Study protocol of the TEC-ORL clinical trial: a randomized comparative phase II trial investigating the analgesic activity of capsaicin vs Laroxyl in head and neck Cancer survivors presenting with neuropathic pain sequelae.

BACKGROUND: Neuropathic pain is common in cancer survivorship and is one of the most distressing symptoms for patients previously treated for head and neck cancer. Persistent neuropathic pain, when it is ongoing and uncontrolled, has a detrimental effect and erodes patients' quality of life. Patients treated for head and neck cancer are chronic opioid users to manage their post-treatment pain, which may entail an increased risk of addiction and overdose. We propose to evaluate the analgesic activity of high-concentration capsaicin patches for the treatment of head and neck cancer survivors presenting with neuropathic pain sequelae. METHODS: TEC-ORL is a parallel, multicenter randomized comparative phase II study evaluating whether Capsaïcin patches (Qutenza®) reduce neuropathic pain when compared to Amitriptyline (Laroxyl®) in head and neck cancer survivors presenting with neuropathic pain sequelae. The primary efficacy outcome is the rate of patients with a pain reduction of at least two points at 9 months compared to baseline. Assuming that 5% of patients become lost to follow-up, 130 patients will need to be randomized to detect a 25% improvement (i.e., standard: 25%, experimental: 50%) using a one-sided chi-square test with an alpha of 0.05%. According to the recommendations for comparative phase II trials, the target differences and type I error rates are relaxed. Randomized patients will either be treated with a capsaicin 8% (Qutenza®) patch applied at three time intervals in the experimental arm or with Amitriptyline (Laroxyl®) (oral solution 40 mg/ml) taken for 9 months at the recommended daily dose of 25 mg to 75 mg in the control arm. DISCUSSION: TEC-ORL is a randomized comparative phase II trial designed to comprehensively evaluate the analgesic activity of capsaicin compared to Laroxyl in Head and Neck Cancer survivors presenting with neuropathic pain sequelae. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04704453 Date of registration: 2021/01/13.

Improving patient selection for immuno-oncology phase 1 trials: External validation of six prognostic scores in a French Cancer Center.

We compared the performance of six prognostic scores (Royal Marsden Hospital, MDACC: MD Anderson Clinical Center and MDACC + NLR: neutrophil-to-lymphocyte ratio, MD Anderson - immune checkpoint inhibitors (MDA-ICI), GRIm: Gustave Roussy Immune Score and LIPI: Lung Immune Prognostic Index) in predicting overall survival (OS) in phase I trial patients treated with immune checkpoint inhibitors (ICI). Medical records of patients with advanced solid tumors enrolled in ICI phase I trials between 2015 and 2018 at Institut Universitaire du Cancer de Toulouse-Oncopole were reviewed. The performance of prognostic scores on OS was compared using different criteria. A total of 259 patients were included. Median age was 63 years (range: 18-83). Main primary cancers were melanoma (19%), head and neck (16%), lung (13%) and bladder (10%). With a median follow-up of 15 months (95% confidence interval [CI] = [11.6;17.5]), median OS was 12.5 months (95% CI = [10.3;16.0]). All scores were associated with OS. The MDACC, LIPI and GRIm scores performed better than the others. Concordance of risk group assignment between the scoring systems was poor. According to our results, the MDACC, GRIm and LIPI scores better suited to ICI phase I settings. Adequate scoring would allow better patient selection in early ICI trials, especially during the critical period of dose escalation, and in proof-of-concept expansion cohorts.

Value of peri-operative chemotherapy in patients with CINSARC high-risk localized grade 1 or 2 soft tissue sarcoma: study protocol of the target selection phase III CHIC-STS trial.

BACKGROUND: The value of chemotherapy in soft tissue sarcoma (STS) remains controversial. Several expert teams consider that chemotherapy provides a survival advantage and should be proposed in high-risk (HR) patients. However, the lack of accuracy in identifying HR patients with conventional risk factors (large, deep, FNCLCC grade 3, extremity STS) is an issue that cannot be neglected. For example, while the FNCLCC grading system is a powerful tool, it has several limitations. CINSARC, a 67-gene signature, has proved to be an additional independent factor for predicting metastatic spread and outperforms histological grade. Regardless of FNCLCC grade, CINSARC stratifies patients into two separate prognostic groups: one with an excellent prognosis (low-risk (LR) CINSARC) and the other with a worse outcome (HR-CINSARC) in terms of metastatic relapse. Here we evaluate the role of chemotherapy in grade 1-2 STS patients with HR-CINSARC and assess the prognostic value of CINSARC in patients treated with standard of care. METHODS: CHIC is a parallel, randomized, open-label, multicenter study evaluating the effect on metastasis-free survival of adding perioperative chemotherapy to standard of care in patients with grade ½ STS sarcoma defined as HR by CINSARC. In this target selection design, 600 patients will be screened with CINSARC to randomize 250 HR-CINSARC patients between standard of care and standard of care plus chemotherapy (4 cycles of 3 weeks of intravenous chemotherapy with doxorubicin in combination with dacarbazine or ifosfamide according to histologic subtype). LR-CINSARC patients will be treated by standard of care according to the investigator. The primary endpoint is metastasis-free survival. Secondary endpoints include overall survival, disease-free survival and safety. Furthermore, the prognostic value of CINSARC will be evaluated by comparing LR-CINSARC patients to HR-CINSARC patients randomized in standard of care. DISCUSSION: CHIC is a prospective randomized phase III trial designed to comprehensively evaluate the benefit of chemotherapy in HR-CINSARC patients and to prospectively validate the prognostic value of CINSARC in grade ½ STS sarcoma patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04307277 Date of registration: 13 March 2020.

Dose-painting multicenter phase III trial in newly diagnosed glioblastoma: the SPECTRO-GLIO trial comparing arm A standard radiochemotherapy to arm B radiochemotherapy with simultaneous integrated boost guided by MR spectroscopic imaging.

BACKGROUND: Glioblastoma, a high-grade glial infiltrating tumor, is the most frequent malignant brain tumor in adults and carries a dismal prognosis. External beam radiotherapy (EBRT) increases overall survival but this is still low due to local relapses, mostly occurring in the irradiation field. As the ratio of spectra of choline/N acetyl aspartate> 2 (CNR2) on MR spectroscopic imaging has been described as predictive for the site of local relapse, we hypothesized that dose escalation on these regions would increase local control and hence global survival. METHODS/DESIGN: In this multicenter prospective phase III trial for newly diagnosed glioblastoma, 220 patients having undergone biopsy or surgery are planned for randomization to two arms. Arm A is the Stupp protocol (EBRT 60 Gy on contrast enhancement + 2 cm margin with concomitant temozolomide (TMZ) and 6 months of TMZ maintenance); Arm B is the same treatment with an additional simultaneous integrated boost of intensity-modulated radiotherapy (IMRT) of 72Gy/2.4Gy delivered on the MR spectroscopic imaging metabolic volumes of CHO/NAA > 2 and contrast-enhancing lesions or resection cavity. Stratification is performed on surgical and MGMT status. DISCUSSION: This is a dose-painting trial, i.e. delivery of heterogeneous dose guided by metabolic imaging. The principal endpoint is overall survival. An online prospective quality control of volumes and dose is performed in the experimental arm. The study will yield a large amount of longitudinal multimodal MR imaging data including planning CT, radiotherapy dosimetry, MR spectroscopic, diffusion and perfusion imaging. TRIAL REGISTRATION: NCT01507506 , registration date December 20, 2011.

Randomized phase III trial of metabolic imaging-guided dose escalation of radio-chemotherapy in patients with newly diagnosed glioblastoma (SPECTRO GLIO trial).

BACKGROUND: Glioblastoma (GBM) systematically recurs after a standard 60 Gy radio-chemotherapy regimen. Since magnetic resonance spectroscopic imaging (MRSI) has been shown to predict the site of relapse, we analyzed the effect of MRSI-guided dose escalation on overall survival (OS) of patients with newly diagnosed GBM. METHODS: In this multicentric prospective phase III trial, patients who had undergone biopsy or surgery for a GBM were randomly assigned to a standard dose (SD) of 60 Gy or a high dose (HD) of 60 Gy with an additional simultaneous integrated boost totaling 72 Gy to MRSI metabolic abnormalities, the tumor bed and residual contrast enhancements. Temozolomide was administered concomitantly and maintained for 6 months thereafter. RESULTS: One hundred and eighty patients were included in the study between March 2011 and March 2018. After a median follow-up of 43.9 months (95% CI [42.5; 45.5]), median OS was 22.6 months (95% CI [18.9; 25.4]) versus 22.2 months (95% CI [18.3; 27.8]) for HD, and median progression-free survival was 8.6 (95% CI [6.8; 10.8]) versus 7.8 months (95% CI [6.3; 8.6]), in SD versus HD, respectively. No increase in toxicity rate was observed in the study arm. The pseudoprogression rate was similar across the SD (14.4%) and HD (16.7%) groups. For O(6)-methylguanine-DNA methyltransferase (MGMT) methylated patients, the median OS was 38 months (95% CI [23.2; NR]) for HD patients versus 28.5 months (95% CI [21.1; 35.7]) for SD patients. CONCLUSION: The additional MRSI-guided irradiation dose totaling 72 Gy was well tolerated but did not improve OS in newly diagnosed GBM. TRIAL REGISTRATION: NCT01507506; registration date: December 20, 2011. https://clinicaltrials.gov/ct2/show/NCT01507506?cond=NCT01507506&rank=1.

The GIRAFE phase II trial on MVCT-based "volumes of the day" and "dose of the day" addresses when and how to implement adaptive radiotherapy for locally advanced head and neck cancer.

During exclusive curative radiotherapy for head and neck tumors, the patient's organs at risk (OAR) and target volumes frequently change size and shape, leading to a risk of higher toxicity and lower control than expected on planned dosimetry. Adaptive radiotherapy is often necessary but 1) tools are needed to define the optimal time for replanning, and 2) the subsequent workflow is time-consuming. We designed a prospective study to evaluate 1) the validity of automatically deformed contours on the daily MVCT, in order to safely use the "dose-of the day" tool to check daily if replanning is necessary; 2) the automatically deformed contours on the replanning CT and the time gained in the replanning workflow. Forty-eight patients with T3-T4 and/or involved node >2 cm head and neck squamous cell carcinomas, planned for curative radiotherapy without surgery, will be enrolled. They will undergo treatment with helical IMRT including daily repositioning MVCTs. The contours proposed will be compared weekly on intermediate planning CTs (iCTs) on weeks 3, 4, 5 and 6. On these iCTs both manual recontouring and automated deformable registration of the initial contours will be compared with the contours automatically defined on the MVCT. The primary objective is to evaluate the Dice similarity coefficient (DSC) of the volumes of each parotid gland. The secondary objectives will evaluate, for target volumes and all OARs: the DSC, the mean distance to agreement, and the average surface-to-surface distance. Time between the automatic and the manual recontouring workflows will be compared.

The Impact of a Small Private Online Course as a New Approach to Teaching Oncology: Development and Evaluation.

BACKGROUND: Oncology involves complex care and multidisciplinary management of patients; however, misinformation and ineffective communication remain problematic. OBJECTIVE: The educational objective of our study was to develop a new teaching method to improve cancer treatment and management by emphasizing the link between hospitals (inpatients) and their surrounding communities (outpatients). METHODS: A team of 22 professionals from public and private institutions developed a small private online course (SPOC). Each offering of the course lasted 6 weeks and covered 6 topics: individual health care plans, cancer surgery, ionizing radiation, cancer medicines, clinical research, and oncological supportive care. For participants in the course, we targeted people working in the cancer field. The SPOC used an active teaching method with collaborative and multidisciplinary learning. A final examination was offered in each session. We evaluated participants' satisfaction rate through a questionnaire and the success of the SPOC by participants' completion, success, and commitment rates. RESULTS: Of the total participants (N=1574), 446 completed the evaluation form. Most participants were aged 31 to 45 years. Participants included 56 nurses, 131 pharmacists, 80 from the medical field (including 26 physicians), 53 from patients' associations, 28 health teachers, and 13 students (medical and paramedical). Among the participants, 24.7% (90/446) had an independent medical practice, 38.5% (140/446) worked in a public institution, and 36.8% (134/446) worked in a private institution. After completing the SPOC sessions, 85.9% (384/446) thought they had learned new information, 90.8% (405/446) felt their expectations were met, and 90.4% (403/446) considered that the information had a positive impact on their professional practice. The completion rate was 35.51% (559/1574), the success rate was 71.47% (1025/1574), and the commitment rate was 64.67% (1018/1574). Concerning the cost effectiveness of SPOC compared with a traditional classroom of 25 students, online education became more effective when there were more than 950 participants. CONCLUSIONS: SPOCs improved the management of oncology patients. This new digital learning technique is an attractive concept to integrate into teaching practice. It offered optimal propagation of information and met the students' expectations.

Phase I trial of tipifarnib (R115777) concurrent with radiotherapy in patients with glioblastoma multiforme.

PURPOSE: To conduct a Phase I trial to determine the maximally tolerated dose (MTD) of tipifarnib in combination with conventional three-dimensional conformal radiotherapy (RT) for patients with glioblastoma multiforme. METHODS AND MATERIALS: After resection or biopsy, tipifarnib was given 1 week before and then continuously during RT (60 Gy), followed by adjuvant administration until progression. The tipifarnib dose during RT was escalated in cohorts of 3 starting at 200 mg/day. RESULTS: Thirteen patients were enrolled, and 12 were evaluable for MTD. Of these patients, 7 had undergone biopsy, 4 had partial resection, and 1 had gross total resection. No dose-limiting toxicity (DLT) was observed during the concomitant treatment at 200 mg. All 3 patients at 300 mg experienced DLT during the concomitant treatment: 1 with sudden death and 2 with acute pneumonitis. The MTD was reached at 300 mg. The adjuvant treatment was suppressed from the protocol after a case of pneumonitis during this treatment. Six additional patients were included at 200 mg/day of the new protocol, confirming the safety of this treatment. Of the 9 evaluable patients, 1 had partial response, 4 had stable disease, and 3 had rapid progression; the patient with gross total resection was relapse-free after 21 months. Median survival of the evaluable patients was 12 months (range, 5.2-21 months). CONCLUSION: Tipifarnib (200 mg/day) concurrent with standard radiotherapy is well tolerated in patients with glioblastoma. Preliminary efficacy results are encouraging.

A phase I dose-escalating and pharmacokinetic study of docetaxel and vinorelbine as first-line chemotherapy for metastatic breast cancer.

Docetaxel and vinorelbine are both active drugs as single agents in the treatment of metastatic breast cancer. We performed a phase I dose-escalating and pharmacokinetic study to assess the safety profile of a new combination regimen and the pharmacokinetic interaction of vinorelbine and docetaxel. Patients with metastatic breast cancer received first-line treatment with both drugs on days 1-5. Treatment was restarted on day 21 of each cycle. We had to stop the escalation at the first step of the study (vinorelbine 20 mg/m(2) followed by docetaxel 30 mg/m(2) on days 1 and 5) because of hematological toxicity. In 4 additional patients who received G-CSF supplementation, no major leukopenia occurred, suggesting that the toxicity profile of this combination is very homogenous and focused on neutrophils. We found no pharmacokinetic interaction between the two drugs. These results suggest that a pharmacodynamic interaction was the cause of the hematological toxicity and that sequential regimens should be preferably further explored.

Phase-I study of a new schedule based on increasing days of topotecan administration associated with dose individualisation.

BACKGROUND: The most commonly prescribed schedule of topotecan administration is daily for five days, every 21 days. Both pre-clinical and clinical studies suggest that a more protracted schedule may increase its therapeutic index. The current study was undertaken to determine the maximum tolerated number of days with 30-minute i.v. infusion of topotecan daily at fixed area under the plasma concentration-time curve (AUC) (i.e., 35 microg/Lxh). PATIENTS AND METHODS: Topotecan was administered i.v. over 30 min. The planned levels of number of days of administration were: 7, 10, 13, 15 and 17. The dose was individualized according to the patient's individual topotecan clearance observed after the first infusion of each cycle. RESULTS: Twenty-three patients were enrolled and received 71 cycles of therapy. The 13-day level was defined as the maximum number of days of administration. The main side effects were thrombocytopenia and anaemia, whereas neutropenia was infrequent. The mean (coefficient of variation) observed AUC was 34.6 (21%), and 33.4 (19%) microg/Lxh, for the last day of cycle 1, and of cycle 2, respectively. Confirmed partial responses were observed in one patient with metastatic desmoplastic tumour and in two patients with small round metastatic endocrine carcinoma. CONCLUSION: The recommended number of topotecan administration is 10 days. Beyond the potential clinical interest of topotecan administered for a 10-day period, this is the first trial showing the feasibility of a phase-I study exploring a number of administrations of daily AUC rather than a total dose in mg/m(2).

Cystatin C as a new covariate to predict renal elimination of drugs: application to carboplatin.

BACKGROUND AND OBJECTIVE: The individual dosing of drugs that are mainly eliminated unchanged in the urine is made possible by assessing renal function. Most of the methods used are based on serum creatinine (SCr) levels. Cystatin C (CysC) has been proposed as an alternative endogenous marker of the glomerular filtration rate (GFR). Carboplatin is one of the drugs for which elimination is most dependent on the GFR. A prospective clinical trial including 45 patients was conducted to assess the value of serum CysC as a predictor of carboplatin clearance (CL). METHODS: The patients were receiving carboplatin as part of established protocols. Carboplatin was administered as a daily 60-minute infusion at doses ranging from 290 to 1700mg. A population pharmacokinetic analysis was performed using the nonlinear mixed effect modelling NONMEM program according to a two-compartment pharmacokinetic model. RESULTS: Data from 30 patients were used to test the relationships between carboplatin CL and morphological, biological and demographic covariates previously proposed for prediction of the GFR. The interindividual variability of carboplatin CL decreased from 31% (no covariate) to 14% by taking into account five covariates (SCr, CysC, bodyweight [BW], age and sex). Prospective evaluation of these relationships using the data from the other 15 patients confirmed that the best equation to predict carboplatin CL was based on these five covariates, with a mean absolute percentage error of 13% as an assessment of precision. NONMEM analysis of the whole dataset (n = 45 patients) was performed. The best covariate equation corresponding to the overall analysis was: CL (mL/min) = 110 x (SCr/75)-0.512 x (CysC/1.0)-0.327 x (BW/65)0.474 x (age/56)-0.387 x 0.854sex, with SCr in micromol/L, CysC in mg/L, BW in kilograms, age in years and sex = 0 if male and 1 if female. To put the value of CysC as an endogenous marker of the GFR into perspective, covariate equations without SCr were also evaluated; a better prediction was obtained by considering CysC together with age and BW (interindividual variability of 16.6% vs 23.3% for CysC alone). CONCLUSION: CysC is a marker of drug elimination that is at least as good as SCr for predicting carboplatin CL. The model based on five covariates was superior to those based on only four covariates (with BW, age and sex combined with either SCr or CysC), indicating that CysC and SCr are not completely redundant to each other. Further pharmacokinetic evaluation is needed to determine whether SCr or CysC is the better marker of renal elimination of other drugs.

Dexamethasone as a probe for docetaxel clearance.

PURPOSE: A pilot study was conducted in 23 patients in order to assess the correlation between docetaxel clearance (CL) and pharmacokinetics of dexamethasone. Dexamethasone is mainly 6-beta hydroxylated by CYP3A4, and is regularly used as standard docetaxel premedication. Genotyping of known functional single nucleotide polymorphism (SNP) of CYP3A5 (G22893A) and mdr-1 (G2677T, G2677A, and C3435T) have been performed in order to tentatively correlate genotype with docetaxel and dexamethasone pharmacokinetics. PATIENTS AND METHODS: To be eligible for this study, patients were required to have a solid malignancy for which docetaxel was indicated. A population pharmacokinetic approach was used to determine individual pharmacokinetic parameters of both docetaxel and dexamethasone by Bayesian analysis, and to screen relationships between docetaxel CL and patients' demographic, phenotype and genotype covariates. RESULTS: Three different pharmacokinetic parameters of dexamethasone were significantly correlated with docetaxel CL: dexamethasone plasma clearance (DPC) that ranged between 7.7 and 27.2 l/h, urinary amount of 6beta-hydroxydexamethasone, and the ratio between urinary amount of 6beta-hydroxydexamethasone and unchanged dexamethasone. The best covariate model was docetaxel CL (l/h) = 356 x fu(alpha1-AG) x (1-0.17 x HPMT)(1+0.126 x DPC) where fu(alpha1-AG) is the unbound plasma fraction of docetaxel calculated from alpha1-acid glycoprotein plasma level, and HPMT is hepatic metastasis coded as 1 if present or 0 if absent. No significant difference in docetaxel CL was observed between the several genotypes. CONCLUSIONS: Dexamethasone may be used as a probe to predict docetaxel clearances, hence reducing interindividual variability.

αvß3 Integrin and Fibroblast growth factor receptor 1 (FGFR1): Prognostic factors in a phase I-II clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma.

BACKGROUND: Based on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway. PATIENTS AND METHODS: Patients were treated with 200mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvß3, αvß5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome. RESULTS: For the phase II patients median TTP was 23.1 weeks (95%CI = [15.4; 28.2]) while the median OS was 80.3 weeks (95%CI = [57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4 w (95%CI = [47.3; 97.6]) while median TTP was 18.1 w (95%CI = [16.9; 25.6]). FGFR1 over-expression (HR = 4.65; 95%CI = [1.02; 21.21], p = 0.047) was correlated with shorter TTP while FGFR1 (HR = 4.1 (95% CI = [1.09-15.4]; p = 0.036)) and αvß3 (HR = 10.38 (95%CI = [2.70; 39.87], p = 0.001)) over-expressions were associated with reduced OS. CONCLUSION: Association of 200mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvß3 integrin are independent bad prognostic factors of OS and TTP.

Unexpected high levels of vorinostat when combined with vinorelbine in patients with advanced cancer.

BACKGROUND: This study was a multi-centre, dose-escalation trial in patients with advanced cancers. Primary objective was to determine maximum tolerated dose (MTD) of vorinostat, a competitive inhibitor of histone deacetylase (HDAC), in combination with vinorelbine. Secondary aims were to determine (1) corresponding pharmacokinetics, (2) safety of this regimen, and (3) impact of UGT1A1 and 2B17 polymorphisms on vorinostat pharmacokinetics. METHODS: Starting dose of once daily oral vorinostat was 200 mg for 7 days every 21 days in combination with a 20-min intraveinous weekly infusion of vinorelbine 25 mg/m2, starting 4 hours after the first vorinostat dose. During cycle 1, blood samples were collected at day 1 for vorinostat and at days 1 and 8 for vinorelbine for pharmacokinetic evaluation. RESULTS: Seven patients were included. Most of adverse events observed were mild (grades 0-2) and reversible after treatment discontinuation (hemotological toxicity, asthenia, diarrhea, dyspnea, fever, hyperglycemia and nausea). Two patients had a dose limiting toxicity at the first dose level that consisted of grade 3 hyperglycemia and vinorelbine administration was delayed. The first dose-level was considered as the MDT and therefore dose escalation was stopped. Mean vorinostat plasma AUC was higher than reported previously at a similar dose when used as single agent or in combination with other cytotoxics. There was no obvious vinorelbine-vorinostat interaction nor any correlation with UGT1A1 or 2B17 polymorphisms. CONCLUSION: MDT of the combination was 200 mg oral vorinostat for 7 days in combination with 25 mg/m2 weekly vinorelbine. Severity of hyperglycemia was most likely related to unexpected high vorinostat exposures.