scholarly journals First-in-Human, Multicenter Phase I Study of IPH4102, First-in-Class Humanized Anti-KIR3DL2 Monoclonal Antibody, in Relapsed/Refractory Cutaneous T-Cell Lymphomas: Preliminary Safety, Exploratory and Clinical Activity Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1826-1826 ◽  
Author(s):  
Martine Bagot ◽  
Pierluigi Porcu ◽  
Caroline Ram-Wolff ◽  
Michael Khodadoust ◽  
Maxime Battistella ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Research Funding ◽  
Ex Vivo ◽  
Phase 1 ◽  
Clinical Activity ◽  
Autologous Tumor ◽  
Employment Equity ◽  
T Cell Lymphomas ◽  
Equity Ownership

Abstract KIR3DL2 is expressed in all subtypes of cutaneous T-cell lymphomas (CTCL), irrespective of clinical stage, with the highest prevalence of expression in Sézary syndrome (SS) and transformed mycosis fungoides (MF), two subgroups of patients with a high unmet need for clinically impactful therapies. KIR3DL2 belongs to the killer immunoglobulin-like receptor (KIRs) family and is expressed on minor subpopulations of normal NK, CD8 and CD4 T cells. IPH4102 is a first-in-class anti-KIR3DL2 monoclonal antibody (mAb). It selectively depletes KIR3DL2-expressing cells by recruiting immune effectors. Its main modes of action include antibody-dependent cell-cytotoxicity (ADCC) and -phagocytosis (ADCP). IPH4102 has shown potent efficacy in preclinical models, in particular ex vivo autologous assays using primary CTCL cells. IPH4102 is currently being investigated in a first-in-human dose-finding phase 1 study (NCT02593045) evaluating repeated administrations of single-agent IPH4102 in relapsed/refractory CTCL patients. The primary objective is to assess the safety and tolerability of increasing doses of IPH4102. Secondary objectives include PK, immunogenicity and signals of anti-tumor clinical activity. Exploratory biomarkers aim to characterize KIR3DL2-expressing and non-expressing cells in involved tissue/disease compartments and to monitor changes during IPH4102 treatment. Minimal residual disease (MRD) is measured in the skin, blood and/or lymph nodes. Assessment of ex vivo NK cell-mediated ADCC against autologous tumor cells is also performed pre-dose on SS patient samples. The study has two sequential portions, a dose-escalation followed by a cohort expansion. The dose-escalation portion has a 3+3 design with accelerated titration and aims to determine the maximal tolerated dose (MTD) or recommended phase 2 dose (RP2D). In the cohort expansion portion, two CTCL subtype-specific cohorts will be studied, each to include 10 additional patients to further explore MTD or RP2D. Eligible CTCL patients must have received at least 2 lines of anti-neoplastic systemic therapy. Centrally assessed KIR3DL2 expression on malignant cells in skin or blood is required for inclusion. Patients receive IPH4102 administrations until progression or unacceptable toxicity. Intra-patient dose-escalation is allowed, only past the first complete clinical assessment at week 5 and provided the upper next dose-level is declared safe by the safety committee. Enrollment into study IPH4102-101 started in November 2015 and is currently ongoing. At time of abstract submission, dose-levels #1 to #6 have been completed. A total of 13 patients have been treated at these 6 dose-levels and are evaluable for safety and clinical activity. These patients comprise 10 SS (including 1 with evidence of large-cell transformation), 2 MF and 1 "not-otherwise-specified" CD4+ CTCL. Median age is 71 years (range 50 - 90). For these 13 patients, only grade 1 or 2 related adverse events (AEs) have been reported with IPH4102 treatment. No patient experienced a DLT or a related AE of grade ≥3. No IPH4102-related skin rashes or infections have been observed so far. Results of immuno-phenotyping of patients' blood lymphocytes show consistency of local and central assessments. In addition, ex vivo functional assay results confirm that SS patients' NK cells are functional and able to kill autologous tumor cells through ADCC with IPH4102. Our preliminary data from the phase 1 study of a novel targeted immune therapy show excellent tolerability in advanced CTCL patients. Updated results including exploratory biomarker assessment results will be presented and discussed at the meeting. Disclosures Bagot: Millenium: Other: Investigator in a clinical trial; Kiowa Hakko Kirin: Other: Investigator in a clinical trial; Innate Pharma: Equity Ownership, Other: Investigator in a clinical trial, Patents & Royalties, Research Funding. Porcu:celgene: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Ram-Wolff:Innate Pharma: Other: Investigator in a clinical trial. Battistella:Innate Pharma: Consultancy, Research Funding. Marie-Cardine:Innate Pharma: Research Funding. Mathieu:Innate Pharma: Other: Investigator in a clinical trial. Vermeer:Innate Pharma: Other: Investigator in a clinical trial. Whittaker:Seattle Genetics: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Takeda: Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding. Duvic:Kiowa Hakko Kirin: Other: investigator in a clinical trial, Research Funding; Rhizen Pharmaceuticals: Other: Investigator in a clinical trial; Innate Pharma: Consultancy, Other: Investigator in a clinical trial; Millenium: Other: Investigator in a clinical trial; Angimmune LLC: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial. Bensussan:Innate Pharma: Patents & Royalties, Research Funding. Paturel:Innate Pharma: Employment, Equity Ownership. Bonnafous:Innate Pharma: Employment, Equity Ownership. Widemann:Innate Pharma: Employment. Bonin:Innate Pharma: Employment. Sicard:Innate Pharma: Employment, Equity Ownership. Paiva:Innate Pharma: Employment. Pilz:Innate Pharma: Consultancy. Kim:Kyowa Hakko Kirin: Consultancy, Honoraria, Other, Research Funding; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Consultancy, Other: Investigator in a clinical trial; Seattle Genetics: Consultancy, Other: Investigator in a clinical trial; Merck: Other: Investigator in a clinical trial; Genentech: Other: Investigator in a clinical trial; MiRagen: Consultancy; Neumedicine: Consultancy; Soligenix: Consultancy; Eisai: Consultancy, Other: Investigator in a clinical trial; Actelion: Consultancy, Other: Investigator in a clinical trial; Celgene: Consultancy; Galderma: Consultancy; Horizon: Consultancy.

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

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1959-1959 ◽  
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.

Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1540-1540 ◽  
Author(s):  
Sheeba K. Thomas ◽  
Wael A. Harb ◽  
Joseph Thaddeus Beck ◽  
Gabrail Nashat ◽  
M. Lia Palomba ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Open Label ◽  
Label Dose ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Abstract Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

A Phase 1/2 Study of the Second Generation Selective Inhibitor of Nuclear Export (SINE) Compound, KPT-8602, in Patients with Relapsed Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4509-4509 ◽  
Author(s):  
R. Frank Cornell ◽  
Adriana C Rossi ◽  
Rachid Baz ◽  
Craig C Hofmeister ◽  
Chaim Shustik ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Low Dose ◽  
Phase 1 ◽  
Single Agent ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction - Inhibition of Exportin 1 (XPO1) is a novel treatment approach for multiple myeloma (MM). XPO1 mediates the nuclear export of cell-cycle regulators and tumor suppressor proteins leading to their functional inactivation. In addition, XPO1 promotes the export and translation of the mRNA of key oncoproteins (e.g. c-MYC, BCL-2, Cyclin D). XPO1 overexpression occurs in solid and hematological malignancies, including MM and is essential for MM cell survival. Selinexor, the first oral SINE compound, has shown promising anti-MM activity in phase 1 studies but has been associated with gastrointestinal and constitutional toxicities including nausea, anorexia and fatigue. KPT-8602 is a second generation oral SINE compound with similar in vitro potency to selinexor, however, has substantially reduced brain penetration compared with selinexor, and demonstrated markedly improved tolerability with minimal anorexia and weight loss in preclinical toxicology studies. In murine models of MM, KPT-8602 can be dosed daily (QDx5) with minimal anorexia and weight loss. We have therefore initiated a phase 1/2 first-in-human clinical trial. Methods - This phase 1/2 clinical trial was designed to evaluate KPT-8602 as a single agent and in combination with low dose dexamethasone (dex) in patients (pts) with relapsed / refractory MM (RRMM). KPT-8602 is dosed orally (QDx5) for a 28-day cycle with a starting dose of 5 mg. Low dose dex (20 mg, twice weekly) is allowed after cycle 1 if at least a minimal response (MR) is not observed. The primary objective is to evaluate the safety and tolerability including dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and evidence for anti-MM activity for KPT-8602 single agent and in combination with dex. The pharmacokinetic (PK) and pharmacodynamic (PDn; XPO1 mRNA) profile of KPT-8602 will also be determined. PDn predictive biomarker analysis and ex vivo drug response assays are underway using tumor cells from bone marrow aspirates before treatment, during and at relapse. These analyses include cell death pathway assays by flow and nuclear/cytoplasmic localization of XPO1, NF-ƙB, IƙBα, IKKα, NRIF and p53 by imaging flow and IHC. Results - As of 01-Aug-2016, 6 pts 2 M/4 F, (median of 6 prior treatment regimens, median age of 71) with RRMM have been enrolled. Common related grade 1/2 adverse events (AEs) include thrombocytopenia (3 pts), nausea (2 pts) and diarrhea (2 pts). Grade 3 AEs include neutropenia (1 pt) and dehydration (1 pt). No grade 4 or 5 AEs have been reported. No DLTs have been observed and the MTD has not been reached. 5 pts were evaluable for responses (1 pt pending evaluation): 1 partial response, 1 minimal response, and 3 stable disease; no pts have progressed on therapy with the longest on for >5 months. The PK properties following oral administration showed that 5 mg of KPT-8602 was rapidly absorbed (mean tmax= 1 hr, mean Cmax= 30.6 ng/mL). The mean AUCinf was calculated to be 141 ng•hr/mL. After tmax, KPT-8602 declined at an estimated mean t½ of 4 hr. At the same dose level, XPO1 mRNA expression was the highest (~2.5 fold) at 8 hr post dose. Conclusions - Oral KPT-8602 is well tolerated in heavily pretreated pts with RRMM. Gastrointestinal and constitutional toxicities observed with twice weekly selinexor have not been observed with 5x/week KPT-8602, including in pts on study for >4 months. PK was predictable and in line with selinexor. These early results show encouraging disease control with pts remaining on therapy. Enrollment is on-going. Disclosures Rossi: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Signal Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Research Funding. Hofmeister:Karyopharm Therapeutics: Research Funding; Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Shustik:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richter:Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Jannsen: Speakers Bureau. Chen:Janssen: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Honoraria, Research Funding. Vogl:Takeda: Consultancy, Research Funding; Celgene: Consultancy; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Karyopharm: Consultancy; Acetylon: Research Funding; Constellation: Research Funding. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baloglu:Karyopharm Therapeutics: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics: Employment, Equity Ownership. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Sullivan:Karyopharm Therapeutics: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals First in Human Study with GSK2857916, an Antibody Drug Conjugated to Microtubule-Disrupting Agent Directed Against B-Cell Maturation Antigen (BCMA) in Patients with Relapsed/Refractory Multiple Myeloma (MM): Results from Study BMA117159 Part 1 Dose Escalation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1148-1148 ◽  
Author(s):  
Adam D. Cohen ◽  
Rakesh Popat ◽  
Suzanne Trudel ◽  
Paul G Richardson ◽  
Ed N. Libby ◽  
...  
Keyword(s):  
Stem Cell ◽  
Disease Progression ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Surface Receptor ◽  
Clinical Activity ◽  
Ocular Toxicity ◽  
Employment Equity ◽  
Equity Ownership ◽  
Dose Levels

Abstract Background Expression of BCMA, a cell surface receptor in the TNF superfamily, is restricted to B cells at later stages of differentiation and is requisite for the survival of long lived plasma cells. BCMA is expressed on MM cells at variable levels. GSK2857916 is a humanized IgG1 anti-BCMA antibody conjugated to the microtubule disrupting agent monomethyl auristatin-F via a stable, protease-resistant maleimidocaproyl linker. Upon binding to BCMA, GSK2857916 is rapidly internalized and active drug is released within the cell. GSK2857916 also exhibits enhanced antibody-dependent cell-mediated cytotoxicity resulting from afucosylation of the FC domain which increases affinity to FCγRIIIa expressed on immune effector cells. The rationale for investigating GSK2857916 in MM is supported by the restricted pattern of BCMA expression and by evidence from preclinical studies. Methods BMA117159 (NCT02064387) is a Phase I open-label study investigating safety, pharmacokinetics (PK), pharmacodynamics (PD), antidrug antibodies (ADA) and clinical activity of GSK2857916 in relapsed/refractory MM and other hematologic malignancies expressing BCMA. Dose escalation (Part 1) is conducted exclusively in MM patients; primary objective is safety, determination of maximum tolerated dose (MTD) and recommended phase 2 dose. GSK2857916 is administered every 3 weeks as a1 hr intravenous infusion with no mandatory prophylaxis for infusion related reactions (IRR). Bayesian Logistic Regression Model is applied for dose recommendations. Eligible MM patients must have prior treatments with alkylators, proteasome inhibitors, immunomodulators and stem cell transplantation, if transplant eligible, and have documented disease progression on or within 60 days of last therapy. Additional key inclusion criteria include: ANC >1x109/L; hemoglobin >8 g/dL; PLT >50x109/L; INR <1.5; PTT <1.5xULN; total bilirubin ≤1.25xULN; AST and ALT <1.5xULN; serum creatinine <1.2xULN or calculated creatinine clearance >60 mL/min; albuminuria <500mg/24hr; LVEF >50% and troponin <1xULN. Patients remain on treatment until progression, unacceptable toxicity, consent withdrawal or completing 16 treatment cycles. Blood is collected for PK and ADA analyses; blood and bone marrow aspirates are collected for PD analyses. Results To date 24 MM patients have enrolled and completed the 21 day DLT observation period. Patients were enrolled at the following 8 dose levels: 0.03 (n=1); 0.06 (n=1); 0.12 (n=4); 0.24 (n=4); 0.48 (n=4); 0.96 (n=3); 1.92 (n=4), and 3.4 mg/kg (n=3). The median age is 60 years (range 39-71); 50% are male. Eighty-three percent received ≥4 prior lines. Sixty-three percent had IgG and 29% had IgA types. Seven patients (29%) had adverse cytogenetics defined as del17p13, or t(4;14) . Overall, 23 patients (96%) experienced adverse events (AE); the most frequent (≥20%) regardless of cause were nausea (42%), fatigue (38%), anemia (29%), chills (29%), pyrexia (29%), thrombocytopenia (29%), dry eye (21%), and hypercalcemia (21%). Grade 3/4 AEs reported in ≥10% of patients were thrombocytopenia, anemia, and neutropenia. Eight serious AEs were reported in 6 patients with 1 event of limbal stem cell dysfunction considered drug related; this event has not resolved. There were no AEs leading to treatment discontinuation. Four patients required dose reduction due to AEs: ocular toxicity (n=1), corneal disorder/ocular toxicity (n=1), dry eyes (n=1), and keratitis (n=1). IRRs (all Grade 1 or 2) were reported in 7 patients (29%) across dose levels and occurred with the first dose administration. The most frequent symptoms were chills. No DLTs were reported. Sixteen patients discontinued treatment due to disease progression (n=14), patient decision (n=1), completing 16 cycles of scheduled treatment (n=1); 8 patients are ongoing. There was1 MR at 0.24 mg/kg, and 1 VGPR, 3 PR, and1 MR at doses ≥0.96 mg/kg; resulting in a clinical benefit rate of 25% (unconfirmed responses). Conclusion GSK2857916 was well tolerated with no DLTs up to 3.4mg/kg q3w; MTD was not reached. AEs were manageable with ocular toxicity emerging as the most frequent reason for dose modifications. Clinical activity has been seen at higher doses. Complete safety, ADA, PD, and clinical activity data from all dose levels evaluated in Part 1 for q3w schedule will be presented. Study is funded by GlaxoSmithKline; drug linker technology is licensed from Seattle Genetics Disclosures Cohen: Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy, Research Funding. Trudel:Glaxo Smith Kline: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Equity Ownership, Honoraria; Oncoethix: Research Funding; BMS: Honoraria; Amgen: Honoraria. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees. Anderson:Takeda: Speakers Bureau; AMGEN/Onyx: Speakers Bureau; Celegene: Speakers Bureau. DeWall:GlaxoSmithKline: Employment, Equity Ownership. Ellis:GlaxoSmithKline: Employment, Equity Ownership. He:GlaxoSmithKline: Employment, Equity Ownership. Mazumdar:GlaxoSmithKline: Employment, Equity Ownership. Wang:GlaxoSmithKline: Employment, Equity Ownership. Opalinska:GlaxoSmithKline: Employment, Equity Ownership. Voorhees:GlaxoSmithKline: Research Funding; Celgene, BMS: Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy.

scholarly journals First-in-Human, Phase 1/2 Trial to Assess the Safety and Clinical Activity of Subcutaneous GEN3013 (DuoBody®-CD3×CD20) in B-Cell Non-Hodgkin Lymphomas

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 758-758 ◽  
Author(s):  
Pieternella Lugtenburg ◽  
Rogier Mous ◽  
Michael Roost Clausen ◽  
Martine E.D. Chamuleau ◽  
Peter Johnson ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Clinical Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Introduction: CD20-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the treatment of B-cell non-Hodgkin lymphomas (B-NHL); however, a significant proportion of patients (pts) present with refractory disease or will experience relapse. GEN3013 (DuoBody®-CD3×CD20) is the first subcutaneously administered IgG1 bispecific antibody (bsAb) that targets the T-cell surface antigen CD3 and the B-cell surface antigen CD20, triggering T-cell-mediated killing of B cells. In vitro, GEN3013 efficiently activates and induces cytotoxic activity of CD4+ and CD8+ T cells in the presence of B cells (Hiemstra et al. Blood 2018), and results in long-lasting depletion of B cells in cynomolgus monkeys. Subcutaneous (SC) GEN3013 in cynomolgus monkeys resulted in lower plasma cytokine levels, and similar bioavailability and B-cell depletion, compared with intravenous administration. GEN3013 has higher potency in vitro than most other CD3×CD20 bsAbs in clinical development (Hiemstra et al. HemaSphere 2019). SC GEN3013 in pts with B-NHL is being evaluated in a first-in-human, Phase 1/2 trial (NCT03625037), which comprises a dose-escalation part and a dose-expansion part. Here we report preliminary dose-escalation data. Methods: Pts with CD20+ B-NHL with relapsed, progressive, or refractory disease following anti-CD20 mAb treatment, and ECOG PS 0-2 were included. During dose escalation, pts received SC GEN3013 flat dose in 28-day cycles (q1w: cycle 1-2; q2w: cycle 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Risk of cytokine release syndrome (CRS) was mitigated with the use of a priming dose and premedication with corticosteroids, antihistamines, and antipyretics. Primary endpoints were adverse events (AEs) and dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics (PK), immunogenicity (anti-drug antibodies [ADA]), pharmacodynamics (PD) (cytokine measures; laboratory parameters), and anti-tumor activity (tumor size reduction; objective and best response). Results: At data cut-off (June 28, 2019), 18 pts were enrolled into the dose-escalation part of the trial, with safety data available for pts receiving doses starting at 4 µg. Most pts had diffuse large B-cell lymphoma (DLBCL; n=14) and were heavily pre-treated; 10 pts had received ≥3 prior lines of therapy (overall median [range]: 3 [1-11]). The median age was 58.5 years (range: 21-80), and 13 pts were male. At a median follow-up of 1.9 months, pts received a median of 5 doses (range: 1-14); treatment is ongoing in 6 pts. Twelve pts discontinued treatment due to progressive disease. Six pts died (2 during treatment, 4 during survival follow-up), all due to disease progression and unrelated to treatment. The most common (n≥5) treatment-emergent AEs were pyrexia (n=8), local injection-site reactions (n=7), diarrhea (n=5), fatigue (n=5), and increased aspartate aminotransferase (n=5). The most common Grade (G) 3/4 AEs were anemia (n=3) and neutropenia (n=3). Despite increasing GEN3013 doses, all CRS events were non-severe (initial observation: 3/8 pts, G1: n=1, G2: n=2; following modification of premedication plan [corticosteroids for 3 days]: 6/10 pts, G1: n=4, G2: n=2). Increases in peripheral cytokine (IL6, IL8, IL10, IFNγ, TNFα) concentrations after GEN3013 dosing correlated with clinical symptoms of CRS in most pts. No pts had tumor lysis syndrome or neurological symptoms. No DLTs were observed. GEN3013 PK profiles reflect SC dosing; Cmax occurred 2-4 days after dosing. No ADAs were detected. PD effects following GEN3013 dosing were observed at dose levels as low as 40 µg and included rapid, complete depletion of circulating B cells (if present after prior anti-CD20 therapy) and peripheral T-cell activation and expansion. The first evidence of clinical activity was observed at a dose level of 120 µg, with complete metabolic response observed in a pt with DLBCL. Conclusions: Subcutaneously administered GEN3013, a potent CD3×CD20 bsAb, shows good tolerability and early evidence of clinical activity at low dose levels in heavily pretreated pts with relapsed or refractory B-NHL. All CRS events were non-severe and did not lead to discontinuation. No DLTs were observed. Dose escalation is ongoing; updated data will be presented. Dose expansion will begin upon determining the recommended Phase 2 dose (RP2D) (NCT03625037). Disclosures Lugtenburg: Janssen Cilag: Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria, Research Funding. Mous:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; MSD: Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Clausen:Abbvie: Other: Travel grant to attend ASH 2019. Johnson:Boehringer Ingelheim: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Epizyme: Honoraria, Research Funding; Incyte: Honoraria; Takeda: Honoraria; Genmab: Honoraria; Bristol-Myers Squibb: Honoraria; Kite: Honoraria; Novartis: Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy. Oliveri:Genmab: Employment, Equity Ownership. DeMarco:Genmab: Employment, Equity Ownership. Hiemstra:Genmab: Employment, Equity Ownership, Other: Warrants. Chen:Genmab: Employment. Azaryan:Genmab: Employment. Gupta:Genmab: Employment, Equity Ownership. Ahmadi:Genmab Inc: Employment, Other: stock and/or warrants. Hutchings:Incyte: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Research Funding; Pfizer: Research Funding.

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

Blood ◽  
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.

scholarly journals 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 ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1812-1812 ◽  
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.

scholarly journals 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 ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1874-1874 ◽  
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.

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

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 638-638 ◽  
Author(s):  
Daniel A. Pollyea ◽  
Martin S. Tallman ◽  
Stephane De Botton ◽  
Courtney D. DiNardo ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Median Duration ◽  
Dose Escalation ◽  
Older Patients ◽  
Research Funding ◽  
Standard Treatment ◽  
Phase 1 ◽  
Tumor Lysis Syndrome ◽  
Employment Equity ◽  
Equity Ownership

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 &gt; 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.

A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Patients with Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 117-117 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Steven D. Gore ◽  
Barry Skikne ◽  
Christopher R. Cogle ◽  
Yuhong Ning ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dose Escalation ◽  
Research Funding ◽  
Oral Therapy ◽  
Phase 1 ◽  
Employment Equity ◽  
Dose Escalation Study ◽  
Platelet Counts ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 117 Background: Parenteral azacitidine significantly improves overall survival of subjects with higher-risk MDS and WHO AML (20–30% blasts) compared to conventional care (Fenaux, Lancet Oncol 2009; 10:223). An oral formulation would be a more convenient administration route for patients and allow the evaluation of extended low-dose regimens, which could in turn lead to better treatment efficacy and lower toxicity profiles. The aim of this phase 1 study is to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of increasing doses of orally-administered azacitidine in subjects with MDS or AML. Methods: Subjects aged ≥ 18 years with a diagnosis of MDS or AML (not candidates for other therapies) by WHO criteria were enrolled into this multicenter, Phase 1, dose escalation study. Prior treatment with azacitidine or other demethylating agent was permitted. To allow PD/PK analyses of oral vs. subcutaneous (SC) administration, azacitidine was administered SC (75 mg/m2/day x 7 days) in Cycle 1, then orally in Cycle 2 starting at a dose of 120 mg/day x 7 days of every 28-day cycle. A standard “3+3” dose escalation design was used and an expansion cohort at the MTD was planned. Subjects were evaluated for DLT during the first cycle of oral azacitidine therapy. Azacitidine levels in plasma and urine were measured. DNA methylation was assayed using Illumina's Infinium Human Methylation27 BeadArrays. Response was assessed according to International Working Group (IWG) criteria for MDS (2006) and AML (2003). Results: To date, 45 subjects have enrolled into the study. Forty subjects received both SC and oral azacitidine; 5 subjects received SC azacitidine only. Median age is 70 years (range 31–91). Thirty-four subjects had MDS, 9 AML, and 2 CMML. Median pretreatment WBC and platelet counts of MDS subjects were 2.5 × 109/L (range 0.8–39.4) and 55.0 × 109/L (range 4.0–234.0) respectively. For subjects with AML, the median pretreatment WBC and platelet counts were 1.8 × 109/L (range 0.5–3.4) and 42.8 × 109/L (range 10.0–82.0) respectively. Baseline cytogenetics for subjects with MDS were as follows: 12 complex karyotype; 10 diploid; 1 with −7; 1 with t(11q23) and 10 whose karyotype was unknown. Doses of oral azacitidine evaluated were 120, 180, 240, 300, 360, 480 and 600 mg. The MTD of oral azacitidine on a 7-day QD treatment schedule was 480 mg. The DLT was grade 3 or 4 diarrhea in 2 of 3 subjects enrolled in the 600 mg cohort. Other grade 3 or 4 AEs reported include febrile neutropenia (6 subjects), infection (6 subjects), nausea (2 subjects), vomiting (2 subjects), fatigue (2 subjects), and thrombocytopenia (2 subjects). The bioavailability of oral azacitidine ranged from 5% to 35%. The exposure (AUCinf) of oral azacitidine was highly variable compared to SC exposure, ranging from 15% to 74% (except for one subject whose PK exposure following oral therapy was 167% of his SC exposure). Median duration of oral azacitidine was 5+ cycles (range 1–19+) for subjects with MDS and 2.5+ cycles (range 1–6+) for subjects with AML. Responses were evaluated following 6 cycles of oral therapy. To date, 14 subjects have received ≥ 6 cycles of oral azacitidine: 4 (29%) had complete response (CR), 6 (43%) had stable disease (SD), 3 (21%) had disease progression, and 1 subject (7%) was not evaluated. Among subjects with CR or SD, hematologic improvement by disease-specific IWG criteria included erythroid response (n = 5), platelet response (n = 5) and neutrophil response (n = 3). Fourteen subjects are ongoing, but have not completed 6 cycles of oral therapy; 17 subjects discontinued prior to completing 6 cycles. Changes in DNA methylation were observed in the blood of MDS and AML subjects following SC and oral azacitidine treatment, and a set of CpG loci were identified for which these changes were associated with azacitidine AUCinf and/or Cmax.. In addition, approximately 260 hypomethylated loci were common to both SC and oral therapy. Conclusions: Results to date indicate that a 7-day dosing regimen of oral azacitidine is active and well tolerated, with a manageable side effect profile in subjects with MDS or AML. Oral azacitidine exposure was highly variable and lower than that of SC azacitidine. Changes in DNA methylation were observed in the blood of MDS and AML subjects following SC and oral therapy. Evaluation of prolonged and BID treatment schedules is planned. Disclosures: Garcia-Manero: Celgene: Research Funding. Gore:Celgene: Consultancy, Equity Ownership, Research Funding; Johnson & Johnson: Research Funding. Skikne:Celgene: Employment. Cogle:Celgene: Research Funding, Speakers Bureau; Eisai: Speakers Bureau. Ning:Celgene: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Ward:Celgene: Employment, Equity Ownership.

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