Vanves, France

Efficacy of Personalized Tumorogram-based Therapy in Cancer Established From Patient-derived Organoid

A biopsy of a breast tumor lesion will be performed and transferred to the LIP laboratory at the Institut Curie (Laboratoire d'Investigation Préclinique, Département de Recherche Translationnelle) for processing to establish avatars (patient-derived organoids -PDO). Step 1: Establishment of avatar (PDO): follow-up of line N (standard care) when the tumorogram is established, then follow-up of standard line N+1. - The patient will then be treated (line N) as part of standard care while awaiting the result of the tumorogram. - A drug screening will be carried out on the PDO (~5-10 drugs/patient), which will be progressive and adapted to the clinical context (including treatment history), including drugs used in standard care (cf. list in Table 1). - A personalized tumorogram for each patient will be provided, based on the results of the drug screening (= tumor predicted as sensitive, intermediate, resistant or non-evaluable for each drug tested). - A multidisciplinary committee will be set up for this study, which will meet regularly (~1 time per week) to discuss patients included in the study, obtaining PDOs, drugs to be prioritized in the screening, results of the drug screening and personalized tumorograms. The committee will include at least one oncologist and one biologist from the laboratory. - The multidisciplinary committee will make a therapeutic recommendation based on the personalized tumorogram, which may include several drugs considered sensitive to the tumour - A tumorogram will be considered as informative if it proposes at least one chemotherapy molecule considered as sensitive in the PDO model. - Patients whose PDO could not be obtained, or whose tumorogram was not informative, will receive standard treatment. Step 2: informative tumorogram: follow-up of experimental line N+1 Patients with an informative tumorogram will receive one of the recommended treatments (line N+1) in the event of tumor progression, administered according to standard procedures and validated at medical meetings specific to each center, and their fate will be monitored.

A Phase II Study Evaluating Glofitamab in Combination With Venetoclax Plus Zanubrutinib or Venetoclax Alone in Subjects With Untreated or Relapsed/Refractory High-risk Mantle-cell Lymphoma

Cohort A : 40 subjects will be included and treated Cohort B : 36 subjects will be included and treated Cohort C : 24 subjects will be included and treated Subjects in cohorts A and C will receive during induction phase 12 cycles of Zanubrutinib/Venetoclax/Glofitamab and during maintenance phase 23 cycles of Zanubrutinib/Venetoclax Subjects in cohort B will receive during induction phase 12 cycles of Venetoclax/Glofitamab and during maintenance phase 23 cycles of Venetoclax

Standard of Care +/- 177Lu-PSMA-617 In de Novo mHSPC Patients With Poor PSA Response (PEACE6-Poor Responders)

The study plans to enroll 500 patients over 63 months who will be randomized (1:1) to receive either: (i) Control arm: SoC (ADT+ ARSI (second-generation androgen receptor signaling inhibitors) +/- RT or ADT+ ARSI +/- RT) or (ii) Experimental arm: 177Lu-PSMA-617 + SoC (ADT+ ARSI +/- RT or ADT+ docetaxel + ARSI +/- RT). Response to treatment will be assessed according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Treatment will be continued at least until castration-resistant prostate cancer (CRPC) stage is reached, defined by evidence of cancer progression (either a confirmed PSA rise or a radiographic progression) with serum testosterone being at castrated levels (<0.50 ng/mL). This systemic treatment may be continued after CRPC is reached, based on patient benefit and the investigator's opinion. Treatment may also be terminated at the initiative of either the patient or the investigator for any reason that would be beneficial to the patient, including: unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient request. At the end of treatment period, the follow-up period will last for 102 months (8.5 years). The overall trial duration, including the follow-up, is expected to last 18.5 years.

Study of Mosunetuzumab Plus Lenalidomide Compared to Anti-CD20 Anti-body + Chemotherapy in Follicular Lymphoma FLIPI2-5

This study is a phase III, randomized, open-label, international, multicenter, interventional trial, designed to compare the efficacy and safety of mosunetuzumab in combination with lenalidomide versus anti-CD20 monoclonal antibody (mAb) plus chemotherapy in patients with previously untreated Follicular Lymphoma International Prognostic Index (FLIPI) 2-5 follicular lymphoma This study is composed of a screening period (up to 6 weeks before randomization, i.e., 42 days), a treatment period (30 months i.e., 125w), a safety follow-up period (90 days i.e., 3 months), and a survival follow-up period (up to 7 years after the last randomized patient). The enrollment will last approximately 34 months. The total duration of the study will be therefore approximately 10 years. Once a patient provides written consent, they may enter the screening phase, with a duration up to 6 weeks prior to randomization and initiation of treatment. Upon completion of the required assessments in the screening phase, and fulfillment of the eligibility criteria, patients will be randomized. Investigators will be requested to indicate their treatment choice among permitted immuno-chemotherapy regimens just before randomization. The treatment period for each patient starts with the first intake. The patients will receive protocol-specified treatments until: - inability to achieve a response at the end of induction phase (at M12 evaluation for experimental arm, and at M6 evaluation for control arms), - relapse or progression of the disease, - withdrawal of consent, - or unacceptable toxicity In the experimental arm, patients will be treated for 1 cycle of 3 weeks for mosunetuzumab and then 11 cycles of 4 weeks for mosunetuzumab and lenalidomide (47 weeks, around 11 months) during the induction phase, and for a maximum of 9 additional cycles of 8 weeks during the maintenance phase (72 weeks, around 17 months), up to around 125 weeks (30 months). Patients should start the maintenance phase 7 to 8 weeks after the start of last induction cycle (C12). In the control arm, patients will be treated for 8 or 6 cycles of 3 or 4 weeks for anti-CD20 mAb +cyclophosphamide-doxorubicine-vincristine-prednisone (CHOP) or anti-CD20 mAb + Bendamustine, respectively, depending on the assigned arm (24 weeks, around 5 months) during the induction phase, and for a maximum of 12 additional cycles of 8 weeks during the maintenance phase (96 weeks, around 22 months), up to around 125 weeks (30 months). Patients should start the maintenance phase, 6 to 7 or 7 to 8 weeks after the start of last induction cycle (C8 or C6). The option to cross-over from the control arm to the experimental arm is not allowed. All randomized patients will be followed for progression-free survival and overall survival using the same schedule. Patients will be followed up from End of treatment evaluation every 3 months during the first two years, then every 6 months during the next 3 years, then yearly until the end of study. The end of study will occur when all randomized patients have been followed-up for survival for at least 7 years (or discontinued study early).

POP-UP: a Single-arm, Two-cohort Study: Trimodal Prehab for Upper GI and Pancreatic Cancer

The POP-UP study aims to evaluate the feasibility and preliminary efficacy of an 8-week trimodal pre/posthabilitation program (consisting of personalized Adapted Physical Activity [APA], nutritional assessment, and psychological support) with remote monitoring of the APA sessions and nurse coordination in patients with localized (resectable or borderline resectable) PDAC who are treated with neoadjuvant or induction treatment (FOLFIRINOX: 5-fluorouracil/folinic acid, oxaliplatin, irinotecan) prior to surgery and with resectable OGC treated with perioperative chemotherapy (FLOT: 5-fluorouracil/folinic acid, oxaliplatin, docetaxel). The prehabilitation program will be conducted during neoadjuvant chemotherapy and the 3-5 weeks prior to surgery for a total of 8 weeks before surgery. There will be a total of three prehabilitation hospital days during the prehabilitation program. The preoperative prehabilitation will include: - Once per month, a prehabilitation hospital-day with functional capacities assessment with validated tests made by a physiotherapist or an APA professional (according of center resources/functioning), medical and nurse assessment evaluating performance status, chemotherapy toxicity and tolerance, and nutritional assessment (according to the functioning of each center it will be made by these professionals -with university training on nutrition- or a dietician). A therapeutic training session on the adherence to the prehabilitation program will be done by the nurse (trained in therapeutic education). - Weekly, an APA professional trainer will follow via using app (Activiti®) the APA home-based program. It will be based on the functional capacities assessment made during the prehabilitation hospital day. The exercise training program will consist of twice per week autonomy sessions, supervised and adapted by the APA professional, and once per week a guided session with the APA professional. The patient will have a total of 3 physical activity sessions per week. - Once per week, the nurse practitioner (or case manager, according to center functioning) will evaluate the patient via a videoconference to assess the chemotherapy toxicity and tolerance and patient's weight modifications. The posthabilitation program will start for a total of 8 weeks, one week after surgery discharge. The structure is the same as the prehabilitation program except for the follow of chemotherapy toxicity and tolerance that will be replaced by the follow of the surgical complications/consequences. There will be a total of three posthabilitation days at hospital during the posthabilitation program.

A Study on Tuvusertib (Oral ATR Inhibitor) in Combination With PLX038 (Topo1 Inhibitor) in Patients With Advanced Solid Tumors

This is an open label, multi-centric phase I with, first, a dose escalation step using an adaptation of the Bayesian Optimal INterval (BOIN) drug-combination, followed by 2 dose expansion cohorts using the Simon 2-stage design. Dose escalation step Dose escalation will be conducted on the grid defined by the 4 doses of PLX038 (800 mg/m², 1000 mg/m², 1300 mg/m² and 1700 mg/m² IV every 21 days D1=D22) and 3 doses of Tuvusertib (90 mg, 130 mg and 180 mg QD for 10 days from D3, D3-12). Premedication with anti-emetic agents is not required prior to the initial infusion, but may be used for an individual patient, as needed. starting combination level is c1 (PLX038 800mg/m2 and Tuvusertib 90mg). Groups of 3 patients will be sequentially enrolled. One week between the enrollment of the 1st patient and the 2 following patients is mandatory at a new combination level. The decision to (de)-escalate one of the two agents depends on the outcome of all patients treated at the current combination. Expansion cohorts Two expansion cohorts are planned, investigating the efficacy and safety in pre-specified populations of interest. Patients will be treated at the RP2D; 25 evaluable patients are needed in each cohort, to account for possible non evaluable patients, up to 28 patients will be enrolled in each cohort. Patients enrolled in the phase I part at the RP2D and fulfilling the eligibility criteria of one of the expansion cohorts will be counted in those 25 evaluable patients.

ECLECTIC: EstroTEP and Circulating Biomarkers for ER-positive HER2-negative Metastatic Breast Cancer Patients

All patients deemed eligible for a second line endocrine therapy will undergo a 18F-FES PET/CT scan and circulating tumor biomarkers assessment (circulating tumor cells (CTC) and, if not available, circulating tumor DNA (ctDNA)). All 18F-FES PET/CT scan will be anonymized and reviewed centrally, and compared to the 18Fluorodeoxyglucose (18F-FDG) PET/CT results before treatment initiation; circulating biomarkers status will be assessed centrally and will remain blinded to investigator and patients. Endocrine therapy in Arm A and C may consist in single agent endocrine therapy or in combination with targeted therapy. Luteinizing Hormone-Releasing Hormone (LH-RH) agonist will be used in combination with endocrine therapy whenever appropriate and per label. Chemotherapy in Arm B may consist in single agent chemotherapy, poly-chemotherapy, or antibody-drug conjugates. Patients who are eligible (per drug label) may receive Poly-adenosine-5'-diphosphate-ribose Polymerase (PARP) inhibitor if allocated to Arm B.

Efficacy of a Systematic Referral to Palliative Care of Patients Who Need for Palliative Care During an Unscheduled Visit in Comprehensive Anticancer Centers

This is a randomized, multicenter, prospective, phase III study conducted in daily emergency rooms of French Regional Comprehensive Cancer Centers. All patients undergoing a visit in the daily emergency room of a participating center and who need for palliative management (PALLIA 10 score > 3/10) will be considered for inclusion in the PALLU study. After signing the written informed consent, patients will be randomized (1:1 ratio) in one of the following arms: - Standard arm : conventional strategy; patients will be managed regardless of their PALLIA-10 score. The need for additional care, including palliative care, will be assessed by the team in charge of the patient, as per routine practice. - Experimental arm : experimental strategy; patients will be systematically referred to a palliative care team. Randomization will be stratified according to the investigation center and pre-existing follow-up by pain management team. The difference of intervention will lie in the fact that patients will be referred or not to a palliative care team but patients from the standard arm may receive palliative care as deemed necessary by the medical oncology team. In this case, the content of palliative care for patients included in both groups will be identical. The end of the study will be the Last Patient Last Visit (LPLV), defined as the date of the 12-month visit of the last patient still alive or when the 192nd death has occurred, whichever occurs first.

Tiragolumab, Atezolizumab and Chemotherapy in Triple Negative Breast Cancer

In the early TNBC setting (cohort A) dedicated to patients with newly diagnosed, previously untreated, non-metastatic disease (tumor stage T1c, nodal stage N1-2, or tumor stage T2-4, nodal stage N0-2), the treatment will consist in: First part: Nab-paclitaxel administered weekly in combination with atezolizumab, tiragolumab and carboplatin, administered every 3 weeks over 12 weeks Second part: Atezolizumab, tiragolumab, doxorubicin and cyclophosphamide, administered every 3 weeks over 12 weeks Patients will undergo surgery of the primary disease 3 to 6 weeks after last neoadjuvant treatment dose, followed by 9 cycles of atezolizumab and tiragolumab administered every 3 weeks. Treatment efficacy will be assessed early on, through 18F-FDG PET/CT during the first two cycles. Patients whose tumor shows no sign of response after two cycles (i.e. no partial or complete metabolic response of the breast tumor according to 18F-FDG PET/CT by PERCIST criteria) would then be switched to standard treatment, per investigator decision. Tiragolumab 600 mg and Atezolizumab 1200 mg administered by IV infusion every 3 weeks after surgery for a total of 9 cycles. In the metastatic TNBC setting (cohort B) dedicated to patients with locally recurrent inoperable or metastatic disease eligible to first line treatment, patients will be included regardless of their PD-L1 tumor expression defined by immunohistochemistry (Ventana SP142) at baseline, but no more than 40% of PD-L1 negative (i.e <1%) will be included. The treatment will consist in nab-paclitaxel administered at d1, d8, d15 of every 28-day cycle, combined with atezolizumab and tiragolumab administered every 3 weeks until disease progression or limiting toxicity. Treatments will be administered until disease progression or limiting toxicity. As the the combination Atezolizumab + Tiragolumab + chemotherapy has never been tested, a safety run-in phase of 10 patients is planned in each cohort to verify the tolerance of the combination

Long-term Cognitive and Functional Impact of Proton-therapy or Modern Fractionated Radiotherapy in Cavernous Sinus Meningioma: an Open-label Randomized 1:1 Phase III Study