) 7 (10) 0 0 0 18 (27)
• In a Phase 1 study, objective responses were reported in a number of patients with MYC-altered RR Vomiting 15 (22) 2 (3) 1 (2) 0 0 18 (27) PR (n=3)
DLBCL treated with CUDC-907 (Haematologica. 2017 Nov;102(11):1923-1930). This Phase 2 study is Hypomagnesemia 12 (18) 2 (3) 1 (2) 0 0 15 (22) SD (n=5)
designed to further explore the efficacy of CUDC-907 in this population of high unmet need Neutropenia 1 (2) 0 9 (13) 3 (4) 0 13 (19) PD (n=25)
(NCT02674750).
Fever 11 (16) 1 (2) 0 0 0 12 (18) NE (n=9)
Phase 2 - Patients and Methods Anemia 2 (3) 3 (4) 6 (9) 0 0 11 (16)
Constipation 7 (10) 4 (6) 0 0 0 11 (16)
• Up to 200 RR DLBCL patients may be enrolled to enrich for a total of 100 patients with confirmed • The most frequently reported Grade ≥3 treatment-related AEs were thrombocytopenia (23.5%),
MYC-altered disease by central immunohistochemistry (IHC) testing. Following central testing, diarrhea (14.7%), neutropenia (13.2%), and hypokalemia (6.3%). In total, 31 (46%) patients reported
patients are placed into one of the following 3 groups for analysis: 0 50 100 150 200 250 300 350 400 450
serious adverse events (SAEs), of which 5 were considered treatment-related: diarrhea (3),
• MYC-altered by IHC (≥40% MYC expression) hypomagnesemia, and CMV viremia.
• Non-MYC-altered by IHC (<40% MYC expression) • Four patients (6%) discontinued treatment due to AEs; (Grade 5 worsening of lymphoma [2], Grade 5
Combined Phase 1 and 2 Analysis
• MYC status unknown/undetermined • When including the 37 DLBCL (14 MYC-altered) patients from the Phase 1 study (Haematologica.
Guillain-Barre Syndrome, and Grade 2 vomiting [related]).
• Key eligibility criteria include confirmed diagnosis of DLBCL (including high grade B-cell lymphoma 2017 Nov;102(11):1923-1930) in a combined analysis of MYC status per study definition, the
with MYC and BCL2 and/or BCL6 rearrangements per 2016 WHO classifications), confirmed
Phase 2 - Efficacy Results following table, DOR, PFS, and overall survival (OS) plots (all times in months) are provided below.
availability of viable biopsy tissue (fresh or archival) for central testing, ECOG score ≤1, 2-4 prior lines • The objective response rates (ORR) in each Group and overall are summarized below by the
of therapy for DLBCL, and ineligible for/failed prior autologous stem cell transplantation. Evaluable and Intent-to-Treat (ITT) population definitions. The median duration of response (DOR) ORR Median Median Median
• The primary endpoint is to assess the objective response rate (ORR) in MYC-altered patients by IHC. and progression-free survival (PFS) times (months) are also provided. Total
Group Evaluable ITT DOR PFS OS
The response-evaluable population in this analysis was defined as any patient who received at least ORR Responses
Median Median Population Population (95% CI) (95% CI) (95% CI)
one dose of CUDC-907 and had a post-baseline disease assessment
Group Total Responses Evaluable ITT DOR PFS
14 29% 23% 13.6 1.4 7
Parameters Study Population (n=68) Population population (95% CI) (95% CI) MYC-altered
(8 CR, 6 PR) (14/48) (14/60) (2.1, NC) (1.2, 2.1) (3.0, NC)
Male, n (%) 40 (59)
MYC-altered by IHC 7 (4 CR, 3 PR) 19% (7/37) 15% (7/46) NC (0.8, NC) 1.4 (1.1, 2.7) 3 18% 14% 8.8 1.4 6.3
Caucasian, n (%) 59 (87) Non-MYC-altered
Non-MYC-altered by IHC 1 (1PR) 10% (1/10) 7% (1/14) NC (NC, NC) 1.4 (1.1, 1.6) (1 CR, 2PR) (3/17) (3/22) (3.3, 14.3) (1.3, 2.7) (3.3, NC)
Age, median years (range) 64 (33-93)
2 13% 9% 10.8 1.3 5.7
Histology, n (%) MYC status unknown 0 0% (0/5) 0% (0/8) N/A 1.35 (0.6, 4.7) MYC unknown
(2 PR) (2/16) (2/23) (1.4, 20.2) (1.0, 2.3) (3.4, 14.4)
Transformed follicular lymphoma 14 (21)
All 8 (4 CR, 4 PR) 15% (8/52) 12% (8/68) NC (0.8, NC) 1.4 (1.3, 1.4) 19 24% 18% 13.6 1.4 6.3
De novo DLBCL 54 (79) All
CI: confidence interval; NC: not calculable/reached (9 CR, 10 PR) (19/81) (19/105) (1.4, 20.2) (1.3, 1.5) (3.9, 14.2)
MYC status
MYC-altered by IHC 46 (68) • Among the 7 Group 1 responders, all were triple-expressors (overexpression of MYC, BCL2, and
BCL6), including both ongoing CRs. Further, 2 of the CRs (including 1 ongoing) were also double-hit
Non-MYC-altered by IHC 14 (21) patients (MYC and BCL2 rearrangements). The table below summarizes the prior therapies and MYC,
MYC status unknown 8 (12) BCL2, and BCL6 status by both FISH (translocation [TL] and copy number gain [CN]) and IHC for all
Stage , n (%) responders.
I-II 10 (21) Prior therapies Prior MYC BCL2 BCL6 DOR
Response
III-IV 56 (82) (Best response) SCT? status status status (months)
CR TL-, CN-
Unknown 2 (3) 1. R-CHOP (CR), 2. R-ICE (SD), 3.R-lenalidomide (PR) No 11.8+
IHC+ (40%) IHC+ (100%) IHC+ (50%)
Screening ECOG PS, n (%) TL+, CN- TL+, CN- TL-, CN-
CR 1. R-EPOCH (PD)
0 28 (41) No 7.7+
2. R + dexamethasone + cytarabine + cisplatin (PD) IHC+ (90%) IHC+ (100%) IHC+ (100%)
1 34 (50) TL-, CN- TL-^ TL-^
CR 1. R-CHOP (CR), 2.R-DICE + HDT + ASCT (CR) Yes 3.7*
2 6 (9) IHC+ (65%) IHC+ (100%) IHC+ (100%)
^ ^

No. of previous treatments, median (range) 2 (2-4) 1. R-CHOP + MTX + cytarabine (CR) TL+, CN+ TL+^, CN-^ TL-^, CN-^
CR No 2.8
Prior stem cell transplant, n (%) 11 (16)
2. R-ICE (PD) IHC+ (95%) IHC+ (100%) IHC+ (75%)
^

1. R-CHOP + MTX + etoposide (PD) TL+^ TL+^ TL-^

Autologous 10 (15) PR 2. R + methylprednisolone + etoposide + cytarabine + No IHC+ (70%) IHC+^ 8.0+
IHC+^
Allogenic 2 (3) cisplatin (PD) Conclusions
1. R-CHOP (CR), 2. R-ICE (SD), 3. R-lenalidomide (SD), TL-, CN- TL-, CN+ TL+, CN-
PR No 2.1 • The Phase 2 results further support the hypothesis from the Phase 1 study that CUDC-907 treatment
4. GemOx (NE) IHC+ (95%) IHC+ (70%) IHC+ (80%)
particularly benefits patients with MYC-altered disease.
TL-, CN- TL-, CN-
Curis, Inc. PR 1. R-EPOCH (CR), 2.GemOx + obinotuzumab (PD) No 0.8 • CUDC-907 treatment has demonstrated durable clinical activity in primarily MYC-altered patients, including
IHC+ (80%) IHC+ (70%) IHC+ (30%)
4 Maguire Road double-hit and double-expressors.
TL-, CN- TL+^ TL-^
Lexington, MA PR 1. R-CHOP (CR), 2. R-ICE + HDT + ASCT (CR) Yes 1.1+ • The biological rationale, tolerable safety profile, and evidence of lasting anti-tumor activity support the
IHC- (12%) IHC+ (90%) IHC- (5%)
02421 *patient discontinued treatment after 7 cycles to pursue SCT; + indicates ongoing; ^denotes per local testing when central results not continued development of CUDC-907 in this population of high unmet need.
available; HDT: high dose therapy; ASCT: autologous stem-cell transplant