Long term follow-up of patients with newly diagnosed glioblastoma treated by intraoperative photodynamic therapy: an update from the INDYGO trial (NCT03048240).

PURPOSE: Glioblastoma remains incurable despite optimal multimodal management. The interim analysis of open label, single arm INDYGO pilot trial showed actuarial 12-months progression-free survival (PFS) of 60% (median 17.1 months), actuarial 12-months overall survival (OS) of 80% (median 23.1 months). We report updated, exploratory analyses of OS, PFS, and health-related quality of life (HRQOL) for patients receiving intraoperative photodynamic therapy (PDT) with 5-aminolevulinic acid hydrochloride (5-ALA HCl). METHODS: Ten patients were included (May 2017 - April 2021) for standardized therapeutic approach including 5-ALA HCl fluorescence-guided surgery (FGS), followed by intraoperative PDT with a single 200 J/cm2 dose of light. Postoperatively, patients received adjuvant therapy (Stupp protocol) then followed every 3 months (clinical and cerebral MRI) and until disease progression and/or death. Procedure safety and toxicity occurring during the first four weeks after PDT were assessed. Data concerning relapse, HRQOL and survival were prospectively collected and analyzed. RESULTS: At the cut-off date (i.e., November 1st 2023), median follow-up was 23 months (9,7-71,4). No unacceptable or unexpected toxicities and no treatment-related deaths occurred during the study. Kaplan-Meier estimated 23.4 months median OS, actuarial 12-month PFS rate 60%, actuarial 12-month, 24-month, and 5-year OS rates 80%, 50% and 40%, respectively. Four patients were still alive (1 patient free of recurrence). CONCLUSION: At 5 years-follow-up, intraoperative PDT with surgical maximal excision as initial therapy and standard adjuvant treatment suggests an increase of time to recurrence and overall survival in a high proportion of patients. Quality of life was maintained without any severe side effects. TRIAL REGISTRATION NCT NUMBER: NCT03048240. EudraCT number: 2016-002706-39.

Development and validation of a model that predicts early death among cancer patients participating in phase I clinical trials investigating cytotoxics.

OBJECTIVE: Selecting patients for phase 1 studies remains challenging. Given the lack of clear and reliable guidance for the estimation of life expectancy, we retrospectively assessed predictive factors of early death (within 90 days following inclusion) among these patients. METHODS: Two hundred fifty-seven consecutive cancer patients enrolled in phase I studies investigating cytotoxics at Oscar Lambret Cancer Center and Institut Claudius Regaud were included in the development database. Univariate and multivariate analyses (logistic regression model) were undertaken to determine the prognostic factors. A probability tree described the rate of early death in the different prognostic subgroups. This prognostic model was then evaluated on a second independent cohort of 128 patients treated at Léon Bérard Cancer Center. RESULTS: The median overall survival was 8.4 months in the dataset population, and the rate of early death was 15%. In multivariate analysis, the two prognostic factors for early death were albumin <38 g/l (OR = 5.21) and lymphocytes <700/mm(3) (OR = 3.88). According to these two parameters, three prognostic subgroups were defined with early death rates of, respectively, 8/121 (6%), 19/119 (16%) and 13/17 (76%). In the validation dataset, the rates of early death according to three prognostic groups were 13/68 (19%), 20/57 (35%) and 3/3 (100%), respectively. CONCLUSION: We do not recommend the enrolment of patients with albumin level below 38g/l and lymphocytes count below 700/mm(3), in phase 1 trial investigating cytotoxics. Our model is helpful to discriminate "patients with reasonable life expectancy" as defined in most phase 1 protocols.

Phase I combining a P-glycoprotein inhibitor, MS209, in combination with docetaxel in patients with advanced malignancies.

PURPOSE: The purpose of this study was to investigate the safety and tolerability of MS209, a potent inhibitor of P-glycoprotein, when given in combination with docetaxel and to determine whether MS209 affects docetaxel pharmacokinetics. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were eligible for this phase I trial. Docetaxel as 1-hour infusion was given alone during the first cycle. MS209 was introduced as of cycle 2 and given orally 30 minutes after docetaxel infusion. The dose escalation scheme followed a modified Fibonacci model with six steps (docetaxel, 60-100 mg/m2 and MS209, 300-1,200 mg per body). RESULTS: A total of 30 patients were treated at five dose levels. Dose-limiting toxicities were febrile neutropenia, infection, stomatitis, dysphagia, and fatigue. The maximum tolerated dose was reached at level 5 (docetaxel, 80-MS: 1,200). Pharmacokinetic analysis failed to show a strong pharmacokinetic interaction between the two compounds, but at the highest dose levels, there is a trend to an increase of docetaxel AUC when this agent is given in combination with MS209. CONCLUSION: MS209 can be given in combination with docetaxel, with limited effect on docetaxel toxicity or pharmacokinetics.

Prognostic factors among cancer patients with good performance status screened for phase I trials.

BACKGROUND: Selecting patients for phase I trials in order to investigate cytotoxic agents is challenging, since there is no clear and reliable guidance to estimate life expectancy among these patients. We retrospectively assessed prognostic factors in cancer patients screened for Phase1 trials between October 1997 and October 2002. METHODS: 148 consecutive patients, screened for inclusion in phase I trials investigating cytotoxic agents, were included in the present study. 70 out of them actually received phase I trial regimens. Univariate and multivariate analysis were undertaken to determine the prognostic factors for overall survival (OS) from the date of screening. RESULTS: The median OS of the 148 patients was 5.7 months. Ninety-two percent of them had PS