Phase IIb Randomized Study of CPX-351 Vs. Conventional Cytarabine + Daunorubicin in Newly Diagnosed AML Patients Aged 60-75: Safety Report.

Abstract Abstract 1033 Poster Board I-55 CPX-351 is a liposomal formulation that encapsulates cytarabine and daunorubicin at a 5:1 molar ratio that is consistently synergistic and avoids antagonism across multiple leukemic and solid tumor cell lines, in vitro. In preclinical observations CPX-351 has been shown to accumulate in bone marrow where it is preferentially taken up by leukemia cells. A recently completed Phase 1 study recommended that 90-minute infusions of 101 u/m2 be given on Days 1, 3, and 5 (1 u = 1 mg cytarabine + 0.44 mg daunorubicin). The results suggested that liposomal encapsulation of this chemotherapy doublet might change the safety profile by reducing non-hematologic toxicities including alopecia, gastrointestinal toxicities (such as mucositis), and hepatic toxicity, while retaining hematopoietic cytotoxicity as evidenced by a high proportion of aplasia achieved and a significant number of complete remissions. A Phase 2 randomized study was initiated comparing CPX-351 with conventional cytarabine + daunorubicin (“7 + 3” regimen) in AML patients aged 60-75. This report summarizes safety data for the first 45 patients. Materials and Methods: Patients with de novo or therapy-related AML or AML evolved from an antecedent hematologic disorder, ECOG PS of 0-2, SCr < 2.0 mg/dL, total bilirubin < 2.0 mg/dL, ALT/AST < 3 x ULN, and cardiac ejection fraction >50% by echo or MUGA were eligible. Patients are randomized 2:1 to receive CPX-351 (100u/m2 Day 1, 3, and 5 by 90 minute infusion) or to “7 + 3” (cytarabine 100mg/m2/d for 7 days by continuous IV infusion and daunorubicin 45-60mg/m2 Day 1, 2 and 3 by IV push). Results: As of Aug. 1, 2009, 45 of the 80 patients enrolled to date have been randomized (31 to CPX-351 and 14 to “7 + 3” Control), treated and completed follow-up sufficient to capture safety data for at least the first induction course. Among this group of 45 patients one or more SAE events, as defined in the protocol, were reported in 15/31 (42%) CPX-351 patients and 5/14 (29%) Control patients. Deaths during induction were infrequently reported in both arms of the study [1 (3%) vs. 1 (7%)]. One patient in each arm of the study died of sepsis related events on Days 20 and 19, respectively. One post-induction death occurred in a patient in the CPX-351 arm who died on Day 83 of an intracranial bleed, 24 days after start of consolidation therapy. Cytopenia-related events associated with treatment of leukemia accounted for the majority of the SAEs in both arms of the study, including 11 of the 15 (73%) SAEs in the CPX-351 arm and 3 of 5 (60%) SAEs in the control arm. These SAEs consisted of fever and febrile neutropenia (13% vs.14%), sepsis (3% vs. 7%), pneumonia (3% vs. 0), major bleeding episodes (3% vs. 0) and a number of minor infections and anemia. Data for all adverse events are available for 41 patients and events occurring in 10 or more patients are presented in the table below. Skin rash was more common with CPX-351 and rigors/chills were more common with “7 + 3”. The majority of other adverse events were similar (±15%) in the two groups. Discussion/Conclusion: In this study, induction mortality to date with CPX-351 is low (3%). The overall toxicity of CPX-351 appears comparable to that due to 7 + 3. As observed in the Phase 1 study of CPX-351, grade 3/4 GI adverse events were distinctly uncommon. No adverse events unique to CPX-351 were observed. CPX-351 exhibits an acceptable safety profile for use in older, newly diagnosed AML patients. Disclosures: Chiarella: Celator Pharmaceuticals: Employment. Louie:Celator Pharmaceuticals: Employment.

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Phase 1 study of the liposomal formulation of eribulin (E7389-LF): Results from the advanced gastric cancer expansion cohort.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4025 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4025-4025

Author(s):

Kensei Yamaguchi ◽

Satoru Iwasa ◽

Motohiro Hirao ◽

Takashi Oshima ◽

Kazuaki Harada ◽

...

Keyword(s):

Gastric Cancer ◽

Febrile Neutropenia ◽

Safety Profile ◽

Phase 1 ◽

Objective Response ◽

Safety Data ◽

Metastatic Breast ◽

Prior Treatment ◽

Phase 1 Study ◽

Expansion Cohort

4025 Background: Eribulin has proven efficacy in previously treated metastatic breast cancer and liposarcoma. E7389-LF is a new formulation that uses liposomes to encapsulate eribulin, which is anticipated to improve eribulin concentration in tumor tissues. In the dose-expansion part of a phase 1 study of E7389-LF, the safety profile was acceptable and 2 patients (pts) out of 10 with gastric cancer (GC) had an objective response. Thus, the GC cohort was expanded for further evaluation. Here, we report efficacy and safety data from the phase 1 expansion cohort of pts with advanced GC who were treated with E7389-LF. Methods: Eligible pts were those with GC who had no alternative standard or effective therapy options after ≥2 prior chemotherapy regimens. Target total enrollment was 32 pts (10 pts in the initial GC cohort plus an additional 22 pts in the expanded cohort). E7389-LF 2.0 mg/m2 was administered intravenously once every 3 weeks. Tumor responses were assessed every 6 weeks (± 1 week) by RECIST v1.1. Results: At data cutoff (Oct 16, 2020), 34 pts with GC were enrolled (10 pts in the initial GC cohort; 24 pts in the expanded GC cohort) with a median of 5 prior therapies (range, 2–11). Previous immune checkpoint inhibitor (ICI) therapy was reported for 26 (76.5%) pts. All pts were evaluable for objective response rate (ORR) and progression-free survival (PFS), and 30 pts were evaluable for overall survival (OS). Among all pts with GC, the ORR was 17.6% (95% CI 6.8–34.5) and the disease control rate was 79.4% (95% CI 62.1–91.3). Median PFS was 3.7 months (95% CI 2.7–4.3) and median OS was 7.6 months (95% CI 6.7–15.4). The ORRs were 19.2% (95% CI 6.6–39.4) in ICI-pretreated pts and 12.5% (95% CI 0.3–52.7) in pts without prior ICI therapy. Median PFS was similar regardless of prior treatment with ICIs (3.7 months [95% CI 2.7–5.6] in ICI-pretreated pts vs 3.4 months [95% CI 1.0–4.3] in pts without prior ICI therapy); however, the PFS rate at 6 months in ICI-pretreated pts was higher vs the rate in pts without prior ICI therapy (35.9% [95% CI 17.2–55.1] vs 0%, respectively). Median OS was also longer in ICI-pretreated pts (evaluable pts, n = 23) vs pts without prior ICI therapy (evaluable pts, n = 7) (10.0 months [95% CI 6.7–not estimable] vs 6.7 months [95% CI 3.1–8.5], respectively). Common grade ≥3 adverse events included neutropenia (41.2%), leukopenia (29.4%), and anemia (26.5%). In cycle 1, there were no cases of febrile neutropenia among the 22 pts treated with prophylactic peg-GCSF; among pts who did not receive prophylactic peg-GCSF, 16.7% of pts had febrile neutropenia. Conclusions: E7389-LF had a manageable safety profile and encouraging activity in pts with heavily treated GC. In pts with GC, prior treatment with ICIs might enhance the potential efficacy of E7389-LF. These results support further development of E7389-LF for advanced GC. Clinical trial information: NCT03207672.

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An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with castrate-resistant prostate cancer (CRPC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.5062 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 5062-5062

Author(s):

G. R. MacVicar ◽

A. Greco ◽

J. Reeves ◽

J. Maleski ◽

J. Holmlund ◽

...

Keyword(s):

Adverse Events ◽

Phase 1 ◽

Single Agent ◽

Safety Data ◽

Preliminary Evidence ◽

Open Label ◽

Serious Adverse Events ◽

Vein Thrombosis

5062 Background: Antiapoptotic Bcl-2 family proteins are overexpressed in CRPC and contribute to resistance to therapy. The oral pan-Bcl-2 inhibitor AT-101 (Bcl-2, Bcl-XL, Bcl-W, Mcl-1) is active as a single agent and in combination in in vitro and in vivo tumor models and as a single agent in CRPC. The Phase 1 portion of the study determined the recommended dose for phase II to be D (75mg/m2 q3weeks) in combination with P (5mg b.i.d. on days 1–21), and AT-101 at 40mg b.i.d. on days 1–3 of each 21-day cycle, and was previously reported. Methods: Men ≥18 years of age with chemotherapy-naïve CRPC (N = 36). Safety (NCI CTCAE v3.0) and efficacy (Bubley Criteria for PSA) were assessed at 3-wk intervals. Radiological assessments were performed at 6-wk intervals for pts with soft tissue disease and bone scans were performed after cycle 6 and at the completion of therapy. Results: 36 patients (pts) have been enrolled in the study. Twenty-four (67%) pts achieved a partial response (PR) (>50% PSA decline), and 26 (72%) pts treated had at least a 30% decrease in PSA level. Nine of 19 pts (47%) with measurable disease had a PR. One PR was unconfirmed per RECIST. Thirteen pts (36%) completed >10 cycles of therapy (range 2–24) thus far. Four pts remains active. Safety data is available for 31 pts. The most common (>20%) Adverse Events (AEs) include: fatigue (68%), nausea (52%), diarrhea (45%), alopecia (32%), constipation and dysgeusia (26%), and neutropenia and vomiting (26%). Neutropenia was the only gr. 4 event occurring in more than one pt (3pts). Serious Adverse Events (SAEs) considered related were reported in 5 pts (16%). The only SAEs reported in 2 or more pts were urinary tract infection (3 pts) and deep vein thrombosis (2 pts) and none were considered related. No ileus has been reported. Conclusions: AT-101 when given in combination with D/P is well tolerated and shows preliminary evidence of efficacy in pts with CRPC. A randomized trial is ongoing. [Table: see text]

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A Phase 1 and Correlative Biological Study of CSL360 (anti-CD123 mAb) in AML

Blood ◽

10.1182/blood.v112.11.2956.2956 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2956-2956 ◽

Cited By ~ 5

Author(s):

Andrew W. Roberts ◽

Simon He ◽

Kenneth F Bradstock ◽

Mark S Hertzberg ◽

Simon T S Durrant ◽

...

Keyword(s):

Adverse Events ◽

Dose Level ◽

De Novo ◽

Biological Effects ◽

Phase 1 ◽

Dose Range ◽

Clinical Signs ◽

Biological Study

Abstract CD123 (IL-3Rα) is a phenotypic marker of putative leukemic stem cells (LSC) in AML (Jordan, Leukemia2000;14:1777). We and others have found that CD34+38− cells from AML patients (pts) express high levels of CD123, in contrast to absence of expression on CD34+38− cells in normal individuals. Binding of CD123 by monoclonal antibody (mAb) 7G3 inhibits IL-3-dependent signalling and proliferation in vitro. In a NOD-SCID xenograft model 7G3 inhibits human AML engraftment, but not normal human hematopoiesis (Lock ASH2007; Abs161). CSL360, a recombinant chimeric IgG1 mAb derived from 7G3, binds the same epitope. CSL360 concentrations ≥ 0.1μg/mL in vitro inhibited 90% AML cell growth in the presence of supraphysiological IL-3 levels. Preclinical toxicology studies with doses up to 100 mg/kg weekly × 4 in cynomolgus monkeys showed no CSL360-related effects in clinical signs, hematology, chemistry, urinalysis, gross pathology or histopathology. A Phase 1 study of safety, pharmacokinetics (PK) and bioactivity of CSL360 in relapsed, refractory or high risk AML began in March 2007. Pts receive 12 weekly iv infusions if not withdrawn early due to treatment-related toxicity or disease progression. Additional treatments may be given to pts who achieve a response. Bone marrow aspirates/trephine samples are obtained at screening, after dose 3 and before doses 5 and 11. More than 180 infusions have been administered to 26 AML pts (21 M, 5 F; 17 de novo, 8 MDS-related, 1 treatment-related AML) in 5 dose level cohorts: 0.1, 0.3, 1.0, 3.0 and 10 mg/kg. There is no intra-patient dose escalation. PK parameters over the dose range, estimated in 19 pts over 7 days after doses 1 and 4, were linear with dose-proportional increases in the AUC and Cmax; dose 1 Cmax ranged from 0.62 – 287.33 μg/mL and dose 4 Cmax from 1.02 – 178.22 μg/mL. CSL360 mean plasma half-life (dose 1, 83 ± 33 h; dose 4, 117 ± 59 h) appears to be independent of dose and treatment number. Dose 1 systemic clearance (0.21 ± 0.16 L/h) and volume of distribution (0.39 ± 0.22 L/kg) were relatively low, consistent with this size IgG. In all pre-treatment samples anti-CSL360 antibody titers were negative, determined by enzyme immunoassay. Anti-CSL360 antibodies were detected post-treatment in 8/12 pts; these antibodies have not been fully quantified or characterised. CSL360 has been well tolerated; a MTD has not been defined. Seven pts received all 12 doses, 13 pts were withdrawn due to progressive disease or investigator’s decision, 3 pts were withdrawn in association with infections, 2 pts withdrew consent, and 1 pt is ongoing. Three serious adverse events have been considered possibly related or related to CSL360: 1 invasive fungal infection (Gr 5), and 2 infusion reactions (Gr 2; hospitalised). Other adverse events are consistent with expectations for the disease population. Of 8 pts in the 3 mg/kg and 10 mg/kg cohorts who are evaluable for response after ≥ 4 doses, 1 complete response (CR) has been observed. A 22 yr old male, de novo FAB M1 cytogenetically normal AML, who had relapsed post-2 allogeneic SCT, achieved a morphologic leukemia free state after 3 doses (3.0 mg/kg) and CR after 12 doses, sustained for > 9 weeks. The pt received 17 doses before withdrawal to treat co-morbidities. Flow cytometry studies with anti-CD123 antibodies demonstrated dose-dependent CSL360 coating of both AML blasts and LSC. Saturation of target antigen on marrow and blood cells was observed 1 day after dosing at 0.3mg/kg, associated with decreased expression of CD123 detected by an antibody to a different epitope. At higher dose levels saturation of CD123 was maintained 7 days post dosing, associated with ongoing reduction in surface CD123 expression. In a representative sample, plasma from a pt treated at 10 mg/kg specifically inhibited IL-3-induced proliferation of AML blasts ex vivo, indicating sufficient circulating concentration of CSL360 to inhibit IL-3 mediated effects in vivo. Effects of CSL360 on proliferation and apoptosis of AML cells in treated patients are being investigated. These preliminary results show anti-CD123 mAb therapy with CSL360 is safe and tolerable; biological effects have been demonstrated; a sustained CR was achieved in 1 advanced, refractory AML pt. The study is continuing, with 20 evaluable patients to be accrued and treated at 10 mg/kg weekly; at this dose level the PK and correlative assays predict that complete blockade of IL-3 signalling through CD123 can be achieved in vivo.

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Safety profile of avelumab in patients with advanced solid tumors: A JAVELIN pooled analysis of phase 1 and 2 data.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3059 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3059-3059 ◽

Cited By ~ 5

Author(s):

Karen Kelly ◽

Jeffrey R. Infante ◽

Matthew H. Taylor ◽

Manish R. Patel ◽

Michael S. Gordon ◽

...

Keyword(s):

Adverse Events ◽

Safety Profile ◽

Phase 1 ◽

Safety Data ◽

Pooled Analysis ◽

Clinical Activity ◽

Thyroid Disorder ◽

Phase 2 ◽

Phase 2 Trial ◽

Grade 3

3059 Background: Avelumab is a fully human IgG1 anti–PD-L1 antibody with clinical activity in several tumor types. Pooled safety data from a large phase 1 trial in various tumors and a phase 2 trial in Merkel cell carcinoma (NCT01772004, NCT02155647) were analyzed to further characterize the safety profile of avelumab. Methods: Patients (pts) received avelumab 10 mg/kg 1-hour IV Q2W until progression, unacceptable toxicity, or withdrawal. Treatment-related adverse events (TRAEs) were graded by NCI CTCAE. In post hoc analyses, immune-related adverse events (irAEs) were identified via an expanded AE list and medical review, and infusion-related reaction (IRR) events were identified based on prespecified MedDRA terms, occurring within 1 day or related symptoms that resolved within 2 days of infusion. Results: In 1,738 pts analyzed (phase 1, n = 1,650; phase 2, n = 88) who received ≥1 dose of avelumab for a median of 12 weeks (range 2-138), the most common any grade TRAEs were fatigue (n = 307, 18%), IRR (n = 295, 17%), and nausea (n = 150, 9%). 177 pts (10%) had a grade ≥3 TRAE; most common were fatigue and elevated lipase (17 [1%] each). TRAEs led to discontinuation in 107 pts (6%). Four pts (0.2%) died due to a TRAE. Any grade irAEs occurred in 247 pts (14%), which were grade ≥3 in 39 pts (2%) and considered serious in 43 pts (2%). The most common any grade irAEs were thyroid disorder (n = 98, 6%) and rash (n = 90, 5%). Other irAEs (eg, colitis, hepatitis, pneumonitis, adrenal insufficiency, myositis) each occurred in < 2%. irAEs led to discontinuation in 34 pts (2%). IRR or related symptoms (eg, chills, pyrexia, hypersensitivity) occurred in 439 pts (25%), which were grade 3 in 9 pts (0.5%) and grade 4 in 3 pts (0.2%). An IRR occurred at first infusion in 79% and within first 4 doses in 99%; 63/439 pts (14%) had IRR recurrence in later cycles. IRR led to dose interruption in 152 (9%), infusion rate reduction in 124 (7%), and discontinuation in 35 pts (2%). Conclusions: This large pooled analysis confirms that avelumab has an acceptable safety profile. A minority of pts experienced a grade ≥3 TRAE or irAE and discontinuation due to TRAEs was uncommon. IRRs mostly occurred at first infusion and the rate of recurrence was low. Clinical trial information: NCT01772004, NCT02155647.

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627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0627 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A663-A663

Author(s):

Keegan Cooke ◽

Juan Estrada ◽

Jinghui Zhan ◽

Jonathan Werner ◽

Fei Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Growth ◽

Mouse Models ◽

T Cell Activation ◽

Phase 1 ◽

Phase 1 Study ◽

Human T Cells

BackgroundNeuroendocrine tumors (NET), including small cell lung cancer (SCLC), have poor prognosis and limited therapeutic options. AMG 757 is an HLE BiTE® immune therapy designed to redirect T cell cytotoxicity to NET cells by binding to Delta-like ligand 3 (DLL3) expressed on the tumor cell surface and CD3 on T cells.MethodsWe evaluated activity of AMG 757 in NET cells in vitro and in mouse models of neuroendocrine cancer in vivo. In vitro, co-cultures of NET cells and human T cells were treated with AMG 757 in a concentration range and T cell activation, cytokine production, and tumor cell killing were assessed. In vivo, AMG 757 antitumor efficacy was evaluated in xenograft NET and in orthotopic models designed to mimic primary and metastatic SCLC lesions. NSG mice bearing established NET were administered human T cells and then treated once weekly with AMG 757 or control HLE BiTE molecule; tumor growth inhibition was assessed. Pharmacodynamic effects of AMG 757 in tumors were also evaluated in SCLC models following a single administration of human T cells and AMG 757 or control HLE BiTE molecule.ResultsAMG 757 induced T cell activation, cytokine production, and potent T cell redirected killing of DLL3-expressing SCLC, neuroendocrine prostate cancer, and other DLL3-expressing NET cell lines in vitro. AMG 757-mediated redirected lysis was specific for DLL3-expressing cells. In patient-derived xenograft and orthotopic models of SCLC, single-dose AMG 757 effectively engaged human T cells administered systemically, leading to a significant increase in the number of human CD4+ and CD8+ T cells in primary and metastatic tumor lesions. Weekly administration of AMG 757 induced significant tumor growth inhibition of SCLC (figure 1) and other NET, including complete regression of established tumors and clearance of metastatic lesions. These findings warranted evaluation of AMG 757 (NCT03319940); the phase 1 study includes dose exploration (monotherapy and in combination with pembrolizumab) and dose expansion (monotherapy) in patients with SCLC (figure 2). A study of AMG 757 in patients with neuroendocrine prostate cancer is under development based on emerging data from the ongoing phase 1 study.Abstract 627 Figure 1AMG 757 Significantly reduced tumor growth in orthotopic SCLC mouse modelsAbstract 627 Figure 2AMG 757 Phase 1 study designConclusionsAMG 757 engages and activates T cells to kill DLL3-expressing SCLC and other NET cells in vitro and induces significant antitumor activity against established xenograft tumors in mouse models. These preclinical data support evaluation of AMG 757 in clinical studies of patients with NET.Ethics ApprovalAll in vivo work was conducted under IACUC-approved protocol #2009-00046.

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1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1471 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S659-S659

Author(s):

Angela Talley ◽

Archie Thurston ◽

Grayson Moore ◽

Myriah M Satterfield ◽

Erika L Manyak ◽

...

Keyword(s):

Adverse Events ◽

Healthy Volunteers ◽

Controlled Trial ◽

Phase 1 ◽

Safety Data ◽

Elderly Subjects ◽

Independent Contractor ◽

Serious Adverse Events ◽

Healthy Elderly ◽

Dose Proportional

Abstract Background SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14. Conclusion Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Disclosures Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)

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Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle East Respiratory Syndrome Coronavirus

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab036 ◽

2021 ◽

Author(s):

Sumathi Sivapalasingam ◽

George A Saviolakis ◽

Kirsten Kulcsar ◽

Aya Nakamura ◽

Thomas Conrad ◽

...

Keyword(s):

Middle East ◽

Adverse Events ◽

Phase 1 ◽

Human Monoclonal Antibody ◽

Preclinical Study ◽

Middle East Respiratory Syndrome ◽

Lung Pathology ◽

Phase 1 Study ◽

Serious Adverse Events ◽

Dipeptidyl Peptidase 4

Abstract Background REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. Methods Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. Results Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. Conclusions REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.

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The combination of venetoclax, lenalidomide, and rituximab in patients with newly diagnosed mantle cell lymphoma induces high response rates and MRD undetectability.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7505 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7505-7505

Author(s):

Tycel Jovelle Phillips ◽

Alexey Valeryevich Danilov ◽

David Alan Bond ◽

Alex Francisco Herrera ◽

Kami J. Maddocks ◽

...

Keyword(s):

Phase 1 ◽

Safety Data ◽

Standard Of Care ◽

Primary Objective ◽

Clinical Activity ◽

Newly Diagnosed ◽

Grade 5 ◽

Unrelated Condition ◽

Mantle Cell ◽

Grade 3

7505 Background: MCL is a rare lymphoma without a standard of care but several regimens have demonstrated clinical activity, the majority based on traditional chemotherapy. We hypothesized that adding venetoclax (V) to R2 would be safe and effective in MCL pts irrespective of age, morphology or stage. Here we present safety and efficacy data from the on-going phase 1b study of R2 + V in pts with newly diagnosed MCL. Methods: This multi-center phase 1 study (NCT03523975) enrolled pts aged ≥18 yrs with untreated MCL. The primary objective was to characterize the safety and tolerability of R2 + V and determine the MTD. During induction (12 months (m)) pts received lenalidomide (L) 20 mg daily on day 1-21, Rituximab (R) was given weekly during c1 then on day 1 of every even cycle, V was escalated over 4 weeks to 400 mg beginning day 8. Each cycle is 28 days (d). The DLT period was 42 d beginning C1D8. In maintenance, R every 8 weeks for 36m, L at 10 mg or half of last dose during induction for 24 m and V for minimum 12 m. No pts have been transplanted. Pts with progression (PD) came off study. MRD was analyzed in parallel with scans during induction by clonoSEQ assay (Adaptive Biotechnologies). Results: As of Feb. 1st, 2021, we have enrolled all 28 planned pts on study. Pt characteristics/responses are summarized in Table. Among the 28 pts who have received at least one dose, the median treatment duration so far is 278d (IQR 170-560), with 24 pts still on treatment (Tx). 1 pt is off from a unrelated condition. All pts escalated to V 400 mg w/o any DLTs noted. Treatment-emergent adverse events (TEAEs) were reported in 100% of pts, and grade 3+ TEAEs were reported in 26 (93%) patients. The most common all-grade TEAEs (≥50% of pts), regardless of relationship to study Tx, were fatigue, neutropenia and diarrhea. Grade ≥3 TEAEs reported in ≥50% pts were neutropenia (68%) and thrombocytopenia (50%). No pts have withdrawn or d/c Tx due to AEs. There was one grade 5 event, in a non-evaluable pt, related to a PE that occurred prior to DLT period. In the 28 evaluable pts the ORR (CR/PR) was 96% (27/28 pts) with CR/CRu of 89%. Of the responding pts, two had PD, one w/ CR and one w/ PR. All pts with PD had baseline TP53 mutation. MRD testing was successful in all pts. At time of submission 20 of 28 (71%) were MRD - at 10-6. Conclusions: Interim results show that at the MTD the combination of V 400 mg daily, L 20 mg, with R is safe with a manageable toxicity profile and a high ORR and MRD - in pts with newly diagnosed MCL. Safety data is consistent with the AE profile noted for each drug without any unexpected or unique AEs. Updated results including BH3 profiling will be presented at the meeting. Clinical trial information: NCT03523975. [Table: see text]

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Final Results of Phase 1/1b Study of Tenalisib, Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽

10.1182/blood-2019-123954 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2831-2831 ◽

Cited By ~ 1

Author(s):

Swaminathan P. Iyer ◽

Brad M. Haverkos ◽

Jasmine Zain ◽

Radhakrishnan Ramchandren ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Board Of Directors ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: 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; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.

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