Cruejouls, France

HEM ISMART-D: Trametinib + Dexamethasone + Chemotherapy in Children with Relapsed or Refractory Hematological Malignancies

HEM-iSMART is a master protocol with sub-protocols. The overarching objective is that introducing targeted therapy using a biomarker driven approach for treatment stratification may improve the outcome of children with R/R acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) It is characterized by a shared framework that allows for the investigation of multiple IMPs and generate pivotal safety and efficacy evidence within the sub-protocols to establish and define the benefits and risks of new treatments for children with R/R leukemia. Sub-Protocol D within HEM-iSMART, is a phase I/II, multicenter, international, open-label clinical trial designed to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of trametinib in combination with dexamethasone, cyclophosphamide and cytarabine in children, adolescents and young with R/R ALL and LBL. Patients with actionable alterations in the RAS-RAF-MAPK pathway will be eligible for sub-protocol D including but not limited to KRAS, NRAS, HRAS, FLT3, PTPN11, MAP2K1, MP2K1 hotspot mutations, cCBL; NF1 del.

A Study to Characterize the Safety, Tolerability, and Preliminary Efficacy of CFT1946 As Monotherapy and Combination Therapy in Subjects with BRAF V600 Mutant Solid Tumors

Study Evaluating the Benefit of Adding Ipilimumab to the Combination of Atezolizumab and Bevacizumab in Patients With Hepatocellular Carcinoma Receiving First-line Systemic Therapy

Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks fourth in terms of cancer-related mortality worldwide . Unfortunately, the diagnosis of HCC is often made late in the cure of the disease when the tumour has spread outside the liver parenchyma as portal vein invasion or distant metastases. In the history of HCC patients, a significant proportion will sooner or later face systemic therapies as they are no longer eligible for radical or locoregional therapies. Cytotoxic chemotherapy and hormonal therapies have never shown significant benefit on overall survival (OS) . The first systemic therapy to show a significant beneficial impact on HCC outcome was the tyrosine kinase inhibitor (TKI) sorafenib, an anti-angiogenic agent (AAA) with anti-proliferative properties on HCC . For nearly a decade, all systemic therapies tested in randomised controlled trials as first-line systemic therapy (1L) head-to-head with sorafenib, or as 2L after sorafenib failure have not shown significant benefit. In 2018, Kudo et al. showed that lenvatinib, another TKI with anti-angiogenic properties, was at least equivalent to sorafenib in 1L in the REFLECT non-inferiority trial [5]. Other AAA TKIs with anti-cancer properties on HCC cells have demonstrated efficacy in 2L: regorafenib after progression on sorafenib in 2017 , and cabozantinib after progression on or intolerance to sorafenib in 2018 . In addition, ramucirumab, a monoclonal antibody targeting VEGFR-2, has shown significant benefit in a specific subpopulation of HCC patients with high baseline alpha-fetoprotein levels ≥ 400 ng/ml . However, all these options were strictly palliative with no long-term survivors and lack of potential recovery. Immuno-oncology (IO) approaches have completely revolutionised the paradigm of systemic HCC therapies with nonetheless a significant increase in median OS in IO-based combination strategies, but also the emergence of the possibility of long-term survivors and, for some patients, hope for a complete response and possibly a final cure.

ELVN-002 in HER2 Mutant Non-Small Cell Lung Cancer

There are 4 parts to the trial. Part 1 is a dose escalation with ELVN-002 monotherapy for people with advanced stage solid tumors that have a HER2 mutation, amplification or high HER2 over-expression. Part 2 is an ELVN-002 monotherapy dose exploration where additional people may be enrolled at dose levels that have cleared the dose escalation in Part 1 to further evaluate the safety, tolerability, pharmacokinetics and clinical activity. Part 3 is a dose expansion of ELVN-002 monotherapy which will enroll up to 40 patients people with advanced stage HER2 mutant non-small cell lung cancer. Patients in Part 3 will be randomized 1:1 to receive one of two dose levels. Part 4 is a combination dose escalation where, based on the results of Part 1 and 2, a combination of ELVN-002 and either fam-trastuzumab deruxtecan-nxki (in HER2 mutant non-small cell lung cancer) or trastuzumab emtansine (in HER2 positive breast cancer) will be evaluated for safety and tolerability.

REVErsing Airway Remodelling With Tezepelumab

Tezepelumab is a human IgG2l monoclonal antibody (mAb) directed against TSLP. Double-blind, randomized controlled trials comparing Tezepelumab treatment against placebo demonstrate net positive benefits in asthma patients. Animal research currently indicates that blocking TSLP can prevent bronchial remodelling in murine models (Chen et al. 2013), but no such observations have been attempted in humans. Within this context, the aim of this protocol is to perform a first randomized controlled trial evaluating how Tezepelumab affects the bronchial morphology (and computed tomographic variables in general) of asthmatic patients. In parallel, the investigators also hope to reproduce clinical benefits and perform a transcriptomic study that will juxtapose changes in genetic expression with changes in bronchial morphology and inflammatory signatures. The general hypothesis is that tezepelumab treatment is capable of at least partially reversing bronchial remodelling as detected on computed-tomographic (CT) scans. The investigators also expect such reversal to occur within a unique physiological repair environment that will be reflected by transcriptomic profiles. The primary objective of this protocol is therefore to compare the change-from-baseline in the average percentage bronchial wall area (%WA = (wall area (mm2)/ (wall area (mm2) + lumen area (mm2)))×100) for patients with asthma and undergoing 6 months of tezepelumab treatment with a similar population treated via placebo. Secondarily, continued treatment effects associated with longer treatment (12 months) or remanence after treatment stopping at 6 months will also be quantified. Study arms will additionally be compared in terms of: - Changes in radiomics (CT-scan data); - Changes in exacerbation rates and lung function; - Changes in serum club cell secretory protein (CCSP); - Changes in nasal single-cell transcriptomic signatures. This study also has an exploratory component designed to characterize the physiological repair environment. In depth radiomic and transcriptomic (including single-cell analyses) profiling will be performed. Finally, the capacity of baseline data to predict the response to tezepelumab will also be explored.

GastrOesophageal Tumor, Immune Microenvionnment (GOTIM)

Clinical Study of Antibody-Drug Conjugate MYTX-011 in Subjects With Non-Small Cell Lung Cancer

The study will be conducted in 2 parts. Part 1 will assess the safety and tolerability of MYTX-011 and identify the dose to be studied in Part 2. Part 2 will include subjects with NSCLC with cMET overexpression or MET amplification/exon 14 skipping mutations, populations with a current unmet medical need.

Digital Phenotyping in Women Over 70 Years of Age Treated for Breast Cancer With Any Type of Treatment

BACKGROUND: In metropolitan France in 2017, 58,968 new cases of breast cancer (BC) were estimated, of which 25,283 (46.7%) involved women older than 65 years. Older patients with cancer often present complex health needs, in particular because of the burden of comorbidities combined with the effects of aging, the cancer and its treatments. GrannyFit aims to use an activity tracker to identify and describe various digital profiles (physical activity, sleep) in women over 70 years of age treated de novo or recurrent (local or distant) BC. METHODS: GrannyFit is a prospective, national, multicenter, single-arm open-label study. It will include a total of 200 participants over the age of 70 years treated for de novo or recurrent (local or distant) BC. Participants will receive a Withing Steel activity tracker, which they will be asked to wear 24 h per day for 12 months. The principal assessments will be performed at baseline, at 6 months and at 12 months. The investigators will evaluate clinical (e.g. comorbidities), lifestyle, quality of life, fatigue, and physical activity parameters. All questionnaires will be completed on a REDCap form, via a secure internet link. DISCUSSION: GrannyFit will make it possible, through the use of an activity tracker, to visualize changes, over a one-year period, in the lifestyle of older BC patients. This study identify more precisely the unmets needs of this population and optimize their care through specific paths. This trial will also pave the way for interventional studies on physical activity and sleep interventions in this population.

A Study of NVL-520 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1)

In Phase 2, study patients will be enrolled into 5 distinct expansion cohorts: - Cohort 2a: ROS1-positive NSCLC naïve to Tyrosine Kinase Inhibitor (TKI) therapy and up to 1 prior chemotherapy and/or immunotherapy. - Cohort 2b: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy. - Cohort 2c: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy. - Cohort 2d: ROS1-positive NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy. - Cohort 2e: ROS1-positive solid tumor and progressed on any prior therapy.