A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR).

BACKGROUND: Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. METHODS: This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). DISCUSSION: Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06059014.

Qualitative evaluation of motives for acceptance or refusal of early palliative care in patients included in early-phase clinical trials in a French comprehensive cancer center: the PALPHA study.

PURPOSE: The integration of palliative care (PC) into oncological management is recommended well before the end of life. It improves quality of life and symptom control and reduces the aggressiveness of end-of-life care. However, its appropriate timing is still debated. Entry into an early-phase clinical trial (ECT) represents hopes for the patient when standard treatments have failed. It is an opportune moment to integrate PC to preserve the patient's general health status. The objective of this study was to evaluate the motives for acceptance or refusal of early PC management in patients included in an ECT. METHODS: Patients eligible to enter an ECT were identified and concomitant PC was proposed. All patients received exploratory interviews conducted by a researcher. Their contents were analyzed in a double-blind thematic analysis with a self-determination model. RESULTS: Motives for acceptance (PC acceptors: n = 27) were both intrinsic (e.g., pain relief, psychological support, anticipation of the future) and extrinsic (e.g., trust in the medical profession, for a relative, to support the advance of research). Motives for refusal (PC refusers: n = 3) were solely intrinsic (e.g., PC associated with death, negative representation of psychological support, no need for additional care, claim of independence). CONCLUSIONS: The motives of acceptors and refusers are not internalized in the same way and call for different autonomy needs. Acceptors and refusers are influenced by opposite representations of PC and a different perception of mixed management.

Unexpected severe hepatic and skin toxicities during high dose methotrexate course for osteosarcoma.

INTRODUCTION: high dose methotrexate (HD-MTX) regimen is used in osteosarcoma, leukemia and lymphoma treatment. Osteosarcoma is mostly diagnosed in children and adolescents. Most frequent methotrexate toxicities are mucositis, myelosuppression, renal failure, hepatitis and necrotizing encephalopathy. Toxicities increase with renal impairment, denutrition, in older patients, with some pharmacogenetics factors or with drug interactions. CASE REPORT: We report a 16th years old woman diagnosed with osteosarcoma and experienced an unexpected severe hepatic and skin toxicities as toxic epidermal necrolys, Steven Johnson syndrome. MANAGEMENT AND OUTCOME: This toxicity occurred despite acid folinic rescue performed as good practice recommendation. Fourteen hours after methotrexate administration, renal failure was observed and after 72 h an erythematous rash and epidermal detachment with toxic epidermal necrolys. Seven days after methotrexate administration, hepatic failure began until grade IV cytolysis. High dose of folinic acid were administered during all severe toxicities. Methotrexate were not longer administered to this young patient and chemotherapy with ifosfamide (IFO), doxorubicine and cisplatin were performed in this patient and complete histologic response were observed in the surgical bone resection. DISCUSSION: No classical toxicities risk factors were identified in this patient but a homozygote mutation of MTHFR gene and homozygote SLCO1B1 gene mutation were found. MTHFR and SLCO1B1 are both implicated in methotrexate metabolism.

Ductal adenocarcinoma of the prostate: Clinical and biological profiles.

BACKGROUND: Ductal adenocarcinoma (DAC) is a rare and aggressive subtype of prostate cancer (PCa). In the present study, we analyzed the clinical and biological characteristics of DAC, in comparison with high grade conventional acinar PCa. METHODS: Samples and data were retrospectively collected from seven institutions and centrally reviewed. Immunohistochemistry was performed on tissue microarrays to assess the expression of candidate proteins, based on the molecular classification of PCa, including ERG, PTEN, and SPINK1. SPOP mutations were investigated from tumor DNA by Sanger sequencing. Relationships with outcome were analyzed using log-rank analysis and multivariable Cox regression. RESULTS: Among 56 reviewed prostatectomy specimens, 45 cases of DAC were finally confirmed. The pathological stage was pT3 in more than 66% of cases. ERG was expressed in 42% of DAC, SPINK1 in 9% (all ERG-negative), and two cases (ERG-negative) harbored a SPOP mutation. Compared to high grade conventional PCa matched for the pathological stage, cell proliferation was higher (P = 0.04) in DAC, and complete PTEN loss more frequent (P = 0.023). In multivariate analysis, SPINK1 overexpression (P = 0.017) and loss of PSA immunostaining (P = 0.02) were significantly associated with biochemical recurrence. CONCLUSION: these results suggest that, despite biological differences that highlighted DAC aggressiveness, the molecular classification recently proposed in conventional PCa could also be applied in DAC.

Current Systemic Treatment Options for Tenosynovial Giant Cell Tumor/Pigmented Villonodular Synovitis: Targeting the CSF1/CSF1R Axis.

OPINION STATEMENT: Adequate surgical resection remains the treatment of choice for tenosyovial giant cell tumor (TGCT). However, diffuse type TGCT (D-TGCT) is more difficult to resect and has a higher rate of recurrence (up to 50 %), which is often multiple. D-TGCT is rarely lethal and only rare cases of metastases have been described. Nevertheless, patients might have a significant decline in their quality of life due to multiple operations, which may sometimes result in a partial loss of function of the affected joint and may also be associated with perioperative morbidity and secondary arthrosis. As of today, no systemic treatment is approved for this rare disease. The aims of systemic therapy in the context of a non-lethal tumor are to reduce surgical morbidity and to preserve function and patient quality of life. Because TGCT is associated with characteristic cytogenetic abnormalities resulting in the overexpression of CSF1, systemic therapies targeting the CSF1/CSF1R axis (imatinib, nilotinib, emactuzumab, and PLX3397) have been tested in patients with locally advanced or relapsed D-TGCT. The more recent and more specific CSF1R inhibitors have shown a very interesting clinical activity with acceptable toxicity in early phase trials. These results will need to be confirmed in larger, ideally randomized, trials. But the high rate of clinical and functional improvement seen in some patients with advanced D-TGCT, often after multiple operations, suggests that these inhibitors will likely have a role in the management of patients with an inoperable disease; the definition of "inoperable TGCT" still requires refinement to reach a consensus. Another point that will need to be addressed is that of "the optimal duration of therapy" for these patients. Indeed, we and others have observed often prolonged clinical benefit and symptomatic relief even after treatment was stopped, with both monoclonal antibodies and tyrosine kinase inhibitors. Responses were observed very early on with emactuzumab and PLX3397, and patients experienced significant symptom improvement within a few weeks of starting therapy (2-4 weeks). Another possible application of CSF1R inhibitors could be used either as a preoperative or postoperative therapy for patients with operable TGCT. However, we currently lack sufficient follow-up to adequately address these questions which will each require specific trial designs. Overall, the striking clinical activity of CSF1R specific inhibitors in TGCT has created great enthusiasm among clinicians, and further development of these agents is clearly medically needed. Nevertheless, further investigations are necessary to validate those treatments and assess how to best incorporate them among other treatment modalities into the overall therapeutic strategy for a given patient.

Added value of whole-exome and RNA sequencing in advanced and refractory cancer patients with no molecular-based treatment recommendation based on a 90-gene panel.

INTRODUCTION: The objective was to determine the added value of comprehensive molecular profile by whole-exome and RNA sequencing (WES/RNA-Seq) in advanced and refractory cancer patients who had no molecular-based treatment recommendation (MBTR) based on a more limited targeted gene panel (TGP) plus array-based comparative genomic hybridization (aCGH). MATERIALS AND METHODS: In this retrospective analysis, we selected 50 patients previously included in the PROFILER trial (NCT01774409) for which no MBT could be recommended based on a targeted 90-gene panel and aCGH. For each patient, the frozen tumor sample mirroring the FFPE sample used for TGP/aCGH analysis were processed for WES and RNA-Seq. Data from TGP/aCGH were reanalyzed, and together with WES/RNA-Seq, findings were simultaneously discussed at a new molecular tumor board (MTB). RESULTS: After exclusion of variants of unknown significance, a total of 167 somatic molecular alterations were identified in 50 patients (median: 3 [1-10]). Out of these 167 relevant molecular alterations, 51 (31%) were common to both TGP/aCGH and WES/RNA-Seq, 19 (11%) were identified by the TGP/aCGH only and 97 (58%) were identified by WES/RNA-Seq only, including two fusion transcripts in two patients. A MBTR was provided in 4/50 (8%) patients using the information from TGP/aCGH versus 9/50 (18%) patients using WES/RNA-Seq findings. Three patients had similar recommendations based on TGP/aCGH and WES/RNA-Seq. CONCLUSIONS: In advanced and refractory cancer patients in whom no MBTR was recommended from TGP/aCGH, WES/RNA-Seq allowed to identify more alterations which may in turn, in a limited fraction of patients, lead to new MBTR.

Xevinapant Combined with Pembrolizumab in Patients with Advanced, Pretreated, Colorectal and Pancreatic Cancer: Results of the Phase Ib/II CATRIPCA Trial.

PURPOSE: Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers by modulating the NFκB pathway in immune cells. PATIENTS AND METHODS: Adult patients with non-high microsatellite instability advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer were enrolled in this phase Ib/II study and received pembrolizumab 200 mg every 3 weeks intravenously, and ascending doses of oral xevinapant (100, 150, and 200 mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with colorectal cancer were enrolled in expansion cohorts to assess preliminary efficacy. RESULTS: Forty-one patients (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose escalation. The RP2D was identified as xevinapant 200 mg/day + pembrolizumab 200 mg every 3 weeks. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12%, and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin, and rash seen in 20%, 15%, and 15% of patients, respectively). The best overall response according to RECIST1.1 was partial response (confirmed) in 1 (3%), stable disease in 4 (10%), and progressive disease in 35 (88%). CONCLUSIONS: Xevinapant combined with pembrolizumab was well tolerated with no unexpected AEs. However, antitumor activity was low.

Rationale for Prostate-Specific-Membrane-Antigen-Targeted Radionuclide Theranostic Applied to Metastatic Clear Cell Renal Carcinoma.

Prostate-specific membrane antigen (PSMA), whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma, is also highly expressed in the neovessels of various solid tumors, including clear cell renal cell carcinoma (ccRCC). In the VISION phase III clinical trial, PSMA-targeted radioligand therapy (PRLT) with lutetium 177 demonstrated a 4-month overall survival OS benefit compared to the best standard of care in heavily pretreated metastatic prostate cancer. Despite the improvement in the management of metastatic clear cell renal cell carcinoma (mccRCC) with antiangiogenic tyrosine kinase inhibitor (TKI) and immunotherapy, there is still a need for new treatments for patients who progress despite these drugs. In this study, we discuss the rationale of PRLT applied to the treavtment of mccRCC.

Reasons for acceptance and refusal of early palliative care in patients included in early-phase clinical trials in a regional comprehensive cancer centre in France: protocol for a qualitative study.

INTRODUCTION: A few studies have highlighted the potential synergy between early palliative care and inclusion in an early-phase clinical trial that may improve quality of life, reduce symptoms of exhaustion related to the side effects of treatment and allow patients to complete their treatment protocol. The primary objective of this qualitative study is to evaluate the reasons for acceptance or refusal of early palliative care in patients included in early-phase clinical trials. METHOD AND ANALYSIS: All patients from the Centre Léon Bérard (Comprehensive Cancer Centre in Lyon, France) who consent to one of the early-phase clinical trials proposed at the centre will be invited to participate in this study. The cohort will consist of a subgroup (n=20) of patients who accept palliative care together with their clinical trial, and a second subgroup (n=20) of patients who decline it. Patients will be interviewed in exploratory interviews conducted by a psychology researcher before the start of their clinical trial. The interviews will be audio-recorded. Patients will also be asked to complete quality of life and anxiety/depression questionnaires both before the beginning of the treatment and at the end of their clinical trial. The content of the interviews will be analysed thematically. Descriptive and comparative statistical analysis of both cohorts will also be conducted. ETHICS AND DISSEMINATION: Personal data will be collected and processed in accordance with the laws and regulations in force. All patients will give informed consent to participate. This study complies with reference methodology MR004 of the Commission Nationale de l'Informatique et des Libertés. The protocol has received the validation of an ethics committee (Groupe de Réflexion Ethique du CLB, number: 2020-006). The results will be disseminated through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04717440.

[Bispecific antibodies targeting CD3 in oncology and hematology]. / Anticorps bispécifiques ciblant CD3 en oncologie solide et onco-hématologie.

Bispecific therapies targeting CD3, so-called T-cell engagers (TCE), belong to the new spectrum of anti-tumor immunotherapies stimulating T-lymphocytes. TCE are unique constructs targeting the MHC-independent CD3 epsilon subunit (CD3e) and a tumor antigen. To date, only blinatumomab have reached market agreements in lymphoid malignancies with constructs targeting CD3exCD19. Other TCE are in advances development, with promising results targeting CD20 and BSMA in lymphoma and myeloma. These successes have relaunched the development of TCE in solid tumors, bringing mixed results so far (notably in terms of tolerance). Still, TCE pave the way to new immunotherapy in tumors considered to be refractory to inhibitors of immune checkpoints such as prostate cancer or colorectal cancer.

[Treatment of testicular germ cell tumors relapse]. / Actualités dans le traitement à la rechute des patients atteints de tumeurs germinales.

Seminomatous (SGCT) and non-seminomatous (NSGCT) germ cell tumors (GCT) are rare but their incidence are increasing. We will discuss different therapeutic strategies in relapse disease: patients with stage I germ cell tumor have an excellent prognosis with a cure rate approaching 98-99 %, whatever the histology and the chosen treatment (surveillance strategy or adjuvant treatment). Relapses are observed among 20% of patients with stage I SGCT or low risk NSGCT and 50 % of patients with high risk NSGCT. Patients are treated according to the international prognosis group (IGCCCG) for SGCT and low risk NSGCT, naïve of chemotherapy. After an adjuvant treatment, the protocol must be adapted to the number of previous cycles (1 or 2 BEP) and to the prognosis group. Five to 50% of patients relapse after a first line of metastatic chemotherapy according to initial prognosis group. Dose-dense chemotherapy according to the GETUG13 protocol reduces the risk of relapse for the patients with poor-risk group NSGCT and unfavorable tumor marker decline. The prognosis of patients with relapsed or refractory GCT after a first line is more negative since only half of them will be cured by salvage standard chemotherapy. An international therapeutic trial (TIGER) is ongoing in first line salvage treatment evaluating high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation (HSCT). Finally, developing biomarkers for predicting clinical relapse, the management in expert centers of these patients and participation in therapeutic innovation are important perspectives for a better understanding and treatment of these patients with a poorer prognosis.

[Intensification by high dose chemotherapy for germ-cell tumors, still an ongoing subject?] / État des lieux de la chimiothérapie intensive avec support de cellules-souches hématopoïétiques dans le traitement des tumeurs germinales.

More than 80 % of patient with metastatic germ cell tumor are cured with first line chemotherapy. Twenty to 30 % of patients will experience relapse or refractory disease with a very poor long-term prognosis. Most of them had metastatic germ cell tumors with a poor prognosis according to the international germ cell classification collaborative group (IGCCCG). The role of treatment intensification by high dose chemotherapy (HDCT) followed by stem cell rescue has not been demonstrated yet in the first line setting compared to standard chemotherapy. The role of HDCT in first or second salvage is also not yet demonstrated, many studies have been published in this situation with a lot of different regimen. Outside clinical trial, HDCT remains an option in salvage therapy, depending on many factors including prognostics factors, previous therapy, general condition and reference center consideration to select eligible patient who could benefit the most of this approach. Results from the international randomized trial TIGER will provide evidence-based information for HDCT strategy.

Advanced chordoma treated by first-line molecular targeted therapies: Outcomes and prognostic factors. A retrospective study of the French Sarcoma Group (GSF/GETO) and the Association des Neuro-Oncologues d'Expression Française (ANOCEF).

BACKGROUND: To assess the role of first-line Molecular Targeted Therapies (MTTs) in Advanced chordoma (AC) patients. METHODS: Retrospective study of 80 patients treated between January 2004 and December 2015 at 15 major French Sarcoma or Neurooncology Centres. RESULTS: The sex ratio M/F was 46/34. The median age was 59 (6-86) years. The primary sites were the sacrum (50, 62.5%), mobile spine (12, 15.0%), and skull base (18, 22.5%). Metastases were present in 28 patients (36.0%). The first line of MTTs consisted of imatinib (62, 77.5%), sorafenib (11, 13.7%), erlotinib (5, 6.3%), sunitinib (1, 1.2%) and temsirolimus (1, 1.2%). The reported responses were: partial response (5, 6.3%), stable disease (58, 72.5%), or progressive disease (10, 12.5%). Symptomatic improvement was seen in 28/66 assessable patients (42.4%) and was associated with an objective response occurrence (p = 0.005), imatinib (p = 0.020) or erlotinib use (p = 0.028). The median progression-free survival (PFS) was 9.4°months (95% CI, [6.8-16.1]). Two independent factors of poor prognosis for PFS were identified: a skull-based primary location (HR = 2.5, p = 0.019), and the interval between diagnosis and MTT of <52months (HR = 2.8, p < 0.001). The median overall survival (OS) was 4.4°years (95% CI, [3.8-5.6]). Four independent factors of poor prognosis for OS were identified: the presence of liver metastases (HR = 13.2, p < 0.001), pain requiring opioids (HR = 2.9, p = 0.012), skull-based primary location (HR = 19.7, p < 0.001), and prior radiotherapy (photon alone) (HR = 2.5, p = 0.024). The PFS and OS did not significantly differ between the MTT. CONCLUSIONS: The prognostic factors identified require validation in an independent database but are potently useful to guide treatment decisions and design further clinical trials.