Phase 1b Study of TRU-016, an Anti-CD37 SMIP™ Protein, in Combination with Rituximab and Bendamustine in Relapsed Indolent Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3678-3678
Author(s):  
Ajay K. Gopal ◽  
Stefano R Tarantolo ◽  
Naresh Bellam ◽  
Tatyana Feldman ◽  
Anthony R Mato ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Significant Activity ◽  
In Vivo Models ◽  
Bulky Disease ◽  
Overall Response ◽  
Pulmonary Thrombosis ◽  
Wide Range

Abstract Abstract 3678 Background: CD37 is a tetraspanin protein expressed on the surface of normal and transformed B-cells across a wide range of maturational stages and demonstrates death signaling via SHP1. TRU-016 is a novel humanized anti-CD37 SMIP™ (mono-specific protein therapeutic) that has shown significantly greater direct killing of CLL cells than rituximab and greater Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. In preclinical in vitro and in vivo models of NHL significant activity of TRU-016 against multiple cell lines was observed. In a phase 1 study, TRU-016 showed activity in patients (pts) with CLL and NHL was observed. Given the single-agent clinical activity of TRU-016 and synergistic or additive effect of TRU-016 with multiple agents in preclinical models, this trial of TRU-016 with rituximab and bendamustine was conducted to establish the maximum tolerated dose, overall safety, and clinical activity of TRU-016 in pts with relapsed indolent NHL. Methods: Pts with relapsed or refractory indolent B-cell NHL with adequate organ function, ECOG ≤2, absolute neutrophil count ≥1000/μL, platelets'100,000/μL who were not refractory to bendamustine were eligible. After premedication with acetaminophen, diphenhydramine, and hydrocortisone pts received TRU-016 (10 or 20 mg/kg on Days 1 and 15) over 2–3 hrs combined with rituximab 375 mg/m2 (Day 2) and bendamustine 90 mg/m2 (Days 1 and 2) by IV infusion for up to six 28-day cycles. Safety was evaluated using CTCAE 4.03 and response was determined using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007) after every 2 cycles. Results: 12 pts, (9 with follicular lymphoma (FL) and 3 with small lymphocytic lymphoma (SLL)) were treated (6 each dose level). Pt characteristics: median age 57 yrs (range, 51–79), median prior regimens 3 (1–4), 67% ≥ stage III at diagnosis, 4 pts had bulky disease > 5cm. All pts had relapsed after prior rituximab (R) including 3 refractory to their most recent previous treatment. In addition, prior treatments included: CHOP-R (8), RICE (5), single agent R (5), transplant (2). FLIPI scores at study entry (FL pts) were: 8 intermediate, 1 low. The most frequent (>2 pts) adverse events (AEs) were: neutropenia (8), fatigue, nausea, insomnia, and WBC decreased (7 each); anemia, diarrhea, headache, hypophosphatemia, thrombocytopenia, and vomiting (3 each). Grade 3/4 AEs that occurred in >1 pt were neutropenia (6), hypophosphatemia (3), WBC decreased (2). Serious AEs (SAE) included asymptomatic pulmonary thrombosis in 2 pts and febrile neutropenia, pneumonia, myelodysplastic syndrome (pt had prior transplant, CHOP, RICE), deep vein thrombosis, and retinal vein occlusion (last 2 events and pulmonary thrombosis occurred in same pt) in 1 pt each. There was no apparent dose relationship to the SAEs. The best overall response was 10/12 (83%) with 4 CRs (32%). Four responding pts (1 CR, 3 PR) discontinued treatment prior to cycle 6 due to undergoing consolidation with transplant (2), development of myelodysplastic syndrome (1), and delayed neutrophil recovery (1). The 4 discontinuations occurred in the 20 mg cohort and limit the response evaluation of the 20 mg dose. However, after Cycle 2 Day 15, the overall response rate was 67% at 10 mg/kg and 100% at 20 mg/kg. Three of the 4 pts with bulky disease responded to the regimen Conclusions: TRU-016 in combination with rituximab and bendamustine was well-tolerated, induces responses in the majority of patients with relapsed indolent B-NHL. A MTD was not defined. Future combination studies of TRU-016 in NHL are warranted. Disclosures: Mato: Celgene, Milennium, Genentech, Seattle Genetics: Speakers Bureau. Stromatt:Emergent Product Development: Employment.

Phase 1b Study of TRU-016, an Anti-CD37 SMIP™ Protein, in Combination with Bendamustine Vs Bendamustine Alone in Relapsed Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1795-1795
Author(s):  
Farrukh Awan ◽  
Ulrich Jaeger ◽  
Robert Rifkin ◽  
Michael J Thirman ◽  
John C. Byrd ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Adverse Events ◽  
Product Development ◽  
Board Of Directors ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Significant Activity ◽  
Advisory Committees ◽  
In Vivo Models ◽  
Wide Range

Abstract 1795 Background: CD37 is a tetraspanin protein expressed on the surface of normal and transformed B-cells across a wide range of maturational stages and demonstrates death signaling via SHP1. TRU-016 is a novel humanized anti-CD37 SMIP™ (mono-specific protein therapeutic) that has shown significantly greater direct killing of CLL cells than rituximab and greater Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. In preclinical in vitro and in vivo models significant activity of TRU-016 with bendamustine was observed. In a phase 1 study in 57 relapsed and/or refractory CLL patients treated with TRU-016, the maximum tested dose (20 mg/kg) was well tolerated. Given the single-agent clinical activity of TRU-016 and synergistic or additive effect of TRU-016 with multiple agents in preclinical models, this trial of TRU-016 with bendamustine was conducted to establish the maximum tolerated dose, overall safety, and clinical activity of TRU-016 in combination with bendamustine in patients with relapsed CLL. Methods: Patients with relapsed CLL who had 1–3 prior treatments (without prior bendamustine), adequate organ function, ECOG ≤2, and absolute neutrophil count ≥1200/μL were eligible. Patients received TRU-016 (15 or 20 mg/kg) weekly by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles. Bendamustine (70 mg/m2) was administered on Days 1 and 2 of each cycle by IV infusion for up to six 28-day cycles. Safety was evaluated using CTCAE and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 2008 IWCLL Criteria. Results: 12 patients have been treated to date (6 pts at each dose level). Patient characteristics: median age 67 yrs (range, 54–81), 7 patients received 1 and 2 patients received 2 prior regimens, 5 patients had bulky nodes ≥7 cm, 1 had del(17p13.1). All patients were intermediate to high-risk (Rai I/II=75%, III/IV=25%). The most frequent adverse events (>2 pts) were: nausea (8); neutropenia (6); anemia, pyrexia, decreased appetite, hypokalemia, headache, cough (4 each); febrile neutropenia, constipation, diarrhea, dry mouth (3 each); and chills (2). The only grade 3/4 adverse events that occurred in >2 patients were: neutropenia (6) and febrile neutropenia (3). There were 10 serious adverse events reported on 4 patients. Related serious events were febrile neutropenia in 2 patients and autoimmune hemolytic anemia (pre-existing) and urinary tract infection in 1 patient each. There was no apparent dose relationship to adverse event frequency. The best overall response rate at any time according to the investigator was 100% (4 CRs, 2 at each dose) with 9/12 responses occurring at cycle 1. CT scan data, which is necessary to determine IWCLL response, is pending and will be presented. There was no apparent dose relationship to response. Conclusions: TRU-016 in combination with bendamustine was well tolerated and showed a positive response. A randomized trial of TRU-016/bendamustine vs. bendamustine alone is ongoing. Disclosures: Jaeger: Emergent Product Development: Consultancy, Research Funding. Rifkin:Millennium Pharmaceuticals, Inc./Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ONYX: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; INCYTE: Speakers Bureau; Amgen: Speakers Bureau. Stromatt:Emergent Product Development: Employment.

A Phase 1 Trial of TRU-016, An Anti-CD37 Small Modular Immunopharmaceutical (SMIPTM) Protein in Relapsed and Refractory CLL: Early Promising Clinical Activity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3424-3424 ◽  
Author(s):  
Leslie Andritsos ◽  
Richard R Furman ◽  
Ian W Flinn ◽  
Andres Foreno-Torres ◽  
Joseph M. Flynn ◽  
...  
Keyword(s):  
High Risk ◽  
Nk Cell ◽  
Phase 1 ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Clinical Activity ◽  
Pharmacokinetic Data ◽  
Treatment Schedule ◽  
Median Reduction ◽  
Wide Range

Abstract Abstract 3424 Poster Board III-312 Background CD37 is a tetraspanin family member expressed predominantly on normal and transformed B-cells across a wide range of maturational stages. TRU-016 is a novel humanized anti-CD37 SMIP protein. Pre-clinical studies have demonstrated CD37 SMIP protein mediates significantly greater direct killing of CLL cells than rituximab that is dependent upon tyrosine phosphorylation changes at 65 and 50-55 kD. Tru16 also mediates greater NK cell mediated killing of CLL cells as compared to either alemtuzumab or rituximab. A phase I study with TRU-016 was initiated based upon these data. Methods Patients with relapsed/refractory CLL or SLL who had adequate organ function and platelets > 30,000/mm3 were eligible. Seven doses and two different schedules have been studied. The planned doses range from 0.03 mg/kg to 10 mg/kg IV once a week for 4 doses. The second schedule tests 3, 6 or 10 mg/kg on days 1, 3 and 5 the first week followed by 3 weekly doses. Dose escalation and de-escalation is based on CTC AE toxicity grades. Results To date, 32 patients have been treated with TRU-016. In the weekly treatment schedule: 1 patient in each of the first 3 cohorts (0.03, 0.1, and 0.3 mg/kg); 3 patients at 1 mg/kg, 4 patients at 3 mg/kg, 7 patients at 6 mg/kg, and 5 patients at 10 mg/kg. In the TIW loading dose schedule: 8 patients at 3 mg/kg and 2 patients at 6 mg/kg. Genomic data is available for 27 patients and 19 have high risk genomic features [del(17p13.1), n=10, del(11q22.3), n=7, both=2]. The maximum tolerated dose (MTD) has not been reached. 12 serious adverse events have been reported and three may have been related to study drug, including G4 neutropenia, presumed zoster and ITP. Mild (grade 1-2) infusion toxicity has been observed. Limited pharmacodynamic data suggest changes in phosphotyrosine proteins observed pre-clinically that correlated with apoptosis have been observed at 30 minutes and 4 hours into treatment on day 1. Pharmacokinetic data from cohorts 1-7 demonstrate rapid clearance in earlier cohorts with patients in cohort 7 maintaining 10μg/ml plasma concentrations during treatment. Beginning with the 0.3 mg/kg dose, evidence of biological activity has been observed: one partial response (PR) in a patient with 17p del, two patients with leukemia cutis had partial or complete clearing, and in patients with peripheral lymphocytosis the median reduction was 83% (range 13% to 98%). Improvement in cytopenias has also been observed. Enrollment to cohort 8 and 11 is complete and further up-to-date data will be presented. Conclusions To date, TRU-016 is a well tolerated treatment with minimal infusional toxicity and the MTD has not been reached. One PR and a median reduction of 83% in peripheral lymphocytosis have been observed. Encouraging reduction in lymph node/spleen size and improvement in normal hematopoietic function in patients with high risk genomic CLL have been observed at low doses of CD37. The protocol has been amended to explore higher saturating doses of CD37. Future single agent and combination studies of Tru16 in CLL are warranted. Disclosures Flinn: Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stromatt:Trubion Pharmaceuticals: Employment.

scholarly journals A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (1) ◽  
pp. e000530 ◽  
Author(s):  
Aung Naing ◽  
Justin F Gainor ◽  
Hans Gelderblom ◽  
Patrick M Forde ◽  
Marcus O Butler ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Wide Range ◽  
Tumor Types ◽  
Tumor Biopsies

BackgroundSpartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.MethodsIn the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).ResultsPatients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.ConclusionsSpartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types.Trial registration numberNCT02404441.

Cardiac Biomarkers Predict for Ability To Tolerate and Complete Therapy with Lenalidomide ± Dexamathosone in AL Amyloidosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 130-130 ◽  
Author(s):  
Angela Dispenzieri ◽  
Martha Lacy ◽  
Steven Zeldenrust ◽  
Suzanne R. Hayman ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Adverse Events ◽  
Overall Response Rate ◽  
Response Rate ◽  
Troponin T ◽  
Single Agent ◽  
Cardiac Biomarkers ◽  
Al Amyloidosis ◽  
Significant Activity ◽  
Cardiac Biomarker ◽  
Overall Response

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, has been shown to be highly active in patients with multiple myeloma. Methods: We studied the toxicity and efficacy of lenalidomide in patients with symptomatic AL. Patients received single agent lenalidomide. If progression by 3 months or no evidence of hematologic response after 3 cycles, dexamethasone was added. Originally, twenty-three patients (Cohort 1) were enrolled according to study design. Because of a significant early drop out rate and notable activity of the regimen, the trial was modified to include an additional 15 patients (Cohort 2). Baseline characteristics and adverse events are available for all enrolled patients, but at the time of this writing, response data are available for Cohort 1 patients due to short follow-up of Cohort 2, but will be updated by the time of the meeting. Results: Median age was 64 years, with 69% male. Twenty-three were previously treated. Organ involvement was cardiac (67%), renal (64%), hepatic (17%), nerve (17%). Thirty-three, twenty-two, and forty-four percent of patients were cardiac biomarker stage 1, 2, and, 3 respectively. Of the 37 patients, one was a cancel, and 6 have not yet made it through 3 months of protocol treatment and event monitoring. The respective median follow-ups for Cohorts 1 and 2 are 17 and 3.4 months. Of the remaining, 30 patients, within the first 3 cycles of therapy fifteen patients discontinued treatment: 7 early deaths and 8 adverse events or other causes. Three additional patients died 0.5 to 2 months after stopping treatment. The best predictor for early withdrawal and/or death was baseline NT-proBNP and cardiac biomarker staging system (cut-offs for serum troponin T <0.035 ng/ml and NT-proBNP <332 pg/ml--Stage I neither above cut-off; Stage III, both above cut-off; and Stage II, one above cut-off). Figure1 Figure1. Figure 2 Figure 2. Of the twenty 22 patients assessed for response ten patients responded to treatment for an overall response rate of 45%, including 23% organ responders. Among the patients with organ responses, there were four renal responses, two cardiac responses and two liver responses. All but one of the responders had dexamethasone added to their treatment program. The most common grade 3−4 adverse events at least possibly attributable to lenalidomide were neutropenia (38%), thrombocytopenia (21%), fatigue (15%), and rash (12%). Conclusions: Lenalidomide and dexamethasone has significant activity in patients with AL with an overall response rate of 45%. Baseline NT−proBNP may be an effective eligibility screening strategy for subsequent trials.

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.

A Phase 1/2 Study Of KW-2478, An Hsp 90 Inhibitor, In Combination With Bortezomib (BTZ) In Patients (Pts) With Relapsed/Refractory (R/R) Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1967-1967
Author(s):  
Cavanagh Jamie ◽  
Honorata Giongco Baylon ◽  
Priscilla B. Caguioa ◽  
Faith E. Davies ◽  
Mecide Gharibo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Dependent Manner ◽  
Phase 2 ◽  
Hsp90 Inhibition ◽  
Hsp 90

Abstract Background KW-2478 is a potent Hsp 90 inhibitor that binds to Hsp 90 with an IC50 value of 3.8 nmol/L. In preclinical studies, KW-2478 inhibited the in vitro growth of myeloma cell lines at GI50 values of 0.12 – 0.39 µM and markedly inhibited the growth of myeloma xenografts in SCID mice in a dose-dependent manner. In vitro, KW-2478 and BTZ demonstrated synergistic activity against OPM-2/GFP cells and in the NCI-H929 xenograft model, the combination of KW-2478 and BTZ showed greater anti-growth activity than either agent alone. A single-agent Phase 1 study (KW-2478 administered daily x 5 every 14 days), showed no dose limiting toxicity (DLT) and Hsp90 inhibition was observed at doses >71 mg/m2. Aim To establish safety, tolerability and recommended Phase 2 dose (RP2D) of KW-2478 plus BTZ in pts with R/R myeloma and assess overall response rate (ORR) based on International Myeloma Working Group (IMWG) response criteria. The PK and PD of KW-2478 plus BTZ were characterized and progression-free survival (PFS) was investigated. Methods All patients had MM by IMWG criteria, had received at least 1 and no more than 3 prior MM regimens and had not responded or had relapsed, and had adequate renal function. Patients who received prior BTZ could not be refractory. This open-label study had 2 parts: A Phase 1 dose escalation (3 + 3 design) part followed by a Simon 2-stage Phase 2. KW-2478 and BTZ were administered on Days 1, 4, 8 and 11 of a 21-day cycle. In Phase 1, the doses of KW-2478 and BTZ were sequentially escalated until observation of DLT, MTD, or achievement of the maximal planned dose levels (KW-2478 175 mg/m2, BTZ 1.3 mg/m2). PK and PD samples were collected in C1 on Days 1 and 11, and Days 1, 4, 8, and 11, respectively. In Phase 2, if 11 or more responses were observed in the first 27 evaluable pts, then an additional 50 evaluable pts would be enrolled. Response was assessed at the end of each cycle and safety was assessed continuously. Results The study enrolled 95 pts who received at least one dose of study drug: 15 in Phase 1 and 80 in Phase 2; 86 pts received the RP2D (highest planned dose of KW-2478 175 mg/m2 /bortezomib 1.3 mg/m2). Median age was 65; 57% of pts were male. There was 1 DLT (presyncope) in Phase 1. The most common adverse events (AEs) were diarrhea (74%), nausea (61%), fatigue (55%), constipation (46%), vomiting (40%) and peripheral neuropathy (30%). Most AEs were Grade 2; 5 pts had Grade 4 AEs. Five pts had a Grade 4 thrombocytopenia and 3 pts had a Grade 4 neutropenia. The PK profiles for KW-2478 plus BTZ in combination were comparable to each agent’s individual PK profile. In the Phase 1 portion of the trial, Hsp70 levels, a marker of Hsp90 inhibition, increased in the peripheral blood mononuclear cells in all subjects (N = 13). Of the pts who received the RP2D, 79 pts were evaluable for IMWG response. The ORR was 39% (4% CR, 14% VGPR, and 22% PR); in pts who were bortezomib naïve (n = 50), the ORR was 48%. Median PFS was 26.4 weeks and median duration of response had not been reached at the time of this report. Six pts continue treatment at the time of data cut-off. Conclusions KW-2478 plus BTZ was well-tolerated when administered at the doses and schedule studied. Clinical activity was demonstrated in pts with R/R MM (ORR of 39%). PFS was 26.4 weeks Disclosures: Akinaga: Kyowa Kirin Pharmaceuticals: Employment, Equity Ownership. Kurman:Kyowa Kirin Pharmaceuticals: Consultancy. Novak:Kyowa Kirin Pharmaceuticals: Employment.

Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2602-2602 ◽  
Author(s):  
Amita Patnaik ◽  
Patricia LoRusso ◽  
Howard A. Ball ◽  
Erkut Bahceci ◽  
Geoffrey Yuen ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Expansion Phase ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

2602 Background: ASP3026 (3026) is a selective, potent, ATP-competitive, small molecule oral inhibitor of ALK receptor tyrosine kinase that has not previously been tested in humans. A Phase 1 dose-escalation trial, using a 3+3 design, evaluating 3026 as an oral single agent was conducted to investigate PK (Day 1 and Day 28), safety and clinical activity in patients (pts) with advanced malignancies (excluding leukemias) of ECOG PS 2 or less. Methods: 3026 was administered under fasting conditions on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 25 mg QD to 800 mg QD. Results: Thirty pts were enrolled into the dose escalation part of the study. The MTD was determined based on DLT data from cycle 1. Three DLTs were observed: grade 2 nausea and vomiting leading to dose reduction at 525 mg QD; grade 3 rash leading to dose reduction, and grade 3 ALT/AST increase leading to study withdrawal at 800 mg QD. The most common AEs were constipation, vomiting, diarrhea, nausea and abdominal pain, and all AEs were manageable and reversible. Median AUC and Cmax increased proportionally with dose from 25 mg QD to 800 mg QD. There was no evidence of non-linear PK at ASP3026 doses >25 mg QD. The median terminal half-life was approximately 10 - 41 hours. Overall, A3026 appears well absorbed with median Tmax around 3 hours for both Day 1 and Day 28. Terminal T1/2 appears adequate for one daily dosing with median values ranging from approximately 18 to 34 hours. Based on visual inspection of pre-dose (trough) values from Days 8, 15, 22, and 28 it appears that steady-state conditions are achieved by day 28. Conclusions: The MTD of 3026 is 525 mg QD. Treatment with 3026 resulted in a promising safety and PK profile in pts with advanced malignancies. Further evaluation of 3026 in pts with tumors harboring gene mutation or ALK fusion genes in the cohort expansion phase at the MTD is ongoing. Clinical trial information: NCT01401504.

Phase I study of regorafenib in combination with vincristine and irinotecan in pediatric patients with recurrent or refractory solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10507-10507
Author(s):  
Michela Casanova ◽  
Francisco Bautista ◽  
Quentin Campbell Hewson ◽  
Guy Makin ◽  
Lynley V. Marshall ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Ewing Sarcoma ◽  
Pediatric Patients ◽  
Wilms Tumor ◽  
Standard Dose ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Grade 3

10507 Background: In pediatric patients with solid tumors, regorafenib demonstrated acceptable tolerability and preliminary anti-tumor activity. This phase 1 study evaluated regorafenib in combination with vincristine/irinotecan in pediatric patients with rhabdomyosarcoma (RMS) and other solid tumors. Methods: Patients with relapsed/refractory tumors received intravenous vincristine (1.5 mg/m2, Days 1 and 8) and irinotecan (50 mg/m2/day, Days 1–5) plus once-daily oral regorafenib (patients 6– < 24 months: 60 mg/m2 escalating to 65 mg/m2; patients 2– < 18 years: 72 mg/m2 escalating to 82 mg/m2) on either Days 1–14 (concomitant dosing) or Days 8–21 (sequential dosing) during each 21-day cycle. As per protocol, at least 50% of patients were required to have RMS. Results: At the time of the cut-off, of 21 treated patients (RMS, n = 12; Ewing sarcoma, n = 5; neuroblastoma, n = 3; Wilms tumor, n = 1), two had concomitant (72 mg/m2) and 19 had sequential (72 mg/m2, n = 6; 82 mg/m2, n = 13) dosing. Median age was 10 years (1.5–17.0). Patients received a median of 3 cycles (1–17); dose reductions of irinotecan occurred in 62% of patients. Grade 3 dose-limiting toxicities were reported in both patients receiving concomitant dosing (peripheral neuropathy and liver injury; pain, vomiting, febrile aplasia) and one patient each in the sequential groups (rash and elevated AST; thrombocytopenia). Concomitant dosing was discontinued. The maximum tolerated dose and recommended phase 2 dose (RP2D) of regorafenib in the sequential combination was 82 mg/m2. The most common grade ≥3 treatment-emergent adverse events were neutropenia (71%), thrombocytopenia (33%), leukopenia (29%), anemia (24%), and ALT increased (24%). The response rate was 38%, including 1 complete (RMS) and 7 partial responders (5 RMS, 2 Ewing sarcoma); 3 of whom had prior irinotecan. Six (4 with alveolar subtype) of 12 patients with RMS had a response. Nine patients (43%) had stable disease (maximum duration 17 cycles). After the cut-off, partial response was reported for two additional patients (1 RMS, 1 Ewing sarcoma). Conclusions: Regorafenib can be combined at its single agent RP2D of 82 mg/m2 with standard-dose vincristine/irinotecan (with appropriate dose modifications) in pediatric patients with refractory/relapsed solid tumors in a sequential dosing schedule. Clinical activity was observed in patients with sarcoma. Clinical trial information: NCT02085148.

A phase Ib/II study of olutasidenib in patients with relapsed/refractory IDH1 mutant solid tumors: Safety and efficacy as single agent.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16643-e16643
Author(s):  
Robin Lewis Jones ◽  
Teresa Macarulla ◽  
John A. Charlson ◽  
Brian Andrew Van Tine ◽  
Lipika Goyal ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Single Agent ◽  
Median Number ◽  
Clinical Activity ◽  
Tumor Type ◽  
Dna Hypermethylation ◽  
Efficacy Evaluation ◽  
Open Label ◽  
Isocitrate Dehydrogenase 1

e16643 Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in a variety of solid tumors resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, Phase 1, open-label, single-arm study of olutasidenib in non-CNS solid tumors. Methods: Patients with advanced relapsed/refractory (R/R) mIDH1 solid tumors received olutasidenib 150 mg BID, orally. Following a dose confirmation cohort (Phase 1b), patients with intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma (CS), or unspecified mIDH1 solid tumors (Other) were enrolled in a Phase 2 efficacy evaluation (NCT: 03684811). Results: As of 31-Oct-2019, 44 patients with relapsed or refractory mIDH1 solid tumors were treated with olutasidenib. Diagnosis included: IHCC (n = 26), CS (n = 13), and Other (n = 5). The median age was 58 years (range: 29-81) and 43% were male. Median number of prior treatments was 2 (1-10). mIDH1 status was locally determined (IHC, NGS or PCR): R132C (61%), R132G (7%), R132S (7%), R132H (2%), R132L (2%), Others (2%) & unspecified (18%). Fourteen patients discontinued treatment (disease progression [n = 6; 3 IHCC, 2 CS, 1 Other], AE [n = 4; 3 IHCC, 1 CS], PI decision [n = 3; IHCC] & withdraw consent [n = 1; IHCC]). Treatment emergent adverse events (all grades, regardless of attribution) that occurred in > 15% of pts were: nausea (43%), fatigue (25%), decreased appetite (22%), AST increase (18%), ALT increase (16%), and constipation (16%). No protocol-defined DLTs occurred. Best responses by tumor type are shown in the table. Conclusions: Single agent olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in patients with R/R mIDH1 solid tumors. Updated safety and clinical activity, as well as exploratory evaluations of PK/PD will be provided. Clinical trial information: 03684811 . [Table: see text]

scholarly journals Preliminary Results from a Phase 1/2 Study of DSP-7888, a Novel WT1 Peptide-Based Vaccine, in Patients with Myelodysplastic Syndrome (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4335-4335 ◽  
Author(s):  
Shigesaburo Miyakoshi ◽  
Kensuke Usuki ◽  
Itaru Matsumura ◽  
Yasunori Ueda ◽  
Hiromi Iwasaki ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Lower Risk ◽  
Research Funding ◽  
Phase 1 ◽  
Peptide Vaccine ◽  
Clinical Activity ◽  
Otsuka Pharmaceutical ◽  
Grade 3 ◽  
Ctl Induction

Abstract Background: Hypomethylating agents (HMA), including azacitidine (AZA) are currently the first-line treatment option for higher-risk myelodysplastic syndrome (MDS). However, the prognosis of patients after AZA failure is poor with a median overall survival of 5.6 months from the treatment failure (J Clin Onclol 2011;29:3322-7 Prébet T et al.), and currently there are no approved therapeutic options for such patients. Suzuki et al. reported that WT4869, one of the HLA-A*24;02-restricted synthetic peptide vaccine derived from Wilms' tumor 1 (WT1) protein, demonstrated the sign of prolongation of overall survival (OS) with a median OS of 13.0 months in AZA failure higher-risk population, in the phase 1/2 study with MDS patients (Blood 126:2868, 2015;Suzuki et al.). DSP-7888 is a novel WT1-based peptide vaccine which induces the CTLs that recognize WT1 antigens in HLA-A*02:01/06 and HLA-A*24:02 restricted manner, and also includes a WT1-derived helper peptide applicable for various subtypes of HLA-DRB1. DSP-7888 is currently being investigated in a phase 1/2 study to evaluate the safety and efficacy in HLA-A*24:02+ and/or HLA-A*02:01/:06+ MDS patients, with some exploratory biomarker analyses. Methods: The objectives of this study were to assess the tolerability of DSP-7888 treatment in MDS patients in the phase 1 portion and to evaluate preliminary clinical activity of DSP-7888 in higher-risk MDS patients after AZA failure in the study. In phase 1 portion, higher-risk or transfusion-dependent lower-risk MDS patients including the AZA failure population were enrolled, and DSP-7888 was administered at doses of 3.5 to 10.5 mg/body by intradermal injections every two to four weeks in dose-escalation cohorts according to the 3 + 3 design until discontinuation criteria were met. Overall survival was evaluated for primarily clinical activity and hematological response and time to AML were also examined. Delayed type hypersensitivity (DTH), WT1-specific CTL induction and expression of WT1 mRNA in peripheral blood and bone marrow cells were also evaluated as exploratory biomarkers. The clinical data in phase 1 portion as of May 25th 2016 was presented in this report. Results: In phase 1 portion, enrollment of patients and dose-limiting toxicities (DLTs) evaluation were completed. Twelve patients including 7 higher- and 5 lower-risk patients were enrolled in 3.5 and 10.5 mg/body cohorts of 6 patients each, and safety profiles were evaluated. DLTs were not observed in either cohorts and the most common adverse drug reaction (ADR) was injection site reaction (ISR). ISR in 6 patients worsened to grade 3 with continuous treatment of DSP-7888 (2 patients at 3.5 mg/body, and 4 patients at 10.5 mg/body). Five serious ADR including 3 ISR, 1 pyrexia and 1 myocarditis were reported and dose-dependent toxicity was not observed except for ISR. All 12 patients were analyzed for preliminary clinical activity. Eight patients remained in stable disease (SD) with 2 hematological improvements (HI), and disease control rate (SD + any HI) was 66.6 %. Seven high risk AZA failure patients were enrolled, and the current survival time in this population is 7.3-10.8 months. Though preliminary, CTL induction was observed in 6 patients, and a trend of higher CTL induction was observed in patients with grade 3 ISR. DTH response was observed in 10 patients. Conclusions: In the phase 1 portion, DSP-7888 was well-tolerated in MDS patients although ISR was observed in all patients. CTL induction was detected with clinically observed reactions that may suggest preliminary signs of clinical activity. Further evaluation is needed to confirm the clinical potential of DSP-7888, and phase 2 portion is currently ongoing to evaluate the efficacy of DSP-7888 in higher-risk MDS patients after AZA failure. Disclosures Usuki: Nippon Shinyaku: Honoraria; MSD: Honoraria; Kyouwa-Kirin: Honoraria; Novartis: Honoraria; Bristol-Myer-Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; SymBio Pharmaceuticals: Research Funding. Matsumura:Bristol-Myers Squibb Company: Honoraria; Novartis Pharma K.K: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria; Pfizer Japan Inc.: Honoraria. Ueda:Alexion Pharmaceuticals Inc.: Membership on an entity's Board of Directors or advisory committees. Origuchi:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Tagashira:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Naoi:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Naoe:Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; Celgene K.K.: Honoraria, Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding. Heike:Sumitomo Dainippon Pharma: Consultancy; Chugai Pharma: Consultancy; Otsuka Pharma: Consultancy. Miyazaki:Kyowa Kirin: Honoraria; Nihonshinyaku: Honoraria; Celgene Japan: Honoraria; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria.

Sign in / Sign up

Export Citation Format

Share Document