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

NCT03833440 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: 2018-212018-000914-39
• Study Type: interventional
• Target: 114
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Non-small Cell Lung Cancer

Outcome Measures

Primary Outcomes (1)

• the 12-week Disease Control Rate

  in each arm of treatment

  12 weeks

Secondary Outcomes (5)

• Overall Response Rate

  12 months

• Progression-free survival (PFS)

  12 months

• PFS Ratio

  12 months

• Overall Survival (OS)

  6 months

• Duration of Response

  4years

Study Arms (5)

Durvalumab + Monalizumab

EXPERIMENTAL

Drug: Durvalumab (MEDI4736); Drug: Monalizumab (IPH2201)

Durvalumab + MEDI9447

EXPERIMENTAL

Drug: Durvalumab (MEDI4736); Drug: Oleclumab (MEDI9447)

Durvalumab + AZD6738

EXPERIMENTAL

Drug: Durvalumab (MEDI4736); Drug: Ceralasertib (AZD6738)

Docetaxel

ACTIVE COMPARATOR

Drug: DOCETAXEL

durvalumab+savolitinib

EXPERIMENTAL

Drug: Durvalumab (MEDI4736); Drug: Savolitinib

Interventions

Durvalumab (MEDI4736) DRUG

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 + AZD6738; Durvalumab + MEDI9447; Durvalumab + Monalizumab; durvalumab+savolitinib

Monalizumab (IPH2201) DRUG

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

Durvalumab + Monalizumab

Oleclumab (MEDI9447) DRUG

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

Durvalumab + MEDI9447

Ceralasertib (AZD6738) DRUG

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

Durvalumab + AZD6738

DOCETAXEL DRUG

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

Docetaxel

Savolitinib DRUG

600 mg QD 1 cycle = 28 days

durvalumab+savolitinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able and willing to give a signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
• Age \> 18 years.
• Patients must have histologically confirmed diagnosis of advanced (proven advanced stage) or recurrent NSCLC, (both squamous and non-squamous pathologies are accepted; patients with a mixed NSCLC and SCLC component are ineligible)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Body weight \>35kg
• Patients with evidence of radiological progression after more than 6 weeks of a registered second or third line PD1 or PD-L1 inhibitor in monotherapy (to include , Nivolumab, Pembrolizumab, Atezolizumab) or more than 12 weeks for a first line PD-1 or PD-L1 inhibitor in combination with platinum-based chemotherapy.Patients who have received immunotherapy in the maintenance setting can only have had one prior regimen containing PD-1/L1 inhibitor. No intervening treatment between the immunotherapy and entry into this study is permitted.
• Patients with known actionable molecular alteration (EGFR activating mutation, ALK rearrangement, ROS1 rearrangement) should have received a commercially available specific inhibitor
• Patients must have an available archived tissue from a standard tumor biopsy for PD-L1 assessment, done before PD-1 ICI initiation.
• As of Week 1 Day 1, subjects with central nervous system (CNS) metastases must have been treated and must be asymptomatic and meet the following:
• No concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids
• At least 14 days after CNS treatment, clinically stable with no symptoms of CNS metastasis or sequelae of radiation and at least 14 days since last dose of corticosteroids NOTE: Subjects with clinical symptoms or cord compression or with leptomeningeal disease are excluded from the study
• Adequate organ and bone marrow function as defined below:
• Haemoglobin ≥10.0 g/dL (transfusion to achieve this level is not permitted within 2 weeks of first study drug administration)
• Absolute neutrophil count (ANC) 1.5 x (\> 1500 per mm3) (stable off any growth factor within 4 weeks of first study drug administration)
• Platelet count ≥100 x 109/L (\>100,000 per mm3) (transfusion to achieve this level is not permitted within 2 weeks of first study drug administration)

You may not qualify if:

• Individuals deprived of liberty or placed under the authority of a tutor
• Patient unable to understand, read and/or sign an informed consent
• Absence of a measurable target lesion according to RECIST criteria 1.1
• Any symptomatic or untreated brain metastasis
• Any previous treatment with Docetaxel
• Prior randomisation or treatment with durvalumab AZD6738, Medi9447, Monalizumab
• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
• Any previous treatment with a PD1 or PD-L1 inhibitor with the following events:
• Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
• All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
• Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy.
• Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of \> 10 mg prednisone or equivalent per day
• No systemic intervening treatment between progression on ICI and entry into this study
• Last dose of immunotherapy ≤21 days prior to the first dose of study drug.
• The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to the study treatment.

Sponsors & Collaborators

• Assistance Publique Hopitaux De Marseille: lead

Study Sites (1)

Assistance Publique Hopitaux de Marseille

Marseille, 13354, France

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

durvalumab; monalizumab; ceralasertib; Docetaxel; 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• jean-olivier ARNAUD

  Assistance Publique -hôpitaux de Marseille

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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)

Study Record Dates

• First Submitted: February 5, 2019
• First Posted: February 7, 2019
• Study Start: October 8, 2019
• Primary Completion: October 1, 2024
• Study Completion: February 1, 2025
• Last Updated: May 3, 2024

Record last verified: 2024-05

Locations

FR (1)