A phase I/II investigation of nivolumab and ABI-009 (nab-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma: Preliminary efficacy and safety results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11057-11057 ◽  
Author(s):  
Erlinda Maria Gordon ◽  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
Rekha Baby ◽  
Nicole Angel ◽  
...  
Keyword(s):  
Dose Level ◽  
T Cell Activation ◽  
Ewing Sarcoma ◽  
Mtor Inhibitor ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Synergistic Activity ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3

11057 Background: Immune checkpoint inhibitors that promote sustained T cell activation may have synergistic activity with an mTOR inhibitor. This phase 1/2 study is aimed to investigate if ABI-009 a novel albumin-bound mTOR inhibitor is feasible and improve clinical outcomes in combination with nivolumab. Methods: Eligible patients with advanced UPS, LPS, CS, OS, or Ewing sarcoma are treated with the standard dose of nivolumab (240 mg given IV every 3 weeks, Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. Phase 1 portion is a dose-finding study using the 3+3 design. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75 and 100 mg/m2. The primary endpoint is to identify the maximum-tolerated dose (MTD) of ABI-009 + nivolumab, secondary endpoints include disease control rate, progression-free survival (PFS), and overall survival (OS). Exploratory endpoints include correlation of PFS and OS with PD-L1 and other biomarkers. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: 9 patients were treated in Phase 1 (n = 3 each dose level); 5/9 patients had OS, 3/9 CS, and 1 had Ewing sarcoma. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1: Grade 3 treatment-related adverse events (TRAEs) included hyper dyslipidemia (n = 1), and hyperglycemia (n = 1). At Dose 2: Grade 3 TRAEs included increased ALT (n = 1). At Dose 3: Grade 3 TRAEs included hypophosphatemia (n = 1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. The median PFS at dose level 3 has not yet been reached. Conclusions: The MTD was not reached and Dose 3 (100 mg/m2) has been designated as the phase 2 dose of ABI- 009, combinable with nivolumab. Enrollment to phase 2 is ongoing. Clinical trial information: NCT03190174.

Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 287-287 ◽  
Author(s):  
Inger S. Nijhof ◽  
Sonja Zweegman ◽  
Mark-David Levin ◽  
Harry R. Koene ◽  
Aart Beeker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Oral Cyclophosphamide ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3 ◽  
Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

scholarly journals ATIM-24. DOSE FINDING AND DOSE EXPANSION TRIAL OF D2C7 IMMUNOTOXIN (D2C7-IT) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMA (MG)

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi6-vi6
Author(s):  
Annick Desjardins ◽  
Dina Randazzo ◽  
Vidya Chandramohan ◽  
Katherine Peters ◽  
Margaret Johnson ◽  
...  
Keyword(s):  
Dose Level ◽  
Cerebral Edema ◽  
Phase 1 ◽  
Dose Range ◽  
Antibody Fragment ◽  
Genetically Engineered ◽  
Phase 2 ◽  
Who Grade ◽  
Recombinant Immunotoxin ◽  
Grade 3

Abstract BACKGROUND D2C7-IT is a recombinant immunotoxin comprised of a dual-specific antibody fragment targeting EGFRwt and EGFRvIII and a genetically engineered form of the Pseudomonas exotoxin, PE38-KDEL. We report results of a phase 1 trial, with dose expansion at the selected phase 2 dose, evaluating D2C7-IT delivered intratumorally by CED. METHODS Eligible patients are adults with recurrent supratentorial WHO grade III or IV MG; solitary tumor; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS >70%. Two patients per dose level (DL) were to be enrolled in the dose escalation portion (dose range: 40ng/mL to 23,354ng/mL), followed by dose expansion at the selected phase 2 dose (DL13). RESULTS As of 6/07/2019, 51 patients have been treated; 10 patients on the phase 2 dose. Observed dose limiting toxicities include: grade 4 seizure (n=1) on DL3, grade 3 confusion and pyramidal tract syndrome (n=1) on DL13, and grade 4 cerebral edema (n=1) and grade 3 dysphasia (n=1) on DL17. Grade 3 or higher adverse events possibly related to D2C7-IT include: seizure (grade 4, n=2, grade 3, n=3), cerebral edema (grade 4, n=1), hydrocephalus (grade 3, n=5), headache (grade 3, n=4), hemiparesis (grade 3, n=4), dysphasia (grade 3, n=4), lymphopenia (grade 3, n=3), thromboembolic event (grade 3, n=3); and one each of grade 3 elevated ALT, urinary tract infection, fall, wound complication, generalized muscle weakness, confusion, encephalopathy, and somnolence. Fourteen patients are alive. Three patients have partial radiographic response and remain alive without additional therapy more than 46, 27 and 21 months after D2C7-IT infusion. CONCLUSION Dose level 13 was selected as the optimal phase 2 dose and patient accrual is ongoing on the dose expansion arm. Encouraging efficacy results have been observed. A trial of D2C7-IT with checkpoint inhibitor is planned to start in the near future.

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

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3012-3012 ◽  
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.

Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9014-9014 ◽  
Author(s):  
Tara C. Gangadhar ◽  
Bryan J. Schneider ◽  
Todd Michael Bauer ◽  
Jeffrey S. Wasser ◽  
Alexander I. Spira ◽  
...  
Keyword(s):  
Phase 1 ◽  
Phase 2 ◽  
Test Results ◽  
Efficacy And Safety ◽  
Open Label ◽  
Open Label Phase ◽  
History Of ◽  
Grade 3 ◽  
Preliminary Phase ◽  
Clinical Trial Information

9014 Background: ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of epacadostat (a potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus pembrolizumab (E + P) in patients (pts) with advanced tumors. We report preliminary efficacy and safety outcomes for the phase 1/2 NSCLC cohort. Methods: Adult pts with prior platinum-based therapy (tx) and no prior checkpoint inhibitor tx were eligible. Phase 1 dose-escalation tx was E (25, 50, 100, 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 cohort expansion. Efficacy was evaluated by tumor proportion score (TPS [% viable tumor cells, PD-L1 staining]: < 50% and ≥50%) and by prior lines of tx in RECIST 1.1 evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: As of 29OCT2016,43 pts (phase 1, n = 12; phase 2, n = 31) were evaluated. Median age was 65 years, 58% of pts were women, 12% were EGFR-positive, and 23% were KRAS-positive. Most pts had a history of smoking (84%), ≤2 prior lines of tx (84%), and no prior TKI tx (93%). For the 40 efficacy-evaluable pts, ORR (CR+PR) and DCR (CR+PR+SD) were 35% (14/40; 14 PR) and 60% (24/40; 10 SD), respectively. PD-L1 TPS test results were available in 28/40 efficacy-evaluable pts. ORR and DCR for pts with TPS ≥50% and ≤2 prior tx were 43% (3/7; all PR) and 57% (4/7; 1 SD), respectively; for pts with TPS < 50% and ≤2 prior tx, ORR and DCR were 35% (6/17; all PR) and 53% (9/17; 3 SD). Among the 40 efficacy-evaluable pts, 12/14 responses were ongoing (range, 1+ to 519 days) at data cutoff. PFS and biomarker analyses are ongoing. Across all 43 pts, most frequent TRAEs were fatigue (19%), arthralgia (9%), and increased AST (9%); 16% of pts had grade ≥3 TRAEs, and increased lipase (asymptomatic) was the only grade ≥3 TRAE that occurred in > 1 pt (n = 2). Two pts discontinued due to TRAEs (grade 3 increased AST, grade 2 increased ALT [n = 1]; grade 2 brain edema [n = 1]). Conclusions: E + P was generally well tolerated and associated with promising responses in pts with NSCLC. A phase 3 NSCLC study is planned. Clinical trial information: NCT02178722.

Initial results of a phase III investigation of safety/efficacy of nivolumab and ABI-009 (nab-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 21-21
Author(s):  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
Nupur Assudani ◽  
Ahmad Al-Shihabi ◽  
Doris Quon ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Dose Finding ◽  
Phase Iii ◽  
Phase 2 ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma ◽  
Grade 3

21 Background: Objectives: (1) To investigate the MTD of ABI-009 when given with nivolumab, a PD-1 inhibitor, in previously treated advanced undifferentiated pleomorphic sarcoma, liposarcoma, chondrosarcoma, osteosarcoma and Ewing sarcoma; (2) To investigate the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of this combination therapy in the above mentioned patient group, and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: This is an IRB approved protocol with 2 parts. The Phase 1 part is a dose-finding study using the “cohort of three design”, wherein standard doses of nivolumab 240 mg is given iv every 3 weeks (Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75, and 100 mg/m2. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: The Phase 1 part of study is closed, after 9 patients were treated successfully at 3 dose levels. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1 (n=3): Grade 3 treatment-related adverse events (TRAEs) included hyperdyslipidemia (n=1), and hyperglycemia (n=1). At Dose 2 (n=3): Grade 3 TRAEs included increased ALT (n=1). At Dose 3 (n=3): Grade 3 TRAEs included hypophosphatemia (n=1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. Conclusions: The primary objective has been met with no DLTs, the MTD was not reached and Dose 3 has been designated as the phase 2 dose of ABI-009 which is on-going. Clinical trial information: NCT03190174.

scholarly journals Phase 1 First-in-Human Trial of AMV564, a Bivalent Bispecific (2x2) CD33/CD3 T-Cell Engager, in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1455-1455 ◽  
Author(s):  
Peter Westervelt ◽  
Gail J. Roboz ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Sangmin Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dose Level ◽  
T Cell Activation ◽  
Research Funding ◽  
Cell Activation ◽  
Phase 1 ◽  
Disease Stage ◽  
Molecular Abnormalities ◽  
Grade 3

Abstract Background: AMV564 is a novel bivalent, bispecific (2x2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T-cell receptors with strong avidity, thus creating an immune synapse between CD33-expressing cells and T cells, initiating T-cell directed lysis of CD33 expressing cells, and inducing expansion, differentiation and proliferation of T cells. By design, AMV564 has reduced clearance and therefore has a longer half-life (t1/2) than monovalent, bispecific T-cell engagers. In preclinical investigations using both leukemic cell lines and primary cells from AML patients, AMV564 eliminated myeloid blasts with picomolar potency and broad activity independent of cytogenetic or molecular abnormalities, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res 2016;22:5829-38). Methods: This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), cytokine changes, and immunophenotyping are secondary objectives. Key inclusion/exclusion criteria are: adults with relapsed and/or refractory AML after 1-2 prior induction regimens (with a standard anthracycline-based regimen or hypomethylating agent) and no more than 2 prior salvage regimens. AMV564 is administered by continuous intravenous infusion (CIV) for 14 consecutive days for up to 2 induction cycles. AMV564 and cytokine (IL2, IL4, IL6, IL8, IL10, TNF-α, and IFN-γ) concentrations were measured by validated immunoassays. T-cell activation was measured using flow cytometry to quantify T cells expressing CD25, CD38, CD69, or HLA-DR. Results: To date, 19 patients (10 male/9 female) with a median age of 72 years (range 24-84) have been enrolled in 6 dosing cohorts: 0.5, 1.5, 5.0, 15, 50, and 100 mcg/day. Thirteen patients (68%) had secondary AML and/or adverse cytogenetics, including 6 patients (32%) with a p53 mutation. Fifteen patients (79%) had received at least 1 prior salvage regimen and 11 (58%) had received prior intensive chemotherapy, including 6 patients (32%) who had received a high-dose (≥ 1 gm/m2) cytarabine-based regimen. Overall, 18 patients were evaluable for toxicity and response. No dose-limiting toxicity or treatment-related grade ≥ 3 adverse events (AE) were reported. Grade 2 CRS was observed in 1 patient (treated at 50 mcg/day) without a lead-in dose and was managed with drug interruption and 1 dose of tocilizumab. The patient was able to resume dosing and completed the full 14-day scheduled therapy without recurrence of CRS. Subsequent patients treated at 50 mcg/day and above were given a 15 mcg/day lead-in dose for 3 days followed by 11 days at the assigned dose level. The most common grade ≥ 3 treatment-emergent AE has been febrile neutropenia, reported in 39% (7/18) of patients and all considered unrelated to study drug. No patient has died within 30 days of treatment initiation. AMV564 PK was linear with a terminal t1/2 of 2-3 days. Plasma concentrations increased gradually, with times to steady-state concentration of 3-7 days. Marked increases in IL6 (peak concentration, 1.1 ng/mL), IL8 (1.5 ng/mL), and IL10 (0.3 ng/mL) cytokines were observed and increased numbers of activated T-cells were detected post-treatment. Reductions in bone marrow blasts, ranging from 13% to 91%, were observed in 12 of 18 evaluable patients including a partial response after cycle 1 in 1 patient at the 100 mcg/day dose level. Conclusions: AMV564 is well-tolerated and demonstrates anti-leukemic activity through T-cell engagement. AMV564 has a unique PK profile with a gradual increase in drug concentration and thus the potential for controlled T-cell activation. Disclosures Roboz: Daiichi Sankyo: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Rettig:Amphivena Therapeutics: Research Funding; Novimmune: Research Funding. Han:Amphivena Therapeutics, Inc: Employment. Guenot:Amphivena Therapeutics, Inc: Employment. Feldman:Amphivena Therapeutics, Inc: Employment.

Phase I/II study of sunitinib malate in combination with gefitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5097-5097 ◽  
Author(s):  
P. H. Patel ◽  
G. V. Kondagunta ◽  
B. G. Redman ◽  
G. R. Hudes ◽  
S. T. Kim ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Ejection Fraction ◽  
Dose Level ◽  
Egf Receptor ◽  
Phase 1 ◽  
Objective Response ◽  
Cytokine Therapy ◽  
Phase 2 ◽  
Sunitinib Malate ◽  
Grade 3

5097 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGF- and PDGF- receptors with substantial antitumor activity against mRCC (JAMA 2006;295:2516). This study was conducted to evaluate the safety and efficacy of sunitinib in combination with gefitinib, an EGF-receptor inhibitor. Methods: Eligibility included mRCC with clear cell component. The phase 1 part of the study was conducted to determine the maximum tolerated dose (MTD) of sunitinib in combination with gefitinib, and subsequently pts were enrolled in the phase 2 part to further evaluate safety and antitumor activity. Pts were treated with sunitinib at assigned dose level (37.5 mg or 50 mg) orally daily for 4 weeks on, followed by 2 weeks off (Schedule 4/2) and gefitinib at 250 mg daily. The primary endpoint for the phase 2 part of the study was objective response according to RECIST. Results: Forty-two pts were enrolled; 11 pts in phase 1 and 31 pts in phase 2. Median age was 65 years (range: 29–78) and 35 pts (83%) had =2 metastatic sites. Twenty-eight pts (67%) had prior cytokine therapy, 11 pts (26%) had no prior cytokine therapy, and 3 pts (7%) received prior vaccine therapy. Two dose limiting toxicities (DLTs) were observed at the 50-mg dose level (grade 3 fatigue and grade 2 ejection fraction decline), and 37.5 mg on Schedule 4/2 in combination with gefitinib 250 mg daily was determined to be the MTD. The median duration on treatment was 8.3 months for phase 1. Thirty-six pts are evaluable for response and 6 are too early. Eleven pts (30%) achieved a partial response and 15 pts (42%) stable disease. The most common grade 3 treatment-related adverse events observed in phase 1 were diarrhea and nausea (n=2) and for phase 2 were diarrhea (10%) and gastrointestinal hemorrhage (6%). Two pts from phase 2 were withdrawn from the study due to treatment-related adverse event; ejection fraction decline and cardiac arrhythmia, both of which were reversible after treatment discontinuation. Conclusions: The study established dose and feasibility for sunitinib in combination with gefitinib. Early evaluation of the data suggests tolerability for the combination and relative efficacy data compared to sunitinib monotherapy will be assessed with longer patient follow-up. No significant financial relationships to disclose.

A phase I study of the oral administration of irinotecan in combination with the potent P-glycoprotein (P-gp) inhibitor HM30181A.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3032-3032
Author(s):  
Antonio Jimeno ◽  
Mateusz Opyrchal ◽  
Jennifer Robinson Diamond ◽  
Christos Fountzilas ◽  
Bradley Corr ◽  
...  
Keyword(s):  
Oral Administration ◽  
Dose Level ◽  
Phase 1 ◽  
Median Number ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Best Response ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Pharmacologically Active

3032 Background: Irinotecan is a prodrug of the potent topoisomerase inhibitor SN-38. In animals, oral administration of irinotecan with the selective minimally absorbed P-gp inhibitor HM30181A increased the bioavailability of irinotecan. Oral administration of irinotecan may also increase the conversion to SN-38. Objectives: To determine the MTD and DLT of orally administered irinotecan in combination with HM30181A 15 mg on day 1 of a 21-day cycle. Additional objectives include determining the recommended phase 2 dose and the PK of irinotecan and SN-38. Methods: This was a phase 1 dose escalation study enrolling cohorts of 3-6 patients with advanced malignancies. Patients had Hb ≥9 gm/dL, ANC ≥ 1.5x109/L, platelets ≥ 100x109/L, adequate hepatic and renal function, ECOG 0-1 and were not homozygous for UGT1A1*28. Patients were administered HM30181A 15 mg and oral irinotecan 20, 40, 80, 120, 160, 200, 240, 280 and 320mg/m2. Results: Thirty male and female patients, mean age 60.9 (range 33-78) were enrolled into this ongoing study. The most common cancers were ovarian (6), colorectal (4), breast (4), endometrial (3), and pancreatic (3). The median number of cycles administered was 3 (range 1-9). Treatment-related Grade 3-4 AEs were experienced by 12 (40%) subjects. The most common were nausea 7 (23%), vomiting 6 (20%) and abdominal pain 3 (10%). Treatment-related SAEs were experienced by 6 (20%) patients (nausea or vomiting in 4 subjects). DLTs occurred in 2 patients at the 320 mg/m2 dose level (neutropenia and C. Difficile diarrhea) and additional patients are being enrolled at the 280mg/m2 dose level to define the MTD. Acute cholinergic diarrhea has not been observed. The best response was stable disease in 9/21 evaluable patients. PK at the three highest dose levels is summarized below. Conclusions: Oral administration of HM30181A in combination with irinotecan tablets results in pharmacologically active concentrations of SN-38. Confirmation of the MTD when dosed on a 21-day cycle is ongoing. Phase 2 studies are being planned. Clinical trial information: NTC02250157. [Table: see text]

SAINT: Results of a phase 1/2 study of safety/efficacy using safe amounts of ipilimumab, nivolumab, and trabectedin as first-line treatment of advanced soft tissue sarcoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11016-11016 ◽  
Author(s):  
Erlinda Maria Gordon ◽  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
Seiya Liu ◽  
Nicole Angel ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Safety Analysis ◽  
Phase 2 ◽  
First Line ◽  
Efficacy Analysis ◽  
First Line Therapy ◽  
Pre Treatment ◽  
Grade 3

11016 Background: Sarcoma cells are most immunogenic earlier in the disease course and prior to treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Methods: This is an IRB-approved dose-seeking Phase 1/2 protocol using defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks) and escalating doses of T (1.0, 1.2, 1.5 mg/m2 i.v. q 3 weeks), employing the “Cohort of Three” design, followed by a Phase 2 using the MTD of trabectedin. Results: Nine subjects were treated in Phase 1 of the study, and 31 subjects in Phase 2. Safety analysis: at Dose 1: Grade 3 treatment-related adverse events (TRAEs) included fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs included thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs included anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). Efficacy analysis (evaluable patients): At Dose 1: Disease Control Rate (DCR = CR, PR, SD) was 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1), DCR 60%, median PFS, 24 weeks; median OS, > 46 weeks. At Phase 2, MTD Dose 2 (PUPs): Safety analysis (n = 31): Grade 3 TRAEs included fatigue (n = 2), increased ALT (n = 6), increased AST (n = 4), hypernatremia (n = 1), hyponatremia (n = 1), dehydration (n = 1), rash (n = 1), port cellulitis (n = 1), psoriasis exacerbation (n = 1), increased TSH (n = 1), decreased hemoglobin (n = 2), neutropenia (n = 1). Efficacy analysis (N = 23 evaluable): PR (n-5; 2 UPS, 1 synovial sarcoma, 1 liposarcoma, 1 leiomyosarcoma,), BORR 22%, DCR 96%. Median PFS and OS not yet reached. After 4 treatment cycles, one resected tumor showed 80% necrosis and a greater number (30%) of CD8+ killer T cells, in the TME compared to archived pre-treatment tumor. Conclusions: These data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. Phase 2 of the study is on-going. Clinical trial information: NCT03138161.

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

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.

Sign in / Sign up

Export Citation Format

Share Document