Oki, Yasuhiro

SummaryFimepinostat (CUDC‐907), a first‐in‐class oral small‐molecule inhibitor of histone deacetylase and phosphatidylinositol 3‐kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high‐grade B‐cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/orMYCgene rearrangement/copy number gain (MYC‐altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end‐point of overall response (OR) rate for patients with MYC‐IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC‐altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC‐altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three‐protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC‐altered R/R DLBCL/HGBL treated with single‐agent fimepinostat. Combination therapies and/or biomarker‐based patient selection strategies may lead to higher response rates in future clinical trials.

Abstract Background: The prognosis of patients with PTCL remains poor after standard CHOP therapy - the most commonly used combination regimen. Relapses occur in the majority of patients, and curability rates of the relapsed disease are very low. Hence, advances in front-line therapy of PTCL are long overdue. Pralatrexate, a second-generation antifolate, demonstrated a single agent activity in patients with relapsed and refractory PTCL with a response rate of 27%, including complete remissions in 11% of patients (O'Connor et al. J Clin Onc 2011). We conducted a Phase 1 multi-center dose-escalation study of pralatrexate in combination with standard CHOP (Fol-CHOP) in treatment-naïve PTCL patients. Objectives: The primary objective of the study was to determine the maximum tolerated dose (MTD) of pralatrexate when administered with a standard CHOP regimen to patients with newly diagnosed PTCL. The secondary objectives included safety, tolerability, efficacy and pharmacokinetics of pralatrexate in combination with CHOP (Fol-CHOP). Methods: In Part 1 of this 3+3 dose-escalation study, pralatrexate was administered at 10, 15, 20, 25, or 30 mg/m2 as an IV push on days 1 and 8 of a standard 21-day CHOP regimen (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1 and oral prednisone 100 mg on days 1-5). In Part 2 of the study patients were treated at the MTD of pralatrexate established in Part 1, with standard CHOP. In both parts of the study patients were treated with up to 6 cycles of therapy, or until toxicity or disease progression. Patients received antimicrobial prophylaxis, myeloid growth factor support, and "leucovorin rescue" throughout 6 cycles of therapy. Dose-limiting toxicities (DLT) were considered during the 1st cycle of Fol-CHOP and included: Grade 4 infections, treatment-related non-hematological toxicity ≥Grade 3, platelet count < 25 X 109/L at any time, or ANC < 0.5 X 109/L for >7 days despite G-CSF administration. Responses were assessed by the investigator per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: A total of 31 patients have been enrolled (19 in Part 1; 12 in Part 2). MTD was not reached and pralatrexate dose of 30 mg/m2 in combination with CHOP was selected for Part 2 of the study as predefined by the protocol. The majority of patients were male, White, with the median age of 66 yrs (range, 18-78) at the time of enrolment. PTCL diagnoses included: anaplastic large cell lymphoma, anaplastic lymphomakinase-negative (ALCL, ALK-, n=5), peripheral T-cell lymphoma, not-otherwise specified (PTCL-NOS, n=18), and angioimmunoblastic T-cell lymphoma (AITL, n=5). Fol-CHOP was generally well tolerated with median RDI of 98%. Common (≥ 30%) adverse events (AEs) of any grade were fatigue (n=23), constipation (n=20), nausea (n=16), mucositis (n=14), diarrhea (n=12), anemia (n=9), vomiting (n=10) and oral pain (n=10). Most common (≥ 10%) AEs ≥ grade 3 were anemia (n=6), fatigue (n=4) and neutrophil count decreas (n=5). The only Grade >3 treatment-related AEs (≥10%) was neutrophil count decrease (n=4). SAEs were observed in 13 patients, treatment related SAEs were anemia, febrile neutropenia, dehydration, mucositis and nausea. Five patients withdrew from study: 2 due to disease progression, 1 due to AE and 2 due lapse >28 days between doses. In the 27 patients avaluable for response, the investigator assessed objective response (OR) and complete response (CR) rates were 89% wand 67%, respectively. Conclusions: The combination of pralatrexate and CHOP was well tolerated in treatment-naive PTCL patients. MTD of pralatrexate was not reached, and the protocol-defined maximum dose of 30 mg/m2 on days 1 and 8 of a 21-day CHOP cycle was recomended for future studies. The observed OR and CR rates warrant further evaluation of this regimen in newly diagnosed PTCL patients. Disclosures Shustov: Celgene: Other: Publication assistance; Spectrum Pharmaceuticals: Consultancy, Research Funding. Bhat: Spectrum Pharmaceuticals: Employment. Reddy: Spectrum Pharmaceuticals: Employment.

Abstract Background Survival rates for older pts with advanced HL (aged ≥60 yrs) were historically poor with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Reasons may include decreased tolerance of therapy, increased toxicity (particularly with bleomycin), comorbidities, and disease biology. The pivotal phase 3 ECHELON-1 study demonstrated superior 2-yr modified progression-free survival (mPFS) with frontline brentuximab vedotin + doxorubicin, vinblastine and dacarbazine (A+AVD) vs ABVD in pts with stage III/IV cHL (Connors JM et al, NEJM 2018). The study allowed entry of older pts, with no upper age limit. Alternative dosing schedules of the A+AVD regimen have been studied (e.g., sequential brentuximab vedotin before and after AVD; NCT01476410, Evens AM et al, J Clin Oncol 2018). We report efficacy and safety results from ECHELON-1 for older pts with cHL and compare these with those for pts aged <60 yrs. Methods mPFS per independent review facility (IRF) for pts ≥60 years was a prespecified subgroup analysis of ECHELON-1. Additional exploratory safety and efficacy analyses were also assessed and compared with younger pts (<60 yrs). The study was not powered for age-based subgroup analyses; p-values are descriptive without multiplicity adjustment. Results 14% (186/1334) of pts in the intent-to-treat (ITT) population were aged ≥60 yrs (A+AVD, n=84; ABVD, n=102) and included in the sub analyses. Median age (range) of older pts was: A+AVD, 68.0 yrs (60-82); ABVD, 66.0 yrs (60-83). Baseline pt and disease characteristics in older pts were similar in both arms. ECOG PS scores were 0 (36% vs 36%), 1 (52% vs 54%), and 2 (12% vs 10%) in A+AVD and ABVD arms, respectively. Pts received a median of 6 cycles with mean relative dose intensities for each drug (%) in older pts of: A+AVD, 92.3, 96.6, 93.3, and 97.9; ABVD, 97.3, 88.7, 93.3, and 95.9. With median follow-up of ~25 months, 2-yr mPFS per IRF was similar in both arms for older ITT pts (A+AVD 70.3% [95% CI: 58.4, 79.4] vs ABVD 71.4% [95% CI: 60.5, 79.8]; HR=1.00 [95% CI: 0.58, 1.72]; p=0.993). An exploratory analysis of standard PFS per investigator (INV) showed HR=0.85 ([95% CI: 0.49, 1.48]; p=0.576) (Table 1). For older pts with stage IV cHL (A+AVD n=51; ABVD n=67), there was an increase in 2-yr PFS per INV with A+AVD vs ABVD (74.0% [95% CI: 59.5, 84.0] vs 59.9% [95% CI: 45.6, 71.5]; HR, 0.66 [95% CI: 0.34, 1.26]; p=0.20); mPFS per IRF improvement with A+AVD in older stage IV pts was lower (HR=0.80; [95% CI: 0.42, 1.53]). In younger stage III/IV pts (<60 yrs) 2-yr mPFS per IRF and PFS per INV were also higher compared with older pts in both arms (Table 1). 66 of 83 older A+AVD pts required ≥1 dose modification of brentuximab vedotin, reasons were: dose reduction (n=27), dose held (n=4), dose delayed (n=51), brentuximab vedotin discontinued (n=17). In older pts, grade (G) 3/4 AEs occurred in 88% of A+AVD pts vs 80% ABVD pts; for younger pts, rates were 82% (A+AVD) vs 63% (ABVD) (Table 2). In older pts there were 3 (4%) on-study deaths in the A+AVD arm (1 each: hemophagocytosis, neutropenic sepsis, and myocardial infarction) and 5 (5%) with ABVD (all pulmonary-related). In pts <60 yrs, there were 6 on-study deaths (1%) with A+AVD vs 8 (1%) with ABVD. G3 neutropenia in older pts was (70%) A+AVD pts vs (59%) ABVD pts, and febrile neutropenia (FN) in 31 (37%) vs 17 (17%) pts. In older pts who had G-CSF primary prophylaxis (PP) neutropenia was seen in 4/10 (40%) A+AVD pts vs 1/9 (11%) ABVD pts (on-study FN in 3 [30%] vs 2 [22%] pts). In older pts, treatment-emergent peripheral neuropathy (PN) was reported in 54 (65%) of A+AVD pts vs 42 (43%) of ABVD pts (G≥3 in 15 [18%] vs 3 [3%] pts), respectively. In pts <60 yrs PN was reported in 388 (67%) A+AVD pts vs 244 (43%) ABVD pts (G≥3 in 55 [9%] vs 8 [1%] pts), respectively. In older pts at last follow-up, 65% (35/54) of A+AVD pts and 60% (25/42) of ABVD pts had complete resolution (A+AVD, 39%; ABVD, 38%) or improvement (A+AVD, 26%; ABVD, 21%) of PN events. 2% older A+AVD pts had pulmonary AEs (both G1/2 pulmonary infiltration) vs 13% older ABVD pts. Conclusions For older ECHELON-1 pts, mPFS and PFS were similar in both arms. In the larger subgroup of younger pts, mPFS and PFS were improved vs older pts. As expected, incidence of treatment-emergent AEs was higher in older pts, with regimen-specific AEs seen, including fatal pulmonary events in ABVD pts. The high incidence of FN in older A+AVD pts points to the need for G-CSF PP. Disclosures Evens: Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Tesaro: Research Funding; Novartis: Consultancy. Connors:Merck: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Roche Canada: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Seattle Genetics: Honoraria, Research Funding; Janssen: Research Funding; F Hoffmann-La Roche: Research Funding; Bayer Healthcare: Research Funding; Cephalon: Research Funding; Bristol Myers-Squibb: Research Funding; Lilly: Research Funding; Genentech: Research Funding. Younes:Sanofi: Honoraria; Merck: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria; Incyte: Honoraria; Seattle Genetics: Honoraria; Bayer: Honoraria; Novartis: Research Funding; Curis: Research Funding; J&J: Research Funding; Genentech: Research Funding; Takeda: Honoraria; Roche: Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; BMS: Honoraria, Research Funding. Ansell:Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding. Radford:Takeda: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding; Celgene: Research Funding; BMS: Consultancy, Speakers Bureau. Feldman:Seattle Genetics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Celgene: Speakers Bureau; Portola: Research Funding; KITE: Speakers Bureau. Tuscano:Takeda: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Oki:Seattle Genetics: Research Funding; Takeda Millenium: Honoraria, Research Funding; Jazz Pharmaceuticals: Employment. Grigg:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pocock:Kent & Canterbury Hospital: Employment. Dlugosz-Danecka:Roche: Consultancy; Servier: Consultancy. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Engley:Seattle Genetics: Employment. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Miao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jolin:Takeda Pharmaceuticals International Co.: Employment. Gautam:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gallamini:Takeda: Consultancy, Speakers Bureau.

Abstract Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis and repeated recurrence for most subtypes. Currently, anthracycline-based therapies such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like therapies are recommended as the first-line treatment for PTCL, but the prognosis remains poor with most patients relapsing within 5 years. Thus, improved treatment strategies are still needed. Belinostat is a potent, pan-histone deacetylase inhibitor that was recently approved in the United States for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 BELIEF study (O'Connor et al, JCO, 2015) of belinostat in R/R PTCL, which demonstrated durable clinical benefit (objective response rate [ORR] 25.8%) and tolerability. Since belinostat (Bel) and each of the components of the CHOP regimen target different aspects of the cell cycle with different mechanisms of action, there is potential for a synergistic effect of a Bel-CHOP combination treatment regimen for patients with PTCL. Methods: Patients with PTCL received CHOP in association with 1000 mg/m2 of belinostat on various schedules, repeated every 21-days for up to 6 cycles. The cohort schema followed a traditional "3+3" dose escalation design. The objective of Part A of the study was to determine the Maximum Tolerated Dose (MTD) of the Bel-CHOP combination. Once the MTD was determined, at least 10 more patients were to be treated in the Expansion Phase (Part B). Belinostat was to be administered as a 1000 mg/m2 IV infusion once daily for up to 5 days, depending on the assigned cohort (Fig 1). The starting cohort was Cohort 3 (CHOP + 1000 mg/m2 of daily belinostat on Days 1-3). Patients received primary prophylaxis with growth factor (G-CSF) support. Dose-limiting toxicities (DLT) were considered during the 1st cycle and included: non-hematological toxicity Grades 3-4, platelet count &lt; 25 X 109/L at any time or ANC &lt; 0.5 X 109/L lasting more than 7 days despite G-CSF administration. The primary endpoint of the study was the determination of the MTD of the Bel-CHOP combination. Secondary endpoints included safety, tolerability and ORR (complete response [CR] + partial response [PR]) and pharmacokinetics. Results: A total of 23 patients were enrolled in the study, 11 of which were treated in Part A. One patient in Part A was deemed inevaluable because the patient died due to disease progression before completing Cycle 1. The MTD was determined to be 1000 mg/m2 on Days 1-5 (Cohort 5); 12 more patients were then treated at this dose level (Part B). The only DLT experienced in the study was in Cohort 3 (Grade 3 Nausea and Vomiting). At the time of this abstract, 18/23 patients (78%) have completed all 6 cycles of Bel-CHOP, with 87% completing at least 4 cycles. Ten patients (43%) had at least one serious adverse event (SAE) and 18 (78%) had at least one Grade 3 or 4 adverse event (AE). The most frequent Grade 3/4 AEs were hematological in nature: neutrophil count decreased (26%), anemia (22%), neutropenia (17%) and white blood cell count decreased (17%). The ORR for the18 patients that have completed an End of Study Visit is 89% (16/18), with the vast majority achieving a CR [72% (n=13)], and 17% (n=3) a PR. Progressive disease was reported in 2 patients. Conclusions: These results demonstrate that the combination of belinostat with CHOP (Bel-CHOP) is well tolerated, with all components of CHOP and belinostat being given at their standard therapeutic doses. The rates of AEs were consistent with those typically reported with CHOP alone, and clinical activity was demonstrated with a response rate of 89% based on 18 evaluable patients. Thus, Bel-CHOP is a promising new regimen in PTCL that will be further tested in a Phase 3 randomized trial. Table. Table. Figure 1. Summary of Demographic and Baseline Characteristics AITL= angioimmunoblastic T-cell lymphoma; ALCL =anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; NOS = not otherwise specified Figure 1. Summary of Demographic and Baseline Characteristics. / AITL= angioimmunoblastic T-cell lymphoma; ALCL =anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; NOS = not otherwise specified Disclosures Barta: Seattle Genetics: Research Funding. Bhat:Spectrum Pharmaceuticals, Inc: Employment. Song:Spectrum Pharmaceutical, Inc: Employment. Choi:Apectrum Pharmaceuticals, Inc: Employment. Allen:Spectrum Pharmaceuticals, Inc: Employment. Foss:Spectrum Pharmaceuticals; Celgene: Seattle Genetics: Infinity; Millenium: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Abstract Background: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell and natural-killer-cell aggressive non-Hodgkin lymphomas associated with poor prognosis with current therapies. Numerous studies have reported poor survival for PTCL patients with a median Overall Survival (OS) shorter than 2 years and 5-year survival rates of <30%. Traditionally, patients with PTCL have been treated with a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like first-line chemotherapeutic regimen. Unfortunately, the prognosis remains poor with most patients relapsing within 2 years. Thus, improved front line treatment strategies are needed. Pralatrexate (Folotyn) is a folate analogue metabolic inhibitor that was the first drug approved in the US for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 PROPEL study (O'Connor et al, JCO, 2011) of pralatrexate in R/R PTCL, in which pralatrexate monotherapy demonstrated a durable clinical benefit (objective response rate of 29%). Pralatrexate is administered intravenously (IV) at a dose of 30 mg/m2 weekly for 6 weeks of a 7-week treatment cycle. Since pralatrexate and each of the components of the CHOP regimen target different aspects of tumor cell growth and proliferation, there is a potential for synergistic anti-tumor effect, and limited additive toxicities. Objectives: The primary endpoint of the study is the determination of the MTD of pralatrexate in combination with CHOP (Fol-CHOP) in previously untreated PTCL patients. Secondary endpoints included safety, tolerability and ORR (complete response [CR] + partial response [PR]) and pharmacokinetics. Methods: In this study, patients with PTCL received CHOP in combination with pralatrexate, repeated every 3-weeks for up to 6 cycles. Part 1 of the study was to determine the Maximum Tolerated Dose (MTD) of the Fol-CHOP combination. Once the MTD was determined, an additional 10 patients were treated in the Expansion Phase (Part 2). The cohort schema followed a traditional "3+3" design. Pralatrexate was to be administered as 10, 15, 20, 25, or 30 mg/m2 IV push over 3 to 5 minutes on Days 1 and 8 of each cycle. The starting cohort was CHOP + 10 mg/m2 of pralatrexate. Patients received prophylaxis with acyclovir and sulfamethoxazole/trimethoprim during the study and primary prophylaxis with growth factor (filgrastim or pegfilgrastim) support. Dose-limiting toxicities (DLT) were considered during the 1st cycle and included: Severe infections, study treatment-related non-hematological toxicity Grade 3-4, platelet count < 25 X 109/L at any time or ANC < 0.5 X 109/L lasting more than 7 days despite G-CSF administration. Results: A total of 12 patients have been enrolled in Part 1 of the study at the time of abstract submission. Nine patients have completed Cycle 1 and no DLT was reported. Among these nine patients, three patients each were treated at CHOP + 10 mg/m2, 15 mg/m2 and 20 mg/m2 of pralatrexate. One patient (11%) treated with CHOP + 10 mg/m2 had one serious adverse event (SAE) of febrile neutropenia that was deemed unrelated to any study drug. Only four Grade 3 AEs (anemia, constipation, mucosal inflammation, and nausea) were reported, in one patient (11%). The enrollment into the study continues. Conclusions: These interim results demonstrate that the combination of pralatrexate with CHOP (Fol-CHOP) is well tolerated, with all components of CHOP as well as pralatrexate being given at close to or at standard doses. The rates of AEs are comparable to those typically reported with CHOP alone. The study is ongoing to confirm the MTD and to assess preliminary efficacy of the Fol-CHOP combination. Updated results will be presented at the meeting. Disclosures Oki: Novartis: Research Funding. Barta:Celgene, Merck, Seattle Genetics: Research Funding; Janssen: Honoraria, Speakers Bureau. Sharma:Spectrum Pharmaceuticals: Employment. Song:Spectrum Pharmaceuticals: Employment. Mourya:Spectrum Pharmaceuticals: Employment.