Comparative Safety of Two Bendamustine Hydrochloride Formulations; A Ready-to-Dilute Low-Volume, Rapid Infusion Solution, and a Lyophilized Powder: Results from a Phase 1 Study

Abstract Introduction: This phase 1, open-label, randomized, crossover study was performed to test the bioequivalence and safety of an investigational, ready-to-dilute, rapid infusion (low volume) solution of bendamustine hydrochloride (test product [T]), and the approved bendamustine lyophilized powder formulation (reference product [R]). [ClinicalTrials.gov Identifier: NCT02162888] Methods: Patients were eligible to participate if they had a histologically confirmed diagnosis of any malignant disease (excluding chronic lymphocytic leukemia) for which no curative or standard therapy was available. All patients received bendamustine 120 mg/m2 intravenously as T (in 50 mL; 0.9% NaCl) over 10 min and R (in 500 mL; 0.9% NaCl) over 60 min on days 1 and 2 of two consecutive 28-day cycles. Patients were randomly assigned to one of three treatment sequences for the first three doses of study drug: TRR, RTR, RRT; T was given to all patients at cycle 2, day 2 (dose 4) (Figure). Safety was assessed throughout the 56-day treatment period, with events of special interest (expected reactions to bendamustine or underlying disease) recorded during and up to 1 h after administration; up to 24 h after administration; and on cycle 1 days 21 and 28; cycle 2 day 28; and at the end-of-study visit. Safety assessments included reported adverse events (AEs), Eastern Cooperative Oncology Group performance status, vital sign measurements, physical examination, and clinical laboratory assessments. Results: A total of 83 patients were randomized to the 3 treatment sequences; 81 received at least one dose of study drug and comprised the safety population. Fifty-nine (71.1%) patients received four doses of study treatment, with a similar number (67%-77%) of patients in each treatment sequence arm. Reasons for discontinuation were AEs (4 patients), death (3 patients), insufficient therapeutic response (4 patients), lost to follow-up (1 patient), sponsor request (2 patients), investigator request (3 patients), withdrew consent (5 patients), and other (2 patients). The frequency of treatment-emergent AEs (TEAEs) by most recent study treatment are shown in the Table. The most commonly occurring AEs (> 10%) overall were nausea (R 25%, T 19%), fatigue (R 21%, T 22%), dehydration (R 12%, T 15%), decreased appetite (R 11%, T 15%), anemia (R 12%, T 15%), pyrexia (R 6%, T 16%), constipation (R 11%, T 11%), vomiting (R 11%, T 8%), dyspnea (R 5%, T 12%), hypokalemia (R 4%, T 12%), diarrhea (R 6%, T 10%), abdominal pain (R 5%, T 10%), and thrombocytopenia (R 2%, T 11%). The most common AEs occurring during the infusion and within 1 h after infusion were nausea (R 6%, T 8%) and fatigue (R 5%, T 6%); nausea (R 11%, T 9%) and fatigue (R 8%, T 9%) were also most common in the first 24 h. Infusion reactions were experienced by ≤ 2% of patients treated with either T or R. Serious AEs occurring in > 1 patient were abdominal pain (R 1%, T 5%), chest pain (R 2%, T 0), deep vein thrombosis (R 2%, T 0), dehydration (R 1%, T 1%), pericardial effusion (R 1%, T 1%), and vomiting (R 1%, T 3%). Six deaths were reported; the primary cause of death for all six patients was progressive disease. Conclusions: No new safety signals were observed. The fact that all patients who received 4 doses received T as their final dose introduces a source of bias and may explain the increased overall number of TEAEs attributed to T. Sponsor: Eagle Pharmaceuticals, Inc. Table. TEAEs by Most Recent Treatment (Safety Population) Rn = 81 Tn = 73 Events Patients n (%) Events Patients n (%) During or within 1 h after infusion All TEAEs 40 26 (32.1) 38 21 (28.8) Grade 3-4 0 0 1 1 (1.4) Serious AEs 0 0 1 1 (1.4) Within 24 h of infusion All TEAEs 65 34 (42.0) 50 23 (31.5) Grade 3-4 5 4 (4.9) 10 6 (8.2) Serious AEs 2 2 (2.5) 5 2 (2.7) Overall All TEAEs 263 60 (74.1) 348 49 (67.1) Grade 3-4 46 19 (23.5) 66 20 (27.4) Serious AEs 23 12 (14.8) 12 12 (16.4) Figure 1. Study design. Figure 1. Study design. Disclosures Anthony: Eagle Pharmaceuticals, Inc.: Research Funding. Edenfield:Novartis, Astellas/Medivation: Speakers Bureau. Smith:Eagle Pharmaceuticals, Inc.: Employment. Hepner:Eagle Pharmaceuticals, Inc.: Employment, Equity Ownership.

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Phase 1, Open-Label, Randomized, Bioequivalence Study of 2 Bendamustine Hydrochloride Formulations; A Ready-to-Dilute Low-Volume, Rapid Infusion Solution and a Lyophilized Powder Formulation

Blood ◽

10.1182/blood.v126.23.4857.4857 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4857-4857

Author(s):

W Jeffrey Edenfield ◽

Bassam Mattar ◽

Stephen P Anthony ◽

Peter Mutch ◽

Brian Chanas ◽

...

Keyword(s):

Plasma Concentration ◽

Disease Progression ◽

Phase 1 ◽

Geometric Mean ◽

Study Drug ◽

Infusion Test ◽

Rapid Infusion ◽

Open Label ◽

Powder Formulation ◽

Low Volume

Abstract Introduction: This phase 1, open-label, randomized, crossover study assessed the bioequivalence (BE) and safety of an investigational, ready-to-dilute, rapid infusion, low-volume solution of bendamustine hydrochloride (test product [T]) and the approved bendamustine lyophilized powder formulation (reference product [R]). [CT.gov ID NCT02162888] Methods: Eligible patients (Pts) were aged 18 years or older with relapsed or refractory solid tumors or hematologic malignancies excluding chronic lymphocytic leukemia. All Pts received bendamustine 120 mg/m2 intravenously as T (in 50 mL; 0.9% NaCl) over 10 min, and as R (in 500 mL; 0.9% NaCl) over 60 min on days 1 and 2 of two consecutive 28-day cycles. Patients were randomly assigned to 1 of 3 treatment sequences defining the first 3 doses of study drug: TRR, RTR, RRT. T was given to all Pts at cycle 2, day 2. For the first 3 doses, blood samples were collected prior to infusion; mid-infusion (T 5 min, R 30 min); at 5, 15, 30, and 45 min, and at 1, 1.5, 2, 3, 4, 5, and 8 h postinfusion; and 24 h from the start of infusion on day 1 of both cycles. The pharmacokinetic (PK) endpoints for BE were area under plasma concentration-vs-time curve (AUC) from time 0 to the last quantifiable sample collected (AUC0-t) and from time 0 to infinity (AUC0-oo), which were evaluated using a scaled average BE (SABE) method, appropriate for high variability drugs. Other PK endpoints were maximum plasma concentration (Cmax), time to Cmax (tmax), and elimination half-life (t1/2). Safety was assessed by reported adverse events (AEs), Eastern Cooperative Oncology Group performance status, physical examination, and laboratory values throughout the 56-day study period. Results: A total of 83 Pts were randomized to the 3 treatment sequences; 81 received at least one dose of study drug and comprised the safety population; 60 received 3 doses (required for BE analysis). BE analyses were conducted for AUC in this population, and for other patient subsets based on dosing and sample collections deemed evaluable and complete. Here, PK results are presented for the 38 Pts meeting all BE inclusion criteria (Table 1). The BE of T and R was assessed by Reference-SABE for AUC as intra-subject variability for R (SWR) was >0.3 (Table 2). Mean concentration-vs-time is presented in the Figure. The AUC and t1/2 were similar in Pts treated with T and R. Cmax was higher and tmax was shorter in Pts treated with T, consistent with the faster infusion of bendamustine. The overall safety profiles of T and R were similar (Table 3), with serious AEs (SAEs) in 28% of Pts and 6 deaths (all attributable to disease progression). AEs occurring within 24 h of treatment were similar in type and frequency; the only AEs occurring in ≥3% of Pts with either treatment during this period were nausea (R 11%, T 9%), fatigue (R 8%, T 9%), vomiting (R 3%, T 4%), and constipation (R 4%, T 3%). Conclusions: BE of the two bendamustine formulations was demonstrated for AUCs as the upper critical values were <0 and the point estimates of T/R geometric mean ratio fell within 0.80 to 1.25 inclusive. Differences in Cmax and tmax were anticipated from the different infusion rates for the T and R. The safety profile of the two drugs was comparable with no new safety signals. Reported AEs were either known effects of bendamustine or presumed to be related to underlying disease. Sponsor: Eagle Pharmaceuticals, Inc. Table 1. Summary of PK Parameters Parameter Tn = 38 Rn = 38 AUC0-t, ng·h/mL (% CV) 10339.21 (49.3) 10514.87 (55.9) AUC0-¥, ng·h/mL (% CV) 10369.74 (49.2) 10527.76 (55.8) tmax, h (range) 0.18 (0.1-0.4) 1.0 (0.5-1.3) Cmax, ng/mL (% CV) 19158.16 (33.5) 8868.42 (47.4) t1/2, h (% CV) 0.65 (37.3) 0.60 (30.3) CV: coefficient of variation Table 2. Bioequivalence Analyses Results (n = 38) AUC(ng·h/mL) GM1 Test (T) GM1 Reference (R) T/R 90%Confidence Intervals Swr Upper Critical Value AUC0-t 9143.72 9047.81 1.01 0.898-1.145 0.403 -0.09 AUC0--¥ 9173.01 9062.77 1.02 0.899-1.146 0.402 -0.09 GM: geometric mean, Swr: within-patient standard deviation of the reference product1 by SABE Table 3. Summary of AEs Patientsn (%) Tn = 73 Rn = 81 Totaln = 81 Overall AEs 49 (67) 60 (74) 76 (94) SAEs 12 (16) 12 (15) 23 (28) Deaths* 5 (7) 1 (1) 6 (7) Occurring within 24 h of infusion AEs 23 (32) 34 (42) 49 (61) SAEs 2 (3) 2 (3) 4 (5) Deaths 0 0 0 *All attributable to disease progression Figure 1. Mean (± SD) bendamustine plasma concentration versus time for rapid-infusion test (T) and reference (R) formulations Figure 1. Mean (± SD) bendamustine plasma concentration versus time for rapid-infusion test (T) and reference (R) formulations Disclosures Edenfield: Novartis, Astellas/Medivation: Speakers Bureau. Anthony:Eagle Pharmaceuticals, Inc.: Research Funding. Mutch:Eagle Pharmaceuticals, Inc.: Employment. Chanas:Eagle Pharmaceuticals, Inc.: Employment. Smith:Eagle Pharmaceuticals, Inc.: Employment.

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A Phase 1 Study of INCB057643 Monotherapy in Patients with Relapsed or Refractory Myelofibrosis (INCB 57643-103)

Blood ◽

10.1182/blood-2020-134604 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 16-17

Author(s):

Christine Lihou ◽

Gongfu Zhou ◽

Fred Zheng

Keyword(s):

Transcription Factors ◽

Group Performance ◽

Phase 1 ◽

Study Drug ◽

Janus Kinase ◽

Primary Study ◽

Publicly Traded ◽

Bet Inhibitor ◽

Laboratory Values ◽

Consensus Report

Background: Activation of transcription factors that regulate oncogenic processes is frequently observed in cancers such as myelofibrosis (MF). In preclinical studies, tumors associated with dysregulation of transcription factors appear to be responsive to inhibition of bromodomain and extra-terminal motif (BET) protein [Delmore JE, et al. Cell 2011; Shimamura T, et al. Clin Cancer Res 2013]. In addition to exerting a direct effect on tumor cells, BET inhibitors may also modulate tumorigenic inflammation; in a mouse model of MF, BET inhibition in combination with the Janus kinase inhibitor ruxolitinib resulted in decreased inflammation and reduced disease burden [Kleppe M, et al. Cancer Cell 2018]. In the first-in-human study INCB 57643-101, the small-molecule BET inhibitor INCB057643, was safe and generally well tolerated as monotherapy, and demonstrated preliminary efficacy in 2 out of 3 patients with MF when administered alone or in combination with ruxolitinib [Falchook G, et al. Clin Cancer Res 2020]. The INCB 57643-103 trial is designed to further evaluate the safety and tolerability of INCB057643 monotherapy in patients with relapsed or refractory MF. Methods: INCB 57643-103 (NCT04279847) is a phase 1, single-arm, open-label, two-part dose confirmation and expansion study evaluating INCB057643 in patients with measurable histologically or cytologically confirmed (World Health Organization criteria 2016), relapsed or refractory primary MF or secondary MF (post-polycythemia vera, post-essential thrombocythemia). Patients must be ≥18 years of age, have received ≥1 line of prior therapy including ruxolitinib and have no option for therapy known to provide clinical benefit, have a risk category of intermediate-2 or high according to the Dynamic International Prognostic Scoring System, have an Eastern Cooperative Oncology Group performance status 0-2, have a life expectancy of 24 weeks or more, and be willing to provide a pretreatment bone marrow biopsy and/or aspirate at baseline (or an archival sample obtained after most recent therapy). Patients will be excluded if they have received prior treatment with a BET inhibitor; received anticancer treatment within specified intervals before the first administration of study drug or receiving concurrent anticancer therapy; received allogeneic hematopoietic stem cell transplant (6 months or less before enrollment) or have active graft versus host disease or received immunosuppressive therapy after allogeneic transplant 2 weeks or less before study drug treatment; have significant and uncontrolled medical events such as gastrointestinal or cardiovascular; have a history of bleeding disorder or at a high risk of bleeding; or have abnormal hematologic, hepatic, renal, coagulation, or metabolic laboratory values. Approximately 15 patients will be enrolled. Part 1 will evaluate initial safety and tolerability of INCB057643. Up to 6 patients will self-administer oral INCB057643 4 mg once daily (QD) continuously. Doses will be declared tolerable if dose-limiting toxicities (DLT) occur in ≤2 patients and discontinuation due to treatment-related adverse events (TRAEs) occurs in ≤2 patients during the DLT evaluation period. Part 2 will further characterize safety and tolerability as well as evaluate preliminary efficacy. Up to 9 patients will receive INCB057643 at 4 mg QD if the dose is deemed tolerable in Part 1; if not, the starting dose will be 2 mg QD. Treatment may continue as long as benefit is derived and discontinuation criteria are not met. The primary study objective is assessment of safety and tolerability of INCB057643 monotherapy by monitoring the frequency and severity of AEs, performing physical examinations, and collecting vital signs and laboratory values. Secondary objectives include evaluation of anemia response by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) Consensus Report, red blood cell transfusion dependence, spleen volume, rate of spleen response and duration of spleen response by IWG-MRT and ELN Consensus Report, and impact on quality of life. Patients will be assessed every 3 cycles and will receive follow-up for safety for 30-35 days after last dose of study drug. Disclosures Lihou: Incyte: Current Employment, Current equity holder in publicly-traded company. Zhou:Incyte: Current Employment, Current equity holder in publicly-traded company. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company.

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The Bruton's Tyrosine Kinase Inhibitor, PCI-32765, Is Well Tolerated and Demonstrates Promising Clinical Activity In Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): An Update on Ongoing Phase 1 Studies

Blood ◽

10.1182/blood.v116.21.57.57 ◽

2010 ◽

Vol 116 (21) ◽

pp. 57-57 ◽

Cited By ~ 13

Author(s):

Jan A. Burger ◽

Susan O'Brien ◽

Nathan Fowler ◽

Ranjana Advani ◽

Jeff Porte Sharman ◽

...

Keyword(s):

B Cell ◽

Phase 1 ◽

Study Drug ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

B Cell Malignancies ◽

Employment Equity ◽

Bcr Signaling ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 57 Introduction: Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor (BCR) signaling and is not expressed in T-cells or NK-cells. As such, Btk represents an ideal therapeutic target for B-cell malignancies dependent upon BCR signaling. Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) has been reported to have constitutively active BCR signaling. PCI-32765 is a potent, selective, irreversible and orally bioavailable small molecule inhibitor of Btk that has pre-clinical activity in B-cell malignancies (Proc Natl Acad Sci 2010;107(29):13075-80). PCI-32765 was therefore moved forward to a Phase 1 study in B-cell malignancies including patients (pts) with CLL/SLL. A subsequent CLL/SLL-specific Phase 1b study was initiated to further explore safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of PCI-32765. This report includes a composite summary of the CLL/SLL experience in both of these studies. Pts and Methods: Pts with CLL/SLL who had relapsed or refractory disease after >1 prior treatment regimens were eligible for treatment in each of the studies whereas the second Phase 1b study also included a cohort of elderly pts (aged ≥ 65 years) with CLL/SLL who required treatment and were “treatment-naive”. Responses were assessed by the investigator using the International Working Group CLL criteria (Hallek et al, Blood 2008 for pts with CLL) and the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas (Cheson et al, J Clin Oncol 2007 for pts with SLL). Results: To date, 30 CLL/SLL patients (including 4 treatment-naive) have been enrolled across the 2 studies. Eighty-four percent of subjects are men with an overall median age of 68 (range 44–82) years. Of the subjects with prior therapy for CLL/SLL the median number of prior therapies is 3 (range 1–4). Treatment has been well-tolerated; Grade ≥ 3 toxicities have been infrequent (10/30 pts; 33%). Two study-drug related serious adverse events have been reported: 1 case of viral adenitis (Grade 3) and 1 case of viral infection (Grade 2). Two adverse events have led to discontinuation of study drug: a small bowel obstruction (Grade 3) and exacerbation of chronic obstructive disease (Grade 3); both events were reported as unrelated to study drug. No study-drug related deaths have reported. There has been no change in either NK cell or T cell counts. Target inhibition as measured by a probe of Btk drug occupancy showed inhibition of Btk at PCI-32765 exposure levels of ≥ 245 ng•h/mL. Of the 14 patients currently evaluable for response using the pre-defined criteria, the overall response rate is 64% (1 complete remission [CR], 8 partial remissions [PR], and 4 SD). Both studies are ongoing and open to enrollment. An update on response rate, response duration, safety, and PD information will be presented on enrolled patients based on a November 2010 database cut-off. Conclusion: PCI-32765 is a novel oral and selective “first-in-human” inhibitor of Btk that induces objective partial and complete responses in a substantial proportion of pts with CLL/SLL and has a favorable safety profile. These data support further studies of both monotherapy and also combination treatment with PCI-32765 in CLL/SLL. Disclosures: O'Brien: Pharmacyclics, Inc: Honoraria, PI grant. Fowler:Pharmacyclics: Consultancy, Research Funding. Advani:Pharmacyclics, Inc: Honoraria, PI grant. Sharman:Pharmacyclics, Inc: Honoraria, PI grant. Furman:Pharmacyclics, Inc: PI grant. Izumi:Pharmacyclics, Inc: Employment. Buggy:Pharmacyclics, Inc: Employment, Equity Ownership. Loury:Pharmacyclics: Employment, Equity Ownership. Hamdy:Pharmacyclics, Inc: Employment, Equity Ownership.

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Phase I study of TH-302, investigational hypoxia-targeted drug, in combination with sunitinib.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15557 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15557-e15557

Author(s):

Alexander Starodub ◽

Mohammed M. Milhem ◽

Kenneth Lee Pennington ◽

Ebenezer A. Kio ◽

Daniel Bruetman ◽

...

Keyword(s):

Standard Dose ◽

Phase 1 ◽

Treatment Options ◽

Study Drug ◽

Preliminary Evidence ◽

Dose Escalation Study ◽

Neutropenic Sepsis ◽

Hypoxic Fraction ◽

Targeted Drug ◽

Grade 3

e15557 Background: Tumors often consist of highly hypoxic subregions known to be resistant to chemotherapy and radiotherapy. TH-302 is an investigational hypoxia-targeted drug with a 2-nitroimidazole trigger designed to release the DNA alkylator bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. Preclinical models demonstrate that treatment with sunitinib increased the tumor hypoxic fraction, the therapeutic target of TH-302. Initiating TH-302 following sunitinib significantly increased the efficacy of sunitinib in these models. In this phase 1 dose escalation study, TH-302 was combined with standard dose sunitinib. Methods: Eligible patients (pts) for the study (NCT01381822) had advanced RCC, GIST or PNET tumors, evaluable disease by RECIST, ECOG ≤2 and acceptable hematologic, hepatic and renal function. Pts received TH-302 in combination with standard full doses of 50 mg PO sunitinib daily from Day 1 to Day 28 of a 6 week cycle. TH-302 was administered IV on Days 8, 15 and 22. TH-302 starting dose was 240 mg/m2. The study objectives were to determine the MTD, DLTs and RP2D and to evaluate the safety and preliminary efficacy of TH-302 when used in combination with sunitinib. Results: Ten pts were enrolled. Median age: 63 (range 27-72); Female (5)/ Male (5); ECOG 0 (5); ECOG 1 (5); Primary tumor: RCC (6), GIST (4). Median prior chemotherapies: 3 (range: 0-3) including prior sunitinib in 7 pts. No DLTs were observed in the 3 pts at the 240 mg/m2 cohort and 1 pt of 5 DLT evaluable in the 340 mg/m2 cohort had a DLT of stomatitis. Eight pts discontinued (progressive disease (6), pursued other treatment options, adverse event unrelated to study drugs). Three pts had a study drug related SAE (neutropenic sepsis, anemia, hyperthyroidism). Common TH-302 related AEs were nausea and mucosal toxicity and were mostly grade 1 or 2. Grade 3/4 thrombocytopenia and neutropenia were reported in 4 pts and 3 pts, respectively. One of 4 (25%) pts with GIST had a confirmed PR and 3 of 4 (75%) pts with RCC had PRs including 2 with confirmed PRs. Conclusions: TH-302 can be administered in combination with full dose sunitinib. Mucositis was dose limiting. There is preliminary evidence of activity of TH-302 in combination with sunitinib in RCC. Clinical trial information: NCT01381822.

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Safety of epacadostat 100 mg bid plus pembrolizumab 200 mg Q3W in advanced solid tumors: Phase 2 data from ECHO-202/KEYNOTE-037.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3012 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3012-3012 ◽

Cited By ~ 16

Author(s):

Omid Hamid ◽

Todd Michael Bauer ◽

Alexander I. Spira ◽

David C. Smith ◽

Anthony J. Olszanski ◽

...

Keyword(s):

Cell Carcinoma ◽

Checkpoint Inhibitors ◽

Phase 1 ◽

B Cell Lymphoma ◽

Phase 2 ◽

Phase 3 ◽

Indoleamine 2 ◽

Safety Population ◽

Common Grade ◽

Grade 3

3012 Background: The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) facilitates immune tolerance in cancer via T-cell suppression, and IDO1 overexpression is associated with poor survival. Epacadostat, an oral inhibitor of IDO1, has been shown to be well tolerated as monotherapy and in combination with checkpoint inhibitors. ECHO-202/KEYNOTE-037 is a phase 1/2 study evaluating the safety and efficacy of oral epacadostat plus IV pembrolizumab in patients (pts) with advanced tumors. Based on phase 1 outcomes, epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was selected for phase 2 evaluation. This analysis summarizes phase 2 safety experience in the overall population of ECHO-202/KEYNOTE-037 (pooled across tumor types) at an October 29, 2016 data cutoff. Methods: Phase 2 pts were ≥18 years of age with advanced or recurrent melanoma (MEL), non–small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma (UC), triple-negative breast cancer, squamous cell carcinoma of head and neck (SCCHN), ovarian cancer, diffuse large B-cell lymphoma, or microsatellite instability–high colorectal cancer. Results: The overall safety population comprised 244 pts receiving ≥1 study treatment dose. Median age was 63 years, 52% were women, and 91% were white. As of data cutoff, 134 study pts (55%) discontinued study treatment, primarily due to disease progression (n = 97). Median exposure to study treatment was 86 days (range, 1–374 days). TRAEs occurring in ≥5% of pts were fatigue (23%); rash (16%); diarrhea and nausea (7% each); increased alanine aminotransferase, increased aspartate aminotransferase, and pruritus (6% each); and pyrexia (5%). A total of 37 pts (15%) had grade ≥3 TRAEs; the most common grade ≥3 TRAEs were increased lipase (asymptomatic) and rash (3% each). TRAEs led to discontinuation in 3% of pts. Conclusions: Epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was associated with an acceptable safety profile in pts with advanced cancers, supporting continued evaluation of the combination. The phase 3 ECHO-301/KEYNOTE-252 MEL study is ongoing and additional phase 3 studies (NSCLC, UC, RCC, SCCHN) are planned. Clinical trial information: NCT02178722.

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Safety and Pharmacokinetics of Single Intravenous Dose of MGAWN1, a Novel Monoclonal Antibody to West Nile Virus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01178-09 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2431-2436 ◽

Cited By ~ 43

Author(s):

John H. Beigel ◽

Jeffrey L. Nordstrom ◽

Stanley R. Pillemer ◽

Cory Roncal ◽

D. Ronald Goldwater ◽

...

Keyword(s):

Monoclonal Antibody ◽

West Nile Virus ◽

Clinical Laboratory ◽

Phase 1 ◽

Study Drug ◽

Virus Infections ◽

West Nile ◽

Humanized Monoclonal Antibody ◽

Grade 3 ◽

Immunogenicity Assays

ABSTRACT West Nile Virus (WNV) is a neurotropic flavivirus that can cause debilitating diseases, such as encephalitis, meningitis, or flaccid paralysis. We report the safety, pharmacokinetics, and immunogenicity of a recombinant humanized monoclonal antibody (MGAWN1) targeting the E protein of WNV in a phase 1 study, the first to be performed on humans. A single intravenous infusion of saline or of MGAWN1 at escalating doses (0.3, 1, 3, 10, or 30 mg/kg of body weight) was administered to 40 healthy volunteers (30 receiving MGAWN1; 10 receiving placebo). Subjects were evaluated on days 0, 1, 3, 7, 14, 21, 28, 42, 56, 91, 120, and 180 by clinical assessments, clinical laboratory studies, electrocardiograms (ECGs), and pharmacokinetic and immunogenicity assays. All 40 subjects tolerated the infusion of the study drug, and 39 subjects completed the study. One serious adverse event of schizophrenia occurred in the 0.3-mg/kg cohort. One grade 3 neutropenia occurred in the 3-mg/kg cohort. Six MGAWN1-treated subjects experienced 11 drug-related adverse events, including diarrhea (1 subject), chest discomfort (1), oral herpes (1), rhinitis (1), neutropenia (2), leukopenia (1), dizziness (1), headache (2), and somnolence (1). In the 30-mg/kg cohort, MGAWN1 had a half-life of 26.7 days and a maximum concentration in serum (C max) of 953 μg/ml. This study suggests that single infusions of MGAWN1 up to 30 mg/kg appear to be safe and well tolerated in healthy subjects. The C max of 953 μg/ml exceeds the target level in serum estimated from hamster studies by 28-fold and should provide excess WNV neutralizing activity and penetration into the brain and cerebrospinal fluid (CSF). Further evaluation of MGAWN1 for the treatment of West Nile virus infections is warranted.

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Interim results of a phase 1/2 study of JNJ-63723283, an anti-PD-1 monoclonal antibody, in patients with advanced cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.58 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 58-58 ◽

Cited By ~ 1

Author(s):

Emiliano Calvo ◽

Victor Moreno ◽

Enriqueta Felip ◽

Giuseppe Curigliano ◽

Daniel Morgensztern ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Pleural Effusion ◽

Phase 1 ◽

Study Drug ◽

Clinical Activity ◽

Phase 2 ◽

Duration Of Treatment ◽

Safety And Efficacy ◽

Grade 3

58 Background: JNJ-63723283 (JNJ-283), an anti-programmed cell death protein-1 antibody, enhances T cell-mediated cytokine induction and reduces tumor volume in preclinical models. A phase 1/2 study is ongoing to evaluate the safety and efficacy of JNJ-283 in patients (pts) with advanced cancers. Methods: Eligible pts have advanced or refractory solid tumor malignancies. Phase 1 dose escalation starting from 80 mg Q2W was supported by a modified continual reassessment method to identify the recommended phase 2 dose(s) (RP2D). Safety and efficacy of the RP2D(s) will be evaluated in phase 2. Pharmacokinetics (PK), receptor occupancy (RO) and other pharmacodynamic parameters were assessed. Results: As of data cut-off, 32 pts were treated with JNJ-283 80 mg (n = 4), 240 mg (n = 16) or 460 mg (n = 4) Q2W, or 480 mg (n = 8) Q4W; 16 pts remain on study drug. Median duration of treatment was 58 days (range 16 – 240). Median age was 56 years (range 27 - 80) and median prior lines of therapy was 3 (range 1 - 12). One dose-limiting toxicity of grade 3 pleural effusion was reported at 240 mg Q2W. An RP2D of 240 mg Q2W is being evaluated in phase 2. Most common adverse events (AEs) were anemia (28.1%), hypertension (28.1%), diarrhea (21.9%) and hyponatremia (21.9%). Observed serious AEs were pleural effusion, pneumonia and chest pain (6.3% each). Infusion-related AEs of nausea and rash occurred in 6.3% of pts each. Immune-related AEs (irAEs) were reported in 21.8% of pts and were mostly grade 1-2; grade 3 irAEs included pleural effusion, pneumonitis, AST increased and ALT increased. One pt discontinued treatment due to a treatment-related AE. Three pts achieved a partial response at 240 mg Q2W; 18 pts achieved stable disease or better. Preliminary serum JNJ-283 concentrations demonstrated linear PK with dose-proportional increases and interpatient variability generally consistent with monoclonal antibody therapeutics. Preliminary circulating T cell RO demonstrated dose-independent saturation. Conclusions: JNJ-283 displayed a well-tolerated safety profile with preliminary antitumor activity in pts with advanced cancers. The trial is ongoing to further characterize the safety, PK and clinical activity of JNJ-283. Clinical trial information: 2016-002017-22.

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Phase 1 trial of seclidemstat (SP-2577) in patients with relapsed/refractory Ewing sarcoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.11514 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 11514-11514

Author(s):

Damon R. Reed ◽

Sant P. Chawla ◽

Bhuvana Setty ◽

Leo Mascarenhas ◽

Paul A. Meyers ◽

...

Keyword(s):

Abdominal Pain ◽

Ewing Sarcoma ◽

Phase 1 ◽

Single Agent ◽

Plasma Concentrations ◽

Target Lesion ◽

Tumor Shrinkage ◽

Phase 2 ◽

Phase 1 Trial ◽

Grade 3

11514 Background: Ewing sarcoma (ES), a rare bone and soft tissue sarcoma mainly of adolescents and young adults, is characterized by a chromosomal translocation resulting in a fusion oncoprotein. Lysine specific demethylase 1 (LSD1) has been shown to associate with the fusion oncoprotein and promote oncogenic transcriptional activity making LSD1 an attractive target for ES treatment. Seclidemstat is a novel, selective, reversible oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. This is the first report of an LSD1 inhibitor in a Phase 1 trial focused exclusively on ES. Methods: SALA-002-EW16 is a Phase 1 trial of single agent seclidemstat in patients (pts) with relapsed or refractory (R/R) ES. This report describes the completed monotherapy dose escalation. Pts > 12 years received oral SP-2577 twice daily in 28-day cycles under fasting conditions at the assigned dose level. The primary objective was safety and tolerability. Secondary objectives include to determine maximum-tolerated dose (MTD), recommended Phase 2 dose (RP2D), preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 27 pts with R/R ES were enrolled. Pts received escalating doses of SP-2577 at 75 (n = 1), 150 (n = 2), 300 (n = 4), 600 (n = 6), 900 (n = 8), or 1200 mg PO BID (n = 6). The median age was 25 years (range 15–68), 63% were male, and pts had received a median of 3 (range 2–12) prior systemic therapies. There were no treatment-related deaths. The most common ( > 5%) grade 3 treatment-related adverse events (TRAEs) were vomiting (15%), abdominal pain (11%), and hypokalemia (11%). One pt (4%) with grade 3 pancreatitis reported a grade 4 AE of elevated lipase. All remaining grade 3 TRAEs, including hematological TRAEs, were reported in only one pt each. Four pts discontinued study for an AE (weight loss, pancreatitis, vomiting, abdominal pain). Three pts had a dose reduction. The first cycle dose-limiting toxicities were gastrointestinal-related AEs observed in 2 pts at 1200 mg BID. Thus, the MTD/RP2D was established as 900 mg BID. Peak plasma concentrations occurred at a median of 4 hours (h) post-dose and median terminal half-life was 6 h; exposure was dose proportional through 900 mg BID. One pt at 600 mg BID achieved a reduction in target lesions starting at end of C2 with further target lesion tumor shrinkage through end of C4 and C6 (maximum 76% tumor shrinkage) with coincident new non-target lesion appearance at end of C2. Of pts evaluable for response at the end of C2 (12 pts), two additional pts (16.7%) at 600 mg BID and 900 mg BID had overall stable disease. Conclusions: Seclidemstat has a manageable safety profile with proof-of-concept preliminary activity in heavily pretreated pts with relapsed/refractory ES. These data support the planned Phase 2 expansion of seclidemstat as single agent and in combination with chemotherapy in ES and other sarcomas that share similar translocations. Clinical trial information: NCT03600649.

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An Open-Label Phase 1/2 Trial of Bendamustine Combined with Bortezomib for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.3057.3057 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3057-3057

Author(s):

James R. Berenson ◽

Ori Yellin ◽

Alberto Bessudo ◽

Ralph Boccia ◽

Donald S. Gravenor ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Research Funding ◽

Alkylating Agents ◽

Phase 1 ◽

Study Drug ◽

Therapeutic Options ◽

Hematologic Toxicity ◽

Open Label ◽

Grade 3

Abstract Abstract 3057 Background: Multiple myeloma (MM) is an aggressive and incurable disorder with an eventual fatal outcome bringing urgency to the identification of effective treatments for patients who have exhausted standard chemotherapy. New agents, such as lenalidomide and bortezomib have led to a rapid increase in therapeutic options as single agents and in combination with other agents. However, despite this progress nearly all patients will relapse and require additional therapeutic options. Bendamustine is a unique chemotherapeutic agent that combines an alkylating group with a purine-like benzimidazole ring that is approved in the US for the treatment of CLL and refractory indolent B-cell NHL. Bendamustine is approved in Europe for the treatment of MM. Bortezomib is a proteasome inhibitor (PI) that is approved for the treatment of MM and the combination of this PI with alkylating agents including melphalan and cyclophosphamide has proven highly effective in the treatment of MM. Thus, the combination of bortezomib with bendamustine which also possesses alkylating agent properties may enable patients that were previously treated with bortezomib to have additional therapeutic options. In addition, this combination may allow use of lower doses of bortezomib to be used potentially reducing the incidence of peripheral neuropathy as has been observed in other combinations involving bortezomib with other alkylating agents. This study is being conducted to assess the safety and efficacy of bendamustine in combination with bortezomib for the treatment of relapsed/refractory MM. Methods: This open-label, Phase 1/2 study, will enroll up to 40 patients (pts), age ≥18 years, with measurable MM that has relapsed following or is refractory to at least 1 previous treatment. Patients received bendamustine infused intravenously over 1 hour on days 1 & 4 in 3-dose cohorts of 50, 70, or 90 mg/m2 and bortezomib on days 1, 4, 8, & 11 at a fixed dose of 1.0 mg/m2 for up to eight 28-day cycles. Three pts were initially enrolled at each dose cohort. Up to 5 pts were allowed to enroll in each initial cohort if they were all in screening prior to the 3rd pt being enrolled. After the first 3 pts completed cycle 1 of each dose, the cohort was assessed for dose-limiting toxicities (DLT). In this study, a DLT was defined as any study drug related grade 3 or grade 4 non-hematologic toxicity, grade 4 hematologic toxicity, grade 3 thrombocytopenia with grade 3 or 4 hemorrhage, grade 3 febrile neutropenia, grade 3 or grade 4 nausea and vomiting refractory to anti-emetic therapy, or any drug-related deaths. A standard 3+3 approach was used for determining the MTD. The MTD cohort will be expanded so that up to 40 total pts are enrolled. Results: Twenty-five pts with a median age of 62 (44-91) have been enrolled on the study and received at least 1 dose of study drug, and 52% of the pts are male. Patients had received a median of 4 (1-17) prior therapies. Notably, 80% (20/25) of pts had received at least one prior bortezomib-containing regimen. For the Phase 1 portion, 5 pts were enrolled into the 50 mg/m2 cohort, 4 pts were enrolled into the 70 mg/m2 cohort and 5 pts were enrolled into the 90 mg/m2 cohort. No DLTs were observed in the phase 1 portion of the study. The maximum dose (90 mg/m2) was well tolerated. Patients are currently enrolling into the Phase 2 portion of the study and receiving this dose of bendamustine in the combination treatment. To date, the most common grade 3 or 4 adverse events, occurring in more than 10% of pts, were neutropenia (36%), anemia, (24%), thrombocytopenia (24%), and renal failure (12%). A worsening of baseline peripheral neuropathy was reported in 20% of pts. Two (8%) pts were reported to have grade 1, treatment emergent peripheral neuropathy. To date, nearly one-third (8/25) of pts have achieved an MR or PR. To date, 16 pts have been enrolled at the 90 mg/m2 dose of bendamustine and 5 (31%) have achieved an MR or PR. Conclusions: The combination of bendamustine 90 mg/m2 on days 1 and 4 and bortezomib 1.0 mg/m2 on days 1, 4, 8, & 11 appears to be safe and effective in this heavily pre-treated patient population. The phase 2 portion of this study is ongoing. Disclosures: Berenson: Cephalon: Consultancy, Research Funding; Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Bendamustine is approved for CLL and refractory NHL. It is being studied in combiantion with bortezomib for multiple myeloma. Siegel:Cephalon: Research Funding; Amgen: Research Funding; Incyte: Research Funding; Marmatech: Research Funding; Medivation: Research Funding; Caremark/CVS: Consultancy. Swift:Millennium: Speakers Bureau. Ehrman:Cephalon Inc.: Employment. Bensen-Kennedy:Cephalon Inc.: Employment.

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Phase 1/2 Study Of Brentuximab Vedotin In Pediatric Patients With Relapsed Or Refractory (R/R) Hodgkin Lymphoma (HL) Or Systemic Anaplastic Large-Cell Lymphoma (sALCL): Preliminary Phase 2 Data For Brentuximab Vedotin 1.8 Mg/Kg In The HL Study Arm

Blood ◽

10.1182/blood.v122.21.4378.4378 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4378-4378 ◽

Cited By ~ 8

Author(s):

Franco Locatelli ◽

Kathleen A Neville ◽

Angelo Rosolen ◽

Judith Landman-Parker ◽

Nathalie Aladjidi ◽

...

Keyword(s):

Abdominal Pain ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Pediatric Patients ◽

Phase 1 ◽

Brentuximab Vedotin ◽

Phase 2 ◽

Free Survival ◽

Grade 3 ◽

Preliminary Phase

Abstract Background Brentuximab vedotin is a CD30-targeted antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Pivotal phase 2 studies reported the efficacy and manageable toxicities of the drug, leading to its approval by the US FDA for use in adult patients with R/R HL and R/R sALCL in 2011. Data for brentuximab vedotin in children with these lymphomas are currently limited but promising. This ongoing phase 1/2 prospective, open-label, multicenter study is the first clinical trial of brentuximab vedotin conducted exclusively in pediatric patients with R/R HL or R/R sALCL (NCT01492088). The phase 1 portion established the recommended phase 2 dose (RP2D) of brentuximab vedotin in pediatric patients with R/R HL or R/R sALCL as 1.8 mg/kg every 3 weeks (Q3wk), and complete response (CR) and partial response (PR) were reported in 88% of patients at the RP2D. Here, we report preliminary phase 2 response, safety and PK findings for the HL patients receiving the RP2D. Methods The phase 2 portion aimed to enroll 15 response-evaluable HL patients at the RP2D, including those R/R HL patients treated at the RP2D in phase 1 (phase 2 data for the sALCL patients are not reported here). The phase 2 primary objective was overall response rate (ORR; CR + PR) at the RP2D; secondary objectives were time to progression, time to response, duration of response, event-free survival, progression-free survival, overall survival, to characterize PK, to further evaluate safety, and to determine immunogenicity of brentuximab vedotin. Patients with R/R HL aged 5 to<18 years, with measurable disease, who were in their second or later relapse, had failed chemotherapy, and were ineligible for, refused, or previously received stem cell transplant, received brentuximab vedotin 1.8 mg/kg by IV infusion Q3wk for up to 16 cycles until progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses will be assessed both by the investigators and independent review facility per IWG revised response criteria for malignant lymphoma; investigator responses are reported here. Blood samples for PK analysis were collected on day 1 (all cycles) immediately before and 5 minutes after the infusion and on prespecified days during cycles 1, 2, and 8. Results 16 patients with R/R HL received at least 1 dose of brentuximab vedotin at the RP2D; median age was 15 years (range, 8–18); 56% were male; Ann Arbor stage at initial diagnosis was 44% stage II, 6% stage III, 44% stage IV, and 6% unknown; median time from initial diagnosis was 16.7 months (range, 0–38) and 50% had B symptoms at baseline. At data cut-off (June 20, 2013), patients had received a median of 3 cycles of treatment (range, 1–16); 10 (63%) patients had discontinued treatment due to: progressive disease (n=7), AEs (n=2), and allogeneic transplant (n=1). Response data were available for 14 patients at data cut-off. The ORR was 64% (95% confidence interval [CI]: 35, 87); 3 (21%; 95% CI: 5, 51) patients achieved CR and 6 (43%; 95% CI: 18, 71) achieved PR. Reponses were typically observed at C2. 12 of 16 (75%) patients had ≥1 AE, and 7 (44%) had grade ≥3 AEs. The most common (>1 patient) AEs were nausea (38%), pyrexia (31%), neutropenia, paresthesia (each 19%), abdominal pain, upper abdominal pain, constipation, decreased appetite, diarrhea, hepatotoxicity, hypokalemia, leukopenia, myalgia, pharyngitis, and vomiting (each 13%). 7 serious AEs (SAEs) occurred in 5 patients; 4 SAEs in 3 patients were considered related to brentuximab vedotin: grade 3 hepatotoxicity and grade 3 febrile neutropenia (n=1); grade 3 anaphylaxis (n=1); and grade 3 pneumonia (n=1). One patient died on C2D4 of unrelated cardiac arrest due to progressive mediastinum enlargement (disease progression). 2 (13%) patients discontinued, 1 due to grade 3 hepatotoxicity on C1D13 and 1 due to grade 3 peripheral neuropathy on C8D4. Preliminary PK data show that brentuximab vedotin remained detectable in the blood just prior to the next infusion over the treatment period; thus, patients remain exposed to brentuximab vedotin from cycle to cycle. Conclusions Brentuximab vedotin 1.8 mg/kg Q3wk (RP2D) was generally well tolerated in pediatric patients with R/R HL and demonstrated preliminary evidence of activity, with an ORR to date of 64%, including 21% CR. The phase 2 portion is ongoing in pediatric patients with R/R HL and R/R sALCL. Disclosures: Off Label Use: Brentuximab vedotin for the treatment of pediatric patients with relapsed or refractory Hodgkin lymphoma. Franklin:Millennium: The Takeda Oncology Company: Research Funding. Fasanmade:Millennium: The Takeda Oncology Company: Employment, Equity Ownership, Research Funding. Wang:Millennium: The Takeda Oncology Company: Employment. Sachs:Millennium: The Takeda Oncology Company: Employment. Mauz-Koerholz:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees.

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