<p>Figure S3: Forest plots for DFS comparing patients with central Ki-67 high versus low based on quartile cutoffs (exploratory analysis) in (A) ER-positive/HER2-negative breast cancer (n=824) and (B) TNBC (n=454)</p>
BackgroundWe conducted a phase I study to estimate the maximum tolerated dose and describe the dose-limiting toxicities and pharmacokinetics of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy to children with newly diagnosed brainstem or high-grade gliomas.
Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab.Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors.A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration.Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D.
The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children.Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy.Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials.CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success.The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies.Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies.The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.
Background: MF is a serious, life‐threatening MPN characterized by bone marrow fibrosis, splenomegaly, cytopenias, and poor survival. RUX is the only approved treatment (Tx) for Intermediate (Int) or High‐risk MF. FEDR is an oral, selective inhibitor of wild‐type and mutant JAK2 . The published JAKARTA‐2 study demonstrated ≥35% spleen volume reduction (SVR) in 55% of efficacy eligible FEDR‐treated patients (pts) who were resistant or intolerant to RUX per investigator assessment, using a last‐observation‐carried‐forward (LOCF) analysis method. Aims: To confirm the efficacy of FEDR in the JAKARTA‐2 study by employing ITT principles and a more stringent definition of RUX failure than used in the previous analysis ( Fig. A ). The primary endpoint was re‐analyzed in a subset of JAKARTA‐2 pts who were relapsed/refractory (R/R) or intolerant to RUX per the more stringent definition (RUX Failure cohort). Additionally, a sensitivity analysis was performed on a subset of pts in the RUX Failure cohort who had received 6 cycles of FEDR or who had discontinued FEDR before end of cycle 6 (EOC6) for reasons other than study halted by sponsor (Sensitivity cohort). Methods: Pts previously treated with RUX with Int‐ or High‐risk primary, post‐polycythemia vera (PV), or post‐essential thrombocythemia (ET) MF, spleen size ≥5 cm below the costal margin, ECOG PS ≤2, and platelet counts ≥50 × 10 9 /L were enrolled. Pts received a FEDR starting dose of 400 mg QD in continuous 28‐day cycles. The primary endpoint was spleen volume response rate (SVRR): ≥35% SVR from baseline (BL) at EOC6, per blinded central review. A key secondary endpoint was symptom RR (≥50% decrease in total symptom score [TSS] from BL on the MF Symptom Assessment Form [MFSAF]) at EOC6. Results: Of 97 pts enrolled and treated with FEDR, the RUX Failure cohort comprised 79 pts (81%) who met more stringent criteria for RUX R/R (n = 65, 82%) or intolerance (n = 14, 18%). Demographics, baseline disease characteristics, and prior RUX Tx were generally similar between the ITT population and both the RUX Failure and Sensitivity cohorts. In the RUX Failure cohort, median age was 66 yrs (range 38–83), 60% of pts had primary MF, 23% post‐PV MF, and 18% post‐ET MF. Median BL spleen volume was 2946 mL and median spleen size was 18.0 cm (range 5–36). Median prior RUX Tx duration was 11.5 months (range 1.0–62.4). Median number of FEDR cycles received was 7 (range 1–20). SVRR in the RUX Failure cohort was 30% (95%CI 21, 42), markedly consistent with results observed in the ITT population [31% (95%CI 21, 41)]. All pts with BL and EOC6 data (n = 41) showed SVR ( Fig. B ). At EOC6, symptom RR was 27% (95%CI 17, 39); 36/44 evaluable pts (82%) had TSS improvements ( Fig. C ). 66 pts met criteria for the Sensitivity cohort; SVRR was 36% (95%CI, 25, 49) and symptom RR was 32% (95%CI 21, 45). Most common grade ≥3 hematologic TEAEs were anemia (44%) and thrombocytopenia (20%), and grade ≥3 nonhematologic TEAEs were increased lipase (6%), and diarrhea and ALT increase (4% each). TEAEs led to discontinuation for 20% of pts and to dose interruption/reduction for 51% of pts. Six pts died on‐study; no death was considered Tx‐related. Summary/Conclusion: FEDR provided clinically meaningful reductions in splenomegaly and symptom burden in pts with MF for whom RUX had failed. Importantly, data were markedly similar in a cohort of pts who met stringent criteria for prior RUX failure, and efficacy was confirmed in the sensitivity analysis. Safety in this heavily pretreated population with advanced disease was consistent with prior reports. image
