ARRY-382 (PF-07265804) is a selective inhibitor of colony-stimulating factor-1 receptor. We evaluated the safety and preliminary efficacy of ARRY-382 plus pembrolizumab in patients with advanced ...solid tumors.
This was an open-label, multicenter, Phase 1b/2 study (NCT02880371) performed over September 1, 2016 to October 24, 2019. In the Phase 1b dose-escalation, patients with selected advanced solid tumors received ARRY-382 starting dose 200 mg once daily (QD) orally plus pembrolizumab 2 mg/kg intravenously (IV) every 3 weeks (Q3W). Phase 2 patients had: Pancreatic ductal adenocarcinoma (PDA); programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) inhibitor-refractory (PD-1/PD-L1 IR) advanced solid tumors; or platinum-resistant ovarian cancer (prOVCA). Patients received ARRY-382 at the maximum tolerated dose (MTD) of 300 mg QD plus pembrolizumab 200 mg IV Q3W.
Primary endpoints of dose-limiting toxicities (DLT; Phase 1b) and objective response rate (Phase 2) were met. In Phase 1b, 19 patients received ARRY-382 200-400 mg. Three patients reported DLTs. The MTD of ARRY-382 (plus pembrolizumab) was 300 mg QD. In Phase 1b, 2 patients (10.5%) had confirmed partial response (PR): 1 with PDA and 1 with ovarian cancer, lasting 29.2 and 3.1 months, respectively. In Phase 2, there were 27, 19, and 11 patients in the PDA, PD-1/PD-L1 IR, and prOVCA cohorts, respectively. One patient (3.7%) with PDA had a PR lasting 2.4 months. The most frequent ARRY-382-related adverse events were increased transaminases (10.5%-83.3%) and increased creatine phosphokinase (18.2%-50.0%).
Although limited clinical benefit was observed, ARRY-382 plus pembrolizumab was well tolerated.
GRN1005 is a peptide-drug conjugate with the ability to penetrate the blood-brain barrier (BBB) and tumor cells by targeting the low-density lipoprotein receptor-related protein-1. We conducted a ...first-in-human phase I trial of GRN1005 in patients with recurrent glioma.
Patients received GRN1005 by intravenous infusion every 3 weeks. Doses were escalated using a modified Fibonacci scheme. Study objectives included safety, tolerability, identification of the maximum tolerated dose (MTD), pharmacokinetics, and preliminary evidence of efficacy. Tumor extracted from patients undergoing surgery following administration of GRN1005 was analyzed to determine whether therapeutic concentrations of GRN1005 were achieved.
Sixty-three patients received GRN1005 at doses of 30 to 700 mg/m(2) every 3 weeks. Therapy was well tolerated with neutropenia, leucopenia, and fatigue as the most frequent drug-associated grade 3/4 or higher toxicities. The MTD was 650 mg/m(2) every 3 weeks. Dose-limiting toxicities were grade 3 mucositis and grade 4 neutropenia. There was no evidence of central nervous system toxicity or antibody production. Pharmacokinetic analysis showed that exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. Eight of 27 patients dosed ≥ 420 mg/m(2) had stable disease, which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were shown in tumor tissue of surgical patients dosed with ≥ 200 mg/m(2).
GRN1005 delivers paclitaxel across the BBB and achieves therapeutic concentrations in tumor tissue. It has similar toxicity to paclitaxel and appears to have activity in recurrent glioma. The recommended phase II dose is 650 mg/m(2) every 3 weeks.
Aim
Preclinical evidence suggests that oxidized macrophage migration inhibitory factor (oxMIF) may be involved in carcinogenesis. This phase 1 study (NCT01765790) assessed the safety, tolerability, ...pharmacokinetics and antitumour activity of imalumab, an oxMIF inhibitor, in patients with advanced cancer using ‘3 + 3’ dose escalation.
Methods
In Schedule 1, patients with solid tumours received doses from 1 to 50 mg/kg IV every 2 weeks. In Schedule 2, patients with metastatic colorectal adenocarcinoma, non‐small‐cell lung, or ovarian cancer received weekly doses of 10 or 25 mg/kg IV (1 cycle = 28 days). Treatment continued until disease progression, unacceptable toxicity, dose‐limiting toxicity, or withdrawal of consent.
Results
Fifty of 68 enrolled patients received imalumab. The most common treatment‐related adverse events (TRAEs) included fatigue (10%) and vomiting (6%); four grade 3 serious TRAEs (two patients) occurred. The dose‐limiting toxicity was allergic alveolitis (one patient, 50 mg/kg every 2 weeks). The maximum tolerated and biologically active doses were 37.5 mg/kg every 2 weeks and 10 mg/kg weekly, respectively. Of 39 assessed patients, 13 had stable disease (≥4 months in 8 patients).
Conclusions
Imalumab had a maximum tolerated dose of 37.5 mg/kg every 2 weeks in patients with advanced solid tumours, with a biologically active dose of 10 mg/kg weekly. Further investigation will help define the role of oxMIF as a cancer treatment target.
Lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through relocalization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts. On the basis of this ...rationale, lurbinectedin was evaluated in patients with relapsed Ewing sarcoma.
This open-label, single-arm, Basket phase II trial included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, Eastern Cooperative Oncology Group performance status ≤2, adequate organ function, no central nervous system metastasis, and pretreated with ≤2 chemotherapy lines for metastatic/recurrent disease. Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks. Primary endpoint was overall response rate (ORR) as per RECIST v.1.1. Secondary endpoints included time-to-event parameters and safety profile.
ORR was 14.3% 95% confidence interval (CI), 4.0%-32.7%, with median duration of response of 4.2 months (95% CI, 2.9-5.5 months). Median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months), clinical benefit rate was 39.3%, and disease control rate was 57.1%. With 39% censoring, median overall survival was 12.0 months (95% CI, 8.5-18.5 months). Most common grade 3/4 adverse events were neutropenia (57%), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14% each). No deaths or discontinuations were due to toxicity.
Lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile. Lurbinectedin could represent a valuable addition to therapies for Ewing sarcoma, and is currently being evaluated in combination with irinotecan in advanced Ewing sarcoma in a phase Ib/II trial.
Summary
Background
Foretinib is a small-molecule, oral multikinase inhibitor primarily targeting the mesenchymal epithelial transition (MET) factor receptor, and the vascular endothelial growth ...factor receptor 2. We conducted a phase II study to evaluate the single-agent activity and tolerability of foretinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).
Methods
An open-label, single-arm, multicenter trial employing a Simon 2-stage design was conducted with a total of 41 patients planned for the study. One or more responses in the first 14 patients were required in order to progress to the second stage. Foretinib was administered as 240 mg orally for 5 consecutive days of a 14-day treatment cycle (5/9 schedule) to patients with recurrent and/or metastatic SCCHN.
Results
Fourteen patients were enrolled. The study did not meet criteria for continuing to the second stage. A maximum of 30 cycles were administered (median = 4.0). Fifty percent of patients (7/14) showed stable disease (SD), 43 % of patients (6/14) experienced tumor shrinkage and two patients had prolonged disease stabilization for ≥13 months. The most common adverse events were fatigue, constipation and hypertension, which were manageable with additional medication or adjustments to the dosing schedule.
Conclusion
Foretinib 240 mg on a 5/9 schedule was generally well tolerated. SD was the best-observed outcome, with minor tumor shrinkage detected in nearly half of all patients. The efficacy results, prolonged disease stabilization and tolerable side-effect profile, support further investigation, possibly in combination with other targeted agents or cytotoxic chemotherapy for SCCHN.
Osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), undergoes significant hepatic elimination. In this phase 1 study, we assessed the effects of mild and moderate ...hepatic impairment on the pharmacokinetics (PK) of osimertinib in patients with malignant solid tumors. In part A, patients with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, according to the Child-Pugh classification, received a single 80 mg oral dose of osimertinib. Standard PK measures were assessed. In part B, patients could continue osimertinib treatment if deemed clinically appropriate. We compared these study results with a population PK analysis including other osimertinib clinical studies. Geometric mean osimertinib plasma concentrations were lower in patients with mild (
= 7) or moderate hepatic impairment (
= 5) versus normal hepatic function (
= 10):
was reduced to 51% and 61%, respectively; area under the curve was reduced to 63% and 68%, respectively. PK results for the metabolites were similar. No apparent differences in the safety profile were found between patients with normal hepatic function and patients with mild or moderate hepatic impairment. Comparison of these study results with National Cancer Institute-Organ Dysfunction Working Group criteria from population PK analysis showed osimertinib exposure was not affected by hepatic impairment. No dose adjustment is required for osimertinib when treating patients with mild or moderate hepatic impairment. No apparent differences in the safety of osimertinib were found between patients with normal hepatic function and mild or moderate hepatic impairment.
Androgen deprivation therapy (ADT) can lead to metabolic syndrome (MS) and is implicated in ADT-resistance. Metformin showed antineoplastic activity through mTOR inhibition secondary AMPK-activation.
...To investigate whether metformin mitigated ADT-related MS, we conducted a randomized double-blind phase II trial of metformin 500 mg TID or placebo in non-diabetic patients with biochemically-relapsed or advanced PC due for ADT. Fasting serum glucose, insulin, PSA, metformin, weight and waist circumference (WC) were measured at baseline, week 12 and 28. The primary endpoint was a group of MS metrics. Secondary endpoints include PSA response, safety, serum metformin concentrations and analysis of downstream an mTOR target, phospho-S6-kinase.
36 men were randomized to either metformin or placebo. Mean age was 68.4. Mean weight, WC and insulin levels increased in both arms. At week 12 and 28, no statistical differences in weight, WC or insulin were observed in either arm. No significant difference in percentage of patients with PSA <0.2 at week 28 between metformin (45.5%) vs. placebo (46.7%). Analysis in the metformin-arm showed variable down-regulation of phospho-S6 kinase.
In our small study, metformin added to ADT did not show a reduced risk of ADT-related MS or differences in PSA response.
Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of ...dinaciclib in advanced solid tumour patients and assessed pharmacodynamic and preliminary anti-tumour activity.
In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined. In part 2, 8- and 24-h infusions were evaluated. Pharmacokinetic parameters were determined for all schedules. Pharmacodynamic effects were assessed with an ex vivo stimulated lymphocyte proliferation assay performed in whole blood.Effects of dinaciclib on retinoblastoma (Rb) phosphorylation and other CDK targets were evaluated in skin and tumour biopsies. In addition to tumour size, metabolic response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography.
Sixty-one patients were enrolled to parts 1 and 2. The RP2Ds were 50, 7.4 and 10.4 mg m
as 2- 8- and 24-hour infusions, respectively. Dose-limiting toxicities included pancytopenia, neutropenic fever, elevated transaminases, hyperuricemia and hypotension. Pharmacokinetics demonstrated rapid distribution and a short plasma half-life. Dinaciclib suppressed proliferation of stimulated lymphocytes. In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition. Although there were no RECIST responses, eight patients had prolonged stable disease and received between 6 and 30 cycles. Early metabolic responses occurred.
Dinaciclib is tolerable at doses demonstrating target engagement in surrogate and tumour tissue.
This first-in-human (FIH), phase I, multicenter, open-label study was conducted to characterize the safety, tolerability, pharmacokinetics, and preliminary efficacy, and to establish the ...MTD/recommended dose for expansion (RDE) of PCA062 in patients with solid tumors. Adult patients with any solid tumor type and having a documented P-cadherin-positive tumor were enrolled; exceptions to P-cadherin positivity requirement were head and neck squamous cell carcinomas (HNSCC) and esophageal squamous cell carcinoma (ESCC). Dose escalation was guided by an adaptive Bayesian logistic regression model with escalation with overdose control to determine the MTD/RDE. Forty-seven patients were treated at 10 different dose levels of PCA062, ranging from 0.4 to 5.0 mg/kg every 2 weeks administered as a 1-hour intravenous infusion. All enrolled patients discontinued the treatment; primary reason for discontinuation was progressive disease (78.7%). All 47 patients experienced at least one AE, of which 32 patients had a grade ≥3 AE and 37 patients experienced AEs suspected to be study drug related. The MTD of PCA062 was 3.6 mg/kg every 2 weeks and thrombocytopenia was reported as a DLT that was attributed to the known toxicities of the DM1 payload with no P-cadherin-related toxicities. Pharmacokinetics was proportional, and no patients developed antidrug antibodies, suggesting adequate exposure at the doses tested. One patient of 47 achieved a partial response and there was no correlation between tumor P-cadherin expression and clinical efficacy. Because of limited antitumor activity at the MTD level, Novartis has terminated clinical development of PCA062 (NCT02375958).
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