Evaluation of the adverse event profile and pharmacodynamics of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial.

Download Full-text

A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

Investigational New Drugs ◽

10.1007/s10637-020-01055-5 ◽

2021 ◽

Author(s):

Noboru Yamamoto ◽

Toshio Shimizu ◽

Kan Yonemori ◽

Shigehisa Kitano ◽

Shunsuke Kondo ◽

...

Keyword(s):

Liver Function ◽

Solid Tumors ◽

Dose Escalation ◽

Enzyme Inhibitor ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Open Label ◽

Phase 1 Study ◽

Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

Download Full-text

A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3101 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3101-3101

Author(s):

Ying Cheng ◽

Ying Liu ◽

Jinhua Xu ◽

Jing Zhu ◽

Ying Wang ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Solid Tumors ◽

Renal Cancer ◽

Phase I Study ◽

Angiogenesis Inhibitor ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Open Label ◽

Safety And Efficacy

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade>=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade>=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps3161 ◽

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.

Download Full-text

Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.20.3545 ◽

2000 ◽

Vol 18 (20) ◽

pp. 3545-3552 ◽

Cited By ~ 32

Author(s):

Corinne Couteau ◽

Marie-Laure Risse ◽

Michel Ducreux ◽

Florence Lefresne-Soulas ◽

Alessandro Riva ◽

...

Keyword(s):

Febrile Neutropenia ◽

Phase I ◽

Solid Tumors ◽

Pharmacokinetic Study ◽

Topoisomerase I ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Advanced Solid Tumors ◽

Phase Ii Studies ◽

Grade 3

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

Download Full-text

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.7.2494 ◽

1998 ◽

Vol 16 (7) ◽

pp. 2494-2499 ◽

Cited By ~ 12

Author(s):

A M Langevin ◽

D T Casto ◽

P J Thomas ◽

S D Weitman ◽

C Kretschmar ◽

...

Keyword(s):

Steady State ◽

Phase I ◽

Solid Tumors ◽

Phase I Trial ◽

Malignant Tumors ◽

Hepatic Metabolism ◽

Pharmacokinetic Profile ◽

Maximum Tolerated Dose ◽

Volume Of Distribution ◽

Recommended Phase Ii Dose

PURPOSE A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Download Full-text

Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.1992.10.11.1712 ◽

1992 ◽

Vol 10 (11) ◽

pp. 1712-1722 ◽

Cited By ~ 37

Author(s):

W H Wilson ◽

V Jain ◽

G Bryant ◽

K H Cowan ◽

C Carter ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Solid Tumors ◽

Autologous Bone Marrow ◽

Maximum Tolerated Dose ◽

High Dose ◽

Autologous Bone ◽

Hodgkin's Lymphomas ◽

Phase I And Ii

PURPOSE High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS Forty-one patients with drug-resistant Hodgkin's and non-Hodgkin's lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkin's and non-Hodgkin's lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.

Download Full-text

Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma

Journal of Clinical Oncology ◽

10.1200/jco.19.03327 ◽

2020 ◽

Vol 38 (29) ◽

pp. 3398-3406 ◽

Cited By ~ 10

Author(s):

Ingo K. Mellinghoff ◽

Benjamin M. Ellingson ◽

Mehdi Touat ◽

Elizabeth Maher ◽

Macarena I. De La Fuente ◽

...

Keyword(s):

Solid Tumors ◽

Isocitrate Dehydrogenase ◽

Objective Response ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Adverse Event Rate ◽

Low Grade ◽

Lower Grade ◽

Open Label ◽

Isocitrate Dehydrogenase 1

PURPOSE Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 ( IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors. METHODS We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m IDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles. RESULTS In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors. CONCLUSION In patients with m IDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.

Download Full-text