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A Study Evaluating Platinum-Pemetrexed-Atezolizumab (+/-Bevacizumab) for Patients With Stage IIIB/IV Non-squamous Non-small Cell Lung Cancer With EGFR Mutations, ALK Rearrangement or ROS1 Fusion Progressing After Targeted Therapies

NCT04042558

Description:

The objective of this study is to assess the efficacy of the combination of Platinum (carboplatin or cisplatin), Pemetrexed, Atezolizumab+/- Bevacizumab if eligible, in stage IIIB/IV non-squamous non-small cell lung cancer patients with progression-enhancing mutations following targeted therapies.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating Platinum-Pemetrexed-Atezolizumab (+/-Bevacizumab) for Patients With Stage IIIB/IV Non-squamous Non-small Cell Lung Cancer With EGFR Mutations, ALK Rearrangement or ROS1 Fusion Progressing After Targeted Therapies
  • Official Title: A Multicentre Phase II, Open-label, Non-randomized Study Evaluating Platinum-Pemetrexed-Atezolizumab (+/- Bevacizumab) for Patients With Stage IIIB/IV Non-squamous Non-small Cell Lung Cancer With EGFR Mutations, ALK Rearrangement or ROS1 Fusion Progressing After Targeted Therapies

Clinical Trial IDs

  • ORG STUDY ID: GFPC 06-2018
  • NCT ID: NCT04042558

Conditions

  • NSCLC Stage IIIB
  • NSCLC Stage IV
  • EGFR Gene Mutation
  • ALK Gene Rearrangement Positive
  • ROS1 Gene Mutation

Interventions

DrugSynonymsArms
Carboplatin + Pemetrexed + Atezolizumab + BevacizumabCohort with Bevacizumab
Carboplatin + Pemetrexed + AtezolizumabCohort without Bevacizumab

Purpose

The objective of this study is to assess the efficacy of the combination of Platinum (carboplatin or cisplatin), Pemetrexed, Atezolizumab+/- Bevacizumab if eligible, in stage IIIB/IV non-squamous non-small cell lung cancer patients with progression-enhancing mutations following targeted therapies.

Detailed Description

      In patients with an EGFR mutation, several phase III studies comparing EGFR tyrosine kinase
      inhibitors (TKIs) with chemotherapy have shown a benefit of TKI over chemotherapy, with no
      demonstrated benefit on overall survival. After a first line of treatment with a TKI, most
      patients progress and are eligible according to the mechanism of progression to a TKI of 3rd
      generation in case of T790M resistance or chemotherapy. In patients with ALK translocation,
      crizotinib has been shown to be beneficial in first line compared to a platinum
      doublet.Despite these major advances, most patients are progressing after targeted treatments
      and chemotherapy and are facing the problem of anti-PD1 / PDL1 treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort with BevacizumabExperimental4 cycles of induction every 3 weeks with : Carboplatin area under curve 6 mg/mL per minute per IV route or Cisplatin 75 mg/m² per IV route Pemetrexed 500 mg/m² per IV route Atezolizumab 1200 mg per IV route Bevacizumab 15 mg/kg per IV route For patients without disease progression, treatment will be followed by maintenance therapy by Atezolizumab + Pemetrexed and Bevacizumab administered at the same dosage on 3-week cycles
  • Carboplatin + Pemetrexed + Atezolizumab + Bevacizumab
Cohort without BevacizumabExperimental4 cycles of induction every 3 weeks with : Carboplatin area under curve 6 mg/mL per minute per IV route or Cisplatin 75 mg/m² per IV route Pemetrexed 500 mg/m² per IV route Atezolizumab 1200 mg per IV route For patients without disease progression, treatment will be followed by maintenance therapy by Atezolizumab + Pemetrexed administered at the same dosage on 3-week cycles
  • Carboplatin + Pemetrexed + Atezolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patient older than 18 years and no more than 75 year-old

          -  Subject affiliated to an appropriate social security system

          -  Signed informed consent before any trial related activities and according to local
             guidelines

          -  ECOG performance status of 0 or 1

          -  Histologically or cytologically confirmed, stage IIIB/IV non-squamous NSCLC (per the
             Union Internationale contre le Cancer/American Joint Committee on Cancer staging
             system, 7th edition). Patients with stage IIIB had to be not operable (that means not
             eligible for radiochemotherapy followed by a maintenance treatment by Durvalumab).

          -  Patient with a sensitizing mutation in the EGFR gene must have experienced disease
             progression (during or after treatment) or intolerance to treatment with one or more
             EGFR TKIs, such as erlotinib, gefitinib, or another EGFR TKI appropriate for the
             treatment of EGFR-mutant NSCLC

          -  Patient with an ALK fusion oncogene (confirmed in local laboratory) must have
             experienced disease progression (during or after treatment) or intolerance to
             treatment with one or more ALK inhibitors (i.e., crizotinib, alectinib, ceritinib)
             appropriate for the treatment of NSCLC in patients having an ALK fusion oncogene

          -  Patient with a ROS1 fusion oncogene (confirmed in local laboratory) must have
             experienced disease progression (during or after treatment) or intolerance to
             treatment with one or more ROS inhibitors (i.e., crizotinib,) appropriate for the
             treatment of NSCLC in patients having an ROS1 fusion oncogene

          -  No prior chemotherapy treatment for Stage IV non-squamous NSCLC except if less than 3
             cycles, with treatment free-interval of at least 1 year from inclusion since last
             chemotherapy

          -  Patient who has received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or
             chemoradiotherapy with curative intent for non-metastatic disease must have
             experienced a treatment-free interval of at least 6 months from inclusion since the
             last chemotherapy, radiotherapy, or chemoradiotherapy

          -  Patient with a history of treated asymptomatic CNS metastases is eligible, provided he
             meets all of the following criteria:

               -  Only supratentorial and cerebellar metastases allowed (i.e., no metastases to
                  midbrain, pons, medulla, or spinal cord)

               -  No ongoing requirement for corticosteroids as therapy for CNS disease

               -  No stereotactic radiation within 7 days or whole-brain radiation within 14 days
                  prior to inclusion

               -  No evidence of interim progression between the completion of CNS-directed therapy
                  and the screening radiographic study

          -  Measurable disease, as defined by RECIST v1.1

          -  Adequate hematologic and end-organ function, defined by the following laboratory

          -  Adequate method of contraception during the treatment period and at least 5 months
             after the last dose of atezolizumab or 6 months after the last dose of chemotherapy

        Exclusion Criteria:

        Cancer-specific exclusions

          -  Active or untreated CNS metastases as determined by CT or magnetic resonance imaging
             (MRI) evaluation during screening and prior radiographic assessments

          -  Spinal cord compression not definitively treated with surgery and/or radiation or
             previously diagnosed and treated spinal cord compression without evidence that disease
             has been clinically stable for ≥ 2 weeks prior to inclusion

          -  Leptomeningeal disease

          -  Uncontrolled tumour-related pain

               -  Patients requiring pain medication must be receiving a stable regimen at study
                  entry.

               -  Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or
                  metastases causing nerve impingement) should be treated prior to inclusion.
                  Patients should be recovered from the effects of radiation. There is no required
                  minimum recovery period.

               -  Asymptomatic metastatic lesions whose further growth would likely cause
                  functional deficits or intractable pain (e.g., epidural metastasis that is not
                  currently associated with spinal cord compression) should be considered for
                  loco-regional therapy, if appropriate, prior to inclusion.

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures (once monthly or more frequently); Patients with indwelling
             catheters (e.g., PleurX®) are allowed.

          -  Uncontrolled or symptomatic hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12
             mg/dL or corrected serum calcium > ULN)

          -  Patients who are receiving denosumab prior to inclusion must be willing and eligible
             to discontinue its use and replace it with a bisphosphonate instead.

          -  Malignancies other than NSCLC within 5 years prior to inclusion, with the exception of
             those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%)
             treated with expected curative outcome (such as adequately treated carcinoma in situ
             of the cervix, basal or squamous-cell skin cancer, localized prostate cancer treated
             surgically with curative intent, ductal carcinoma in situ treated surgically with
             curative intent)

        General medical exclusions

          -  Women who are pregnant, lactating, or intending to become pregnant during the study

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or any component of the atezolizumab formulation

          -  History of autoimmune disease, including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
             syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
             multiple sclerosis, vasculitis, or glomerulonephritis

               -  Patients with a history of autoimmune-related hypothyroidism on a stable dose of
                  thyroid replacement hormone are eligible for this study.

               -  Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin
                  regimen are eligible for this study

               -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis would
                  be excluded) are permitted provided that they meet the following conditions:

               -  Rash must cover less than 10% of body surface area (BSA).

               -  Well controlled disease at baseline only requiring low potency topical steroids.

               -  No acute exacerbations of underlying condition within the previous 12 months (not
                  requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids,
                  biologic agents, oral calcineurin inhibitors, high-potency or oral steroids)

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis on screening chest CT scan; History of radiation pneumonitis in the
             radiation field (fibrosis) is permitted.

          -  Positive test for HIV. All patients will be tested for HIV prior to inclusion into the
             study; patients who test positive for HIV will be excluded from the study.

          -  Patients with active hepatitis B (chronic or acute; defined as having a positive
             hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with
             past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the
             presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible only
             if they are negative for HBV DNA. Patients positive for hepatitis C virus (HCV)
             antibody are eligible only if PCR is negative for HCV RNA.

          -  Active tuberculosis

          -  Severe infections within 4 weeks prior to inclusion, including, but not limited to,
             hospitalization for complications of infection, bacteremia, or severe pneumonia

          -  Received therapeutic oral or IV antibiotics within 2 weeks prior to inclusion;
             Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
             infection or to prevent chronic obstructive pulmonary disease exacerbation) are
             eligible.

          -  Significant cardiovascular disease, such as New York Heart Association cardiac disease
             (Class II or greater), myocardial infarction, or cerebrovascular accident within 3
             months prior to inclusion, unstable arrhythmias, or unstable angina

          -  Major surgical procedure other than for diagnosis within 28 days prior to inclusion or
             anticipation of need for a major surgical procedure during the course of the study

          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results or renders the patient at high risk from treatment
             complications

          -  Symptomatic brain metastases;

          -  Patients with illnesses or conditions that interfere with their capacity to
             understand, follow and/or comply with study procedures

          -  Concurrent participation in any therapeutic clinical trial

          -  Patient deprived of liberty or placed under the authority of a tutor

          -  Assessed by the investigator to be unable or unwilling to comply with the requirements
             of the protocol

        Exclusion criteria related to medications

          -  Any approved anti-cancer therapy, including hormonal therapy within 14 days prior to
             initiation of study treatment.

          -  Treatment with any other investigational agent with therapeutic intent within 28 days
             prior to inclusion

          -  Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
             anti-PD-1, and anti-PD-L1 therapeutic antibodies

               -  Patients who have had prior anti-cytotoxic T-lymphocyte associated antigen 4
                  (CTLA-4) treatment may be enrolled, provided the following requirements are met:

               -  Last dose of anti-CTLA-4 at least 6 weeks prior to inclusion

               -  No history of severe immune-related adverse effects from anti-CTLA-4 (NCI CTCAE
                  Grade 3/4)

          -  Treatment with systemic immunostimulatory agents (including, but not limited to,
             interferons, interleukin 2) within 4 weeks or 5 half-lives of the drug, whichever is
             longer, prior to inclusion; Prior treatment with cancer vaccines is allowed.

          -  Treatment with systemic immunosuppressive medications (including, but not limited to,
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to inclusion

               -  Patients who have received acute, low-dose (≤ 10 mg oral prednisone or
                  equivalent), systemic immunosuppressant medications may be enrolled in the study.

               -  The use of corticosteroids (≤10 mg oral prednisone or equivalent) for chronic
                  obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for
                  patients with orthostatic hypotension, and low-dose supplemental corticosteroids
                  for adrenocortical insufficiency are allowed.

        Exclusion criteria related to chemotherapy

          -  History of allergic reactions to cisplatin, carboplatin, or other platinum-containing
             compounds

          -  Patients with hearing impairment (cisplatin)

          -  Grade ≥ 2 peripheral neuropathy as defined by NCI CTCAE v5.0 (cisplatin)

          -  CRCL < 60 mL/min for cisplatin or < 45 mL/min for carboplatin using the
             Cockcroft-Gault Method

        Exclusion criteria related to Bevacizumab

          -  Medically uncontrolled hypertension (defined as PAS>150 and/or PAD >100 mmHg)

          -  Prior history of hypertensive crisis or hypertensive encephalopathy

          -  Clinically significant cardiovascular disease (within 6 months prior to inclusion)
             that is uncontrolled by medication or may interfere with administration of trial
             treatment:

               -  Aortic aneurysm requiring surgical repair

               -  Recent arterial thrombosis

               -  Hemoptysis (>one-half teaspoon of bright red blood per episode (within one months
                  prior to inclusion) (grade 2 hemoptysis)

          -  History of documented haemorrhagic diathesis or coagulopathy

          -  Therapeutic anticoagulation

          -  Regular use of aspirin (>325 mg per day),

          -  Nonsteroidal anti-inflammatory agents, or other agents known to inhibit platelet
             function

          -  History of abdominal or tracheosphageal fistula or perforation within 6 months prior
             to inclusion

          -  Core biopsy or other minor surgical procedure within 7 days before bevacizumab

          -  Clinical signs or gastrointestinal obstruction or requirement for routine parenteral
             hydration, nutrition or tube feeding

          -  Evidence of abdominal free air not explained by paracentesis or recent surgical
             procedure

          -  Major surgery within 28 days before enrolment

          -  Serious, non-healing wound, active ulcer or untreated bone fracture

          -  Proteinuria >1g/24h urine collection

          -  All patient with >2+ protein on dipstick urinalysis at baseline must undergo a 24-hour
             urine collection and must demonstrate ≤1g of protein in 24 hours.

          -  Known sensitivity to any component of bevacizumab

          -  Radiation therapy within 21 days before enrolment

          -  Adequate hematologic, liver, and renal function required (including creatinine
             clearance 45 mL/min at baseline and 45 mL/min before the start of any subsequent cycle
             using the Cockcroft-Gault Method)
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) according to RECIST 1.1
Time Frame:After the end of 4 cycles (15 weeks)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:The progression-free survival (PFS)
Time Frame:1 year
Safety Issue:
Description:
Measure:The overall survival
Time Frame:1 year
Safety Issue:
Description:
Measure:The duration of response
Time Frame:1 year
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Centre Francois Baclesse

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