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 STEMRI trial: Magnetic resonance spectroscopy imaging can define tumor areas enriched in glioblastoma stem-like cells.

Despite maximally safe resection of the magnetic resonance imaging (MRI)-defined contrast-enhanced (CE) central tumor area and chemoradiotherapy, most patients with glioblastoma (GBM) relapse within a year in peritumoral FLAIR regions. Magnetic resonance spectroscopy imaging (MRSI) can discriminate metabolic tumor areas with higher recurrence potential as CNI+ regions (choline/N-acetyl-aspartate index >2) can predict relapse sites. As relapses are mainly imputed to glioblastoma stem-like cells (GSCs), CNI+ areas might be GSC enriched. In this prospective trial, 16 patients with GBM underwent MRSI/MRI before surgery/chemoradiotherapy to investigate GSC content in CNI-/+ biopsies from CE/FLAIR. Biopsy and derived-GSC characterization revealed a FLAIR/CNI+ sample enrichment in GSC and in gene signatures related to stemness, DNA repair, adhesion/migration, and mitochondrial bioenergetics. FLAIR/CNI+ samples generate GSC-enriched neurospheres faster than FLAIR/CNI-. Parameters assessing biopsy GSC content and time-to-neurosphere formation in FLAIR/CNI+ were associated with worse patient outcome. Preoperative MRI/MRSI would certainly allow better resection and targeting of FLAIR/CNI+ areas, as their GSC enrichment can predict worse outcomes.

Hypofractionated Stereotactic Re-irradiation and Anti-PDL1 Durvalumab Combination in Recurrent Glioblastoma: STERIMGLI Phase I Results.

BACKGROUND: Hypofractionated stereotactic radiotherapy (hFSRT) is a salvage option for recurrent glioblastoma (GB) which may synergize anti-PDL1 treatment. This phase I study evaluated the safety and the recommended phase II dose of anti-PDL1 durvalumab combined with hFSRT in patients with recurrent GB. METHODS: Patients were treated with 24 Gy, 8 Gy per fraction on days 1, 3, and 5 combined with the first 1500 mg Durvalumab dose on day 5, followed by infusions q4weeks until progression or for a maximum of 12 months. A standard 3 + 3 Durvalumab dose de-escalation design was used. Longitudinal lymphocytes count, cytokines analyses on plasma samples, and magnetic resonance imaging (MRI) were collected. RESULTS: Six patients were included. One dose limiting toxicity, an immune-related grade 3 vestibular neuritis related to Durvalumab, was reported. Median progression-free interval (PFI) and overall survival (OS) were 2.3 and 16.7 months, respectively. Multi-modal deep learning-based analysis including MRI, cytokines, and lymphocytes/neutrophil ratio isolated the patients presenting pseudoprogression, the longest PFI and those with the longest OS, but statistical significance cannot be established considering phase I data only. CONCLUSION: Combination of hFSRT and Durvalumab in recurrent GB was well tolerated in this phase I study. These encouraging results led to an ongoing randomized phase II. (ClinicalTrials.gov Identifier: NCT02866747).

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.

Combining Nivolumab and Ipilimumab with Infliximab or Certolizumab in Patients with Advanced Melanoma: First Results of a Phase Ib Clinical Trial.

PURPOSE: TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors. PATIENTS AND METHODS: TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, N = 6) or certolizumab (400/200 mg, N = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1. RESULTS: Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts. CONCLUSIONS: Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations.

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.

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.

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.

Continuous Infusion of Cilengitide Plus Chemoradiotherapy for Patients With Stage III Non-Small-cell Lung Cancer: A Phase I Study.

INTRODUCTION: Because of our previous preclinical results, we conducted a phase I study associating the specific αvß3/αvß5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non-small-cell lung cancer. PATIENTS AND METHODS: A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months. RESULTS: Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively. CONCLUSION: Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results.