Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Docetaxel

Durvalumab

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

1500 mg, every 4 weeks. CxD1 for each cycle, 1 cycle = 28 days

EXCEPT FOR CYCLE 1 IN ARM C : at C1D8 and cycle 1 = 35 days

c=cycle D= day

Durvalumab (MEDI4736)

1500 mg, every 4 weeks. CXD1 for each cycle, 1 cycle = 28 days

c=cycle D= day

Monalizumab (IPH2201)

3000 mg every 2 week x 4 doses, followed by 3000 mg every 4 weeks. C1D1, C1D15, C2D1, C2D15 and CXD1 for the orther cycles, 1 cycle = 28 days.

c=cycle D= day

Oleclumab (MEDI9447)

240 mg bid in Cycle 1, Days 1-7, followed by 7 days on treatment in each cycle between Days 22 and 28.

CxD22-D28 for each cycle, 1 cycle = 28 days EXCEPT FOR CYCLE 1 : at C1D1,C1D29 and cycle 1 = 35 days

c=cycle D= day

Ceralasertib (AZD6738)

75 mg/m2, every 3 weeks. CxD1 for each cycle, 1 cycle = 21 days

c=cycle D= day

DOCETAXEL

Savolitinib

jean-olivier ARNAUD

Research Hypothesis Lung cancer is the leading cause of cancer-related mortality in France and in western countries, accounting for more than 1.8 million new cases and 1.5 million deaths worldwide in 2012. Recent advances in the management of patients with Non-small Cell Lung Cancer Patients (NSCLC) include the use of therapies targeting oncogenes but a molecular alteration is currently found in only the half of the non-squamous NSCLC . More recently, immune check point inhibitors (ICI), firstly targeting PD-(L)1, became available and demonstrate an overall survival advantage over standard second-line chemotherapy both in squamous and non-squamous NSCLC. Unfortunately, this global overall survival benefit is driven by approximately 20% of the patient's population while a large majority of patients is in fact progressing in the first weeks of treatment.

In the context of personalized medicine, innovative immunotherapy strategies in oncology are based on the principle of immune-contexture and require:

* The identification of biomarkers for assessing the specific immune-contexture of each patient (microenvironment, tumors and effector cells)
* The development of new treatments targeting their appropriate effector cells in monotherapy or combination treatments.

The current PIONEER-Clinical study is aimed at assessing how to overcome resistance to ICIs monotherapies or ICI in combination with platinum-based chemotherapies, with experimental precision immunotherapies combined to Durvalumab in 2nd, 3rd or 4th line, in advanced NSCLC progressors patients after up to 18more than 6 w. of anti PD (L) 1. for ICIs monotherapies and after more than 12w. of anti PD(L)1 in combination with chemotherapies.

Some supplementary blood and tissue samples are aimed at identification of personalized patients' biomarkers, correlation of them with the efficacy endpoints, in order to better understand mechanisms of resistance and improve their future treatment.

Study Design:

During a mandatory post treatment 28-day wash-out period, 135 advanced NSCLC patients with progressive disease evaluated between 6 and 18w. of a second or third line ICI monotherapy; will undergo a screening visit. After signing an informed written consent, if they are found eligible, their participation in the study will ensue.

Treatment allocation will be performed using the randomization module of the eCRF, :

* Arm A: combination of Durvalumab (MEDI4736) + Monalizumab (IPH2201), to target a PD-L1 co-inhibitory pathway
* Arm B: combination of Durvalumab + oleclumab (MEDI9447), to target limitations of antitumor T-cell immunity caused by adenosine receptor signaling (inclusions closed on May 10, 2021)
* Arm C: combination of Durvalumab + AZD6738, to potentially enhance anti- tumour T-cell responses
* Arm D: a standard third or forth-line chemotherapy maintenance (Docetaxel)
* Arm E : combination of Durvalumab + MET kinase inhibitor Savolitinib (AZD6094)

A maximum of 120 patients will be randomized, with 30 patients per arm (4 arms).

Arm A: combination of Durvalumab + NKG2A inhibitor Monalizumab (IPH2201), to target a PD-L1 co-inhibitory pathway

* Arm B: combination of Durvalumab + CD73 antibody MEDI9447, to target limitations of antitumor T-cell immunity caused by adenosine receptor signaling
* Arm C: combination of Durvalumab + ATR inhibitor AZD6738, to potentially enhance anti- tumour T-cell responses
* Arm D: a standard third or forth-line chemotherapy maintenance (Docetaxel).
* Arm E : combination of Durvalumab + MET kinase inhibitor Savolitinib (AZD6094)

Precision Immuno-Oncology for Advanced Non-small Cell Lung Cancer Patients With PD-1 ICI Resistance

Precision Immuno-Oncology for Advanced Non-small Cell Lung Cancer Patients With PD-1 ICI Resistance (PIONeeR Clinical Study)

the proportion of patients with complete response (CR) or partial response (PR) as best overall response over the treatment period.

the date of randomization until the date of event defined as the first documented progression or death from any cause.

measured from the date of randomization to the date of death from any cause

measured in to patients whose Best overall response is either CR or PR. It will be measured from the time of first documented response (CR or PR) until the first documented disease progression or death due to underlying cancer.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Precision Immuno-Oncology for Advanced Non-small Cell Lung Cancer Patients With PD-1 ICI Resistance	NCT03833440	Non-small Cell ...	Durvalumab (MED... Monalizumab (IP... Oleclumab (MEDI... Ceralasertib (A... DOCETAXEL Savolitinib	18 Years -	Assistance Publique Hopitaux De Marseille
Precision Immuno-Oncology for Advanced Non-small Cell Lung Cancer Patients With PD-1 ICI Resistance	NCT03833440	Non-small Cell ...	Durvalumab (MED... Monalizumab (IP... Oleclumab (MEDI... Ceralasertib (A... DOCETAXEL Savolitinib	18 Years -	Assistance Publique Hopitaux De Marseille
Precision Immuno-Oncology for Advanced Non-small Cell Lung Cancer Patients With PD-1 ICI Resistance	NCT03833440	Non-small Cell ...	Durvalumab (MED... Monalizumab (IP... Oleclumab (MEDI... Ceralasertib (A... DOCETAXEL Savolitinib	18 Years -	Assistance Publique Hopitaux De Marseille

Spots Global Cancer Trial Database for monalizumab (iph2201)