Results of a first-in-human phase I study of SRF231, a fully human, high-affinity anti-CD47 antibody.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3064-3064
Author(s):  
Amita Patnaik ◽  
Anna Spreafico ◽  
Alison M. Paterson ◽  
Marisa Peluso ◽  
Jou-Ku Chung ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Clinical Outcomes ◽  
Phase 1 ◽  
Safety Data ◽  
Receptor Occupancy ◽  
Weekly Dose ◽  
Weekly Schedule ◽  
Phase 1 Study ◽  
High Affinity ◽  
Grade 3

3064 Background: CD47 is a transmembrane protein that acts as a “Don’t Eat Me” signal to evade immune recognition. It is overexpressed in multiple cancer subtypes and is associated with poor prognosis. SRF231 is an investigational, fully human, high-affinity CD47-targeting antibody that delivers an activating signal to myeloid cells and displays favorable preclinical characteristics regarding its receptor occupancy/tumor exposure/efficacy relationship. Methods: In a Phase 1 study, SRF231-101 (NCT03512340), patients with advanced solid and hematologic malignancies who had failed standard therapy were enrolled in dose escalation cohorts (accelerated single-patient followed by standard 3+3) to establish the preliminary safety of SRF231 as a monotherapy and identify a dose and schedule suitable for expansion. In addition to collection of safety data, clinical outcomes were evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and SRF231 pharmacokinetic (PK) and pharmacodynamic (receptor occupancy) analyses were performed. Results: As of January 11, 2020, a total of 46 patients were enrolled, 25 in every-3-week intravenous (IV) dosing schedules and 21 in weekly IV dosing schedules. Weekly dosing schedules also explored the use of a 1.0 mg/kg initiation dose. Other than one patient with recurrent follicular lymphoma, all patients had recurrent/refractory solid tumors. The most common treatment emergent adverse events across dosing schedules were low-grade fatigue (43%), headache (35%), and pyrexia (30%). On every-3-week dosing schedules, 2 dose-limiting toxicities (DLTs) were observed: Grade 3 febrile neutropenia and Grade 3 hemolysis, both at a 12.0 mg/kg dose level. On weekly dosing schedules, 3 DLTs were observed: Grade 4 thrombocytopenia (6.0 mg/kg), Grade 4 amylase and lipase increased (4.0 mg/kg with initiation dose), and Grade 3 fatigue (4.0 mg/kg). The maximum tolerated dose was 9.0 mg/kg on an every-3-week and 4.0 mg/kg on a weekly schedule. Receptor occupancy was maintained at > 90% throughout the dosing period with a 4.0 mg/kg weekly dose schedule. Out of 37 patients who were response evaluable by RECIST, there were no complete or partial responders, although prolonged stable disease has been observed. Conclusions: Preliminary data from a Phase 1 study of SRF231, an anti-CD47 antibody, demonstrate that SRF231 may be administered safely and doses of 4.0 mg/kg weekly maintain > 90% receptor occupancy throughout the dosing period. Updated safety data, clinical outcomes, and PK/pharmacodynamic data will be presented. Clinical trial information: NCT03512340 .

A phase I study of APL-501, an anti-PD-1 antibody, in patients with recurrent or advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15125-e15125
Author(s):  
Mark Voskoboynik ◽  
Gary Edward Richardson ◽  
Linda R. Mileshkin ◽  
Catriona M. McNeil ◽  
Lisa Horvath ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Receptor Occupancy ◽  
Median Number ◽  
Unknown Primary ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Grade 3 ◽  
Refractory Solid Tumor ◽  
Ecog Ps

e15125 Background: APL-501 is a humanized monoclonal antibody targeting programmed cell death-1 (PD-1). APL-501 is being evaluated in patients (pts) with advanced recurrent and relapsed solid tumors who had not been previously treated with an immune checkpoint inhibitor in an ongoing 3-part Phase 1 trial (NCT03053466). Herein, we present the emerging pharmacokinetic (PK) and receptor occupancy (RO), safety and preliminary efficacy. Methods: Weight-based dose escalation (1, 3, and 10 mg/kg, Part 1) and Extension (Part 2) has been completed and the study is currently enrolling specific tumor types (MSI-H/dMMR and Carcinoma of Unknown Primary [CUP]) into the Expansion Cohorts (Part 3). Relapsed/refractory solid tumor pts were enrolled in Part 1 and Part 2. Key exclusion criteria included prior therapy targeting PD-1/PD-L1 and uncontrolled CNS metastases. APL-501 was administered IV over 1 hour every 14 days. Serum and PBMCs were collected for PK and RO analysis, respectively. RO was assessed using different T-cell markers measured by flow cytometry of PBMC. Anti-tumor activity was assessed by investigators using RECIST and irRECIST. Safety was assessed using CTCAE, v4.03. Results: As of 31 Dec 2019, 22 pts were enrolled with a mean age of 62.1 (SD: 12.2) years. ECOG PS 0/1 reported at 10/12 pts, respectively. Pts had a median number of 3 prior lines of therapy (range, 1 – 9) and median time to treatment from initial diagnosis was 30.1 months (range, 6.7 – 184.8). Across doses evaluated, APL-501 demonstrated dose proportional PK. One hundred percent (100%) RO was observed across all doses evaluated. No dose limiting toxicities were reported. Fifteen pts (68.2%) had related AEs; two pts (9.1%) had Grade ≥ 3 related AEs to APL-501. Eight pts had stable disease and two pts had partial response by RECIST (esophageal adenocarcinoma and CUP). Seven pts remained on therapy for ≥ 24 weeks. The recommended phase 2 dose (RP2D) has been determined to be 400 mg IV every 14 days (non-weight-based) based on safety and PK modeling. Conclusions: Preliminary results indicate clinical activity of APL-501 in relapsed/refractory malignant disease with a generally tolerable safety profile. The PK and RO profile, across all doses evaluated, appears comparable to marketed PD-1 inhibitors. Continued exploration of APL-501 with the RP2D in CUP and MSI-H/dMMR tumors is being planned. Clinical trial information: NCT03053466 .

scholarly journals Phase 1 Study of Bisthianostat, an Orally Efficacious Pan-HDAC Inhibitor: Part Results of Safety, Pharmacokinetics and Efficacy in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5591-5591
Author(s):  
Hong-Hui Huang ◽  
Jian Hou ◽  
Yang-Ming Zhang ◽  
Yu-Bo Zhou ◽  
Li Jia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Hdac Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Human Study ◽  
Weekly Schedule ◽  
Phase 1 Study ◽  
Expansion Phase ◽  
Grade 3

Background: Multiple myeloma (MM) is the second most common hematological malignancy. This disease remains incurable as nearly all patients will relapse and become refractory to established MM therapy. Thus, new treatment option for relapsed or refractory (R/R) MM is needed, particularly those with different mechanisms of action. One such approach is to inhibit histone deacetylase (HDAC) and produce synergistic anti-myeloma activity via mechanisms of epigenetic modulations. In 2015, panobinostat was approved by US FDA as the first HDACi to treat R/R MM in combination with bortezomib and dexamethasone. Bisthianostat is a novel bisthiazole-based HDACi evolved from the thiazole-thiazoline cap group in natural product Largazole (Nan et al., ACS Med Chem Lett. 2014). It is orally available and displayed inhibition against a series of MM cell lines. Here we presented preliminary in-human findings from CH-020PI study, an ongoing phase 1 study of bisthianostat. (Trial registered at ClinicalTrial.gov: NCT03618602) Methods: CH-020PI is a first-in-human study to investigate the safety, tolerability, pharmacokinetics, and efficacy of bisthianostat in R/R MM patients. It is a single center, open-label, single arm, dose escalating phase I study. A standard 3+3 cohort design with 100mg as the starting dose was used to determine the maximum tolerated dose of bisthianostat. This study comprised two phases: a pharmacokinetics phase and an expansion phase. In the pharmacokinetics phase, a single-dose of bisthianostat was administered on day 1, and then multiple-dose was administered on a twice-weekly schedule for 4 consecutive weeks. Patients in the expansion phase received continuous bisthianostat twice weekly until progressive disease or unacceptable toxicities. Results: Until 30 June 2019, 8 patients were enrolled at 3 dose levels from 100 to 400mg. The median age at enrollment was 62 years (range, 51-70 years). The median number of previous lines of therapy was 5 (range, 2-6). Per protocol, all of 8 patients were evaluable for pharmacokinetics, toxicities and efficacy. In the pharmacokinetic evaluation, for all the 8 patients tested at day 1, the peak concentration of bisthianostat was reached within 2.3 hours; half life time were around 4 hours; bisthianostat uptake represented by AUClast were in good proportion to the level of dose as 100, 200 and 400mg, respectively. Similar results were observed at day 28. Any grade hematological treatment-related adverse events (AEs) occurred in 4 of 8 patients (50%), while grade 3/4 hematological AEs occurred in 2 (25%) patients. Any grade non-hematological treatment-emergent AEs were observed in 3 (37.5%) patients; no grade 3/4 non-hematological AEs were reported. No patient discontinued the treatment of bisthianostat due to AEs. Except patient 007 (200mg cohort) experienced a grade 2 nausea, no patients experienced diarrhea, nausea, or vomiting. It is worthy to note that gastrointestinal toxicity is common with the use of panobinostat, a FDA-approved HDAC inhibitor. Overall single-agent efficacy was modest, and stable disease (SD) was observed in 4 (50%) patients. At the time of data cut-off for statistical analysis, no dose-limiting toxicity has been observed. Conclusions: Bisthianostat proved to be well absorbed and tolerated. It exhibited modest anti-tumor efficacy in our cohort of heavily pretreated patients with R/R MM. This phase I clinical trial is currently ongoing, and future trials should compare different doses and schedules of the combination in order to optimize the treatment tolerability and enhance its efficacy. Disclosures No relevant conflicts of interest to declare.

385 A first-in-human study of lemzoparlimab, a differentiated anti-CD47 antibody, in subjects with relapsed/refractory malignancy: initial monotherapy results

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A410-A410 ◽  
Author(s):  
Jordan Berlin ◽  
Wael Harb ◽  
Alex Adjei ◽  
Yan Xing ◽  
Paul Swiecicki ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Human Study ◽  
Evaluation Criteria ◽  
Receptor Occupancy ◽  
High Dose ◽  
Weekly Dose ◽  
Response Data ◽  
Good Laboratory

BackgroundCD47 blockade using SIRPα-Fc or anti-CD47 antibodies results in inhibition of the ‘do not eat’ signal and activation of phagocytosis and has emerged as a promising cancer treatment strategy. However, targeting CD47 leads to various hematological toxicities, particularly anemia and thrombocytopenia. Lemzoparlimab (also known as TJ011133 or TJC4) is a fully human, anti-CD47 IgG4 antibody that is endowed with a red blood cell (RBC) sparing property and unique binding epitope, potentially differentiating itself from other CD47 axis targeting therapies.MethodsThis phase 1 study (NCT03934814) is comprised of 2 parts. Part 1 consists of lemzoparlimab monotherapy dose escalation and 2 separate dose escalations of combination therapy with pembrolizumab or rituximab. The study is a standard 3+3 design. Part 2 is a dose expansion study. During monotherapy dose escalation, patients with relapsed/refractory solid tumors were administered an intravenous weekly dose (1 to 30 mg/kg) of lemzoparlimab to determine tolerability, safety, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and iRECIST. Preliminary data from fully enrolled monotherapy cohorts in Part 1 are reported as of 17 July 2020.ResultsTwenty patients with relapsed/refractory solid tumors were enrolled to monotherapy dose escalation cohorts (1, 3, 10, 20 and 30 mg/kg). Lemzoparlimab toxicity was manageable up to 30 mg/kg without a dose-limiting toxicity (DLT) observed. The most common treatment-related adverse events (TRAEs) were anemia (30.0%, n=6), fatigue (25.0%, n=5), infusion-related reactions (20.0%, n=4), and diarrhea (15.0%, n=3). All TRAEs were Grade 1 or 2. A transient, non-dose-dependent average reduction of 1.5 mg/dL (range: 0.4–2.6 mg/dL) in hemoglobin during the first cycle was observed across all cohorts consistent with the results of pre-clinical good laboratory practice toxicity studies. Laboratory or clinical evidence of hemolysis was not observed in any cohort. Preliminary results indicate the PK of lemzoparlimab appears to be linear at mid- to high dose levels following a single dose. CD47 receptor occupancy shows complete saturation on peripheral T cells at peak concentrations of 20 mg/kg and above.ConclusionsLemzoparlimab appears safe up to 30 mg/kg with favorable PK and PD characteristics in patients with relapsed/refractory solid tumors to date. No TRAEs greater than Grade 2 have been observed. Results will be updated at presentation including available tumor response data.Trial RegistrationNCT03934814Ethics ApprovalThe study was approved by IRB, approval number 20190733.

Preliminary safety, pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy of uliledlimab (TJ004309), a differentiated CD73 antibody, in combination with atezolizumab in patients with advanced cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2511-2511
Author(s):  
Francisco Robert ◽  
Ecaterina Elena Dumbrava ◽  
Yan Xing ◽  
Elizabeth Mills ◽  
James L. Freddo ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Solid Tumors ◽  
Clinical Investigation ◽  
Phase 1 ◽  
Critical Role ◽  
Receptor Occupancy ◽  
Clinical Activity ◽  
Tumor Resistance ◽  
Phase 1 Study ◽  
Naive Patient

2511 Background: CD73 is implicated in tumor resistance to checkpoint immunotherapy (CPI) and plays a critical role in adenosine-mediated immune suppression. Uliledlimab, a differentiated CD73 antibody, inhibits the adenosine pathway in a non-competitive and unique intra-dimer binding mode. Uliledlimab suppresses tumor growth when combined with a PD-(L)1 inhibitor in multiple pre-clinical models. Methods: This 3+3 dose-escalation phase 1 study (NCT03835949) evaluated safety, tolerability, PK, PD and preliminary efficacy in cancer patients. Uliledlimab was administered intravenously at doses of 5, 10 or 15 mg/kg weekly (QW) or 15 or 20 mg/kg every 3 weeks (Q3W) alone in the first cycle and in combination with atezolizumab (1,200 mg Q3W) starting on week 4. Soluble CD73 in serum and CD73 receptor occupancy (RO) in circulating CD19+ B cells were measured. Expression of PD-L1, CD73 and A2A receptor was analyzed in baseline tumor specimens (n = 14). Tumor responses were assessed by RECIST/iRECIST. Results: As of 17 January 2021, 20 patients with advanced solid tumors were enrolled (M:F 8:12; mean age = 64; median prior regimens = 3 (range 1-9)). Uliledlimab was well-tolerated with no dose limiting toxicity. The most common treatment-related adverse events were first dose infusion related reactions (65%, n = 13) most commonly comprising chills/rigors, nausea, and vomiting (Grade 1 or 2) that resolved in subsequent infusions. PK appears linear at doses ≥ 10 mg/kg and modelling indicated a mean derived effective half-life of ̃19 days. Soluble CD73 was undetectable and complete RO was achieved in all patients after the first dose at ≥ 10 mg/kg. Anti-drug antibody was detected in 3/20 patients (15%). Among 13 efficacy-evaluable patients dosed at ≥ 10 mg/kg, complete response (CR = 1) and partial response (PR = 2) were observed in 3 patients (ORR = 23%) together with 3 stable disease (SD) patients (DCR = 46%). One PD-(L)1 inhibitor naïve patient with clear cell ovarian cancer achieved CR at 10 mg/kg QW and remains on study after 12 months. Two patients with NSCLC dosed at 15 mg/kg QW and 20 mg/kg Q3W, respectively, achieved PR. One patient failed nivolumab and the other received no prior PD-(L)1 inhibitor treatment. CD73 was expressed on 78% (mean) of malignant cells from archival tumor specimens in responders compared to 23% in non-responders. Conclusions: Uliledlimab is safe and well tolerated up to 20 mg/kg Q3W and 15 mg/kg QW. Full saturation of circulating and cell-bound CD73 was achieved at doses ≥ 10 mg/kg. Uliledlimab exhibited evidence of clinical activity in both PD-(L)1 treatment naïve and refractory cancer patients with high archival tumor expression of CD73. The results of this phase 1 study encourage further clinical investigation to evaluate the efficacy of uliledlimab in the treatment of solid tumors. Clinical trial information: NCT03835949.

Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor: Preliminary results from a phase 1 study in patients with advanced malignant solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3552-3552 ◽  
Author(s):  
W. A. Messersmith ◽  
S. Krishnamurthi ◽  
B. A. Hewes ◽  
C. M. Zacharchuk ◽  
R. Abbas ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Solid Tumors ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Human Tumor ◽  
Dependent Manner ◽  
Phase 1 Study ◽  
Once Daily ◽  
Grade 3

3552 Background: Bosutinib (SKI-606) is a potent, low molecular weight, orally active, competitive inhibitor of both Src and Abl tyrosine kinases. Elevations of Src kinase activity occur in a variety of human tumor types and are correlated with aggressiveness. We conducted a phase 1 study in patients (pts) with advanced solid tumors to assess tolerability, safety, pharmacokinetics (PK), and preliminary antitumor activity of bosutinib. Methods: Patients in cohorts of 3–6 received 50, 100, 200, 300, 400, 500 or 600 mg bosutinib orally on study day 1 and then once daily beginning on day 3. Timed blood samples were collected on days 1–3, 15 and 16 for PK analysis. Tumor assessments (modified RECIST criteria) were made at baseline and the end of every third cycle (21 days/cycle). Collection of tissue samples for analysis of Src biomarkers was optional. Results: Preliminary data are presented for 51 pts (median 57 years, 57% women). Three pts who received 600 mg bosutinib/day had drug-related dose-limiting toxicity of grade 3 diarrhea (2 pts) and grade 3 rash (1 pt). Gastrointestinal (GI) toxicity was reported among 6 pts in the 500-mg maximum tolerated dose (MTD) lead-in cohort so that 400 mg was selected as the MTD. Drug-related adverse events (AEs), any grade, occurring in =25% of pts were nausea (67%), diarrhea (55%), anorexia (45%), vomiting (43%), asthenia (41%). The only grade 3 drug-related AE occurring in =5% of pts was diarrhea (14%). After oral administration, bosutinib exposure increased in a dose-dependent manner. Multiple-dose exposure was nearly 2- to 3-fold higher than single-dose exposure. Mean elimination half-life was approximately 17 to 21 hours, supporting a once-daily dosing regimen. Six pts had stable disease >15 weeks (2 pts each with breast, colorectal cancer, non-small cell lung cancer [NSCLC]) and 1 pt had stable disease >52 weeks (pancreatic cancer). Conclusions: Bosutinib was generally well tolerated with predominantly gastrointestinal AEs. Accrual and evaluation of an expanded cohort restricted to patients with colorectal, pancreatic, and NSCLC tumors is ongoing. The patient with pancreatic cancer has had stable disease >52 weeks. No significant financial relationships to disclose.

scholarly journals O83 Phase 1 study of an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A2.1-A2
Author(s):  
Ronnie Shapira-Frommer ◽  
Marloes GJ van Dongen ◽  
Konstantin Dobrenkov ◽  
Elliot Chartash ◽  
Fang Liu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Grade 5 ◽  
Crossover Phase ◽  
Grade 3 ◽  
Ecog Ps

BackgroundMK-5890 is a humanized agonist monoclonal antibody that binds to CD27 to provide a costimulatory signal that enhances T-cell–mediated responses. This first-in-human phase 1 study of MK-5890 evaluated the safety and efficacy of escalating doses of MK-5890 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors.MethodsKey eligibility criteria included histologically or cytologically confirmed advanced solid tumor, measurable disease by RECIST v1.1, and ECOG PS ≤1. MK-5890 was tested alone (dose range, 2-700 mg) or with pembrolizumab (fixed dose, 200 mg). Patients with disease progression following MK-5890 monotherapy were eligible to cross over to combination treatment. The primary objective was safety and tolerability. Objective response rate by investigator per RECIST v1.1 was also evaluated. The database cutoff for this analysis was May 30, 2019.ResultsOf 44 patients enrolled, 25 received MK-5890 and 19 received MK-5890 plus pembrolizumab; their median age was 59.0 years, 61.4% were female, 47.7% had ECOG PS 1, and 13.6% previously received immune checkpoint inhibitor therapy. In the initial phase, dose-limiting toxicities (DLTs) were reported in 3 patients receiving MK-5890 and 1 patient receiving MK-5890 plus pembrolizumab; all DLTs were associated with infusion-related adverse events. Maximum tolerated dose was defined. Treatment-related adverse events (TRAEs) were reported in 40 patients (90.9%): 22 patients (88.0%) receiving MK-5890 and 18 patients (94.7%) receiving MK-5890 plus pembrolizumab. The most common TRAEs were fatigue (28.0%) and infusion-related reactions (28.0%) with MK-5890 and fatigue (36.8%) and pruritus (31.6%) with MK-5809 plus pembrolizumab. Grade 3-4 TRAEs were reported in 10 patients (22.7%): 6 patients (24.0%) receiving MK-5890 and 4 patients (21.1%) receiving MK-5890 plus pembrolizumab; no grade 5 events were observed. One patient (4.0%) achieved a partial response (PR) with MK-5890 and 1 patient (5.3%) achieved a PR with MK-5890 plus pembrolizumab. Fourteen patients entered the crossover phase to receive MK-5890 plus pembrolizumab. In the crossover phase, no DLTs were reported. TRAEs were reported in 12 patients (85.7%); the most common were pruritus (21.4%), rash (21.4%), and headache (14.3%). One patient (7.1%) reported grade 3-4 TRAEs of increased amylase and increased lipase; no grade 5 events were observed. Two patients (14.3%) achieved a complete response and 2 patients (14.3%) achieved a PR.ConclusionsTreatment with MK-5890, alone and in combination with pembrolizumab, demonstrated an acceptable safety profile. Early antitumor activity was observed in patients with advanced solid tumors in both monotherapy and combination therapy arms.

Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4074-4074 ◽  
Author(s):  
Jean-Charles Soria ◽  
John H. Strickler ◽  
Ramaswamy Govindan ◽  
Seungjean Chai ◽  
Nancy Chan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Ecog Performance Status ◽  
Grade 3

4074 Background: Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase inhibitor that demonstrated encouraging preliminary clinical activity and manageable adverse events (AEs) in its first-in-human phase 1 study in advanced solid tumors (NCT01703481). Here we report results from pts with CCA from this study. Methods: This 4-part study enrolled pts age ≥ 18 years (y) with advanced solid tumors. Dose escalation (part 1) followed a 3+3 design, with pts receiving ascending doses of erdafitinib continuously or intermittently (7 days on/7 days off). Subsequent parts required FGFR gene alterations in the tumor, including activating mutations and translocations or other FGFR-activating aberrations. Part 2 was a pharmacodynamics cohort. Parts 3 and 4 were dose-expansion cohorts for recommended phase 2 doses of 9 mg once daily (QD) and 10 mg intermittently, respectively. Results: Eleven pts with FGFR-aberrant CCA were treated at 9 mg QD (n = 1) or 10 mg intermittent (n = 10). Median age was 60 y; 7 of 11 pts were female (64%). 73% of pts had ECOG performance status 1. All had prior systemic therapy. Median treatment duration with erdafitinib was 5.3 months (mo). Systemic erdafitinib exposure, per Cmax and AUC, in CCA pts was similar to other indications. The most common AEs were stomatitis (82%), hyperphosphatemia (64%), dry mouth (55%), dysgeusia (45%), dry skin (45%), and asthenia (45%), mostly grade 1/2 severity. No drug-related grade ≥3 AEs were reported in > 1 pt except grade 3 stomatitis (n = 2; 18%). The objective response rate, all confirmed partial responses (PRs) per RECIST 1.1, was 27.3% (3/11; 95% CI 6, 61); an additional 27.3% (3/11) had stable disease as their best response. Overall disease control rate was 55%. All 3 PRs were at the 10 mg intermittent dosage, and the median duration of response was 12.9 mo. With a median follow-up of 5.1 mo, median progression-free survival was 5.1 mo (95% CI 1.6, 16.4). As of the cutoff date, 2 pts continue on study treatment. Conclusions: Erdafitinib showed encouraging clinical activity and minimal toxicity in pts with advanced CCA and FGFR alterations. These results warrant further study. Clinical trial information: NCT01703481.

Phase 1 study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2503-2503
Author(s):  
Dan Liu ◽  
Jifang Gong ◽  
Tianshu Liu ◽  
KunYan Li ◽  
Xianli Yin ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Early Death ◽  
Pancreatic Acinar Cell ◽  
Efficacy Evaluation ◽  
Phase 1 Study ◽  
Multiple Tumor ◽  
Grade 3

2503 Background: Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a promising therapeutic strategy for multiple tumor types. SHR-1701 is a novel bifunctional anti-PD-L1/TGF-βRII agent. This dose escalation and expansion phase 1 study aimed to evaluated the safety and preliminary anti-tumor acitivity of SHR-1701 in refractory solid tumors. Methods: The dose escalation period was initiated by accelerated titration (1 mg/kg Q3W) and then switched to 3+3 scheme (3, 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W). The dose expanded at doses of 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W. The primary objectives were to determine the safety profile, MTD, and RP2D of SHR-1701. Results: 17 pts (1 mg/kg Q3W [n = 1]; 3, 10, 20 and 30 mg/kg Q3W [n = 3 each]; 30 mg/kg Q2W [n = 4]) were enrolled in dose escalation part. No DLT was observed and MTD was not reached. Another 32 pts (10 mg/kg Q3W [n = 8]; 20 and 30 mg/kg Q3W [n = 9 each]; 30 mg/kg Q2W [n = 6]) were enrolled in dose expansion part. Of 49 enrolled pts, 33 pts (67.3%) had received ≥2 lines of prior systemic therapy. As of data cutoff on Oct 30, 2020, the median duration of SHR-1701 exposure was 6.0 weeks (range, 2.0-78.6). The most common reported TRAEs were increased ALT/AST, anemia, hypothyroidism, and increased bilirubin/conjugated bilirubin, with incidence > 15%. The incidence of irAEs reported by the investigator was 46.9% and 4 pts received systemic corticosteroids. Hypothyroidism and rash were the most common irAEs with incidence > 10%. The incidence of Grade ≥3 TRAEs was 18.4%. The incidence of Grade ≥3 irAEs was 10.2%. 1 pt suffered early death for liver failure more likely caused by tumor progression. PK analysis showed a linear dose-exposure relationship with SHR-1701 dosing from 1 to 30 mg/kg. The peripheral PD-L1 target occupancy rate exceeded 90%, and nearly complete TGF-β1 trapping was detected in all dose groups. Of 49 enrolled pts, 45 pts completed at least once efficacy evaluation. The ORR was 17.8% (95% CI, 8.0%-32.1%), with 8 pts achieving PR (2 lung adenocarcinoma, 1 HCC, 1 ESCC, 1 dMMR-CRC, 1 renal cancer, 1 epiglottis cancer, and 1 pancreatic acinar cell carcinoma). The DCR was 40.0% (18/45; 95% CI, 25.7%-55.7%). Majority of responses (7/8) were still ongoing, and the median DoR had not been reached yet. Based on data of saftety, PK, PD, and efficacy, we recommended 30 mg/kg Q3W as the RP2D. Conclusions: SHR-1701 showed acceptable safety profile and encouraging antitumor activity in refractory solid tumors, establishing the foundation for further exploration. Clinical trial information: NCT03710265.

scholarly journals P863 KEYNOTE-022 parts 4 and 5: pembrolizumab plus trametinib for patients with solid tumors or BRAF wild-type melanoma

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A10.2-A11
Author(s):  
Michele Maio ◽  
Matteo Carlino ◽  
Anthony Joshua ◽  
Elaine McWhirter ◽  
Antoni Ribas ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Phase 1 ◽  
Safety Data ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Wild Type ◽  
Open Label ◽  
Skin Reactions ◽  
Grade 3

BackgroundPembrolizumab+dabrafenib+trametinib demonstrated promising antitumor activity and acceptable tolerability in BRAF-mutant melanoma in phase 1/2 KEYNOTE-022 parts 1 and 2 (NCT02130466). Pembrolizumab+dabrafenib+trametinib numerically prolonged PFS and DOR versus placebo+dabrafenib+trametinib but had a higher grade 3-5 TRAE rate in part 3. KEYNOTE-022 parts 4 and 5 evaluated pembrolizumab+trametinib.MethodsIn part 4 (open-label, 3+3 dose-finding) patients with advanced solid tumors (irrespective of BRAF status) or unresectable/metastatic BRAF wild-type melanoma received pembrolizumab 200 mg Q3W with trametinib as concurrent (2 or 4 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD]) or intermittent dosing (2 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD; 1 week off/2 weeks on]). Interim MTDs identified in part 4 were confirmed in part 5 using a modified toxicity probability interval design. The primary objectives were safety, tolerability, and ORR by investigator assessment per RECIST v1.1 of the maximum administered or tolerated dose (MAD/MTD) of pembrolizumab+trametinib. Safety was analyzed for all patients who received ≥1 dose of study drug; patients treated during the trametinib run-in who discontinued study before receiving pembrolizumab were included; patients who did not complete trametinib run-in or receive ≥66% of planned doses during the 6-week dose-limiting toxicity (DLT) evaluable period were not included for DLT evaluation. AEs were graded per NCI CTCAE v4.ResultsOf 42 enrolled patients, most were female (61.9%); median age was 55.0 years; 57.1% had received ≥2 prior lines of therapy. At database cutoff (June 26, 2019), median follow-up was 9.0 months (range, 1.4-25.6 months). Of 38 DLT-evaluable patients, 10 had DLTs (table 1). Dosing regimens were selected for confirmation in part 5 based on safety data. Any-grade TRAEs occurred in 39 (92.9%) patients; grade 3-4 TRAEs occurred in 19 (45.2%), none were grade 5. TRAEs led to discontinuation in 8 (19.0%) patients. Immune-mediated AEs occurred in 12 (28.6%) patients, most commonly severe skin reactions (n=6; 14.3%), pneumonitis (n=3; 7.1%), hypothyroidism (n=2; 4.8%). The MTD of concurrent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg with 2 weeks of trametinib run-in (ORR, 0/16; 0%) and the MTD of intermittent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 2 mg with 2 weeks of run-in (ORR, 4/15; 26.7%).Abstract P863 Table 1DLT, TRAE, and ORR in KEYNOTE-022 parts 4 and 5ConclusionsBoth concurrent or intermittent pembrolizumab+trametinib dosing were feasible and the combination showed antitumor activity in patients with advanced solid tumors or advanced BRAF wild-type melanoma.

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