Phase I/II Trial of Immunotherapy With Durvalumab and Tremelimumab With Continuous or Intermittent MEK Inhibitor Selumetinib in NSCLC: Early Trial Report

10047 Background: MEK inhibitors have confirmed effects on malignant tumors, especially for those induced by RAS/RAF dysfunction. There is no effective drug in clinic for NRASm advanced melanoma. HL-085 is a selective MEK inhibitor, showing good safety and efficacy in preclinical studies. This study is a phase I/II study to evaluate the safety, tolerability, pharmacokinetic and preliminary anti-cancer activity of HL-085 in patients(pts) with NRASm advanced Melanoma. Methods: The phase I/II study is conducted using a “3+3” regimen for dose escalation. The pts are treated with HL-085 at a starting dose of 0.5mg BID to 18mg BID. Adverse events (AEs) are reported per NCI CTCAE version 5.0. Preliminary anti-cancer activity is evaluated by ORR, DCR, PFS and DoR. Results: Total 33 pts were enrolled in the study. The histologic types were acral (51.4%), mucosal (27.2%) and other (21.2%). The NRAS mutation types were Q61 (72.7%), G12 (18.2%) with half for G12D, and G13 (9.1% ). Most AEs were G1 or G2, and the most common drug-related AEs were rash, increased creatine phosphokinase, peripheral edema, increased alanine aminotransferase and aspartate aminotransferase. No dose-limited toxicity was observed. PK analysis was shown linear PK profile with no obvious accumulation. Among 12 evaluable pts over 9 mg, 4 pts were at the stage of M1c with 1 liver metastasis. Average targeted tumor size was 74.6mm with the largest 184 mm. 10 pts achieved tumor shrinkage [ 60% with Q61, 20% with G12D, 10% each with G12S and G13R]. 4 pts ( 2 acral, 1 mucosal and 1 other, each pt has mutaiton type of Q61R,Q61L, Q61K and G12S respectively ) had confirmed partial response(PR) [median treatment duration 26.6 weeks (wks) with longest 47.6 wks]). 6 pts achieved stable disease (SD) (median treatment duration 15.72 wks with longest 24 wks), and 66.7% were over 14 wks . The median PFS was 17.4 wks, and confirmed best ORR was 33.3% with DCR 83.3% . Conclusions: Our data demonstrated that HL-085 is well tolerated, with manageable side-effects and promising anti-cancer activity in pts with NRASm advanced melanoma. Clinical trial information: NCT 03973151.

Download Full-text

725MO Phase I study of the combination of the dual RAF/MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Results of efficacy in low grade serous ovarian cancer

Annals of Oncology ◽

10.1016/j.annonc.2021.08.1168 ◽

2021 ◽

Vol 32 ◽

pp. S728

Author(s):

S. Banerjee ◽

R. Grochot ◽

R. Shinde ◽

J. Lima ◽

M. Krebs ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase I ◽

Phase I Study ◽

Mek Inhibitor ◽

Low Grade ◽

Serous Ovarian Cancer

Download Full-text

Smartphone measurements of physical activity and fitness are associated with early trial discontinuation of patients in (hemato)oncology phase I/II clinical trials

Supportive Care in Cancer ◽

10.1007/s00520-020-05902-2 ◽

2020 ◽

Author(s):

Joeri A. J. Douma ◽

Sonja Zweegman ◽

Mieke Alberts ◽

Sandy Kruyswijk ◽

Niels C. W. J. van de Donk ◽

...

Keyword(s):

Physical Activity ◽

Clinical Trials ◽

Physical Fitness ◽

Phase I ◽

Walking Distance ◽

Optimal Cutoff ◽

Early Trial ◽

Cutoff Values ◽

Steps Per Day ◽

Trial Discontinuation

Abstract Background Patients, who discontinue early, do not benefit from phase I/II clinical trials (early-phase clinical trials (EPCT)). In this study, associations between objective smartphone measurements of physical activity and fitness and early trial discontinuation in patients with cancer participating in EPCT were investigated. Methods Before start of treatment, physical activity (steps/day) and physical fitness (meters walked in 6 min) were measured with a smartphone, and patient-reported physical function (PRO-PF) was assessed (EORTC QLQ-C30-PF). Early trial discontinuation was defined as discontinuation ≤ 28 days. Univariable logistic regression analyses were performed to study associations of physical activity, fitness, and function with early trial discontinuation. Optimal cutoff values of physical activity and fitness were assessed with ROCs, based on positive predictive values (PPV). Results Median (interquartile range (IQR)) step count was 4263 (2548–6897) steps/day, mean ± standard deviation 6-min walking distance was 477 ± 120 m and median (IQR) PRO-PF score was 83 (67–95) points. Fourteen patients (12%) discontinued the trial early. Smartphone measurements of physical activity in units of 100 steps per day (odds ratio (OR) = 0.96, 95% CI = 0.94–0.99, p = 0.01), physical fitness (OR = 0.99, 95% CI = 0.98–0.99, p < 0.01), and PRO-PF (OR = 0.97, 95% CI = 0.94–1.00, p = 0.03) were associated with early trial discontinuation. Optimal cutoff values were < 900 steps for physical activity and < 285 m for physical fitness. PPV for early trial discontinuation was 100% in patients who walked both < 1500 steps per day and < 300 m in 6 min. Conclusions Objective smartphone measurements of physical activity and fitness are associated with early trial discontinuation. However, cutoff values should be externally validated in a larger cohort before implementation in clinical practice.

Download Full-text

A Phase I Trial of the VEGF Receptor Tyrosine Kinase Inhibitor Pazopanib in Combination with the MEK Inhibitor Trametinib in Advanced Solid Tumors and Differentiated Thyroid Cancers

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-18-1881 ◽

2019 ◽

Vol 25 (18) ◽

pp. 5475-5484 ◽

Cited By ~ 6

Author(s):

Razelle Kurzrock ◽

Douglas W. Ball ◽

Marianna L. Zahurak ◽

Barry D. Nelkin ◽

Vivek Subbiah ◽

...

Keyword(s):

Tyrosine Kinase ◽

Phase I ◽

Tyrosine Kinase Inhibitor ◽

Receptor Tyrosine Kinase ◽

Phase I Trial ◽

Kinase Inhibitor ◽

Mek Inhibitor ◽

Vegf Receptor ◽

Advanced Solid Tumors ◽

Differentiated Thyroid Cancers

Download Full-text

Early-phase trials compared to first- and second-line FDA-approved treatments in patients with advanced gallbladder cancer and cholangiocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13020 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13020-e13020

Author(s):

Ishwaria Mohan Subbiah ◽

Apostolia Maria Tsimberidou ◽

Aung Naing ◽

Vivek Subbiah ◽

Ahmed Omar Kaseb ◽

...

Keyword(s):

Phase I ◽

Drug Administration ◽

Univariate Analysis ◽

Hepatic Arterial Infusion ◽

Progression Free Survival ◽

Mek Inhibitor ◽

Phase I Trials ◽

Second Line ◽

Prior Therapy ◽

Metastatic Setting

e13020 Background: Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few effective therapeutic options. We compared prognostic factors and clinical outcomes of CC/GC pts treated on phase I trials with that of their first-, second-line and last Food and Drug Administration (FDA)-approved therapy given in setting of metastatic disease. Methods: We retrospectively reviewed electronic medical records of patients with GC and CC evaluated in the phase I program clinic from November 2004 to March 2011. Results: Of the 72 patients with CC or GC, 32 (44%) were not enrolled on a trial mainly due to clinical deterioration (n=25). Of 40 treated patients (GC=6; CC=34; median age 60 years; median prior systemic therapies = 3), 8 (20%) had stable disease (SD) > 6 months; 3 (8%) achieved a partial response (PR); SD > 6 months/PR was observed mainly on protocols with hepatic arterial infusion drug administration and/or angiogenic inhibitors, anti-her2/neu agents or a novel MAPK/ERK kinase (MEK) inhibitor. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0; p=0.95), 3.0 months (95% CI 2.3, 4.6; p=0.98), and 3.0 months (95% CI 2.4, 3.9; p=0.79) for their first-, second-, and last systemic therapy with FDA-approved agents given in the metastatic setting, respectively. In univariate analysis, factors associated with a shorter Phase I PFS were > 3 metastatic sites, elevated ALT (>56 IU/L), serum creatinine (>1.6mg/dL), and CA19-9 (>35U/mL). Conclusions: In heavily pretreated patients, PFS in the clinical trials setting remained poor but did not differ significantly from that of their first-line, second-line, and last prior therapy with FDA-approved agents. Response rate (SD >6 months/PR) of 28% was seen in trials with locoregional treatment or inhibitors of angiogenesis, her2/neu or MEK.

Download Full-text