Enasidenib Monotherapy Is Effective and Well-Tolerated in Patients with Previously Untreated Mutant- IDH2 (m IDH2) Acute Myeloid Leukemia (AML)

Abstract Background: Enasidenib (AG-221) is an oral, selective inhibitor of mIDH2 proteins. Results from the AG221-C-001 phase 1/2 dose-escalation and expansion study of enasidenib monotherapy showed an overall response rate (ORR) of 40.3% and median overall survival (OS) of 9.3 months in patients with m IDH2 relapsed or refractory (R/R) AML (Stein, Blood, 2017). Like patients with R/R AML, older patients with untreated AML who are not candidates for standard induction therapy due to advanced age, poor performance status, comorbidities, poor-risk cytogenetics, or other factors, pose a therapeutic challenge. Treatment options for these patients are limited and outcomes are poor. Reported here are clinical outcomes for older patients with previously untreated m IDH 2 AML who received enasidenib monotherapy in the AG221-C-001 study (NCT01915498). Methods: The phase 1 dose-escalation and expansion portions of the study included patients aged ≥ 60 years with previously untreated AML who were not candidates for standard treatment and had ECOG PS scores of 0-2. Patients in the dose-escalation phase received enasidenib doses of 50-650 mg/day, and all patients in the expansion phase received enasidenib 100 mg/day, in continuous 28-day treatment cycles. ORR included complete remission (CR), CR with incomplete count recovery (CRi/CRp), partial remission (PR), and morphologic leukemia-free state (MLFS), per modified IWG 2003 response criteria for AML. OS was defined as the time from first dose to death from any cause. Event-free survival (EFS) was defined as the time from first dose to relapse, progressive disease (PD), or death, whichever came first. Safety was assessed by treatment-emergent adverse event (TEAE) reporting and TEAEs were graded for severity per CTCAE version 4.0. Results: Of 239 patients in the phase 1 dose-escalation and study expansion, 37 patients (15.5%) had previously untreated m IDH2 AML. At data cutoff (14 Oct 2016), 4 patients with previously untreated AML (11%) remained on-study: 3 patients in CR, and 1 patient with stable disease at cycle 13. Median age was 77 years (range 58-87); 62% of patients were aged ≥ 75 years (Table 1). Median number of enasidenib treatment cycles was 6 (range 1-23) and median follow-up was 7.9 months (range 0.5-23.7). Seven patients (19%) attained CR, with a median time to CR of 5.6 months (range 3.4-12.9) (Table 2). ORR was 37.8% (95%CI 22.5, 55.2). The median duration of CR was not reached (NR) (95%CI 3.7, NR) and median duration of any response was 12.2 months (2.9, NR) (Table 2). Three patients proceeded to transplant; at data cutoff, all 3 patients remained in remission. Among all 37 patients, median OS was 10.4 months (95%CI 5.7, 15.1) and median EFS was 11.3 months (3.9, NR). Median OS for responding patients (n=14) was 19.8 months (95%CI 10.4, NR) and for non-responders was 5.4 months (2.8, 12.4). The most frequent TEAEs (any grade or cause) were fatigue (43%), nausea (41%), and decreased appetite (41%). The most frequent treatment-related TEAEs were hyperbilirubinemia (30%) and nausea (22%) (Table 3). The only serious treatment-related TEAEs reported for more than 1 patient were IDH differentiation syndrome (n=3, 8%) and tumor lysis syndrome (n=2, 5%). Treatment-related TEAEs led to dose modification for 3 patients (8%), dose interruption for 7 patients (19%), and treatment discontinuation for 1 patient (3%). Conclusions: Enasidenib induced hematologic responses in these older patients with previously untreated m IDH2 AML who were not candidates for standard treatment. Approximately 1 in 5 of these patients attained CR and 1 in 3 patients had a response with enasidenib monotherapy. Responses were durable: at a median of 7.9 months of follow-up, median CR duration was not reached and median duration of any response was > 1 year. Median OS and EFS were also promising (10.4 months and 11.3 months, respectively). Rates of treatment-related TEAEs were low and only 1 patient discontinued treatment due to a TEAE. These results suggest enasidenib may benefit older adults with m IDH2 AML who are not fit to receive cytotoxic chemotherapy. These encouraging findings have prompted follow-up studies of enasidenib in older patients with previously untreated m IDH2 AML, such as the Beat AML Master Trial (NCT03013998). Disclosures Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. De Botton: Servier: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Agios: Honoraria, Research Funding. DiNardo: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding. Kantarjian: Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; Novartis: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding. Collins: BMS: Research Funding; Arog: Research Funding; Agios: Research Funding; Celgene Corporation: Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Xu: Celgene Corporation: Employment, Equity Ownership. Tosolini: Celgene Corporation: Employment, Equity Ownership. Gupta: Celgene Corporation: Employment, Equity Ownership. Agresta: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Stein: Seattle Genetics: Research Funding; GSK: Other: Advisory Board, Research Funding; Constellation Pharma: Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding.

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A Phase I/II Trial of the KSP Inhibitor ARRY-520 In Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.1959.1959 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1959-1959 ◽

Cited By ~ 4

Author(s):

Jatin J Shah ◽

Jeffrey A. Zonder ◽

Adam Cohen ◽

Donna Weber ◽

Sheeba Thomas ◽

...

Keyword(s):

Multiple Myeloma ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Clinical Activity ◽

Employment Equity ◽

Heavily Pretreated ◽

Equity Ownership ◽

Ksp Inhibitor

Abstract Abstract 1959 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. Inhibition of KSP induces mitotic arrest and cell death. ARRY-520 is a potent, selective KSP inhibitor. Cancers such as multiple myeloma (MM) which depend on the short-lived survival protein MCL-1 are highly sensitive to treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of ARRY-520 administered intravenously (IV) on Day 1 and Day 2 q 2 weeks without/with granulocyte-colony stimulating factor (G-CSF). Patients (pts) with relapsed/refractory (RR) MM with 2 prior lines of therapy (including both bortezomib and an immunomodulatory agent, unless ineligible for or refusing to receive this therapy) were eligible. Cohorts of at least 3 pts were enrolled in a classical 3 + 3 dose escalation design. Pts were treated for 2 cycles (4 weeks) to evaluate safety prior to dose escalation. Results: Twenty five pts have been treated to date, with a median age of 60 years (range 44–79) and a median of 5 prior regimens (range 2–16). All pts received prior bortezomib or carfilzomib, 21 pts received prior lenalidomide, 17 pts prior thalidomide, and 18 pts had a prior stem cell transplant. Pts received ARRY-520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7, 6 evaluable). A dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose (MTD) without G-CSF. As neutropenia was the DLT, dose escalation with prophylactic G-CSF support was initiated, at doses of 1.5 mg/m2/day (n = 7, 6 evaluable), 2.0 mg/m2/day (n = 6) and 2.25 mg/m2/day (n = 2) with G-CSF. Both the 2.0 mg/m2/day and 2.25 mg/m2/day dose levels were determined to be non-tolerated, with DLTs of febrile neutropenia (FN) (2 pts at 2.0 mg/m2/day and both pts at 2.25 mg/m2/day) and Grade 3 mucositis (both pts at 2.25 mg/m2/day). One out of 6 evaluable pts at 1.5 mg/m2/day also developed a DLT of FN. In an attempt to optimize the Phase 2 dose, an intermediate dose level of 1.75 mg/m2/day with G-CSF is currently being evaluated. The most commonly reported treatment-related adverse events (AEs) include those observed with other KSP inhibitors, such as hematological AEs (thrombocytopenia, neutropenia, anemia, leukopenia), fatigue, mucositis and other gastro-intestinal AEs. Pts displayed linear PK, a low clearance and a moderate volume of distribution, with moderate-to-high inter-individual variability in PK parameters. The median terminal elimination half life is 65 hours. The preliminary efficacy signal as a single agent is encouraging with 2 partial responses (PR) observed to date per IMWG and EBMT criteria in a heavily pretreated population (23 evaluable pts). A bortezomib-refractory pt with 8 prior lines of therapy, including a tandem transplant, treated at 1 mg/m2/day of ARRY-520 obtained a PR after Cycle 6, with urine protein and kappa light chain levels continuing to decline over time. He remains on-study after 15 months of ARRY-520 treatment. A pt with 2 prior lines of therapy, including prior carfilzomib, has obtained a PR after Cycle 8 at 2 mg/m2/day of ARRY-520, and she is currently ongoing after 4.5 months on therapy. Fifteen pts had a best response of stable disease (SD), including 1 pt with a thus far unconfirmed minimal response, and 6 had progressive disease. A total of 10 pts (43%) achieved a PR or SD lasting > 12 weeks. Several additional pts have shown other evidence of clinical activity, with decrease in paraproteins, increase in hemoglobin levels and regression of plasmacytomas. The median number of cycles is 4 (range 1–28+). Treatment activity has not correlated with any baseline characteristics or disease parameters to date. Conclusions: : The selective KSP inhibitor ARRY-520 has been well tolerated, and shows promising signs of single agent clinical activity in heavily pretreated pts with RR MM. Prophylactic G-CSF has enabled higher doses to be tolerated. No cardiovascular or liver enzyme toxicity has been reported. Enrollment is ongoing at 1.75 mg/m2/day with G-CSF support, and a planned Phase 2 part of the study will be initiated as soon as the MTD is determined. Complete Phase 1 data will be disclosed at the time of the meeting. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Zonder:Millennium: Consultancy, Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Research Funding; Celgene:; Novartis:; Proteolix: . Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Kaufman:Celgene: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria; Merck: Research Funding; Genzyme: Consultancy. Walker:Array Biopharma: Employment, Equity Ownership. Freeman:Array Biopharma: Employment, Equity Ownership. Rush:Array Biopharma: Employment, Equity Ownership. Ptaszynski:Array Biopharma: Consultancy. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

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Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v124.21.1741.1741 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1741-1741 ◽

Cited By ~ 11

Author(s):

Craig H. Moskowitz ◽

Andres Forero-Torres ◽

Bijal D. Shah ◽

Ranjana Advani ◽

Paul Hamlin ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Phase 1 ◽

Objective Response ◽

Antibody Drug Conjugate ◽

Employment Equity ◽

Non Hodgkin Lymphoma ◽

Equity Ownership ◽

Grade 3

Abstract Background CD19, a B-cell specific marker, is expressed in the majority of patients with B-cell non-Hodgkin lymphoma (NHL). SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. Methods This ongoing phase 1, open-label, dose-escalation study investigates the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD19A in patients with relapsed or refractory B-cell NHL (NCT 01786135). Eligible patients are ≥12 years of age and must have a confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL), including transformed follicular histology; mantle cell lymphoma (MCL); follicular lymphoma grade 3 (FL3); Burkitt lymphoma; or B-cell lymphoblastic lymphoma. Patients must be relapsed or refractory to at least 1 prior systemic regimen. Patients with DLBCL or FL3 must have also received intensive salvage therapy with or without autologous stem cell transplant (SCT), unless they refused or were deemed ineligible. A modified continual reassessment method is used for dose allocation and maximum tolerated dose (MTD) estimation. SGN-CD19A is administered IV on Day 1 of 21-day cycles (0.5–6 mg/kg). Response is assessed with CT and PET scans according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results To date, 44 patients have been treated: 39 patients (89%) with DLBCL (including 10 with transformed DLBCL), 4 (9%) with MCL, and 1 (2%) with FL3. Median age was 65 years (range, 33–81). Patients had a median of 2 prior systemic therapies (range, 1–7), and 10 patients (23%) had autologous SCT. Twenty-six patients (59%) were refractory to their most recent prior therapy, and 18 (41%) were relapsed. Patients received a median of 3 cycles of treatment (range, 1–12) at doses from 0.5–6 mg/kg. Eleven patients (25%) remain on treatment, and 33 have discontinued treatment (18 due to progressive disease [PD], 5 for investigator decision, 5 for adverse events [AE], 4 because of patient decision/non-AE, and 1 for SCT). No dose-limiting toxicity (DLT) in Cycle 1 has been reported. Treatment-emergent AEs reported in ≥20% of patients were blurred vision (59%), dry eye (39%), fatigue (39%), constipation (32%), keratopathy (23%), and pyrexia (20%). Corneal exam findings consistent with superficial microcystic keratopathy were observed in 25 patients (57%) and were mostly Grade 1/2. Grade 3/4 corneal AEs were observed in 4 patients at the higher doses; the majority resolved or improved to Grade 1/2 at last follow-up. Corneal AEs were treated with ophthalmic steroids, and during the trial steroid eye drop prophylaxis was instituted with each dose of study drug. SGN-CD19A ADC plasma exposures were approximately dose-proportional. Accumulation was observed following multiple dose administrations, consistent with a mean terminal half-life of about 2 weeks, suggesting less frequent dosing might be possible. In the 43 efficacy-evaluable patients, the objective response rate (ORR) is 30% (95% CI [17, 46]), including 7 complete responses (CRs; 16%) and 6 partial responses (PRs; 14%). Of the 13 patients with an objective response, 8 are still on study with follow-up times of 0.1–31 weeks; 2 are no longer on study; and 3 had subsequent PD or death with response durations of 14, 19, and 31 weeks. Table Best Clinical Response by Disease Status Relative to Most Recent Therapy, n (%) Relapsed N=17 Refractory N=26 Total N=43 CR 5 (29) 2 (8) 7 (16) PR 4 (24) 2 (8) 6(14) SD 4 (24) 9 (35) 13 (30) PD 4 (24) 13 (50) 17 (40) ORR (CR + PR), (95% CI) 53 (28, 77) 15 (4, 35) 30 (17, 46) Conclusions To date, SGN-CD19A has shown evidence of clinical activity with an ORR of 30% and CR rate of 16%. Enrollment in the trial is ongoing to further refine optimal dose and schedule. SGN-CD19A is generally well-tolerated. No DLTs have been observed in tested dose levels. Observed ocular AEs are manageable with steroid eye drops and dose modifications. The high response rate (53%) in relapsed patients and low rate of bone marrow suppression or neuropathy suggest that SGN-CD19A could be incorporated into novel combination regimens in earlier lines of therapy. Disclosures Moskowitz: Merck: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use. . Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Shah:Pharmacyclics: Speakers Bureau; SWOG: Consultancy; Celgene: Consultancy, Speakers Bureau; NCCN: Consultancy; Seattle Genetics, Inc.: Research Funding; Janssen: Speakers Bureau. Advani:Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Hamlin:Seattle Genetics, Inc.: Consultancy, Research Funding. Kim:Bayer: Consultancy; Eli Lily: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding, Travel expenses Other.

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Ponatinib Efficacy and Safety in Patients with the T315I Mutation: Long-Term Follow-up of Phase 1 and Phase 2 (PACE) Trials

Blood ◽

10.1182/blood.v124.21.4552.4552 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4552-4552 ◽

Cited By ~ 7

Author(s):

Michael J. Mauro ◽

Jorge E. Cortes ◽

Andreas Hochhaus ◽

Michele Baccarani ◽

Timothy P. Hughes ◽

...

Keyword(s):

Research Funding ◽

Progressive Disease ◽

Phase 1 ◽

Efficacy And Safety ◽

Employment Equity ◽

Long Term Follow Up ◽

T315i Mutation ◽

Equity Ownership

Abstract Background: Resistance to tyrosine kinase inhibitors (TKIs) in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib is the only approved oral TKI that inhibits the T315I mutant, which is uniformly resistant to other TKIs. Here we report long-term follow-up of the efficacy and safety of ponatinib in pts with the T315I mutation at baseline from the Phase 1 (Ph1) and PACE trials. Methods: The Ph1 trial (NCT01207440) evaluated safety and anti-leukemic activity of ponatinib (2-60 mg qd) in pts with CML or Ph+ ALL (N=81); the PACE trial (NCT00660920) evaluated efficacy and safety of ponatinib (45 mg qd) in CML and Ph+ ALL pts (N=449) resistant/intolerant to dasatinib or nilotinib or with the T315I mutation. Data reported are for pts with the T315I mutation at baseline, detected by Sanger sequencing at a central lab. Results: The Ph1 and PACE trials included 19 (29%) and 128 (29%) pts with the T315I mutation, respectively. Median age and median time since diagnosis were 47 and 2.7 years for Ph1, and 53 and 3.6 years for PACE.Pts were heavily pretreated: 89% in Ph1 and 84% in PACE had received ≥2 prior TKIs. As of Jan 6, 2014, median follow-up was 42 (1-59) months in Ph1, and 20 (0.1-40) months in PACE; 58% Ph1 (92% CP-CML) and 33% PACE (52% CP-CML) pts remained on study. Most-common reasons for discontinuation: administrative decision (16%) and progressive disease (16%) for Ph1, and progressive disease (31%) and adverse events (AEs; 13%) for PACE. Of the pooled chronic phase (CP)-CML pts, 75%, 72%, and 61% achieved MCyR, CCyR, and MMR, respectively, with deeper responses (MR4, MR4.5) observed in over a third of the pts (Table). MaHR was achieved in 58%, 27% and 38% of pooled AP-CML, BP-CML and Ph+ ALL pts, respectively. For Ph 1 CP-CML pts, 3-year CCyR duration estimates were 80%. For PACE CP-CML pts, 2-year MCyR/CCyR duration, PFS and OS estimates were 93%/79%, 72% and 82%, respectively. Only 1 CP-CML pt in PACE lost MCyR and 1 transformed to AP-CML. For AP-CML, BP-CML, and Ph+ ALL, estimated OS/PFS at 2 years was 69%/54%, 14%/10%, and 10%/N/A, respectively. The most frequent treatment-emergent AEs (TEAEs) observed in Ph1 CP-CML pts were dry skin (83%), rash (83%), arthralgia (75%), fatigue (75%), headache (67%), abdominal pain (58%), hypertension (58%), hypertriglyceridemia (58%), myalgia (58%), and nausea (58%). None of the 19 serious TEAEs that occurred in Ph1 CP-CML pts occurred in >1 pt. The most common (≥25%) TEAEs in PACE CP-CML pts were rash (48%), dry skin (42%), headache (41%), abdominal pain (39%), nausea (36%), constipation (33%), fatigue (33%), thrombocytopenia (28%), myalgia (28%), hypertension (27%), arthralgia (25%), and upper respiratory tract infection (25%). Most common (≥5 %) serious TEAEs in PACE CP-CML pts were acute myocardial infarction (8%), pancreatitis (8%), atrial fibrillation (6%), coronary artery disease (6%), congestive cardiac failure (5%), pneumonia (5%), cerebral infarction (5%), pyrexia (5%), increased lipase (5%), and dyspnea (5%). Arterial thrombotic events occurred in 1 (8%) Ph1, and 20 (31%) PACE pts. Venous thromboembolic events occurred in 1 (8%) Ph1, and 3 (5%) PACE pts. Despite the higher median dose intensity for T315I CP-CML pts (38 vs 30.8 mg/day overall CP-CML) in PACE, the safety profiles were similar. For CP-CML pts in PACE, responses achieved by 12 months were generally maintained after dose reduction primarily to manage AEs: 100% maintained MCyR; 100% maintained CCyR, and 79% maintained MMR. Conclusions: In Ph+ leukemia pts with the T315I mutation, where effective treatment options are limited, ponatinib continued to exhibit deep and durable responses with up to 6 years follow-up. Dose reductions to manage AEs did not impact maintenance of cytogenetic responses. The response rates and safety profile of T315I pts were comparable to, if not better than, those observed in the overall population of refractory CML and Ph+ ALL pts in ponatinib clinical trials. Table. Responses at Any Time in Ponatinib Treated Pts with T315I Mutation Phase 1 PACE Phase 1 and PACE Pooled n (%) n (%) n (%) CP-CML N=12 N=64 N=76 MCyR 11 (92) 46 (72) 57 (75) CCyR 10 (83) 45 (70) 55 (72) MMR 9 (75) 37 (58) 46 (61) MR4 7 (58) 25 (39) 32 (42) MR4.5 4 (33) 21 (33) 25 (33) AP-CML N=1 N=18 N=19 MaHR 0 11 (61) 11 (58) BP-CML N=2 N=24 N=26 MaHR 0 7 (29) 7 (27) Ph+ ALL N=4 N=22 N=26 MaHR 2 (50) 8 (36) 10 (38) Disclosures Mauro: ARIAD Pharmaceuticals, Inc.: Consultancy. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Kantarjian:ARIAD Pharmaceuticals, Inc., Pfizer, Amgen: Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

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Long-Term Follow-up of a Phase 1 Study of Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML)

Blood ◽

10.1182/blood.v124.21.4558.4558 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4558-4558 ◽

Cited By ~ 2

Author(s):

Moshe Talpaz ◽

Jorge E. Cortes ◽

Hagop Kantarjian ◽

Neil P. Shah ◽

Dale Bixby ◽

...

Keyword(s):

Research Funding ◽

Phase 1 ◽

Dose Intensity ◽

Cytogenetic Response ◽

Molecular Response ◽

Employment Equity ◽

Duration Of Response ◽

Heavily Pretreated ◽

Equity Ownership

Abstract Background: Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) active against native and mutated forms of BCR-ABL, and is approved for patients with refractory CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia and those with the T315I mutant. Long-term follow-up of the anti-leukemic activity and safety of ponatinib in patients with CML or Ph+ ALL in this phase 1 clinical trial is reported. Methods: Patients (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose-escalation, phase 1 study (NCT00660920). Ponatinib was dosed once daily (2 mg-60 mg). Intra-patient dose escalation was permitted. The 43 patients who had CP-CML are the focus of this analysis (data as of 6 Jan 2014). Median follow-up for CP-CML patients was 42.5 (1.7-59.1) months. Results: The median age of patients was 55 years; median time since diagnosis was 6.6 years. Patients were heavily pretreated (61% received ≥3 prior TKIs; 37% received 2 prior TKIs). At baseline, 63% of patients had BCR-ABL mutations (28% with T315I). At the time of analysis, 56% of patients remained on study. Significant anti-leukemic activity was observed: major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4 (MR4) rates were 72%, 65%, 51%, and 40% respectively; 76% of patients with MCyR and 54% with MMR are estimated (Kaplan-Meier [KM]) to maintain response for at least 4 years (3-year KM estimates: 76% MCyR, 70% CCyR, 54% MMR; Figure 1). 15 patients started at a dose of 30 mg or below, and 10 of these patients (67%) achieved MCyR; all were receiving a dose of 30 mg or below at time of response (Table 1). Of 28 patients with CCyR, 22 remained on study (16 with continuous CCyR); of 22 patients with MMR, 19 remained on study (11 with continuous MMR). Adverse events (AEs, 23%) and progression (9%) were the most common reasons for discontinuation. Of the 10 patients that discontinued due to AEs, 5 were in MCyR and, of those, 1 was in MMR. The most common treatment-emergent AEs were rash (63%), fatigue (61%), abdominal pain (58%), headache (56%), and arthralgia (54%). The most common treatment-emergent AEs occurring after 1 year of therapy were fatigue (35%), hypertension (31%), and abdominal pain (30%). Treatment-emergent arterial thrombotic events (AE [SAE]) were observed in 37% [28%] of patients (composite of cardiovascular 28% [19%], cerebrovascular 9% [7%], and peripheral vascular 12% [7%] events), and venous thromboembolic AEs were observed in 5% [no SAEs] of patients. Updated data will be presented. Conclusions: With a median follow-up of 42.5 months in CP-CML patients (maximum follow-up, 59.1 months), ponatinib continues to provide benefit to heavily pretreated patients with limited treatment options. Substantial and durable responses were observed with ponatinib, and responses were observed in patients treated with doses at or below 30 mg. The most common treatment-emergent AEs occurring after one year of therapy were similar to the overall AE profile, albeit with lower incidence rates. Risk and benefit considerations should be evaluated when utilizing ponatinib in this patient population. Figure 1: Duration of Response in CP-CML Patients Figure 1:. Duration of Response in CP-CML Patients aLoss of response is defined as a single time point at which the criteria for response are not met. Table 1: Ponatinib Response Rate for CP-CML Patients by Dose Starting Dose MCyR MMR N (%) Dose intensity*, Median (min, max) N (%) Dose intensity*, Median (min, max) 4 mg, N=3 2 (67) 3.7 (3.5, 3.9) 1 (33) 14.3 (14.3, 14.3) 15 mg, N=7 5 (71) 14.8 (14.7, 23.7) 4 (57) 15.0 (14.7, 36.6) 30 mg, N=5 3 (60) 27.4 (10.6, 29.6) 1 (20) 29.9 (29.9, 29.9) ≤30 mg, N=15 10 (67) 14.8 (3.5, 29.6) 6 (40) 15.0 (14.3, 36.6) 45 mg, N=14 13 (93) 44.5 (23.4, 45.0) 11 (79) 43.5 (16.6, 45.0) 60 mg, N=14 8 (57) 42.6 (14.2, 59.3) 5 (36) 56.5 (14.7, 59.5) *Dose intensity (mg/day) until time of response for responders only Disclosures Talpaz: ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Cortes:ARIAD Pharmaceuticals, Inc., BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Shah:ARIAD, BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Hu:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Turner:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Druker:BMS: Research Funding; ARIAD Pharmaceuticals, Inc.: PI and co-investigator on clinical trials, PI and co-investigator on clinical trials Other; MolecularMD: Consultancy, Equity Ownership. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Mauro:ARIAD Pharmaceuticals, Inc.: Consultancy.

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Resolution of Sickle Cell Disease Manifestations in Patients Treated with Lentiglobin Gene Therapy: Updated Results from the Phase 1/2 Hgb-206 Group C Study

Blood ◽

10.1182/blood-2019-128894 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 990-990 ◽

Cited By ~ 5

Author(s):

Julie Kanter ◽

John F. Tisdale ◽

Markus Y. Mapara ◽

Janet L. Kwiatkowski ◽

Lakshmanan Krishnamurti ◽

...

Keyword(s):

Gene Therapy ◽

Research Funding ◽

Phase 1 ◽

Globin Gene ◽

Post Treatment ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background β-globin gene transfer into hematopoietic stem cells (HSCs) could reduce or eliminate sickle cell disease (SCD)-related manifestations. LentiGlobin for SCD gene therapy contains autologous CD34+ cells transduced with the BB305 lentiviral vector (LVV), encoding a human β-globin gene with the anti-sickling T87Q mutation (βA-T87Q). The safety and efficacy of LentiGlobin for SCD is being evaluated in the ongoing Phase 1/2 HGB-206 Study (NCT02140554). The initial 7 patients (Group A) were treated with LentiGlobin made from bone marrow harvested HSCs. The protocol was modified to improve HbAT87Q production by including pre-harvest red blood cell (RBC) transfusions, increasing the total busulfan exposure, and using a refined LentiGlobin manufacturing process (Group B, n=2). An additional modification was made for Group C patients where HSC collection by plerixafor mobilization followed by apheresis was instituted. Data from these Group C patients are discussed here. Results from patients in Groups A and B are reported separately. Methods Patients (≥ 18 years) with severe SCD (including those with recurrent vaso-occlusive crisis [VOC] and acute chest syndrome [ACS]) were screened for eligibility. Patients received 240 µg/kg of plerixafor 4-6 hours prior to HSC collection via apheresis. CD34+ cells were transduced with BB305 LVV. Patients underwent myeloablative busulfan conditioning and subsequent LentiGlobin drug product (DP) infusion. Patients were monitored for adverse events (AEs), engraftment, vector copy number (VCN), total hemoglobin (Hb) and HbAT87Q expression, hemolysis markers, and SCD clinical manifestations. Data are presented as median (min-max). Results: As of 7 March 2019, 19 Group C patients, aged 26 (18-36) years, had initiated mobilization/apheresis and 13 patients were treated with LentiGlobin for SCD gene therapy. Median DP VCN, % transduced cells, and CD34+ cell dose in the 13 treated patients were: 3.8 (2.8-5.6) copies/diploid genome (c/dg), 80 (71-88) %, and 4.5 (3.0-8.0) x 106 CD34+ cells/kg, respectively. The median follow-up was 9.0 (1.0-15.2) months. Twelve patients achieved neutrophil and platelet engraftments at a median of 19 (15-24) days and 28 (19-136) days, respectively. As of the data cut-off, engraftment was not yet evaluable in 1 patient at 1-month post-infusion. All patients stopped red blood cell (RBC) transfusions within about 3 months post-LentiGlobin gene therapy. Median total hemoglobin (Hb) and Hb fractions in patients at various time points are shown in Figure 1. Median HbS levels were at or below 50% in all patients with at least 6 months follow-up. The median total Hb at last visit in 8 patients with at least 6 months of follow-up, was 11.5 (10.2-15.0) g/dL, with a corresponding HbAT87Q median contribution of 5.3 (4.5-8.8) g/dL and a median HbS 5.7 (4.8-8.0) g/dL. Of these 8 patients, 6 had a history of VOCs or ACS. The median annualized VOC+ACS rate in these patients was 5.3 (3-14) pre-treatment and decreased to 0 (0-2) post-treatment. One Grade 2 VOC was observed 3.5 months post-treatment. No ACS or serious VOCs were observed in Group C patients' post- treatment. Lactate dehydrogenase, reticulocyte count, and total bilirubin at last visit post-LentiGlobin infusion were 225.0 (130.0-337.0) U/L, 150.0 (42.1-283.0) 109/L, 22.2 (3.42-39.3) µmol/L, respectively, trending towards normalization. The most common non-hematologic Grade ≥ 3 AEs were febrile neutropenia (n=10) and stomatitis (n=7) post-DP infusion. Serious AEs were reported in 6 patients post-LentiGlobin treatment, most common being nausea and vomiting. To date, there have been no DP-related AEs or graft failure, vector-mediated replication competent lentivirus detected, or clonal dominance reported. Longer follow-up and additional patient data will be presented. Summary The safety profile of LentiGlobin gene therapy for SCD remains consistent with single-agent busulfan conditioning and underlying disease. Patients in HGB-206 Group C experienced high-level, sustained expression of gene-therapy derived hemoglobin, with median HbS levels reduced to ~50% and median total Hb levels of 11.5 g/dL at 6 months. The cessation of clinical complications (no ACS or serious VOCs) and decreased hemolysis suggest a strong therapeutic effect after LentiGlobin gene therapy in patients with SCD. Disclosures Kanter: Peerview: Honoraria; NHLBI: Membership on an entity's Board of Directors or advisory committees; Rockpointe: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Imara: Consultancy; Jeffries: Consultancy; Modus: Consultancy; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; bluebird bio, Inc: Consultancy; Medscape: Honoraria; Sangamo: Consultancy. Kwiatkowski:Terumo: Research Funding; Novartis: Research Funding; Apopharma: Research Funding; Imara: Consultancy; Celgene: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy. Schmidt:German Cancer Research Center, Heidelberg, Germany: Employment; GeneWerk GmbH, Heidelberg, Gemrany: Equity Ownership. Miller:bluebird bio, Inc.: Employment, Equity Ownership. Pierciey:bluebird bio, Inc.: Employment, Equity Ownership. Huang:bluebird bio, Inc.: Employment, Equity Ownership. Ribeil:bluebird bio, Inc.: Employment, Equity Ownership. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Walters:AllCells, Inc: Consultancy; TruCode: Consultancy; Editas Medicine: Consultancy.

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A Phase I/II Study of AZD2811 Nanoparticles (NP) As Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory AML/MDS Patients Not Eligible for Intensive Induction Therapy

Blood ◽

10.1182/blood-2019-130635 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3919-3919

Author(s):

William B. Donnellan ◽

Ehab L. Atallah ◽

Adam S. Asch ◽

Manish R. Patel ◽

Jay Yang ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Slow Release ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Naïve ◽

Equity Ownership ◽

Refractory Aml

Background: Aurora kinases (AurK) represent potential targets for anticancer therapy in hematological malignancies and solid tumors. AurK B inhibitor AZD1152 (barasertib) showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of AurKB, when given as 2-4hr IV on days 1 and 4, offers a prolonged drug exposure in vivo, mimicking the AZD1152 7-day continuous IV infusion. This is an update on the first-in-man dose-escalation study of AZD2811NP in pts with relapsed/refractory AML/MDS or treatment-naïve patients (pts) not eligible for intensive induction therapy (NCT03217838). The primary objectives are to determine the Maximum Tolerated Dose (MTD) and safety profile of AZD2811NP monotherapy and in combination with azacitidine. The secondary objectives are to evaluate the pharmacokinetic (PK) profile, Biologically Effective Dose (BED), and preliminary efficacy (CR, CRi, PR, 6 month OS). Methods: Pts received a 2-hour IV infusion on Day 1 and 4 of each 28-day cycle (Cy) for doses up to 600mg, extending to a 4 h IV infusion for dosages > 600 mg. In the ongoing dose escalation, 3-6 pts have been sequentially enrolled in cohorts ranging from 100 mg to 800 mg per infusion (Day 1 & 4), i.e. from 200 mg to 1,600 mg per cycle in monotherapy setting, according to a modified continuous reassessment method (mCRM) dose escalation design. AZD2811NP was also combined with azacitidine (75 mg day 1 to 7 or the 5-2-2 schedule) starting at an AZD2811NP dose of 400 mg D1 and D4 every 4 weeks. Study treatment was continued until disease progression, intolerability, or when discontinuation criteria were met. Results: Currently, 30 pts have enrolled of which 29 pts (12 females and 17 males) received study treatment in 5 monotherapy cohorts and 2 azacitidine combination cohorts, with ages ranging from 53 to 85 years. Nineteen pts had relapsed/refractory AML, 9 pts had MDS and 1pt had MDS/MPN. Monotherapy cohort 5 (800 mg D1 & D4) and combination cohort 4c (600mg D1 & D4 + Azacitidine) are currently enrolling. Of the 19 pts in monotherapy cohorts 1-5, 18 pts discontinued (due to consent withdrawal [2], early disease related deaths [2], other reason [1], or completed follow up [13; 11 pts after Cy1, 2 pts after Cy2]) and 1 pt is still on therapy. Nine pts were treated in combination with azacitidine, and of these, 3 pts are still on therapy and 6 pts have discontinued AZD2811NP (due to death [1], consent withdrawal [2], or completed follow up [3; 2 pts after Cy2, 1 pt after Cy4]). Adverse events that occurred in ≥ 20% of pts were mainly myelotoxicity, nausea and fatigue. One dose-limiting toxicity (DLT) has been observed in the monotherapy arm (esophageal infection) and one DLT in the combination setting (late neutropenia recovery). Two deaths were due to the underlying disease and 1 due to a serious adverse event of Gr 5 sepsis not related to study drug. AZD2811 total and released blood PK exposure appears broadly dose proportional with a terminal t1/2 of ~ 30-50 hours. Released blood PK exposure is ~ 1% of total PK exposure. Conclusion: AZD2811NP is documented to be well tolerated at doses up to 600 mg on Day 1 & 4 every 28 days in monotherapy setting and up to 400 mg (D1 & 4) in combination with azacitidine. The monotherapy and combination therapy dose escalations are ongoing. Updated results including preliminary efficacy data will be presented. Additional dose finding and expansion cohorts of AZD2811NP in combination with venetoclax are planned. Disclosures Atallah: Pfizer: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy. Yang:AstraZeneca: Research Funding; Agios: Consultancy. Eghtedar:Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Verastem Oncology: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Borthakur:Merck: Research Funding; Oncoceutics: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Eisai: Research Funding; Novartis: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding. Charlton:AstraZeneca: Employment; GSK: Equity Ownership. MacDonald:AstraZeneca: Employment, Equity Ownership. Korzeniowska:AstraZeneca: Employment. Sainsbury:AstraZeneca: Employment, Equity Ownership. Strickland:Sarah Cannon Development Innovations: Employment. Overend:AstraZeneca: Employment, Equity Ownership. Adelman:AstraZeneca: Employment, Equity Ownership. Fabbri:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Smith:AstraZeneca: Employment, Equity Ownership. Pease:AstraZeneca: Employment, Equity Ownership. Cosaert:AstraZeneca: Employment. OffLabel Disclosure: AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of Aurora Kinase B (AurKB), is an investigational agent in clinical trials for human cancers including AML/MDS.

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AG-636 for the Treatment of Adults with Advanced Lymphoma: Initiation of a Phase 1 Clinical Study

Blood ◽

10.1182/blood-2019-123420 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1286-1286

Author(s):

Scott F. Huntington ◽

Avyakta Kallam ◽

Frank G. Basile ◽

Danielle Ulanet ◽

Huansheng Xu ◽

...

Keyword(s):

T Cell ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Hematologic Malignancies ◽

Employment Equity ◽

Expansion Phase ◽

Bayer Corporation ◽

Equity Ownership

Background: Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme involved in the de novo synthesis of pyrimidines, key building blocks for RNA and DNA biosynthesis. Inhibitors of DHODH are currently in clinical use for the treatment of rheumatoid arthritis (leflunomide) and multiple sclerosis (teriflunomide). Brequinar, a more specific and potent DHODH inhibitor, was evaluated in several phase 1 trials in patients with advanced solid tumors in the 1990s and demonstrated little evidence of antitumor activity; however, patients with hematologic malignancies were not evaluated in those studies. More recent preclinical studies show that cell lines and in vivo models derived from hematologic malignancies are highly sensitive to inhibition of DHODH. AG-636, a novel small molecule DHODH inhibitor, demonstrated strong in vitro and in vivo anti-tumor activity across diverse models of lymphoma and acute leukemia, supporting the evaluation of AG-636 as a treatment for patients with lymphoma and other hematologic malignancies. A phase 1, multicenter, open-label study investigating AG-636 for the treatment of patients with advanced lymphoma began enrollment on May 24, 2019 (NCT03834584). Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of AG-636 and to characterize its dose-limiting toxicities (DLTs) when given to patients with advanced lymphoma. The study includes a dose escalation phase followed by an expansion phase. Approximately 54 adults (42 in the dose escalation phase and 12 in the expansion phase) with advanced lymphoma refractory to standard treatment, will be enrolled at up to 6 centers in the United States. Broad inclusion criteria enable patients with Hodgkin, Diffuse Large B-Cell (DLBCL), Follicular, Peripheral T-Cell, Cutaneous T-Cell, Mantle Cell, and less common subtypes of lymphoma as defined in 2017 by the World Health Organization to enroll. There are no limits on the number of prior lines of therapy and patients may have received prior stem cell transplant or chimeric antigen receptor T-cell therapy. Patients with active central nervous system disease are excluded. Patients must have an Eastern Cooperative Oncology Group performance status ≤2, an absolute neutrophil count ≥1.0×109/L, a platelet count ≥75×109/L, a serum total bilirubin level ≤1.5×upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase levels ≤3.0×ULN, and a creatinine clearance ≥30 mL/min (Cockcroft-Gault formula). AG-636 is given as an oral capsule once daily for 2-5 days each week, with 1 cycle of therapy defined as 4 consecutive weeks of treatment. During the dose escalation phase of the study, successive cohorts of patients will be treated with increasing doses of AG-636 to estimate the MTD. The study employs a 2-parameter adaptive Bayesian logistic regression model using escalation with overdose control to guide dose escalation and to estimate the MTD. The MTD is the highest dose that is unlikely (<25% posterior probability) to cause DLTs in ≥ 33% of participants in their first cycle of treatment. Secondary objectives include the safety and tolerability of AG-636, its pharmacokinetics and pharmacodynamics (via measurement of plasma dihydroorotate concentrations), and characterization of any anti-lymphoma activity that may be associated with AG-636 treatment. The dose-expansion phase of the study will treat approximately 12 additional patients at the MTD in order to better characterize the safety, pharmacokinetics, and pharmacodynamics of the dose that may be suggested for future studies. Further expansion may be undertaken if AG-636 shows high activity in specific subtypes of lymphoma, either in the clinic or in preclinical models. The experience in this study with the pharmacokinetics, pharmacodynamics, and safety of AG-636 will inform the optimal starting dose and regimen for evaluation in subsequent studies. Disclosures Huntington: Celgene: Consultancy, Research Funding; Pharmacyclics: Honoraria; DTRM Biopharm: Research Funding; Genentech: Consultancy; Bayer: Consultancy, Honoraria; AbbVie: Consultancy. Basile:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Ulanet:Agios: Employment, Equity Ownership. Xu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yin:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mobilia:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Cooper:Agios: Employment, Equity Ownership. Shah:AstraZeneca: Honoraria; Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria. Leonard:Merck: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy; Gilead: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; Sutro Biopharma: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; Epizyme, Inc: Consultancy; AstraZeneca: Consultancy; Merck: Consultancy; AstraZeneca: Consultancy. von Keudell:Bayer: Consultancy; Genentech: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Bayer: Consultancy. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria.

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JCARH125, Anti-BCMA CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase 1/2 Multicenter Study (EVOLVE)

Blood ◽

10.1182/blood-2018-99-113548 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 957-957 ◽

Cited By ~ 48

Author(s):

Sham Mailankody ◽

Myo Htut ◽

Kelvin P. Lee ◽

William Bensinger ◽

Todd Devries ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Car T Cells ◽

Car T ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: B-cell maturation antigen (BCMA) is expressed on malignant plasma cells and is an attractive therapeutic target for multiple myeloma. BCMA CAR T-cells, antibody drug conjugates and bispecific T-cell engagers have demonstrated substantial preclinical and clinical activity to date. JCARH125 is a BCMA-targeting CAR T product containing a lentiviral CAR construct with a fully human scFv, optimized spacer, 4-1BB co-stimulatory and CD3z activation domains. The construct has shown minimal tonic signaling and lack of inhibition by soluble BCMA. JCARH125 is generated using a manufacturing process developed to optimize various aspects, including increased consistency of cell health, in the drug product. Methods: EVOLVE (NCT03430011) is a multi-center, phase 1/2 trial of JCARH125 in patients with relapsed and/or refractory multiple myeloma, who have received 3 or more prior regimens, which must include autologous stem cell transplant, a proteasome inhibitor, immunomodulatory drug and an anti-CD38 monoclonal antibody, unless not a candidate (i.e. contraindicated) to receive one or more of the above treatments. Lymphodepleting chemotherapy (LDC) consisting of 3 days of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) is given 2 to 7 days prior to JCARH125 infusion. A single dose of JCARH125 is given on day 1. Dose escalation is determined using the modified toxicity probability interval 2 (mTPI-2). A minimum of 3 patients are evaluated at each dose level (DL). The first 2 DLs evaluated were 50 and 150x 106 CAR+ T cells. Additional DLs are planned, followed by an expansion at the recommended phase 2 dose (RP2D). The primary objectives of the phase 1 portion are safety and identifying a RP2D. Results: At the time of the July 12, 2018 data analysis, 19 patients have been enrolled (i.e. apheresed) and 13 patients dosed with JCARH125. Only one patient was unable to receive JCARH125, due to sepsis after LDC, leading to death before JCARH125 administration. Eight patients were evaluable for safety (≥ 1 mo follow-up). (n = 5 DL1; n = 3 DL2). Three patients (all from DL1) were evaluable for confirmed response (≥ 2 mo follow-up) per International Myeloma Working Group (IMWG) criteria. Data reported here are from these initial 8 patients. Median follow-up is 5 weeks (range 4 - 13 weeks). Median age is 53 years (range 36 - 66) with a median time from diagnosis of 4 years (range 2 - 12). Patients had received a median of 10 prior regimens (range 4 - 15). Of these 8 patients, 4 (50%) were refractory (no response or progression within 60 days of last therapy) to bortezomib, carfilzomib, lenalidomide, pomalidomide and an anti-CD38 monoclonal antibody. Seven of 8 (88%) had prior autologous stem cell transplant and 4 of 8 (50%) have IMWG high risk cytogenetics. As of the data cut, no DLTs have been observed at the first 2 DLs. Cytokine release syndrome (CRS), all grade 1 or 2, was observed in 6 of 8 (75%) patients. Median onset of CRS was 9 days (range 4 - 10) with a median duration of 4.5 days (range 2 - 19 days). None of the patients with grade 2 CRS required vasopressor support and only 1 patient received tocilizumab. No patients had grade ≥ 3 CRS. Three of 8 (38%) patients experienced neurologic adverse events (AE). Two patients had grade 1 events, and 1 had a grade 3 event (lethargy), which resolved within 24 hours after receiving steroids. Onset of neurologic AEs was 9,11 and 12 days with a duration of 2, 3 and 1 days respectively. Notably, the patient who experienced grade 3 neurotoxicity (NT), developed secondary plasma cell leukemia (PCL) just prior to receiving LDC. All 8 patients have evidence of objective response (≥ MR), including the patient with secondary PCL. 3 patients, all treated at DL1 (50 x 106 CAR+ T-cells), have confirmed responses (1 PR, 2 sCR) with the remainder unconfirmed (1 CR, 2 VGPR, 1 PR, 1 MR). As of the data cut, no patients have progressed. Additional clinical and translational data on at least 30 patients and additional follow up of at least 4 months will be available at time of presentation. Conclusion: At initial lower dose levels, JCARH125 showed an acceptable safety profile with no DLTs reported thus far. Incidence of grade ≥ 3 NT was low and no grade ≥ 3 CRS has occurred with clear clinical activity. Although durability of response and response rate in a greater number of patients remain to be determined, early experience with JCARH125 support a favorable risk-benefit profile and rapid clinical development. Disclosures Mailankody: Takeda: Research Funding; Janssen: Research Funding; Physician Education Resource: Honoraria; Juno: Research Funding. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Devries:Junot Therapeutics: Employment. Piasecki:Juno Therapeutics: Employment, Equity Ownership; Cascadian Therapeutics: Patents & Royalties; Amgen: Patents & Royalties. Ziyad:Juno Therapeutics: Employment, Equity Ownership. Blake:Celgene: Employment, Equity Ownership. Byon:Juno Therapeutics: Employment, Equity Ownership. Jakubowiak:Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria.

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Ivosidenib (AG-120) Induced Durable Remissions and Transfusion Independence in Patients with IDH1-Mutant Relapsed or Refractory Myelodysplastic Syndrome: Results from a Phase 1 Dose Escalation and Expansion Study

Blood ◽

10.1182/blood-2018-99-111264 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1812-1812 ◽

Cited By ~ 10

Author(s):

Courtney D. DiNardo ◽

Justin M. Watts ◽

Eytan M. Stein ◽

Stephane de Botton ◽

Amir T. Fathi ◽

...

Keyword(s):

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Hematologic Malignancies ◽

Advisory Board ◽

Employment Equity ◽

Transfusion Independence ◽

Starting Dose ◽

Equity Ownership ◽

Advisory Role

Abstract BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

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TNB383B.0001: A Multicenter, Phase 1, Open-Label, Dose-Escalation Andexpansion Study of TNB-383B, a Bispecific Antibodytargeting BCMA in Subjects with Relapsed or Refractorymultiple Myeloma

Blood ◽

10.1182/blood-2019-123220 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1874-1874 ◽

Cited By ~ 2

Author(s):

Ben Buelow ◽

Anita D'Souza ◽

Cesar Rodriguez ◽

Ravi Vij ◽

Rajneesh Nath ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

T Cells ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Open Label ◽

Employment Equity ◽

High Affinity ◽

Equity Ownership

Introduction Multiple myeloma (MM) is an incurable plasma cell malignancy with an estimated incidence in 2019 of ~32,000 in the United States. Although median survival is greater than 8 years, treatment options are limited for patients who relapse on or are refractory to standard treatment regimens containing proteasome inhibitors, immune-modulating drugs and anti-CD38 antibodies (triple refractory). Novel therapies are critical to the treatment of these patients. Chimeric antigen receptor T cells (CAR-Ts) and T-cell redirecting Bispecific Antibodies (T-BsAbs) targeting B-cell maturation antigen (BCMA) -a protein found exclusively on the surface of plasma cells- have shown efficacy against relapsed/refractory MM in early phase clinical trials. However, toxicity from over-activation of T-cells still hinders these approaches. Utilizing Teneobio's proprietary next generation sequencing (NGS)-based discovery tool incorporating in silico analysis of heavy chain only/fixed light chain antibody sequences (HCA/Flic, respectively) to enrich for antigen specific antibodies, we made a high affinity αBCMA HCA and a library of αCD3 Flic antibodies that showed a >2 log range of EC50s for T cell activation in vitro. TNB-383B combines a high affinity αBCMA HCA with a low-activating αCD3 Flic; in preclinical studies TNB-383B showed equivalent anti-tumor efficacy but significantly reduced cytokine secretion compared to BCMA-targeted T-BsAbs incorporating a strongly-activating αCD3 (similar in strength to the αCD3s used in other T-BsAbs currently in clinical trials). A Phase 1 study investigating the safety, pharmacokinetics, and preliminary activity of TNB-383B in patients with relapsed/refractory multiple myeloma (RRMM) is ongoing and described. This trial represents, to the best of our knowledge, the first reported clinical trial of a HCA/Flic hybrid antibody in humans. Study Design TNB383B.0001 (NCT03933735) is an open-label, multi-center study of TNB-383B in patients with RRMM. The study is divided into escalation (Arm A, N=24) and expansion (Arm B, N=48) arms. Subjects who have received 3 or more prior lines of therapy with exposure to a PI, an IMiD, and an anti-CD38 antibody are eligible for this study. Documentation of BCMA expression by tumor cells is not required for entry, although prior treatment with a BCMA-targeted agent is an exclusion criterion. Other key inclusion/exclusion criteria include EGFR of >30ml/min, ANC ≥1000/mm3 and platelets ≥50,000/mm3 and minimal bone marrow biopsy requirements on-study. Subjects must be admitted for 48 hours following the 1st dose in Cycle 1 (21-day cycle length), but TNB-383B may be administered on an outpatient basis thereafter. Dose Escalation TNB-383B is administered as an intravenous infusion. Dose escalation is proceeding via a 3+3 design with fixed (as opposed to weight based) doses per protocol. Arm B will be initiated once the maximum tolerated dose (MTD, or recommended phase 2 dose, RP2D) has been selected. Patients will be treated until progression, unacceptable toxicity, or other discontinuation criteria are met. One patient has been enrolled thus far. Statistical Methods and Study Endpoints In Arm A occurrence of dose limiting toxicities (DLTs) will drive identification of the MTD (or RP2D in line with standard practices. In Arm B accrual will be suspended if more than 33% of subjects experience a DLT event. Adverse events, laboratory profiles, physical exams, and vital signs will be assessed throughout the study. Adverse events will be graded according to the NCI CTCAE, version 5.0. Concentrations of TNB-383B and Anti-Drug Antibodies (ADA) will be determined at designated time points throughout the study. Values for standard pharmacokinetic parameters of TNB-383B including the maximum observed serum concentration (Cmax), the time to Cmax, area under the concentration-time curve, clearance, and terminal half-life will be determined using non-compartmental methods. The activity endpoints (determined using the IMWG uniform response criteria) include overall response rate, progression-free survival and overall survival. The relationship between biomarkers, including soluble BCMA and A Proliferation Inducing Ligand (APRIL; the endogenous ligand for BCMA), and activity will be assessed. Disclosures Buelow: Teneobio, Inc.: Employment, Equity Ownership. Rodriguez:Takeda, Amgen: Consultancy, Speakers Bureau. Vij:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Genentech: Honoraria; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria; Sanofi: Honoraria. Nath:Teneobio, Inc.: Consultancy. Snyder:Teneobio, Inc.: Consultancy. Pham:Teneobio, Inc.: Employment, Equity Ownership. Patel:Teneobio, Inc.: Employment, Equity Ownership. Iyer:Teneobio, Inc.: Employment, Equity Ownership.

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