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

NCT ID: NCT03509584

Last Updated: 2023-06-15

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-07
• Study Completion Date: 2019-07-02

Brief 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

Non-small Cell Lung Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

part #1a

non-small cell lung cancer (NSCLC) patients with bone metatase(s) eligible for localized hypo-fractionated radiotherapy

Group Type: EXPERIMENTAL

hypofractionated radiotherapy

Intervention Type: RADIATION

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

nivolumab

Intervention Type: DRUG

administration of nivolumab

part #1b

non-small cell lung cancer (NSCLC) patients with bone metatase(s) eligible for localized hypo-fractionated radiotherapy

Group Type: EXPERIMENTAL

hypofractionated radiotherapy

Intervention Type: RADIATION

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

nivolumab

Intervention Type: DRUG

administration of nivolumab

Ipilimumab

Intervention Type: DRUG

administration of ipilimumab

part #2a

NSCLC patients eligible for a localized radiotherapy of one target lesion (outside the brain)

Group Type: EXPERIMENTAL

hypofractionated radiotherapy

Intervention Type: RADIATION

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

nivolumab

Intervention Type: DRUG

administration of nivolumab

part #2b

NSCLC patients eligible for a localized radiotherapy of one target lesion (outside the brain)

Group Type: EXPERIMENTAL

hypofractionated radiotherapy

Intervention Type: RADIATION

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

nivolumab

Intervention Type: DRUG

administration of nivolumab

Ipilimumab

Intervention Type: DRUG

administration of ipilimumab

Interventions

hypofractionated radiotherapy

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

Intervention Type: RADIATION

nivolumab

administration of nivolumab

Intervention Type: DRUG

Ipilimumab

administration of ipilimumab

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Advanced NSCLC
• One site of measureable disease by RECIST 1.1
• Eligible for localized palliative radiotherapy of a bone lesion as per current national and international recommendations (part #1) or
• Ability to tolerate hypo-fractionated radiotherapy of a tumoral lesion chosen according to the lower risk of radiation adverse event (lymph node > subcutaneous > liver > bone > lung) (part #2)
• Received at least one prior line of therapy for incurable or metastatic NSCLC
• Disease progression at study entry

Exclusion Criteria

• Received systemic anticancer therapy within the previous 21 days
• Human immunodeficiency virus (HIV), hepatitis B or C, or severe/uncontrolled infections or concurrent illness, unrelated to the tumor, requiring active therapy
• Any condition requiring concurrent systemic immunosuppressive therapy
• Known immunodeficiency disorders, either primary or acquired
• Bone lesion with indication of surgery (part #1) ; especially in case of spinal compression.
• Known leptomeningeal disease
• Active malignancies within 12 months with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome
• Prior treatment with immune checkpoints inhibitors
• Administration of a live, attenuated vaccine within 30 days prior to first dose of study drug
• Long-term use of systemic corticosteroids (unless to a dose of 20mg of methylprednisolone)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique Hopitaux De Marseille

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Urielle Desalbres

Role: STUDY_DIRECTOR

Assistance Publique Hôpitaux de Marseille

Locations

Assistance Publique Hôpitaux de Marseille

Marseille, , France

Countries

France

Other Identifiers

2017-001198-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2017-21

Identifier Type: -

Identifier Source: org_study_id