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

Study Overview
=================
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.

Official Title
-----------------
Phase I Multicenter Trial Combining Nivolumab, Alone or With Ipilimumab, Plus Hypo-fractionated Radiotherapy for Pretreated Advanced Stage Non-small Cell Lung Cancer Patients

Conditions
-----------------
Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Radiation: hypofractionated radiotherapy
* Drug: nivolumab
* Drug: Ipilimumab


Participation Criteria
=================
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: part #1a<br>non-small cell lung cancer (NSCLC) patients with bone metatase(s) eligible for localized hypo-fractionated radiotherapy | Radiation: hypofractionated radiotherapy<br>* Stereotactic hypo-fractionated irradiation (3 x 8 Gys) radiotherapy fraction<br>Drug: nivolumab<br>* administration of nivolumab<br>|
| Experimental: part #1b<br>non-small cell lung cancer (NSCLC) patients with bone metatase(s) eligible for localized hypo-fractionated radiotherapy | Radiation: hypofractionated radiotherapy<br>* Stereotactic hypo-fractionated irradiation (3 x 8 Gys) radiotherapy fraction<br>Drug: nivolumab<br>* administration of nivolumab<br>Drug: Ipilimumab<br>* administration of ipilimumab<br>|
| Experimental: part #2a<br>NSCLC patients eligible for a localized radiotherapy of one target lesion (outside the brain) | Radiation: hypofractionated radiotherapy<br>* Stereotactic hypo-fractionated irradiation (3 x 8 Gys) radiotherapy fraction<br>Drug: nivolumab<br>* administration of nivolumab<br>|
| Experimental: part #2b<br>NSCLC patients eligible for a localized radiotherapy of one target lesion (outside the brain) | Radiation: hypofractionated radiotherapy<br>* Stereotactic hypo-fractionated irradiation (3 x 8 Gys) radiotherapy fraction<br>Drug: nivolumab<br>* administration of nivolumab<br>Drug: Ipilimumab<br>* administration of ipilimumab<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of immune related adverse events | evaluate the safety of the combination of the radiotherapy plus nivolumab alone or in combination with ipilimumab, by physical examinations | 48 weeks |