Magnetismm-3: An Open-Label, Multicenter, Non-Randomized Phase 2 Study of Elranatamab (PF-06863135) in Patients with Relapsed or Refractory Multiple Myeloma

Abstract Background: Multiple myeloma (MM) is a hematological B-cell malignancy that remains incurable for most patients. Almost all patients, including those who initially respond to treatment, are expected to relapse and subsequently cycle through multiple lines of treatment. The addition of proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies has improved patient outcomes; however, survival of patients after these agents is very poor and highlights an unmet medical need in the relapsed/refractory MM population. Elranatamab (PF-06863135) is a humanized bi-specific antibody that targets both BCMA-expressing MM cells and CD3-expressing T cells, with binding resulting in T-cell mediated cytotoxicity. Elranatamab preclinical studies have demonstrated anti-tumor activity and delayed tumor progression. A Phase 1 study, MagnetisMM-1 (ClinicalTrials.gov ID: NCT03269136), with the aim of characterizing the efficacy, safety, pharmacokinetics, and pharmacodynamics of elranatamab as single agent and in combination with immunomodulatory agents for patients with relapsed/refractory MM is ongoing. Study Design and Methods: MagnetisMM-3 is an open-label, multicenter, non-randomized, Phase 2 study to evaluate the efficacy and safety of elranatamab monotherapy in patients with relapsed/refractory MM who are refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody (ClinicalTrials.gov ID: NCT04649359). Approximately 150 patients will be enrolled to one of two independent parallel cohorts: those naïve to BCMA-directed therapies (Cohort A) and those with previous exposure to BCMA-directed therapy (Cohort B). The primary endpoint is objective response rate, according to International Myeloma Working Group [IMWG] response criteria. Secondary endpoints include duration of response, cumulative complete response (CR) rate, duration of cumulative CR, progression-free survival, time to response, minimal residual disease negativity rate, overall survival, safety, plasma concentrations, and immunogenicity of elranatamab. Key inclusion criteria are age ≥18 years, MM diagnosis according to IMWG criteria and with measurable disease based on IMWG criteria as defined by at least 1 of the following: Serum M-protein ≥0.5 g/dL by SPEP, Urinary M-protein excretion ≥200 mg/24 hours by UPEP; Serum immunoglobulin free light chain ≥10 mg/dL (≥100 mg/L) and abnormal serum immunoglobulin kappa to lambda free light chain ratio (<0.26 or >1.65). Eligible patients should also have ECOG performance status ≤2, be refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody and be relapsed/refractory to their last treatment regimen. Key exclusion criteria are smoldering MM, active plasma cell leukemia, amyloidosis, POEMS syndrome, active, uncontrolled bacterial, fungal or viral infections, stem cell transplant within 12 weeks of enrollment, any other active malignancy within 3 years prior to enrollment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ), or having received previous administration of an investigational drug within 30 days or 5 half-lives (whichever is longer) of the first dose of elranatamab. This study is, or is planned to be, open at centers in the USA, Australia, Canada, Belgium, France, Germany, Japan, Poland, Spain, and the UK. Disclosures Lesokhin: Genetech: Research Funding; Serametrix, Inc: Patents & Royalties; pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding. Iida: Ono: Honoraria, Research Funding; Glaxo SmithKlein: Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Research Funding; Amgen: Research Funding. Ma: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Sullivan: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Raab: Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees.

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A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2021-147335 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3675-3675

Author(s):

David M Ross ◽

Alejandro Arbelaez ◽

Lynette C.Y. Chee ◽

Chun Yew Fong ◽

Devendra Hiwase ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Phase 2 ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Maximum Increase ◽

Phase 2 Study ◽

Dose Levels

Abstract Background: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias, including anemia and thrombocytopenia. KER-050, a modified activin receptor type IIA inhibitor, is designed to target transforming growth factor-β ligands, including activin A. In preclinical studies, KER-050 promoted the maturation of progenitors across the full spectrum of erythropoiesis and thrombopoiesis and elicited bone anabolic effects. In a Phase 1 study in healthy participants, KER-050 treatment resulted in robust and sustained increases in reticulocytes (RETs), hemoglobin (HGB), and platelets. Increases in the bone formation marker bone specific alkaline phosphatase were also observed. Here we report results of an ongoing Phase 2 study to evaluate whether KER-050 provides therapeutic benefit in MDS patients with anemia. Aims: Evaluate safety, tolerability, pharmacodynamics and efficacy of ascending doses of KER-050 in participants with MDS in an open-label, 2-part Phase 2 study. Methods: IPSS-R very low-to-intermediate risk MDS patients (both RS+ and non-RS) with anemia (HGB <10g/dL or requiring RBC transfusions) are enrolled. In Part 1, ascending dose cohorts receive KER-050 subcutaneously every 4 weeks for 4 doses starting at 0.75mg/kg until a recommended Part 2 dose is determined. Part 2 dose expansion will begin following Part 1, with treatment extended to 2 years. Safety endpoints include incidence of adverse events (AEs); erythroid efficacy endpoints (≥8 weeks duration) include rates of transfusion independence (TI) in transfused participants, reduction in RBC transfusions by ≥4 units or ≥50% reduction in high transfusion burden participants (HTB) and HGB increase ≥1.5g/dL in non-transfused (NT) and low transfusion burden (LTB) participants. Results are reported for efficacy-evaluable participants in cohorts 1 and 2 of Part 1 dose escalation, defined as having ≥8 weeks of HGB and transfusion data. Results: At data cut-off (July 10, 2021) with median follow-up of 140 days (range 1 to 169 days), 17 participants had received ≥1 dose of KER-050 across 3 dose levels: 0.75 mg/kg, 1.5 mg/kg and 2.5 mg/kg. Baseline characteristics are described in Table 1. No related serious AEs, dose-limiting toxicities, or dose modifications were reported. One participant developed grade 2 maculopapular rash after the first dose which was considered treatment related, resolved and did not recur with subsequent doses. No other related AEs were reported. Two discontinued study drug prior to end of treatment: 1 due to participant decision, 1 due to death unrelated to study drug. None developed high risk MDS or AML. In 10 efficacy-evaluable participants, overall erythroid response rate was 60% (n=6/10). 33% (n=1/3) NT participants had a HGB increase of ≥1.5g/dL sustained ≥ 8 weeks. 5 of 7 transfused participants (71%) (n=1/2 LTB and n=4/5 HTB; n=2/3 non-RS and n=3/4 RS+) had erythroid responses sustained ≥8 weeks (range 8-20 weeks, ongoing) and 57% (n=4/7) achieved TI (Figure 1, Panel A). Maximum increase from baseline in RETs observed in transfused responders (TR) (n=5) was 24.6 x10 9/L (mean), range 10.5- 41.6 x10 9/L from day 1-29 with increases in RETs seen after each dose (Panel B). Maximum reduction in serum ferritin in TR was 40.4% (mean), range 10-66%, and maximum increase in soluble transferrin receptor (sTfR) was 52.8% (mean), range 29.8-116.4%. Increases in platelets were observed in TR (Panel C). Mean baseline platelet count for TR was 234 x10 9/L (range 104-401 x10 9/L), and maximum increase from baseline was 130 x10 9/L (mean), range 32-235 x10 9/L. No participants required dose reduction due to thrombocytosis. Summary: Erythroid responses have been observed in RS+ and non-RS MDS patients including reduction in transfusion burden at the initial dose levels. Observed increases in RETs and sTfR and observed decreases in ferritin suggest that KER-050 treatment is potentially associated with increased erythropoiesis. Increases in platelets have been observed in TR. These data support the potential of KER-050 as a treatment for multilineage cytopenias in MDS by potentially targeting multiple stages of hematopoiesis. As of data cut-off, KER-050 has been well tolerated. Dose escalation is ongoing in this Phase 2 study of anemic patients with MDS; data from planned cohorts from Part 1 will be presented. Part 2 dose expansion phase is expected to initiate prior to the meeting. Figure 1 Figure 1. Disclosures Ross: Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Keros Therapeutics: Consultancy, Honoraria. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fong: AbbVie: Consultancy; Amgen: Consultancy; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Phizer: Consultancy; Novotech: Honoraria; Specialised Therapeutics: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Wight: Jannsen: Honoraria, Other: Travel subsidies; Abbvie: Honoraria, Other: Travel subsidies. Rovaldi: Keros Therapeutics: Current equity holder in publicly-traded company. Furutani: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gaggi: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jiang: Keros Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Natarajan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ordonez: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

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PTG-300 Eliminates the Need for Therapeutic Phlebotomy in Both Low and High-Risk Polycythemia Vera Patients

Blood ◽

10.1182/blood-2020-137285 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-35 ◽

Cited By ~ 2

Author(s):

Marina Kremyanskaya ◽

Yelena Ginzburg ◽

Andrew T. Kuykendall ◽

Abdulraheem Yacoub ◽

Jay Yang ◽

...

Keyword(s):

High Risk ◽

Iron Deficiency ◽

Board Of Directors ◽

Research Funding ◽

Dose Finding ◽

Phase 2 ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Phase 2 Trial

Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels <45% in an effort to reduce the incidence of thrombotic events [Marchioli NEJM 2013]. Since, they are seen periodically, PV patients likely spend significant time with hematocrit levels >45%, thereby potentially increasing their risk of thrombosis. Symptomatic iron deficiency represents a challenge in PV as it is commonly present at diagnosis [Ginzburg Leukemia 2018] and worsens after repeated and/or frequent TP, and often symptomatic from their iron deficiency. We hypothesized that both iron deficiency and expanded erythropoiesis in PV lead to suppression of hepcidin, the body's main negative regulator of iron metabolism, and that hepcidin suppression enhances iron absorption and availability for enhanced erythropoiesis in TP-requiring PV patients. We previously demonstrated that PTG-300, a hepcidin-mimetic, caused dose-related anemia in preclinical studies. In a phase 2 trial in β-thalassemia, PTG-300 leads to a sustained (3-7 days) decrease in serum iron and transferrin saturation (TSAT) but did not demonstrate off-target effects. The current study aims to compare the iron status and phlebotomy requirements in high TP-requiring PV patients before and during treatment with PTG-300 (Figure 1). Methods. PTG-300-04 is a 3-part Phase 2 trial consisting of (1) a 28-week dose-finding; (2) a 12-week blinded randomized withdrawal (1:1) PTG-300 vs placebo; and (3) a 52-week open label extension (Figure 1). Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and ≥3 phlebotomies with or without concurrent cytoreductive therapy to maintain hematocrit ≤45% in the 24 weeks prior to enrollment. PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly were adjusted to maintain hematocrit <45%. Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. After instruction, each of the patients self-administered the drug at home. Eight subjects have been treated for ≥3 months with PTG-300 (Figure 2a). Three subjects have been randomized. During the open label dose finding portion of the study, all subjects were phlebotomy-free with the exception of one subject. Three subjects completed part 1 (28 weeks) with no TP as compared to 3-5 TP required in a similar period prior to study initiation. During the 28-week dose-finding period, the hematocrit was continuously controlled below 45% in all but two subjects' (Figure 2b). Two subjects had hematocrits transiently >45% but remained below 45% after phlebotomy in one and dose increase in both. Furthermore, erythrocyte numbers decreased (Figure 2c) and MCV increased in all but two subjects. These findings suggest a redistribution of iron within erythropoiesis. Lastly, prior to treatment, mean iron-related parameters were consistent with systemic iron deficiency while serum ferritin increased progressively toward normal range. Most frequent adverse events were injection site reaction (ISR) reported by three patients. Most of the reactions were grade 1-2 and were transient in nature and no patient discontinued the drug. Conclusions. The current results indicate that PTG-300 is an effective agent for the treatment of PV, reversing iron deficiency and eliminating the need for TP in PV patients. Elimination of TP requirements for 7 months in TP-dependent PV patients is significant and unexpected. The effect of PTG-300 on PV-related symptoms is also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. PTG-300 looks very promising in eliminating the therapeutic phlebotomies in both low and high-risk patients. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Dynavax: Current equity holder in publicly-traded company. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Jannsen: Research Funding; Protagonist: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Verstovsek:PharmaEssentia: Research Funding; Blueprint Medicines Corp: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding. Hoffman:Forbius: Consultancy; Dompe: Research Funding; Protagonist: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Randomized Phase 2 Study of Subcutaneous Daratumumab Plus Carfilzomib/Dexamethasone Versus Carfilzomib/Dexamethasone Alone in Patients with Multiple Myeloma Who Have Been Previously Treated with Intravenous Daratumumab to Evaluate Retreatment (LYNX)

Blood ◽

10.1182/blood-2019-123486 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1831-1831

Author(s):

Nizar Bahlis ◽

Jeffrey A. Zonder ◽

Susan Wroblewski ◽

Ming Qi ◽

Thomas Renaud ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Phase 2 Study ◽

Equity Ownership ◽

Randomized Phase 2

Background: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. The intravenous (IV) formulation of daratumumab is approved in many countries for use as monotherapy in relapsed/refractory multiple myeloma (RRMM), and in combination with standard-of-care regimens in RRMM and patients with NDMM who are transplant ineligible. A subcutaneous (SC) formulation of daratumumab is currently under investigation in several ongoing studies. In the phase 3 COLUMBA study, daratumumab SC was shown to be non-inferior to daratumumab IV, demonstrating similar efficacy and pharmacokinetics, with a significantly decreased rate of infusion-related reactions and reduced administration time. The randomized phase 2 LYNX (MMY2065) study will evaluate the efficacy and safety of retreatment with subcutaneous daratumumab in patients with RRMM who were previously exposed to daratumumab IV therapy. Study Design and Methods: In this ongoing, multicenter, open-label, randomized phase 2 study, approximately 230 patients with prior exposure to daratumumab will be randomized 1:1 to receive daratumumab plus carfilzomib and dexamethasone (D-Kd) or carfilzomib and dexamethasone (Kd) alone. Patients must have received 1 to 2 prior lines of therapy (at least one of which included daratumumab IV) with the daratumumab-based therapy completed ≥3 months prior to randomization. Eligible patients must have achieved a partial response or better (as defined by International Myeloma Working Group [IMWG] criteria) to daratumumab-based therapy, with a duration of response of ≥4 months. Patients must not have discontinued daratumumab due to a daratumumab-related adverse event or received prior treatment with carfilzomib. All patients will receive 20 mg/m2 carfilzomib IV on Day 1 of Cycle 1, escalated to 70 mg/m2 on Days 8 and 15; carfilzomib 70 mg/m2 will be administered on Days 1, 8, and 15 of each 28-day cycle thereafter. Dexamethasone 40 mg will be administered (IV or PO) QW for Cycles 1-9 and then on Days 1, 8, and 15 from Cycle 10 onwards. Patients in the D-Kd group will also receive daratumumab SC (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc.]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. The primary endpoint is the rate of patients achieving a very good partial response or better. Secondary endpoints include overall response rate, rate of patients achieving complete response or better, progression-free survival, overall survival, overall MRD-negativity rate, time to next treatment, pharmacokinetics, and safety. The ClinicalTrials.gov identifier is NCT03871829. Disclosures Bahlis: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Zonder:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wroblewski:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Renaud:Janssen: Employment, Equity Ownership. Jackson:Janssen: Employment, Equity Ownership. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.

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Efficacy and Safety of Retreatment with Bortezomib in Patients with Multiple Myeloma: Interim Results From RETRIEVE, a Prospective International Phase 2 Study.

Blood ◽

10.1182/blood.v114.22.3866.3866 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3866-3866 ◽

Cited By ~ 2

Author(s):

Maria Teresa Petrucci ◽

Igor W. Blau ◽

Paolo Corradini ◽

Meletios A. Dimopoulos ◽

Johannes Drach ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Bortezomib Treatment ◽

Best Response ◽

Phase 2 Study ◽

Grade 3

Abstract Abstract 3866 Poster Board III-802 Bortezomib (Velcade®) retreatment has been shown to be active and well tolerated in patients with relapsed multiple myeloma (MM) in a number of retrospective studies and a small prospective phase 4 study (EVEREST). This large, prospective, international, multi-center, open-label phase 2 study was conducted to confirm the efficacy and safety of retreatment with bortezomib in MM patients who had previously responded (at least partial response [PR]) to bortezomib-based therapy as their most recent prior treatment. Patients had to have previously tolerated bortezomib 1.0 or 1.3 mg/m2 alone or in combination and have had a treatment-free interval (TFI; time from last dose of initial bortezomib treatment to first dose of bortezomib retreatment) of ≥6 months. Additional eligibility criteria included progressive disease or relapse from complete response (CR) by EBMT criteria, no MM therapy (except maintenance with dexamethasone, thalidomide, or interferon) since the last dose of initial bortezomib treatment, KPS ≥60, and adequate renal, hepatic, and hematologic function; patients with grade ≥2 peripheral neuropathy or neuropathic pain (as defined by NCI CTCAE v3.0) were excluded. Patients received bortezomib at the last tolerated dose (1.0 or 1.3 mg/m2) during initial treatment on days 1, 4, 8, and 11 for up to eight 21-day cycles, either alone or in combination with dexamethasone at the investigator's discretion. Response was assessed by EBMT criteria every 6 weeks during treatment and then every 2 months until disease progression. Adverse events (AEs) were graded according to NCI CTCAE v3.0. A total of 130 patients received at least 1 dose of bortezomib retreatment and were included in the safety population. Patients had a median age of 67 years, 57% were male, and 16% had KPS '70%. Median time from diagnosis of MM was 4.5 years (range 0–14 years); median number of prior therapies was 2; 15, 80, 23, and 12 patients had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib therapy). Best response by EBMT criteria to initial bortezomib treatment was CR in 26% and PR in 74% of patients; median time to progression and TFI after initial bortezomib treatment were 17.9 months and 14.3 months, respectively. Last tolerated dose of previous bortezomib therapy was 1.3 mg/m2 and 1.0 mg/m2 for 62% and 29% of patients, respectively; 9% received another dose. Patients received a median 7.0 (range 1–8) cycles of bortezomib retreatment (23% of patients completed all 8 cycles); 72% of patients received concomitant dexamethasone. A total of 126 patients were evaluable for response. In the 126 response-evaluable patients, the overall response rate (ORR; CR+PR) by best confirmed response (EBMT criteria) was 40%; in addition, 18% of patients achieved minimal response (MR), to give a CR+PR+MR rate of 58%. After a planned secondary efficacy analysis, the ORR (CR+PR) by single best response was 55% (75% ≥MR). Median time to best confirmed response (≥MR) was 2.9 months; time to first response was 1.5 months. Analysis of ORR by patient subgroups showed comparable results in patients who did versus did not receive concomitant dexamethasone (42% vs 32%), in those who received ≤1.0 mg/m2 vs 1.3 mg/m2 bortezomib (35% vs 41%), and in those aged ≤65 years vs >65 years (45% vs 36%). ORR was 67%, 39%, 33%, and 25% in patients who had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib), respectively. Analysis of best confirmed responses according to response to initial bortezomib showed that 63% and 52% of patients who achieved a CR or PR, respectively, to initial bortezomib treatment responded to retreatment. Most (98%) patients experienced a treatment-emergent AE; 60% experienced a grade 3/4 AE, and 32% experienced a serious AE; there were 8 deaths, 2 of which (due to sepsis and stroke) were possibly treatment-related. The most common grade 3/4 AEs were thrombocytopenia (35%), neutropenia (7%), diarrhea (7%), and pneumonia (5%). AEs leading to dose reductions or discontinuations were reported for 22% and 12% of patients, respectively. The incidence of neuropathy was 39%, including 9% grade 3; 4% of patients discontinued treatment due to PN; 61% of neuropathy events resolved or improved within a median 1.3 months. These results confirm that bortezomib retreatment is a well-tolerated, feasible, and active therapeutic option for heavily pretreated MM patients without evidence of cumulative toxicity. Disclosures: Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dimopoulos:Ortho-Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Drach:Janssen-Cilag: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Johnson and Johnson: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Final Results From a Pivotal, Multicenter, International, Open-Label, Phase 2 Study of Romidepsin In Progressive or Relapsed Peripheral T-Cell Lymphoma (PTCL) Following Prior Systemic Therapy

Blood ◽

10.1182/blood.v116.21.114.114 ◽

2010 ◽

Vol 116 (21) ◽

pp. 114-114 ◽

Cited By ~ 7

Author(s):

Bertrand Coiffier ◽

Barbara Pro ◽

H. Miles Prince ◽

Francine M Foss ◽

Lubomir Sokol ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Systemic Therapy ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Phase 2 ◽

Open Label ◽

Advisory Committees ◽

Prior Systemic Therapy

Abstract Abstract 114 Background: Romidepsin is a potent HDAC inhibitor approved by the FDA for patients (pts) with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. Durable clinical benefit and tolerability of romidepsin in pts with recurrent or refractory PTCL have been previously observed in a phase 2 trial conducted by the National Cancer Institute. The aim of this phase 2, single-arm, open-label registration study was to evaluate the activity of romidepsin in a larger number of pts with progressive or relapsed PTCL. Methods: Pts with histologically confirmed PTCL (PTCL NOS, angioimmunoblastic T-cell lymphoma, ALCL [ALK-1 negative], other subtypes) who failed or were refractory to ≥ 1 prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Exclusions included inadequate bone marrow or other organ function and significant cardiovascular abnormalities. Pts received romidepsin 14 mg/m2 as a 4-h IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for stable disease (SD) or response. The primary endpoint was rate of complete response (CR + CRu) as evaluated by a central Independent Review Committee (IRC) using International Working Criteria for non-Hodgkin's lymphoma. IRC assessment consisted of a 2-step process, with initial radiographic review of images (CT, MRI) followed by an overall clinical assessment based on the radiology evaluations, photographs, and relevant clinical parameters. Secondary endpoints included objective response rate (ORR): CR + CRu + partial response (PR), investigator-assessed responses, duration of response, time to response, and safety. Results: 131 pts from 48 US, European, and Australian sites were enrolled and received at least 1 dose of romidepsin (as-treated population); 130 patients had histologically confirmed PTCL by central review. Mean age of all pts was 59.4 y (range, 20–83) and median time since diagnosis was 1.25 y (range, 0–17). Median number of prior systemic therapies was 2 (range, 1–8). 21 pts (16%) had failed a prior stem cell transplant. Responses assessed by the IRC are noted in the table below. Longest duration of response is 26+ mo and 16 (94%) of the 17 pts with a CR had not progressed as of the data cutoff (March 31, 2010). Investigator-assessed responses included 21 pts (16%) with CR + CRu, 18 pts (14%) with PR for an ORR of 30%. Currently, 13 pts continue to receive treatment (range, 10–36 cycles). Adverse events (AEs) were reported in 126 of 131 pts (96%). AEs reported in ≥ 20% of pts were nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). AEs ≥ grade 3 were reported for 86 pts (66%), with the most common (≥ 5%) being pneumonia (5%), pyrexia (5%), sepsis (5%), and vomiting (5%). 60 pts (46%) had at least 1 serious AE: the most frequently reported (≥ 5%) were pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). 22 pts (17%) withdrew due to AEs. 8 pts (6%) died within 30 days of the last dose of romidepsin; 1 death, due to sepsis, was assessed as possibly related to treatment. Conclusions: Complete and durable responses were observed with single agent romidepsin in pts with relapsed PTCL. These data support the therapeutic potential for romidepsin in relapsed PTCL and suggest that romidepsin is a strong candidate for inclusion in future novel regimens for these diseases. As of the data cutoff (March 31, 2010), the median duration of follow-up for CR is 8.2 mo. Disclosures: Coiffier: Gloucester: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Romidepsin is not currently approved for the treatment of peripheral T-cell lymphoma (PTCL). Pro:Celgene: Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding. Foss:Celgene: Consultancy; Eisai: Consultancy, Speakers Bureau; Merck: Speakers Bureau; Allos: Consultancy, Speakers Bureau; Cephalon: Speakers Bureau. Sokol:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caballero:Celgene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:Roche: Consultancy, Honoraria; Bayer: Honoraria. Padmanabhan:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shustov:Celgene: Research Funding. Nichols:Celgene: Employment. Carroll:Celgene: Employment. Balser:Gloucester Pharmaceutical: Consultancy. Horwitz:Celgene: Consultancy, Honoraria.

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An Open-Label Phase 2 Study Of Ofatumumab In Combination With a Novel AKT Inhibitor (Afuresertib) In Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.4175.4175 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4175-4175

Author(s):

Christine I. Chen ◽

Susi Snitzler ◽

Trina Wang ◽

Harminder Paul ◽

Lisa W Le ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Treatment Phase ◽

Phase 2 ◽

Akt Inhibitor ◽

Advisory Committees ◽

Phase 2 Study ◽

Previously Treated ◽

Grade 3

Abstract Introduction Ofatumumab is a novel anti-CD20 monoclonal antibody which led to impressive single-agent responses of 47-58% in a phase 2 study of CLL patients (pts) with refractory disease (Wierda et al 2010). Unfortunately, response durations were short (median 5.6-7.1 mos). In order to improve upon these results, we combined ofatumumab with a novel pan-AKT kinase inhibitor, afuresertib (GSK2110183). The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in relapsed/refractory hematologic malignancies (Spencer et al ASH 2011). We present an interim analysis of the initial 19 of 31 planned pts in an ongoing trial of ofatumumab and afuresertib in relapsed/refractory CLL. Methods Previously treated CLL pts who have received at least one prior fludarabine-containing regimen with disease progression are eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV is administered weekly for 8 doses, then once every 4 week cycle for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allows for evaluation of pharmacodynamic (PD) changes in phosphoproteins and pharmacokinetic (PK) studies. Pts are assessed for safety and response on day 1 of each cycle. Pts achieving SD, PR or CR by the end of the Treatment Phase proceed to the Maintenance Phase with single-agent afuresertib for a maximum of 12 mos (12 cycles). Results Demographics: To date, 19 pts have been enrolled. Median age is 65 yrs (range 43-76), baseline median Hb 108g/L (range 80-145), absolute lymphocytes 29.7 x109/L (range 1.0-464.9), β2M 4.42mg/L (range 1.42-3.21), bulky nodes ≥5cm in 5 pts (32%), organomegaly in 8 pts (42%), del17p/del11q on FISH in 9 pts (47%), and ZAP70+ in 13 pts (68%). Eight pts (42%) were fludarabine-refractory; only 2 pts had received prior alemtuzumab. The median number of prior therapies was 2 (range 1-6). Toxicity: Hematologic: 4 pts (21%) developed Gr 3-4 neutropenia during at least 1 cycle; 1 pt (5%) had a febrile neutropenia event. Only 2 pts (10.5%) have developed Gr 3-4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Most common related grade 3-4 toxicities were GI: dyspepsia (53%), diarrhea (37%), nausea (21%), temporally related to oral afuresertib and easily managed symptomatically. Infusion reactions to ofatumumab were frequent (12 pts; 63%) with grade 3 reactions in 3 pts. Five pts (26%) developed non-infectious pneumonitis, with 3 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation with weekly ofatumumab infusions. Most infections were mild, with only 1 grade 3 cellulitis. Efficacy: Of the 19 response-evaluable pts receiving a median of 6 cycles (range 1-9), 8 pts (42%) have achieved a PR, 11 SD (58%), and no CR. Response onset was rapid at a median 0.9 mos (range 0.8-2.8). At a median follow-up of 6.8 mos (range 0.3-12.9 mos), 5 pts (26%) have progressed and one patient has died after cycle 1 on therapy due to progressive CLL. PD Studies: CD19+ cells are assayed for phosphorylated AKT and its downstream targets RAS40 and GSK3 in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Peripheral blood samples are collected at screening and on cycle 1 day 10, after dosing with afuresertib. Of the 7 patients evaluated thus far, 5 demonstrated constitutive AKT phosphorylation at baseline. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. Conclusion Preliminary results from this phase 2 study suggests that a combination of ofatumumab plus a novel oral AKT inhibitor, afuresertib, has activity in previously treated CLL and is generally well-tolerated with minimal myelotoxicity. Response data are encouraging but whether durable responses can be achieved requires more mature follow-up. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Off-label use of ofatumumab and afuresertib for the treatment of relapsed/refractory CLL. Smith:GSK: Employment, Equity Ownership. Johnston:Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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A Prospective Phase 2 Study of Venetoclax and Low Dose Ara-C (VALDAC) to Target Rising Molecular Measurable Residual Disease and Early Relapse in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-152583 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1261-1261

Author(s):

Ing S Tiong ◽

Sun Loo ◽

Emad Uddin Abro ◽

Devendra Hiwase ◽

Shaun Fleming ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Phase 2 ◽

Advisory Committees ◽

Early Relapse ◽

Phase 2 Study ◽

Measurable Residual Disease ◽

Acute Myeloid

Abstract Introduction Rising molecular measurable residual disease (MRD) is an arbiter of clinical relapse in acute myeloid leukemia (AML). Venetoclax (VEN) is active against IDH and NPM1 mutant (mt) AML as monotherapy (Konopleva et al, 2016 and Chua et al, 2020) and can yield MRD negative remission when combined with low dose ara-C (LDAC) in patients unfit for intensive chemotherapy (DiNardo and Tiong et al, 2020). In a retrospective study, we showed that VEN in combination with hypomethylating agents or LDAC could erase rising NPM1mt MRD in 6/7 cases (Tiong et al, 2020). We now present a prospective phase 2 study of VEN and LDAC in patients with molecular MRD failure or oligoblastic AML relapse. Methods This multicenter phase 2 study stratified patients into oligoblastic relapse (marrow blasts 5-15%; Group A), or molecular MRD failure (Group B) as defined by the European LeukemiaNet (ELN) recommendations (failure confirmed by 2 interval samples) (Schuurhuis et al, 2018). Patients received VEN 600 mg (days 1-28) and LDAC 20 mg/m 2 (days 1-10). Primary objectives were morphologic or MRD response (≥1 log reduction) in groups A and B, respectively. Key secondary objectives were allogeneic hematopoietic cell transplantation (allo-HCT) realization and relapse-free (RFS) and overall survival (OS). The study had Alfred Health ethics approval (196/19). NPM1mt and other fusion transcript levels (per 10 5 ABL) from bone marrow were analyzed by RT-qPCR, IDH1 and IDH2 by Bio-Rad TM droplet digital PCR. Results The study enrolled 32 patients, with 29 evaluable (cut-off date 15/7/21). The median age of the study population was 62 years; 79% had intermediate cytogenetic risk, 66% NPM1mt, 11% FLT3-ITD and 37% IDH1/IDH2 mt. Most received prior intensive chemotherapy (93%) and 2 (7%) allo-HCT in first remission. Median interval from AML diagnosis to study entry was 12.6 months (Table 1). After a median follow-up of 7.9 months, patients had received a median of 3 cycles (range 1-14) of VEN-LDAC, with 13 patients ongoing. The main reasons for treatment cessation were allo-HCT (n=10; 34%) or donor lymphocyte infusion (n=2; 7%), treatment failure (n=3) or an adverse event (n=1). Hematologic complete/incomplete response (CR/CRi) among 11 patients with oligoblastic relapse (group A) was 73% and included: CR (n=5, 45%) or CRi (n=3, 27%), with an additional patient with morphologic leukemia-free state and 2 patients with stable disease. Overall, across both groups, median RFS and OS were not reached, estimated at 78% and 91% at 1 year, respectively. Among 18 patients with molecular MRD failure (group B) treated with VEN+LDAC, molecular response (≥1 log reduction) was achieved in 72%, and the RFS and OS were estimated at 83% and 87% at 1 year, respectively. Analysis of a sub-group of patients with NPM1mt (n=18); 6 and 12 from Groups A and B, respectively revealed the median NPM1mt transcript level at study entry to be 8985 copies (IQR 826, 94,431). A molecular response was achieved in 14 (78%) patients, including 9 (50%) with complete molecular remission (CR MRD-), with most responses achieved within 2 cycles of therapy (Figure B). Treatment with VEN-LDAC was generally well tolerated, with 15 serious adverse events reported within the first 2 cycles, including infection (n=6; 19%) and febrile neutropenia (n=3; 9%). Only one subject discontinued treatment due to stroke. Conclusions In this prospective study, in patients with first oligoblastic relapse or MRD failure, VEN in combination with LDAC induced a high rate of molecular MRD remission that was rapidly achieved, resulting in a high rate of survival at 12-months (>90%) and with low toxicity. Follow-up is ongoing to determine the durability of response. Treatment of patients with MRD or early clinical failure may represent an attractive clinical trial setting for investigation of novel, non-intensive AML therapies. This approach will be investigated in a future multi-arm, precision-based platform trial called INTERCEPT (Investigating Novel Therapy to Target Early Relapse and Clonal Evolution as Pre-emptive Therapy in AML). Figure 1 Figure 1. Disclosures Tiong: Servier: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Consultancy. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Fleming: Amgen Inc: Research Funding. Bajel: Amgen: Speakers Bureau; Abbvie, Amgen, Novartis, Pfizer: Honoraria. Fong: Amgen, BMS: Speakers Bureau; Amgen: Research Funding; AbbVie, Amgen, Novartis, Pfizer, Astellas: Honoraria. Wei: Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: This presentation will discuss the use of venetoclax in targeting measurable residual disease and early relapse of acute myeloid leukemia.

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Phase II Trial of Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized with NFKB2 Rearrangement. (Proteasome Inhibitor NFKB2 Rearrangement Driven Trial, PINR)

Blood ◽

10.1182/blood-2018-99-119337 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2011-2011

Author(s):

Leon Bernal-Mizrachi ◽

Craig E. Cole ◽

Leonard Heffner ◽

Ajay K Nooka ◽

Ravi Vij ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Interim Analysis ◽

Proteasome Inhibitor ◽

Research Funding ◽

Treated Patient ◽

Data Monitoring Committee ◽

Caspase 8 ◽

Open Label ◽

Advisory Committees

Abstract Introduction: Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for multiple myeloma (MM). The oral boron-containing selective and reversible proteasome inhibitor ixazomib has shown to induce deep and durable responses (Kumar RK et la, Blood 2016. 128(20):2415-2422). Triplets containing ixazomib, has shown to be more efficacious than doublet regimens in the relapse setting (Moreau P, et al. N Engl J Med 2016. 374:1621-1634).However, to date there is not companion diagnostics capable of predicting PI response. We have recently discovered that MM patients resistant to PI lack of the ankyrin (ANK) and death domain (DD) present in the 3'-end of NFKB2. Loss of NFKB2 3'end frequently resulted from a structural rearrangements. We found that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation. Activation of this caspase resulted from NFKB2 interaction with FADD/caspase-8/p62 (unpublished data). Based on this findings, we design this study to examine the efficacy of NFKB2 break apart FISH to predict the response to the duplet ixazomib and dexamethasone (Id) vs ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients (1-3 lines of therapy). Methods: In this phase 2 biomarker driven open label trial, relapse patients with <4 lines of therapy were randomized to ixazomib 4 mg weekly 3 of 4 weeks and 40 mg weekly dexamethasone vs Id plus 25 mg of lenalidomide daily days 21/28, based on the status of NFKB2 rearrangement in plasma cells. Patients were screened for NFKB2 rearrangement was detected by NFKB2 break apart FISH. Patients without NFKB2 rearrangement received Id and patients with NFKB2 rearrangement were subsequently randomized in a 1:1 fashion to receive Id or IRd. The primary endpoint is to compare the response rate of Id or IRd at 4 cycles according to the rearrangement status of NFKB2 Results: At the moment of interim analysis, 26 patients have achieved 4 cycles of treatment. All treatment groups (NFKB2 FISH [-] Id, n=16, NFKB2 FISH [+] Id, n=6 and IRd, n=4) received a median of 2 prior lines of therapy. A higher ORR was observed in NFKB2 FISH negative treated with Id compared with NFKB2 FISH positive (56.3% CI:29.9%-80.3% vs. 16.7% CI:0.4%-64.1%, P=0.16), including significantly higher rates of ≥very good partial response, ≥ partial response, ≥ minimal response (12%, 37.5%, 6% vs. 0%, 0%, 16%, respectively). ORR for IRd arm is for now 25% CI:0.6%-80.6%. Patients that continue treatment after cycle 4 that achieve minimal response or better improved their depth of response in 6% in Id treated NFKB2 FISH negative patients and 25% of IRd treated NFKB2 FISH negative patients. The most common (≥10%) grade 2/4 include pneumonia 20% (Id treated NFKB2 FISH negative), thrombocytopenia 16% (Id NFKB2 FISH positive), neutropenia 60% (IRd NFKB2 FISH positive. Treatment discontinuations only occurred in 1 Id treated patient (5%). Conclusion: Interim analysis demonstrate a trend higher efficacy of ixazomib with dexamethasone in MM patients with negative NFKB2 break-apart FISH compared to those with a positive test. Efficacy and toxicity of the triplet regimen are comparable to what is seen in Tourmaline 1 trial. This study was registered at www.clinicaltrials.gov as # NCT02765854. Disclosures Bernal-Mizrachi: Takeda Pharmaceutical Company: Research Funding; Kodikaz Therapeutic Solutions: Consultancy, Equity Ownership. Cole:Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees; University of Michigan: Employment. Heffner:ADC Therapeutics: Research Funding; Kite Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kelkar:Empire Genomics: Employment. Lonial:Amgen: Research Funding. Kaufman:Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Roche: Consultancy; BMS: Consultancy; Janssen: Consultancy.

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Interim Results from Fight-203, a Phase 2, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of Pemigatinib (INCB054828) in Patients with Myeloid/Lymphoid Neoplasms with Rearrangement of Fibroblast Growth Factor Receptor 1 (FGFR1)

Blood ◽

10.1182/blood-2018-99-110388 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 690-690 ◽

Cited By ~ 12

Author(s):

Srdan Verstovsek ◽

Alessandro M. Vannucchi ◽

Alessandro Rambaldi ◽

Jason R. Gotlib ◽

Adam J. Mead ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Phosphate Binders ◽

Phase 2 ◽

Open Label ◽

Employment Equity ◽

Advisory Committees ◽

Lymphoid Neoplasms ◽

Equity Ownership

Abstract Introduction: Myeloid/lymphoid neoplasms (MLNs) with rearrangement of FGFR1 on chromosome band 8p11 are rare but aggressive neoplasms characterized by heterogeneous presentation with myeloid and/or lymphoid proliferation, extramedullary involvement, and rapid progression to blast phase (Strati P, et al., Leuk Lymphoma. 2018;59:1672-1676). FGFR1 gets constitutively activated through fusion genes involving various partner genes, most frequently ZMYM2-FGFR1 or BCR-FGFR1 as consequence of a t(8;13)(p11;q12) or a t(8;22)(p11;q11), respectively. Chemotherapy is usually ineffective, effective targeted treatment has not been described, and allogeneic hematopoietic stem cell transplant (alloHSCT) is the only potentially curative option. Pemigatinib, a selective, potent, oral inhibitor of FGFR1, 2, and 3, has shown efficacy in patients with FGF/FGFR-activated tumors, including cholangiocarcinoma and urothelial carcinoma. We report interim results from the ongoing fight-203 study (NCT03011372) of pemigatinib in patients with FGFR1-rearranged MLNs. Methods: Fight-203 is a phase 2, open-label study enrolling patients ≥ 18 years of age with FGFR1-rearranged MLN. Patients enrolled in the study must have progressed on ≥ 1 prior treatment and be ineligible for alloHSCT. Patients receive a daily oral dose of pemigatinib 13.5 mg on a 21-day cycle (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint is overall clinical benefit rate, which includes complete clinical (CR) or partial clinical response (PR), and either complete or partial cytogenetic response (CCyR, PCyR). Secondary endpoints include duration of response/benefit, progression-free survival, overall survival, and safety/tolerability. Efficacy is assessed by evaluation of bone marrow histomorphology changes, standard cytogenetic and FISH evaluation of the FGFR1 rearrangement, and PET/CT scan. Results: At data cutoff (July 23, 2018), 14 patients were enrolled. Ten patients who had ≥ 1 response assessment were included in the analysis (Table). Patients received an average of 6.9 cycles of pemigatinib (range, 2-12 cycles). Median number of prior lines of therapy was 3 (range, 0-5), including 2 patients who received alloHSCT. Eight patients (80%) had a major CyR, including 6 patients with CCyR and 2 with PCyR. Eight patients (80%) had a CR or PR in bone marrow, peripheral blood, and extramedullary disease. One patient died of progression to myeloid blast crisis, 2 patients were bridged to alloHSCT, and 7 patients are ongoing. The most common treatment-emergent adverse events (AEs) were hyperphosphatemia (n=7 [70%]), diarrhea (n=5 [50%]) and anemia (n=5 [50%]); hyperphosphatemia was managed with diet and phosphate binders. Nine events in 4 patients (40%) were grade 3/4; 2 of these events (diarrhea and leukopenia) in 2 patients were related to pemigatinib. There were no drug-related AEs leading to dose interruption, dose reduction, or discontinuation. Conclusions: Pemigatinib showed promising efficacy, with an 80% major CyR rate accompanied by complete or partial remission, and was generally well tolerated by patients with FGFR1-rearranged MLN. The protocol was amended to allow continuous dosing, and the study is currently enrolling. Disclosures Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gotlib:Blueprint Medicines: Consultancy, Honoraria, Research Funding; Deciphera: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Promedior: Research Funding; Kartos: Consultancy; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mead:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy; Evotek: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elstar: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Hernandez Boluda:Incyte: Consultancy; Novartis: Consultancy. Asatiani:Incyte: Employment, Equity Ownership. Lihou:Incyte: Employment, Equity Ownership. Zhen:Incyte: Employment, Equity Ownership. Reiter:Incyte: Consultancy, Honoraria.

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Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽

10.1182/blood-2018-99-120155 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3011-3011 ◽

Cited By ~ 1

Author(s):

Lucia Masarova ◽

Jorge E. Cortes ◽

Keyur P. Patel ◽

Susan M. O'Brien ◽

Graciela M. Nogueras González ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Genetics Research ◽

Phase 2 Study ◽

Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

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