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Immunotherapy combined with low-dose chemotherapy in paediatric cancer

Phase I/II trial evaluating anti-PD1 (Nivolumab) in combination with metronomic chemotherapy in children and teenagers with refractory/relapsing solid tumours or lymphoma (Metro-PD1).

Ongoing, not recruiting
Cancer types
Solid tumours
Trial phase


€ 230,000
ACF donation
€ 438,000
Estimated trial cost

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 intervention

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.

Trial design

This is a phase I/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. 102 patients will be recruited.

In the first stage, which was completed in November 2020, the combination of three metronomic chemotherapies (cyclophosphamide + vinblastine + capecitabine) with nivolumab was tested in a stepwise approach and deemed feasible and safe.

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, Centre Léon Bérard CLB-IHOPe, Lyon, France (Coordinating Investigator)
  • Dr. Nicolas André, Hôpital pour Enfants de “La Timone” AP-HM, Marseille, France (Sub Investigator)
  • Dr. Leen Willems, UZ Gent (Sub Investigator)


  • Centre Oscar Lambret, Lille, France

ACF co-funding partners:

  • KiCa Fund, managed by the King Baudouin Foundation, and KickCancer
  • Alexine Clarysse Fund

Our role

Consortium building
Financial support

Why we support this trial

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Expected survival benefit

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Use in a population with high unmet needs

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€ 230,000
ACF donation
€ 438,000
Estimated trial cost

Questions about participation?

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Questions about this trial?

The Anticancer Fund
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More info: NCT03585465

André, N., et al. (2014). Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol., 11(7), 413-31. doi:10.1038/nrclinonc.2014.89.

Annels, N.E., et al. (2014). 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., 63(2), 175-83. doi:10.1007/s00262-013-1502-y

Melero, I., et al. (2015). Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer, 15(8), 457-72. doi:10.1038/nrc3973

Otsubo, D., et al. (2015). Early-phase Treatment by Low-dose 5-Fluorouracil or Primary Tumor Resection Inhibits MDSC-mediated Lung Metastasis Formation. Anticancer Research, 35(8), 4425-31.

Vincent, J., et al. (2010). 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Research, 70(8), 3052-61. doi:10.1158/0008-5472.CAN-09-3690

Author: Kristine Beckers (Trial Manager)

Last updated: January 2020