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Phase I Multicenter Trial Combining Nivolumab, Ipilimumab and Hypo-fractionated Radiotherapy for Pretreated Advanced Stage Non-small Cell Lung Cancer Patients

NCT03509584 · Status: TERMINATED · Phase: PHASE1 · Type: INTERVENTIONAL · Enrollment: 6

Last updated 2023-06-15

No results posted yet for this study

Summary

Nivolumab is superior to docetaxel monotherapy as second line treatment in advanced stage non-small cell lung cancer (NSCLC) patients. However, the long term survival advantage seems to be limited to a 20% proportion of treated patients. To date, no definitive biomarker, including tumor cells or infiltrative cells PD-L1 expression, has been demonstrated to predict nivolumab (or other PD1 or PD-L1 inhibitors) efficacy. Ipilimumab has also suggested efficacy in the same patient population. Finally, the addition of ipilimumab to nivolumab has a suggested better efficacy over nivolumab alone in advanced stage NSCLC patients with an acceptable safety profile.

In parallel, hypo-fractionated radiotherapy alone has been suggested to elicit the immune system activity as demonstrated by the occurrence of an abscopal effect. Some case reports in melanoma but also lung cancer patients reinforced this hypothesis.

Furthermore, preclinical and clinical data suggest that radiation may have a synergistic effect with antibodies targeting the immune checkpoints (PD1, PD-L1, CTLA4) and improve antitumor efficacy. Moreover, it has been shown that fractionated radiotherapy delivered in combination with aPD-1 or aPD-L1 mAbs is able to generate efficacious CD8þ T-cell responses that will in turn improve local tumor control, long-term survival, and protection against tumor rechallenge.

Therefore, the combination of single fraction or hypo-fractionated radiotherapy with the anti PD1 nivolumab and/or the anti CTLA4 ipilimumab warrants further investigation. However, a large number of doses, sequences and schedules remain possible. In order to select the best combination, a mathematical modeling of immunotherapy in cancer and its synergy with radiotherapy has been set up. This work provides with mathematical formulas to link the drug serum concentrations of nivolumab and ipilimumab, and the dose of radiation therapy, to the immune response. In silico, the single and three fractions schedule have been found to have the same efficacy while activation of the immune response seems to be better using a hypo-fractionated (less than 6 fractions) radiotherapy in vivo.

Conditions

Interventions

RADIATION

hypofractionated radiotherapy

Stereotactic hypo-fractionated irradiation (3 x 8 Gys) radiotherapy fraction

DRUG

nivolumab

administration of nivolumab

DRUG

Ipilimumab

administration of ipilimumab

Sponsors & Collaborators

  • Assistance Publique Hopitaux De Marseille

    lead OTHER

Principal Investigators

  • Urielle Desalbres · Assistance Publique Hôpitaux de Marseille

Study Design

Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Model
PARALLEL

Eligibility

Min Age
18 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2018-06-07
Primary Completion
2019-07-02
Completion
2019-07-02

Countries

  • France

Study Locations

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Entities

Drugs
Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT03509584 on ClinicalTrials.gov