Immunotherapy combined with low-dose chemotherapy in paediatric cancer
Phase 2 trial evaluating anti-PD1 (Nivolumab) in combination with metronomic chemotherapy in children and teenagers with refractory/relapsing solid tumours or lymphoma (Metro-PD1).
- Solid tumour
- Paediatric cancer
Why this trial?
Solid tumours represent about 30% of all paediatric cancers. Some examples of solid tumours that occur in children but never develop in adults are neuroblastoma, osteosarcoma and retinoblastoma. Most children with solid tumours achieve a 5-year tumour-free survival, but 30% suffer from recurrent or refractory solid tumours.
Controlling recurrent and refractory tumours is challenging because of the high failure rate of traditional treatment regimens, including chemotherapy, surgery and radiotherapy. There is a high need to establish new treatment options to raise the 20% survival rate of children with recurrent or refractory solid tumours.
Why this drug?
Compared to conventional high-dose chemotherapy, metronomic chemotherapy (MC) includes lower doses of chemotherapy that are given more frequently. Three examples of drugs that can be given in a metronomic regimen are cyclophosphamide, capecitabine and vinblastine.
Cyclophosphamide has shown to enhance anti-tumour immune responses by depleting Treg cells or disrupting their functions. Capecitabine has indicated to reduce the number of myeloid-derived suppressor cells (MDSC), which inhibit the anticancer activity of the immune system. Vinblastine induces dendritic cell (DC) maturation, stimulating a strong anti-tumour immune response. The combination of these metronomic anticancer agents strengthens the re-establishment of the anti-tumour effect of the immune system by targeting different cellular actors of the immune system.
Nivolumab is a programmed death 1 monoclonal antibody (anti-PD1) which works as an immune checkpoint inhibitor. It prevents activated T-cells from attacking the cancer, thus allowing the immune system to clear the cancer cells.
Very limited preclinical and clinical data about the combination of anti-PD1 and metronomic chemotherapy is reported so far, even though this combination suggests a synergic anticancer effect.
This is a phase II, multi-centric, prospective open-label, multi-arm trial in patients 4-18 years old diagnosed with recurrent or refractory solid tumours and lymphoma that have progressed despite standard therapy, or for which no effective standard therapy exists. 96 patients will be recruited by 8 French CLIP² centres.
In the first stage, the most feasible and safe metronomic chemotherapy out of three regimens (cyclophosphamide + vinblastine or capecitabine or cyclophosphamide + vinblastine + capecitabine), given in combination with nivolumab, will be identified.
In the second stage, the efficacy of nivolumab in terms of progression-free survival, when given in combination with the metronomic chemotherapy regimen retained after the first stage, will be evaluated. The toxicity and safety of the combination will also be determined. The duration of the treatment will be 2 years or up to progression or unacceptable toxicity.
- Dr. Pierre Leblond, Peadiatrics Dept., Centre Oscar Lambret, Lille, France (Coordinating Investigator)
- Dr. Nicolas André, Hôpital pour Enfants de “La Timone” AP-HM, Marseille, France (Sub Investigator)
- Centre Oscar Lambret, Lille, France
ACF co-funding partners:
- Alexine Clarysse Fund
André N, and al. Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol. 2014; 11: 413-31.
Annels NE and al. The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer. Cancer Immunol Immunother. 2014;63:175-83.
Melero I, and al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15:457-72.
Otsubo D and al. Early-phase Treatment by Low-dose 5-Fluorouracil or Primary Tumor Resection Inhibits MDSC-mediated Lung Metastasis Formation. Anticancer Res. 2015 ;35:4425-31.
Vincent J et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010;70:3052-61.