Absence of interaction of cabazitaxel on the pharmacokinetics of midazolam: Results of a drug–drug interaction study in patients with advanced solid tumors.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 126-126 ◽  
Author(s):  
Olivier Rixe ◽  
John Sarantopoulos ◽  
Chung-Tsen Hsueh ◽  
A. Craig Lockhart ◽  
Sharona Ross ◽  
...  
Keyword(s):  
Single Dose ◽  
Solid Tumors ◽  
Locally Advanced ◽  
Hepatic Function ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Fixed Sequence ◽  
Normal Hepatic Function ◽  
Grade 3

126 Background: Cabazitaxel (Cbz) is approved in combination with prednisone/prednisolone for the treatment of men with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen. In vitro studies showed that Cbz is mainly metabolized through CYP3A, resulting in inhibition of this family of enzymes. Midazolam (Mdz) is primarily metabolized by CYP3A4. We aimed to determine the effect of Cbz on CYP3A activity by comparing the pharmacokinetic (PK) properties of Mdz when administered alone and following co-administration with Cbz. Methods: An ongoing safety and PK study of Cbz in patients with metastatic or locally advanced solid tumors and varying degrees of hepatic impairment (NCT01140607) included a cohort with normal hepatic function to assess the effect of a single Cbz dose on the PK profile of a single dose of Mdz. This was an open-label, two-period, fixed-sequence study in patients aged between 45 and 60 years with advanced solid tumors and normal hepatic function. A single dose of Mdz (2 mg) was administered orally alone (Day –1) and at the end of a 1-hour infusion of Cbz (25 mg/m2) (Day 1), with a 24-hour interval between the two administrations of Mdz. Endpoints included AUC and AUClastof Mdz with and without Cbz administration, and safety evaluations. Results: Of the 13 patients enrolled and treated in the cohort, 11 patients were included in the PK analysis. Exposure (AUC and AUClast) and other PK parameters after a single administration of Mdz alone and in combination with Cbz (Day 1) were similar. The AUC ratio for Mdz administered alone or with Cbz was 0.97 (90% CI: 0.76–1.23). The AUClast ratio for Mdz administered alone or with Cbz was 1.04 (90% CI: 0.81–1.34). All 13 patients had ≥1 adverse event (AE), 11 (84.6%) experienced a Grade 3–4 AE, and 4 (30.8%) experienced a serious AE. The majority of Grade 3–4 AEs were haematological and no new or unexpected safety findings were observed. Conclusions: In this study, Cbz did not increase the plasma exposure of Mdz. This indicates that Cbz is not a CYP3A inhibitor in the clinical setting and can be administered in combination with drugs metabolized by CYP3A. Clinical trial information: NCT01140607.

Phase I dose-escalating study of PM02734 in a 24-hour infusion schedule every 21 days in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2511-2511
Author(s):  
T. R. Evans ◽  
A. Oaknin ◽  
R. J. Jones ◽  
A. Vandermeeren ◽  
C. Coronado ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase Ii Studies ◽  
Flat Dose ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Escalating

2511 Background: PM02734 is a chemically synthesized depsipeptide with a broad spectrum of activity against solid tumors in vitro (breast, colon, lung, neuroblastoma, prostate, sarcoma and thyroid) and in vivo (breast, prostate, melanoma); as well as an acceptable non-clinical toxicology profile. Methods: Patients (pts) with metastatic or advanced solid tumors were enrolled in a phase I, open-label, dose-escalating study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT) and recommended dose (RD) of PM02734 infused over 24 hours every 21 days (d). The starting dose was 0.48 mg/m2. Cohorts of 1–6 pts were treated at different dose levels. Results: Thirty seven pts were treated in this study. The median age was 55 years (40–75), sex: males/females 20/19. The median PS was 1 (range 0–2). The most frequent cancer types were colon/ gastric/ sarcoma (n=8/5/5). Most patients were heavily pretreated, with a median of prior therapy lines of 4 (1–12). Patients were treated at 8 dose levels (0.48, 0.72, 1.0, 1.6, 2.4, 3.6, 5.4, and 6.8 mg/m2), the MTD was 6.8 mg/m2 and the RD was 5.4 mg/m2 (10 mg flat dose).Common toxicities grade ≤ 2 included asthenia, nausea/emesis, lymphopenia, injection site reactions and asymptomatic elevated transaminases (TAs). DLT were grade 3 asymptomatic, reversible TA elevations at 6.8 mg/m2. Preliminary PK data is characterized by long half life (>100 h), a wide distribution and high inter-patient variability. Clearance was not correlated with dose or body surface area (BSA), therefore, flat dose was implemented and the RD was explored with this schedule. Efficacy data showed one complete response (CR) of +28 months observed in a pt with metastatic large cell esophageal carcinoma, and five more showed stable disease (SD) for more than 3 months in different histologies. Conclusions: PM02734 shows to be safe, well tolerated and with evidence of activity (1 CR and 5 SD > 3 months) in pts with advanced solid tumors. The DLT was grade 3 asymptomatic and reversible TA elevations, and the RD for further phase II studies is 10 mg. [Table: see text]

An open-label, randomized, parallel-group study of the pharmacokinetics of trifluridine as a component of TAS-102 versus FTD alone.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 751-751 ◽  
Author(s):  
Weijing Sun ◽  
Lee S. Rosen ◽  
Drew W. Rasco ◽  
Kenichiro Yoshida ◽  
Jabed Seraj ◽  
...  
Keyword(s):  
Single Dose ◽  
Solid Tumors ◽  
Phase 1 ◽  
Geometric Mean ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Antitumor Effects ◽  
Multiple Doses ◽  
Parallel Group ◽  
Grade 3

751 Background: TAS-102 is a novel oral combination therapy of FTD plus tipiracil hydrochloride (TPI) with FTD:TPI molar and weight ratios of 1:0.5 and 1:0.471, respectively. FTD is a thymidine-based nucleoside analog that has shown antitumor effects in preclinical and clinical studies. TPI stabilizes orally administered FTD by inhibiting thymidine phosphorylase and TAS-102 has shown efficacy in refractory metastatic colorectal cancer. The objective of this study was to show that TPI, administered with FTD as TAS-102, increases exposure to FTD in patients with advanced solid tumors. Methods: This is a Phase 1, randomized, open-label, pharmacokinetic study of TAS-102 in patients with advanced solid tumors. On the morning of Day 1, one group received TAS-102 35 mg/m2 and the other group received FTD 35 mg/m2. Both groups received TAS-102 35 mg/m2 on the evening of Day 1, then twice daily on Days 2-5 and 8-12 in a 28-day cycle. Blood samples were collected to evaluate FTD AUC0-last and Cmax (primary endpoints). Results: Overall, 44 patients (50% male, mean age 57 years) were treated. After a single dose, the ratio of the geometric mean of FTD AUC0-last and Cmax were 38- and 22-fold higher, respectively (Table) following TAS-102 vs FTD alone. After multiple doses (Day 12 in Cycles 1, 2, or 3), FTD AUC and Cmax were ~3- and 2-fold higher, respectively, than after a single dose of TAS-102 (Day 1). For TPI, AUC and Cmax were similar after single and multiple doses of TAS-102. After Cycle 1, FTD did not accumulate with successive cycles of TAS-102 treatment. The most commonly reported treatment-related adverse events were nausea (47.7%), fatigue (31.8%), and anemia (27.3%), with Grade 3-4 events at 4.5%, 2.3%, and 18.2%, respectively. Grade ≥ 3 decreases in neutrophil counts were observed in 42.9% of the TAS-102 group. Conclusions: TPI, in combination with FTD, substantially increased exposure to FTD vs FTD alone. Clinical trial information: NCT01867866. [Table: see text]

An open-label expanded-access study to evaluate the safety, tolerability, and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and hepatic impairment.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2559-2559
Author(s):  
Wasif M. Saif ◽  
Lee S. Rosen ◽  
Michelle A. Rudek ◽  
Weijing Sun ◽  
Dale Randall Shepard ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Hepatic Impairment ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
Hepatic Function ◽  
Moderate Hepatic Impairment ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Impaired Hepatic Function ◽  
Grade 3

2559 Background: The Phase 3 RECOURSE study showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (Mayer et al. N Engl J Med 2015;372:1909-19). A Phase 1 open-label study evaluated the safety and pharmacokinetics of FTD/TPI in patients with advanced solid tumors and varying degrees of hepatic impairment to inform dosing recommendations for these patients. Methods: Patients aged ≥18 years with advanced solid tumors, an Eastern Cooperative Oncology Group performance status ≤2, normal hepatic function, and mild, moderate, or severe impaired hepatic function according to the National Cancer Institute criteria were enrolled. Patients received FTD/TPI 35 mg/m2 orally twice daily on days 1-5 and days 8-12 of each 28-day cycle, except for those with severe impaired hepatic function (dose was to be determined). Results: 24 patients were enrolled to normal (n=8), mild (n=10), and moderate (n=6) groups. Study enrollment was stopped as 5/6 patients in the moderate group experienced elevated bilirubin levels (grade ≥3). The other baseline characteristics were similar across groups. Overall, 12 patients (50%) had at least 1 adverse event leading to study discontinuation: 2 in normal, 5 in mild, and 5 in the moderate hepatic impairment groups. Pharmacokinetic results are summarized in the table. Conclusions: The exposure to FTD or TPI was not increased by hepatic impairment and the patients who experienced grade 3 and 4 increased total bilirubin were not overexposed to FTD or TPI. Clinical trial information: NCT02301104. [Table: see text]

A phase 1b, open-label, dose-escalation study to evaluate camidanlumab tesirine (Cami) as monotherapy in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2556-2556
Author(s):  
Igor Puzanov ◽  
Patricia LoRusso ◽  
Kyriakos P. Papadopoulos ◽  
Christopher T. Chen ◽  
Yvan LeBruchec ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Single Agent ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

2556 Background: Depletion of tumor-infiltrating CD25+ regulatory T cells (Tregs), which inhibit tumor-specific immune responses, could contribute to tumor eradication. Cami (ADCT-301), an anti-CD25, pyrrolobenzodiazepine-based antibody-drug conjugate, targets CD25+ Tregs. A mouse surrogate has shown potent antitumor activity in solid tumor models. Here we report preliminary data from the monotherapy arm of a phase 1b trial of Cami in pts with selected advanced solid tumors. Methods: The monotherapy dose-escalation part of this open-label study enrolled pts (aged ≥18 years) with selected advanced solid tumors and no suitable existing therapy. The primary objective was to characterize safety and tolerability, and to identify the recommended phase 2 dose of Cami monotherapy. Secondary and exploratory objectives included evaluation of preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Pts received Cami every 3 weeks (1 cycle) with dose escalation per a 3+3 design. Disease control rate (DCR) was assessed (complete and partial responses [CR, PR] and stable disease). Results: At data cut-off (Dec 17, 2020), 44 pts were enrolled, with primary tumor types (stage IVA/B: 27 pts; 61.4%) of colorectal (15 pts; 34.1%), pancreatic (14 pts; 31.8%), head and neck, ovarian/fallopian tube, and renal cell carcinoma (all 3 pts; 6.8%), non-small cell lung cancer (2 pts; 4.5%), gastric, esophageal/GEJ, melanoma, and triple-negative breast cancer (each 1 pt; 2.3%). Median (range) age was 60.5 (33–82) years; median (range) number of prior systemic therapies was 4 (1–9). Pts received a median (range) of 2 (1–6) Cami cycles at doses of 20–150 µg/kg. Median (range) treatment duration was 22 (1–178) days. No dose-limiting toxicities were reported. The maximum tolerated dose (MTD) was not reached. All-grade treatment-emergent adverse events (TEAEs) in ≥20% pts were nausea (18 pts; 40.9%), decreased appetite and fatigue (each 16 pts; 36.4%), constipation (13 pts; 29.5%), abdominal pain (11 pts; 25%), and rash (10 pts; 22.7%). The only Grade ≥3 TEAE in ≥10% pts was anemia (5 pts; 11.4%). Grade 3 autoimmune AEs (colitis, immune-mediated AE, systemic inflammatory response syndrome) and neurologic AEs (dysphagia and asthenia, but not GBS) were reported in 3 (6.8%) and 2 (4.5%) pts, respectively. 1 (2.3%) Cami-related TEAE led to treatment withdrawal; no Cami-related TEAEs were fatal. DCR was 25% (95% CI: 11.1, 34.7); 11/44 pts attained stable disease. No pts had CR or PR. Conclusions: Dose escalation of Cami monotherapy is complete. The safety profile is encouraging and MTD was not reached. PK/PD data will be presented. 150 µg/kg is the highest dose investigated for single-agent Cami and the highest to be investigated combined with pembrolizumab in selected advanced solid tumors in the current protocol. Funding: ADC Therapeutics SA NCT03621982. Clinical trial information: NCT03621982.

scholarly journals Surufatinib Plus Toripalimab in Patients with Advanced Solid Tumors: A Single-Arm, Open-Label, Phase 1 Trial

2020 ◽  
Author(s):  
Yanshuo Cao ◽  
Ming Lu ◽  
Yu Sun ◽  
Jifang Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Trial ◽  
Open Label Phase ◽  
Grade 3

Abstract BackgroundPreclinical studies have supported a potential synergistic antitumor activity between surufatinib and anti-programed death ligand-1 (PD-L1). We describe here the results of a single-arm, open-label phase 1 trial to evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, an inhibitor of PD-L1.MethodsThis is an open-label, dose escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose escalation stage, 3 cohorts of patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with a fixed dose of toripalimab 240 mg, every 3 weeks (Q3W), to evaluate maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Additional patients were enrolled in the dose expansion phase to further assess the efficacy, safety, and PK profile.ResultsFrom April 1, 2019 to July 10, 2020, 31 patients were screened, of which 28 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity (DLT), a grade 3 hyperthyroidism. The top 3 most common treatment-related adverse events of ≥ grade 3 were transaminases increased (17.9%), hypertension (14.3%) and blood bilirubin increased (10.7%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Overall objective response rate was 22.2% [95% confidential interval (CI) 8.6‒42.3], and disease control rate reached 81.5% (95% CI 61.9‒93.7). ConclusionsSurufatinib plus toripalimab was well-tolerated, with no unexpected safety signals, and showed promising antitumor activity in patients with advanced solid tumors. Trial registrationclinicaltrials.gov, NCT03879057; Registered March 18, 2019, https://clinicaltrials.gov/ct2/show/NCT03879057

Phase I dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3045-3045 ◽  
Author(s):  
Takashi Seto ◽  
Taito Esaki ◽  
Fumihiko Hirai ◽  
Shuji Arita ◽  
Kaname Nosaki ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Troponin T ◽  
Geometric Mean ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Primary Tumor Site ◽  
Grade 3

3045 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has been shown to enhance the antitumor activity of gemcitabine in xenograft models (Zabludoff SD et al. Mol Cancer Ther 2008;7:2955–66). Methods: This open-label dose-escalation study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients (pts) with advanced solid tumors (NCT00937664). Pts received AZD7762 iv alone on days 1 and 8 of a 14-day cycle (Cycle 0), followed by AZD7762 plus gemcitabine 1000 mg/m2 on days 1 and 8 of 21-day cycles, in sequential ascending AZD7762 dose cohorts. Results: 20 pts (mean age 60 years) received AZD7762 at doses of 6 (n=3), 9 (3), 21 (6), and 30 mg (8). The most common primary tumor site was lung (n=14). All pts had received ≥1 prior chemotherapy and 18 had metastatic disease. Dose-limiting toxicities (DLTs) occurred in two of six evaluable pts (both 30 mg cohort): one, grade 3 (CTCAE, v3.0) elevated troponin T (Cycle 0; AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated AST and ALT (Cycle 1; combination therapy). Thus, the 30 mg dose was regarded as non-tolerable. DLTs resolved following treatment discontinuation. The most frequently reported adverse events (AEs) in Cycle 0 (AZD7762 monotherapy) were bradycardia (50%), hypertension (25%) and fatigue (15%). Overall, the most common AEs were bradycardia (55%), neutropenia (45%), and hypertension, fatigue, and rash (30% each). AEs grade ≥3 were reported in 11 pts, the most common being neutropenia (45%) and leukopenia (25%). No pt died due to an AE. AZD7762 exposure (Cmax, AUC) increased in an approximately linear manner. Gemcitabine did not appear to affect AZD7762 PK. Arithmetic mean t½ and geometric mean CL of AZD7762 across the dose groups were 16.1–19.4 h and 22.0–32.7 L/h, respectively during the monotherapy cycle, and 15.6–18.3 h and 21.1–24.4 L/h, respectively in combination with gemcitabine. There were no objective responses; five pts (all lung cancer) had stable disease. Conclusions: The maximum tolerated dose of AZD7762 in combinationwith gemcitabine 1000 mg/m2 was determined as 21 mg in Japanese pts.

Safety, tolerability, and pharmacokinetics (PK) of rilotumumab in Japanese patients (pts) with advanced solid tumors.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 130-130
Author(s):  
Toshihiko Doi ◽  
Rui Tang ◽  
Yilong Zhang ◽  
Elwyn Loh ◽  
Richard Lizambri ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Solid Tumors ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Locally Advanced ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Open Label ◽  
Eligibility Criteria ◽  
Dose Escalation Study

130 Background: Rilotumumab (R) is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor, the only known MET receptor ligand. The MET pathway has been identified as a potentially useful target for therapeutic blockade in oncology. R has been studied in multiple phase 2 trials either as monotherapy or combination therapy, including a phase 2 trial in gastric cancer combining R with epirubicin, cisplatin, and capecitabine. A phase 1 study was done to evaluate the safety, tolerability, and PK of R in Japanese pts. Methods: An open-label, dose-escalation study was performed with R at 10 mg/kg (Cohort 1A), escalating to 20 mg/kg (Cohort 1B) if no dose-limiting toxicities (DLTs) were observed. Key eligibility criteria were Japanese pts with unresectable locally advanced or metastatic carcinoma, age ≥ 20 yr, ECOG ≤ 1, and refractory to standard treatment (tx). Pts received R as an intravenous infusion on days 1 and 15 of each 28-day cycle, except for cycle 1 in which the day 15 dose was skipped to facilitate PK analysis. DLTs were evaluated in cycle 1. Results: A total of 9 pts were enrolled (1A, n = 3; 1B, n = 6). No DLTs were noted. As of 17 April 13, tx-emergent AEs were reported in 89% of pts. Tx-emergent AEs occurring in > 1 pt overall were vomiting (33%), diarrhea (22%), decreased hemoglobin (22%), hypoalbuminemia (22%), and nausea (22%). One grade 3 tx-emergent AE was observed (decreased hemoglobin; 10 mg/kg). Tx-related AEs were reported in 56% of pts. One grade ≥ 2 tx-related AE was observed (hypoalbuminemia; 20 mg/kg). 8 pts discontinued R due to disease progression; 1 pt remained on the investigational product. Mean exposure of R (Cmax and AUC) appeared to be doubled as dose increased from 10 to 20 mg/kg. The estimated mean CL was approximately 0.2 mL/hr/kg in both cohorts, suggesting a linear PK from 10 to 20 mg/kg. The terminal half-life of R was about 15 days. Conclusions: R monotherapy had an acceptable safety profile in Japanese pts with advanced solid tumors. These phase 1 safety and PK data support the further evaluation of R combined with chemotherapy in Japanese pts with MET-positive metastatic gastric cancer. Clinical trial information: NCT01791374.

Trial in progress: A phase 1-2 multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABN401 in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3157-TPS3157
Author(s):  
Dae Ho Lee ◽  
Aflah Roohullah ◽  
Byoung Chul Cho ◽  
Charlotte Rose Lemech ◽  
Paul L. de Souza ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Locally Advanced ◽  
Local Therapy ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Open Label

TPS3157 Background: c-MET (hepatocyte growth factor (HGF) receptor) overexpression, either by gene amplification, or mutation is associated with oncogenic transformation in numerous malignancies including lung, gastric, skin, renal, colorectal, and pancreatic cancers. ABN401 inhibits the activation of c-MET by reversibly interfering with the binding of c-Met tyrosine kinase to adenosine triphosphate (ATP) and blocking the receptor's downstream signaling that has demonstrated efficacy in NSCLC and gastric cancer in mouse xenograft and PDx models. This clinical trial is in progress in patients with advanced cancers. Methods: ABN401 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study in patients with advanced solid tumors, and dose-expansion (phase 2) in patients with targeted indications and c-MET biomarker expression (NCT04052971). The phase 1 explores ascending daily doses of oral ABN401 monotherapy in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). A preplanned extension (pilot expansion) study has been initiated based on predefined positive efficacy signals at intermediate doses up to 10 NSCLC patients who have c-MET alteration. Once RP2D is determined, the phase 2 expansion of up to 10-29 patients in four specific tumor-type cohorts is planned, utilizing a Simon's optimal two-stage design to evaluate the clinical activity of ABN401. ABN401-001 study began enrolling patients in August 2019 and is ongoing in Korean and Australia. Dose escalation up to cohort 4 has been completed, enrollment to cohort 5 began in November 2020. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria and safety findings reviewed by the DRC, which will determine the RP2D and MTD. Key Phase 1 eligibility criteria include 1) histological or cytological diagnosis of melanoma or any type of carcinoma or sarcoma and 2) refractory metastatic disease, or refractory locally advanced disease not amenable to local therapy. For the extension (pilot expansion) study, patients must have NSCLC with MET exon 14 skipping, MET amplification and/or c-MET overexpression. An exploratory study is being conducted for co-development of a companion diagnostic (CDx) system including a CTC device and ddPCR kit through liquid biopsy. Clinical trial information: NCT04052971.

Efficacy of HX008 in high microsatellite instability/mismatch repair–defificient (MSI-H/dMMR) solid tumors: Results from a multicenter phase II open-label study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2572-2572
Author(s):  
Jing Huang ◽  
Yan Song ◽  
Suxia Luo ◽  
Xianli Yin ◽  
Enxiao LI ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Objective Response ◽  
Initial Response ◽  
Subsequent Treatment ◽  
Advanced Solid Tumors ◽  
Second Line ◽  
Open Label ◽  
Grade 3

2572 Background: The subsequent treatment choices are limited for the patients with advanced solid tumors who had failed the standard therapies. PD-1 blockade monotherapy demonstrated robust antitumor activity in patients with MSI-H/dMMR. The aim of this study is to identify the efficacy and safety of HX008, an anti-PD-1 monoclonal antibody, in patients with advanced MSI-H/dMMR solid tumors. Methods: Eligible patients were age ≥18 years with histologically/cytologically confirmed advanced MSI-H/dMMR solid tumors, who have failed at least one line of standard systemic therapy. MSI-H/dMMR status was assessed centrally. Patients received HX008 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed 9 weeks after the first treatment, then every 6 weeks for the first year of therapy, and every 12 weeks thereafter. The primary end point was objective response rate (ORR) per RECIST1.1. Results: One hundred patients were enrolled from October 2018 to December 2020, with a median age of 53 (range 20-74) years. All of the patients were ≥ second-line patients. The most common cancer types were colorectal cancer (N=74) and gastric cancer (N=10). Median follow-up is 8.97 (range 0.03-25.53) months at the time of data cutoff. Among 86 patients who had reached the initial response evaluation, there were 8 CR, 33 PR, 24 SD, 17 PD and 4 NE. ORR was 47.67% (95%CI 36.79%-58.73%), and DCR was 75.58% (95%CI 65.13%-84.20%). ORR and DCR for the 66 colorectal cancer patients were 50% (95%CI 37.43-62.57%) and 75.76% (95%CI 63.64-85.46%). Median PFS was not reached (95%CI 6.18-NR) for all enrolled patients, while the 6-month and 12-month PFS rates were 62.66% (95%CI 50.98%-72.31%) and 52.70% (95%CI 39.96%-63.94%), respectively. Median OS was not reached. Treatment-related adverse events occurred in 77 patients (77%). Twelve patients (12%) had grade 3 or 4 treatment-related adverse events and there were no grade 5 treatment-related adverse events. The grade 3 or 4 treatment-related adverse events with incidence >1% included anemia (2%) and leukopenia (2%). Immune-related adverse events were observed in 15 patients (15%), including hypothyroidism in 9 patients (all were grade 1-2), and hepatitis, hyperglycemia, myocarditis, creatin kinase/creatin kinase MB increased, hypopigmentation of the vulva, rash, each in 1 patient. Conclusions: HX008 as a ≥second-line therapy showed promising efficacy and a manageable safety profile in patients with MSI-H/dMMR advanced solid tumors. Clinical trial information: NCT03704246.

Phase I dose escalation of KD033, a PDL1-IL15 bispecific molecule, in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2568-2568
Author(s):  
Jason J. Luke ◽  
Anthony J. Olszanski ◽  
Igor Puzanov ◽  
Dan Lu ◽  
Adrian Hackett ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Cell Activation ◽  
Nk Cell ◽  
Phase 1 ◽  
Locally Advanced ◽  
Advanced Solid Tumors ◽  
Efficacy Evaluation ◽  
Open Label

2568 Background: IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, but unlike IL-2, IL-15 does not expand regulatory T cells (Tregs), does not mediate activation-induced cell death and may have an improved therapeutic index. KD033 is a fusion antibody combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 (or its mouse cross reactive surrogate molecule, srKD033) has been extensively characterized in multiple in vitro and in vivo nonclinical studies. The fusion of anti-PD-L1 antibody to IL-15 significantly increases the maximal-tolerated dose (MTD) of srKD033 in mice compared to free IL-15. In addition, srKD033 has exhibited increased efficacy in rejecting tumors in mice as compared to the combination of its individual components, anti-PD-L1 antibody and IL-15. Methods: This is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety and tolerability and the MTD of KD033. Secondary objectives include characterization of PK and immunogenicity, evaluation of CD8 T and NK cell activation and assessment of best overall response and duration of response. KD033 is administered by IV infusion over 30 minutes every 14 days. Accelerated intra-patient dose escalation across the initial three dose levels, followed by 3+3 escalation thereafter, is investigating dose ranges from 3 µg/kg to 600 µg/kg. Efficacy evaluation is planned in an expansion cohort of patients with PD-1/L1 refractory tumors. Results: A total of 7 patients have received treatment. Three patients were dosed in Cohort 1 and four patients were dosed in Cohort 2. Through two dose escalation cohorts (3 µg/kg – 25 µg/kg), no dose-limiting toxicities have been reported. Grade 1-2 treatment-related toxicities, when observed, resolved within 24 hours with supportive management. 6 patients are evaluable for treatment response with one patient (adenoid cystic carcinoma) in the first cohort having stable disease for more than 6 months. Conclusions: KD033 has been well tolerated early in dose escalation with on-mechanism pharmacodynamics consistent with IL-15 agonism. Clinical trial information: NCT04242147.

Sign in / Sign up

Export Citation Format

Share Document