Phase I study of oral LBH589, a novel deacetylase (DAC) inhibitor in advanced solid tumors and non-hodgkin’s lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3500-3500 ◽  
Author(s):  
H. M. Prince ◽  
D. George ◽  
A. Patnaik ◽  
M. Mita ◽  
M. Dugan ◽  
...  
Keyword(s):  
Parotid Gland ◽  
Solid Tumors ◽  
Phase 1 ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Peripheral Blood Lymphocytes ◽  
Advanced Solid Tumors ◽  
Post Dose ◽  
Western Blots

3500 Background: LBH589 is a novel deacetylase inhibitor (DACi) which induces apoptosis of tumor cells at nanomolar levels. In this phase 1 study, we evaluated the safety and tolerability of LBH589 in pts with advanced solid tumors or non-hodgkins lymphoma. Methods: LBH589 was administered orally on Monday, Wednesday, and Friday (MWF) weekly. Western blots on peripheral blood lymphocytes were used to study histone acetylation (HA). Plasma PK profiles were analyzed on Days 1 and 15. Results: Thirty two pts have been treated (Median age 63 years; 18 M, 14 F). Pts received 15 mg (3), 30 mg (10), the dose-limiting toxicity level (DLT), or 20 mg (19), the maximum tolerated dose (MTD). Tumor types included: CTCL (10), renal cell (6), melanoma (6), prostate (4), hepatic (1), rhabodomyosarcoma (1), mesothelioma (1), colon (1), bladder (1), and parotid gland (1). Three DLTs were reported; G3 diarrhea and transient G4 thrombocytopenia at 30 mg and G3 fatigue at 20 mg. The most common adverse events were anorexia, nausea, fatigue, diarrhea and transient thrombocytopenia. Of the 1,057 ECGs, 1 pt (20 mg) had a QTcF of 503 msec, an isolated event after the first dose with no recurrence on continued therapy. The mean change in QTcF from baseline was < 10 msec during the first cycle in all cohorts. No increase in HA was seen at 15 mg, but did increase in 50% of pts at 72 hrs post dose in both the 20 mg and 30 mg cohorts. LBH589 was rapidly absorbed in plasma (Tmax 1.5 hr), then declined with a mean terminal half-life of 16 hrs. Cmax and AUC increased linearly with doses between 15–30 mg. Two cutaneous T- cell lymphoma (CTCL) pts achieved a complete response (5 and 7 months) and 4 CTCL pts attained a partial response (6.5, 8, 9 and 18+ months). Stable disease was achieved in 7 pts: CTCL-2 pts (2 and 3 months); RCC-2 pts (3.5 and 7 months); melanoma-1 pt (4 months), mesothelioma-1 pt (2.5 months) and parotid gland-1 pt (5 months). Fifteen pts progressed on treatment and 4 pts were not evaluable for response. Conclusions: At 20 mg MWF every week, LBH589 oral produced a sustained pharmacodynamic effect on HA for ≥72 hours post dose in 50% of pts. Cardiac data indicates no clinically-significant effect on QTcF. Preliminary evidence of tumor response was observed at this dose and schedule in CTCL pts. No significant financial relationships to disclose.

Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3161-TPS3161
Author(s):  
Ecaterina Elena Dumbrava ◽  
Amit Mahipal ◽  
Xin Gao ◽  
Geoffrey Shapiro ◽  
Jason S. Starr ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Peripheral Blood Mononuclear

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

Phase I trial of paclitaxel in children with refractory solid tumors: a Pediatric Oncology Group Study.

1993 ◽  
Vol 11 (12) ◽  
pp. 2324-2329 ◽  
Author(s):  
C A Hurwitz ◽  
M V Relling ◽  
S D Weitman ◽  
Y Ravindranath ◽  
T J Vietti ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Phase I ◽  
Solid Tumors ◽  
Plasma Concentrations ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clonic Seizure ◽  
Fine Motor ◽  
Phase Ii Trials

PURPOSE A phase I study was performed to describe the principal toxicities and identify the maximum-tolerated dose (MTD) of Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in children with therapy-resistant solid tumors. Additionally, the pharmacokinetic disposition of Taxol in children was studied, and preliminary evidence of the activity of Taxol against pediatric solid tumors was assessed. PATIENTS AND METHODS Twenty-four-hour continuous infusions of Taxol were administered every 21 days to children (median age, 12 years; range, 2 to 22) with refractory solid tumors. Doses ranged from 200 to 420 mg/m2, there was no intrapatient dose escalation. RESULTS A total of 62 courses of Taxol were administered to 31 patients. Two patients developed acute anaphylaxis during their second infusion of taxol at doses of 200 mg/m2 and 350 mg/m2, respectively. No other allergic reactions were documented. Myelosuppression occurred at all dose levels, but was of short duration (< or = 7 days) and did not appear to increase with consecutive courses or at higher dosage levels. A stocking-and-glove peripheral neuropathy became evident at doses > or = 290 mg/m2. Dose-limiting neurotoxicity occurred at 420 mg/m2 and comprised a significant fine-motor and peripheral neuropathy in one patient, and a tonic-clonic seizure in another. End-of-infusion plasma concentrations ranged from 0.40 to 6.4 mumol/L, and were not found to be dose-dependent over the range of doses studied. A complete response was documented in one patient, partial response in two, and minimal response in one for an overall response rate of 13%. CONCLUSION Neurotoxicity was dose-limiting when Taxol was administered by 24-hour continuous infusion to pediatric patients with relapsed solid tumors. In this population, the recommended dose for phase II trials is 350 mg/m2/d.

Tolerability and safety of oral neratinib (HKI-272) in Japanese patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14505-e14505
Author(s):  
Y. Ito ◽  
K. Hatake ◽  
S. Takahashi ◽  
M. Yokoyama ◽  
M. Suenaga ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Japanese Patients ◽  
Maximum Tolerated Dose ◽  
Primary Diagnosis ◽  
Continuous Treatment ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Continuous Administration

e14505 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. In non-Japanese pts, neratinib was found to have clinical activity against solid tumors and dose-limiting toxicity (DLT) of diarrhea. The maximum tolerated dose (MTD) was 320 mg daily and the recommended dose (RD) was 240 mg because of the diarrhea. In this phase 1 study, the MTD was determined and safety and preliminary efficacy were assessed in Japanese pts with advanced solid tumors. Methods: Pts (3- 6/cohort) received 80, 160, 240, or 320 mg oral neratinib. Each pt participated in only 1 dose group and received single doses of neratinib followed by 1 wk of observation; pts then received daily continuous administration at the same dose. DLTs were assessed from the first single dose to the end of 14 days of continuous treatment. Pharmacokinetics (PK) will be analysed via a noncompartmental method. Tumor measurements were made at screening and at the end of every 8 weeks (2 cycles) by RECIST. Results: Preliminary data for 21 pts as of 30 Oct 2008 are presented. Pts had a median age [range] of 61 yrs [39–78], were 62% male, and had all received ≥2 prior chemotherapy regimens. Tumor types at primary diagnosis were advanced colorectal (81%), breast (14%), and gastric (5%) cancer. Median duration of neratinib treatment [range] was 10 wks [3–29].Two patients at the 320-mg dose had DLTs of diarrhea plus anorexia. Therefore the MTD was determined to be 240 mg. Neratinib-related AEs, any grade in ≥25% of pts included diarrhea (95%), fatigue (67%), anorexia (43%), nausea (43%), abdominal pain (38%), decreased hemoglobin (38%), increased AST (33%), and rash (29%). Neratinib-related AEs, grade ≥3 in ≥1 pts were anorexia (3 pts) and diarrhea (2 pts). Two pts had partial response (PR), 8 pts had stable disease (SD) ≥8 wks, 2 had SD≥16 wks, 9 had progressive disease. The 2 pts with PR had ErbB-2+ advanced breast cancer. PK analysis is still ongoing. Conclusions: In Japanese pts, the MTD for neratinb was determined to be 240 mg and the RD will be confirmed as 240 mg. Neratinib is tolerable and demonstrates preliminary antitumor activity in pts with solid tumors. [Table: see text]

Tumor drug distribution and target engagement of MLN9708, an investigational proteasome inhibitor, in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3077-3077 ◽  
Author(s):  
Alessandra Di Bacco ◽  
Allison Berger ◽  
Neeraj Gupta ◽  
Feng Gao ◽  
Stephen Blakemore ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Active Form ◽  
Drug Distribution ◽  
Maximum Tolerated Dose ◽  
Target Engagement ◽  
Learning Program ◽  
Post Dose ◽  
Tumor Biopsy

3077 Background: MLN9708 is a potent investigational proteasome inhibitor, which upon intravenous (IV) administration immediately hydrolyzes to the active form MLN2238. MLN9708 is currently being evaluated in a phase 1 trial in solid tumors (NCT00830869). This trial has a dose-escalation arm and five expansion cohorts: non-small cell lung cancer (NSCLC), soft tissue sarcoma, head and neck cancer, prostate cancer, and a tumor biopsy cohort of mixed histology. The purpose of the tumor biopsy cohort was to obtain pre- and post-dose biopsies to determine drug distribution and target engagement in post-dose tumor samples. The latter was measured by the increase in levels of ATF-3, a marker of unfolded protein response/endoplasmic reticulum stress, which is upregulated in response to proteasome inhibition. Methods: The tumor biopsy cohort included 20 patients dosed at the maximum tolerated dose who consented to core needle biopsies during screening and after either the first or second dose of MLN9708 (IV 1.76 mg/m2; 4–20 hours post-dose). Tumor biopsies were individually weighed, homogenized, and analyzed for the presence of MLN2238 using a quantified LC/MS/MS methodology. ATF-3 levels in tumors were determined by an immunohistochemical assay (IHC) on six sections for each tumor biopsy. Tumor area was identified using Aperio Genie, a machine learning program for pattern recognition, and the percentage of ATF-3 positive area in the tumor was measured. Results: Biopsies from 20 patients were collected for assessment of drug distribution and target engagement. Ten patients with paired pre- and post-dose biopsies of sufficient size were considered evaluable for PK analysis; MLN2238 was present in all 10 (100%) post-dose biopsies analyzed. Tumor pairs from 7 patients passed quality control by H&E staining for tumor content and were evaluable for ATF-3 IHC. Six of 7 paired samples (86%) showed a statistically significant (p<0.05) increase in post-dose ATF-3 levels. Conclusions: Overall, emerging data from MLN9708 phase 1 solid tumor analysis show that MLN2238 is present in tumors and demonstrates target engagement upon inhibition of the proteasome in tumor tissue biopsies.

A phase 1/2 study of intermittent, high dose sunitinib in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2591-2591
Author(s):  
Maria Rovithi ◽  
Mariette Labots ◽  
Richard Honeywell ◽  
Albert J. Ten Tije ◽  
Rita Ruijter ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Population Expansion ◽  
Maximum Tolerated Dose ◽  
Blood Levels ◽  
High Dose ◽  
Advanced Solid Tumors ◽  
Treatment Benefit ◽  
Flat Dose ◽  
Heavily Pretreated

2591 Background: Despite widespread clinical integration, refinement of treatment with sunitinib is actively pursued. Sub-therapeutic blood levels rather than true resistance and tumor adaptation through drug accumulation have been accounted as reasons for treatment failure. Based on our preclinical data with high dose sunitinib and prospective analyses supporting the concept of intermittent dosing, we designed a phase 1 trial to investigate the feasibility and tolerability of high dose, once weekly (1w) or once every two weeks (2w) sunitinib (NCT02058901). Methods: Eligible were patients (pts) with advanced solid tumors, refractory to standard treatment, measurable disease, WHO ≤ 1. Sunitinib was administered orally 1w or 2w. Starting dose was 200 mg, with cohorts escalating in 100 mg steps until maximum tolerated dose (MTD). Response was evaluated by RECIST 1.1. Treatment continued until progression or unacceptable toxicity. Dedicated PK sampling was performed. Sunitinib plasma concentration was measured by LC-MS. Results: 34 (w) and 24 (2w) pts were included, predominantly with mCRC [56% (1w) and 55% (2w)]. MTD was set at 300 mg (1w) and 700 mg (2w). Most common adverse events were fatigue (79%, one pt with G3), nausea (71%, all G1-2), anorexia (29%, all G1-2). Median PFS of evaluable pts was 2.7 mo (1w) and 2.6 mo (2w), while 39% pts (1w) and 25% pts (2w) had PFS > 5 mo. CT scans in pts with treatment benefit showed extensive tumor necrosis. Mean sunitinib plasma Cmax was 190 [300 mg (1w), range: 185-295] and 476 ng/mL [(700 mg (2w), range: 323-580]. Accumulation was minimal. Conclusions: Once weekly or once every two weeks, high dose sunitinib is feasible and clinically efficacious in heavily pretreated pts with advanced solid tumors, while toxicity remains well manageable. Importantly, no accumulation was recorded and sunitinib exposure was significantly increased, compared to the universal, flat dose. Since increased sunitinib exposure has been correlated to improved outcome, we consider this alternative scheduling as promising strategy to produce enduring clinical benefit in a wider patient population. Expansion cohorts are ongoing. Clinical trial information: NCT02058901.

Phase I trial of chloroquine (CQ)/hydroxychloroquine (HCQ) in combination with carboplatin-gemcitabine (CG) in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3027-3027 ◽  
Author(s):  
Nagla Fawzy Abdel Karim ◽  
Imran Ahmad ◽  
Ola Gaber ◽  
Ihab Eldessouki ◽  
Olugbenga Olanrele Olowokure ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Early Stage ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Late Phase ◽  
Survival Rates ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Grade 3

3027 Background: Autophagy is a catabolic process triggered in cells during periods of stress to enable their survival. Established tumors utilize autophagy to survive periods of metabolic or hypoxic stress. Inhibition of early stage autophagy can rescue cancer cells, while inhibition of late stage autophagy will lead to cell death due to accumulation of damaged organelles. The antimalarial drugs CQ and HCQ inhibit late phase autophagy. The goal of our study is to assess the safety, tolerability and activity of combining CQ/HCQ with CG in advanced solid tumor patients who either progressed on other therapies or in whom CG is a therapeutic option. Methods: This single institution phase 1 dose-escalation study was designed to evaluate the maximum tolerated dose (MTD) of CQ, later substituted with HCQ, in combination with CG in patients with previously treated advanced solid tumors. Secondary objectives were to determine ORR, PFS and OS. A starting dose of 50 mg of CQ/HCQ was used in conjunction with CG, and increased in increments of 50 mg in each dose cohort. Grade 3 or greater toxicity that is treatment-related, and was not self-limited, or controlled in less than 7 days was considered dose limiting toxicity (DLT). Results: Twenty-three patients were enrolled with a median follow up of 6 months. HCQ 100 mg was found to be the MTD in combination with CG with ≥Grade 3 thrombocytopenia and/or neutropenia as dose-limiting. Median OS was 11 months, and the 1- and 3- year overall survival rates were 30% and 7%, respectively. Median progression free survival was 5 months and the 6-, 12-, and 18-months progression-free survivals were 48%, 21% and 14%, respectively (Table). Conclusions: The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes, likely due to the myelosuppressive nature of CG. Clinical trial information: NCT02071537. [Table: see text]

A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 48-48 ◽  
Author(s):  
Michael Friedlander ◽  
Tarek Meniawy ◽  
Ben Markman ◽  
Linda R. Mileshkin ◽  
Paul Harnett ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Autoimmune Hepatitis ◽  
Solid Tumors ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Study Results

48 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that may potentially increase the efficacy of BGB-A317. A phase 1 study identified 60 mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, pharmacokinetic (PK) profile, and preliminary antitumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6–12 patients with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1–3, BGB-290 doses ranged between 20–60 mg PO BID with BGB-A317 2 mg/kg IV Q3W. In DLs 4–5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 31 March 2017, 43 patients [median age 63 years (34–75)] were treated in DLs 1–5. Three patients experienced four dose-limiting toxicities: grade 2 nausea (DL4), grade 2 nausea and grade 2 vomiting (DL5), and grade 4 autoimmune hepatitis (DL5). MTD was identified as BGB-A317 200 mg IV Q3W + BGB-290 40 mg PO BID. The most common adverse event (AE) considered related to both study drugs was fatigue. Immune-related AEs of Grade ≥3 were elevated alanine aminotransferase/aspartate aminotransferase (n = 3), autoimmune hepatitis (n = 3), and hepatitis (n = 1). Complete or partial response was observed in 11 patients, 4 of whom had confirmed PR or CR. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: The combination of BGB-A317 and BGB-290 was generally well tolerated in patients with advanced solid tumors. These results support the continuation of this trial with enrollment into the disease-specific cohorts. Clinical trial information: NCT02660034.

Evolving development of PD-1 therapy: Cetrelimab (JNJ-63723283) from monotherapy to combination with erdafitinib.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3055-3055
Author(s):  
Victor Moreno ◽  
Yohann Loriot ◽  
Piotr Rutkowski ◽  
Carmen Beato ◽  
Enriqueta Felip ◽  
...  
Keyword(s):  
Solid Tumors ◽  
San Francisco ◽  
Phase 1 ◽  
Response Rates ◽  
Nonsmall Cell Lung Cancer ◽  
Complete Response ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Duration Of Treatment ◽  
Grade 3

3055 Background: Cetrelimab (CET) is an investigational checkpoint inhibitor (CI). In part 1 of a first-in-human (FIH) trial (LUC1001; NCT02908906), pts with advanced solid tumors with ≥1 prior treatment received CET 80–800 mg Q2W or 480 mg Q4W. Response rates and safety profiles were similar to other CIs. Based on preclinical and clinical data, a phase 1/2 study (NORSE; NCT03473743) of CET + erdafitinib (ERD) in metastatic urothelial carcinoma (mUC) + FGFR alterations (alt) was initiated and is ongoing. Methods: In LUC1001 Part 2, pts with nonsmall cell lung cancer (NSCLC), melanoma (MEL), or MSI-H/dMMR colorectal cancer (CRC) received CET IV 240 q2w. Overall response rates (ORR = % complete response + partial response [PR] confirmed) were assessed as per RECIST v1.1. Adverse events (AEs) were assessed for all patients receiving CET IV 240 q2w in parts 1 and 2. Results: As of July 1, 2019, 122 pts with NSCLC (n=30); MEL (n=50); or CRC (n= 42) had been treated in Part 2. Median age ranged from 58 to 64 yrs (overall range, 23–86 yrs). Duration of treatment was 8.1 mos (range, 0.0-24.7) for NSCLC; 5.5 mos (range, 0.0-25.0) for MEL; and for 3.0 mos (0.0-16.1) for CRC. ORR was 37% in NSCLC; 53% in PD-L1+ NSCLC (≥50% by IHC), 28% in MEL; 32% in non-uveal MEL, 14% in CRC and 24% in centrally confirmed MSI-high CRC. In all CET IV 240 q2w treated pts in the FIH study (N= 162), treatment-related grade ≥3 and serious AEs were reported in 15% and 12% of pts, respectively. All grade and grade ≥3 immune-related (ir) AEs were reported in 41% and 8% of pts, respectively Most common ir AE: hypothyroidism (8%), asthenia (6%), diarrhea (4%), rash (4%), hyperthyroidism (4%), dyspnea (3%), pruritis (3%) and pneumonitis (3%). There was 1 treatment-related death due to myasthenia gravis. In the phase 1 combination study (NORSE), pts with mUC + FGFR alt (n=17) received fixed-dose CET IV 240 q2w + ERD 6mg, 8 mg or 8mg + up titration (UpT) to 9 mg to establish the RP2D for the combination as CET + ERD 8mg + UpT. In the RP2D group (n=10), 60% had treatment-related grade ≥3 AEs. ORR (all confirmed PR) was 50% in the all treated response-evaluable group (n=16). Conclusions: CET is a CI with efficacy and safety profiles in advanced solid tumors similar to approved CIs. In NORSE phase 1, CET+ ERD demonstrated antitumor activity in mUC with an acceptable safety profile. NORSE phase 2 is evaluating this combination as first-line therapy in pts with mUC with FGFR alt. References: Rutkowski, et al J Clin Oncol.2019; 37 (8 suppl): 31-31. Moreno, et al. ASCO-GU Genitourinary Cancers Symposium. February 13-15, 2020. San Francisco, CA. Clinical trial information: NCT02908906 and NCT03473743 .

A phase I study of a TGF-β receptor I kinase inhibitor YL-13027 in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3098-3098
Author(s):  
Jin Li ◽  
Tianshu Liu ◽  
Hanying Bao ◽  
Zusheng Xu ◽  
Yang Shu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Clinical Investigation ◽  
Maximum Tolerated Dose ◽  
Target Lesion ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Post Dose

3098 Background: Transforming growth factor beta (TGF-β) is upregulated in the majority of tumors, promoting tumor cell proliferation, differentiation, and, modulation of the tumor microenvironment. YL-13027, a small molecule inhibitor of type 1 receptor of TGF-β, is a potent highly selective oral agent that downregulates TGFbR1-dependent pathways in tumor cells. YL-13027 dosed into tumor bearing animals drives tumor growth inhibition and interruption of metastasis. In this first-in-human phase1 study, we characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary efficacy of YL-13027 in patients with advanced solid tumors. Methods: YL-13027 tablets were administered orally, twice daily under fasted conditions for 28 days, for at least two 28 day cycles until disease progression, unacceptable toxicity or withdrawal from the study. Starting with an initial dose of 60 mg, dose escalation in a 3+3 design, and pre-determined PK assessments were applied. Adverse events (AEs) were graded by NCI-CTCAE v5.0. PK analysis was performed using a non-compartmental method. Efficacy was evaluated according to RECIST1.1. Results: As of January 18th 2021, thirteen patients were enrolled sequentially to Cohort-1 (60 mg, n = 2), Cohort-2 (120 mg, n = 1), Cohort-3 (180 mg, n = 3), Cohort-4 (240 mg, n = 4) and Cohort-5 (300 mg, n = 3), having gastrointestinal (n = 9), esophageal (n = 1), gallbladder (n = 1), lung (n = 1) and breast (n = 1) carcinomas. These patients had prior systemic antitumor standard therapies, including multi-line chemotherapy, radiation therapy, molecular targeted therapy, immunotherapy, or surgery. Twelve patients completed the cycle 1 safety observation period, with no cardiovascular toxicities or other DLTs observed. The MTD was not reached. Twelve patients experienced AEs possibly related to YL-13027. The most frequent related TEAEs (all grades/grade ≥3) were gamma-glutamyltransferase increased (38.5%/7.7%), haemoglobin decreased (38.5%/0%), blood alkaline phosphatase increased (23.1%/7.7%), aspartate aminotransferase increased (23.1%/0%) and blood phosphorus decreased (23.1%/0%). A maximum YL-13027 plasma concentration was reached within 2h post dose, and the mean elimination half-life was 4.2h in the steady state. Six subjects were evaluable for efficacy. One triple-negative breast cancer (TNBC) subject (Cohort-4) acquired a Partial Response (38.8% reduction of the target lesion), with the response exceeding 4 cycles, and YL-13027 treatment is continuing. The TNBC patient’s tumor profile indicated genomic mutations of EGFL7p.Q256H(13.50%), TP53p.E51*(10.90%) and NF1p.L21V(8.70%) from the initial tumor specimen at diagnosis. Conclusions: YL-13027 is well tolerated and further clinical investigation is warranted. Clinical trial information: NCT03869632.

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