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1.
Clin Cancer Res ; 30(4): 741-753, 2024 02 16.
Article in English | MEDLINE | ID: mdl-38051741

ABSTRACT

PURPOSE: AcSé-ESMART Arm C aimed to define the recommended dose and activity of the WEE1 inhibitor adavosertib in combination with carboplatin in children and young adults with molecularly enriched recurrent/refractory malignancies. PATIENTS AND METHODS: Adavosertib was administered orally, twice every day on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle, starting at 100 mg/m2/dose and AUC 5, respectively. Patients were enriched for molecular alterations in cell cycle and/or homologous recombination (HR). RESULTS: Twenty patients (median age: 14.0 years; range: 3.4-23.5) were included; 18 received 69 treatment cycles. Dose-limiting toxicities were prolonged grade 4 neutropenia and grade 3/4 thrombocytopenia requiring transfusions, leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4; no recommended phase II dose was defined. Main treatment-related toxicities were hematologic and gastrointestinal. Adavosertib exposure in children was equivalent to that in adults; both doses achieved the cell kill target. Overall response rate was 11% (95% confidence interval, 0.0-25.6) with partial responses in 2 patients with neuroblastoma. One patient with medulloblastoma experienced unconfirmed partial response and 5 patients had stable disease beyond four cycles. Seven of these eight patients with clinical benefit had alterations in HR, replication stress, and/or RAS pathway genes with or without TP53 alterations, whereas TP53 pathway alterations alone (8/10) or no relevant alterations (2/10) were present in the 10 patients without benefit. CONCLUSIONS: Adavosertib-carboplatin combination exhibited significant hematologic toxicity. Activity signals and identified potential biomarkers suggest further studies with less hematotoxic DNA-damaging therapy in molecularly enriched pediatric cancers.


Subject(s)
Arm , Carcinoma , Pyrazoles , Pyrimidinones , Child , Young Adult , Humans , Adolescent , Carboplatin/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Protein-Tyrosine Kinases , Cell Cycle Proteins
2.
Eur J Cancer ; 157: 268-277, 2021 11.
Article in English | MEDLINE | ID: mdl-34543871

ABSTRACT

AIM: Arms E and F of the AcSé-ESMART phase I/II platform trial aimed to define the recommended dose and preliminary activity of the dual mTORC1/2 inhibitor vistusertib as monotherapy and with topotecan-temozolomide in a molecularly enriched population of paediatric patients with relapsed/refractory malignancies. In addition, we evaluated genetic phosphatidylinositol 3-kinase (PI3K)/AKT/ mammalian (or mechanistic) target of rapamycin (mTOR) pathway alterations across the Molecular Profiling for Paediatric and Young Adult Cancer Treatment Stratification (MAPPYACTS) trial (NCT02613962). EXPERIMENTAL DESIGN AND RESULTS: Four patients were treated in arm E and 10 in arm F with a median age of 14.3 years. Main diagnoses were glioma and sarcoma. Dose escalation was performed as per the continuous reassessment method, expansion in an Ensign design. The vistusertib single agent administered at 75 mg/m2 twice a day (BID) on 2 days/week and vistusertib 30 mg/m2 BID on 3 days/week combined with temozolomide 100 mg/m2/day and topotecan 0.50 mg/m2/day on the first 5 days of each 4-week cycle were safe. Treatment was well tolerated with the main toxicity being haematological. Pharmacokinetics indicates equivalent exposure in children compared with adults. Neither tumour response nor prolonged stabilisation was observed, including in the 12 patients whose tumours exhibited PI3K/AKT/mTOR pathway alterations. Advanced profiling across relapsed/refractory paediatric cancers of the MAPPYACTS cohort shows genetic alterations associated with this pathway in 28.0% of patients, with 10.5% carrying mutations in the core pathway genes. CONCLUSIONS: Vistusertib was well tolerated in paediatric patients. Study arms were terminated because of the absence of tumour responses and insufficient target engagement of vistusertib observed in adult trials. Targeting the PI3K/AKT/mTOR pathway remains a therapeutic avenue to be explored in paediatric patients. CLINICAL TRIAL IDENTIFIER: NCT2813135.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Benzamides/administration & dosage , Morpholines/administration & dosage , Neoplasms/drug therapy , Pyrimidines/administration & dosage , Administration, Oral , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzamides/adverse effects , Child , Child, Preschool , Female , Gain of Function Mutation , Humans , Male , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors , Mechanistic Target of Rapamycin Complex 2/genetics , Morpholines/adverse effects , Neoplasm Staging , Neoplasms/diagnosis , Neoplasms/genetics , Pyrimidines/adverse effects , Temozolomide/administration & dosage , Temozolomide/adverse effects , Topotecan/administration & dosage , Topotecan/adverse effects , Treatment Outcome , Young Adult
3.
J Clin Oncol ; 39(32): 3546-3560, 2021 11 10.
Article in English | MEDLINE | ID: mdl-34347542

ABSTRACT

PURPOSE: AcSé-ESMART is a proof-of-concept, phase I or II, platform trial, designed to explore targeted agents in a molecularly enriched cancer population. Arms A and B aimed to define the recommended phase II dose and activity of the CDK4/6 inhibitor ribociclib with topotecan and temozolomide (TOTEM) or everolimus, respectively, in children with recurrent or refractory malignancies. PATIENTS AND METHODS: Ribociclib was administered orally once daily for 16 days after TOTEM for 5 days (arm A) or for 21 days with everolimus orally once daily continuously in a 28-day cycle (arm B). Dose escalation followed the continuous reassessment method, and activity assessment the Ensign design. Arms were enriched on the basis of molecular alterations in the cell cycle or PI3K/AKT/mTOR pathways. RESULTS: Thirty-two patients were included, 14 in arm A and 18 in arm B, and 31 were treated. Fourteen patients had sarcomas (43.8%), and 13 brain tumors (40.6%). Main toxicities were leukopenia, neutropenia, and lymphopenia. The recommended phase II dose was ribociclib 260 mg/m2 once a day, temozolomide 100 mg/m2 once a day, and topotecan 0.5 mg/m2 once a day (arm A) and ribociclib 175 mg/m2 once a day and everolimus 2.5 mg/m2 once a day (arm B). Pharmacokinetic analyses confirmed the drug-drug interaction of ribociclib on everolimus exposure. Two patients (14.3%) had stable disease as best response in arm A, and seven (41.2%) in arm B, including one patient with T-acute lymphoblastic leukemia with significant blast count reduction. Alterations considered for enrichment were present in 25 patients (81%) and in eight of nine patients with stable disease; the leukemia exhibited CDKN2A/B and PTEN deficiency. CONCLUSION: Ribociclib in combination with TOTEM or everolimus was well-tolerated. The observed activity signals initiated a follow-up study of the ribociclib-everolimus combination in a population enriched with molecular alterations within both pathways.


Subject(s)
Aminopyridines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Everolimus/therapeutic use , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Purines/therapeutic use , Temozolomide/therapeutic use , Topotecan/therapeutic use , Adolescent , Age Factors , Aminopyridines/adverse effects , Aminopyridines/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Child , Child, Preschool , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/genetics , Cyclin-Dependent Kinase 6/metabolism , Everolimus/adverse effects , Everolimus/pharmacokinetics , Female , Humans , Infant , Male , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/pathology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Purines/adverse effects , Purines/pharmacokinetics , Temozolomide/adverse effects , Temozolomide/pharmacokinetics , Time Factors , Topotecan/adverse effects , Topotecan/pharmacokinetics , Treatment Outcome
4.
Eur J Cancer ; 150: 53-62, 2021 06.
Article in English | MEDLINE | ID: mdl-33892407

ABSTRACT

PURPOSE: AcSé-ESMART is a European multicentre, proof-of-concept multiarm phase I/II platform trial in paediatric patients with relapsed/refractory cancer. Arm G assessed the activity and safety of nivolumab in combination with metronomic cyclophosphamide +/- irradiation. EXPERIMENTAL DESIGN: Following a Phase II Simon two-stage design, nivolumab was administered intravenously at 3 mg/kg every 2 weeks of a 28-day cycle, oral cyclophosphamide at 25 mg/m2 twice a day, 1 week on/1 week off. The primary endpoint was objective response rate. Irradiation/radioablation of primary tumour or metastasis could be administered as per physician's choice. Biomarker evaluation was performed by tumour immunohistochemistry, whole exome and RNA sequencing, and immunophenotyping of peripheral blood by flow cytometry. RESULTS: Thirteen patients were treated with a median age of 15 years (range: 5.5-19.4). The main histologies were high-grade glioma, neuroblastoma, and desmoplastic small round cell tumour (DSRCT). The safety profile was similar to those of single-agent nivolumab, albeit haematologic toxicity, mainly lymphocytopenia, was commonly reported with the addition of cyclophosphamide +/- irradiation. Two patients with DSRCT and ependymoma presented unconfirmed partial response and prolonged disease stabilisation. Low mutational load with modest intratumour CD3+ T-cell infiltration and immunosuppressive tumour microenvironment were observed in the tumour samples. Under combined treatment, no positive modulation of circulating T cells was displayed, while derived neutrophil-to-lymphocyte ratio increased. CONCLUSIONS: Nivolumab in combination with cyclophosphamide was well tolerated but had limited activity in this paediatric setting. Metronomic cyclophosphamide did not modulate systemic immune response that could compensate limited T-cell infiltration and the immunosuppressive tumour microenvironment. CLINICALTRIALS. GOV IDENTIFIER: NCT2813135.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , B7-H1 Antigen/antagonists & inhibitors , Biomarkers, Tumor/analysis , Cyclophosphamide/administration & dosage , Immune Checkpoint Inhibitors/administration & dosage , Lymphocytes, Tumor-Infiltrating/drug effects , Neoplasms/drug therapy , Nivolumab/administration & dosage , Tumor-Associated Macrophages/drug effects , Administration, Metronomic , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen/analysis , Biomarkers, Tumor/genetics , Child , Child, Preschool , Cyclophosphamide/adverse effects , Europe , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Lymphocytes, Tumor-Infiltrating/immunology , Male , Mutation , Neoplasms/genetics , Neoplasms/immunology , Nivolumab/adverse effects , Proof of Concept Study , Time Factors , Treatment Outcome , Tumor Microenvironment , Tumor-Associated Macrophages/immunology , Young Adult
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