Clinical Trials /

Combination of Durvalumab and Tremelimumab as Maintenance Treatment in Patients With Non Squamous and Squamous (NSCLC)

NCT03319316

Description:

This is a multicenter, 2-arm open-label, randomized comparative phase II study in each of two separate cohorts (non-squamous NSCLC and squamous NSCLC) according to histology.

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

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination of Durvalumab and Tremelimumab as Maintenance Treatment in Patients With Non Squamous and Squamous (NSCLC)
  • Official Title: Randomized Phase II Study of Durvalumab and Tremelimumab Combination Versus Standard of Care Following First-line Platinum Based Chemotherapy in Two Cohorts of Patients With Non Squamous and Squamous Non-small-cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: EORTC-1643
  • SECONDARY ID: 2017-001827-39
  • NCT ID: NCT03319316

Conditions

  • Squamous Non-small Cell Lung Cancer
  • Non-Squamous Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
DurvalumabCohort 1 - Non-squamous - Arm A
TremelimumabCohort 1 - Non-squamous - Arm A

Purpose

This is a multicenter, 2-arm open-label, randomized comparative phase II study in each of two separate cohorts (non-squamous NSCLC and squamous NSCLC) according to histology.

Detailed Description

      Patients will receive four cycles of standard platinum-based doublet chemotherapy. Upon
      confirmation of response or tumor stabilization, patients will be registered and allocated
      into two cohorts based on the tumor histology and each cohort will be randomized into two
      arms. The experimental arm will receive combination of durvalumab + tremelimumab, the other
      arm is according to standard of care.

      The objective of this trial is to evaluate whether a maintenance approach with the
      combination immunotherapy with durvalumab + tremelimumab improves progression-free survival
      (PFS) compared to standard of care in patients with advanced NSCLC. Each cohort is powered
      separately based on PFS.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 - Non-squamous - Arm AExperimentalPatients receive a maintenance treatment of durvalumab + tremelimumab
  • Durvalumab
  • Tremelimumab
Cohort 1 - Non-squamous - Arm BNo InterventionPatients receive a maintenance treatment of pemetrexed
    Cohort 2 - Squamous - Arm AExperimentalPatients receive a maintenance treatment of durvalumab + tremelimumab
    • Durvalumab
    • Tremelimumab
    Cohort 2 - Squamous - Arm BNo InterventionPatients will have observation

      Eligibility Criteria

              Inclusion Criteria:
      
                -  For inclusion in the study, patients should fulfill the following criteria
      
                     -  Histological diagnosis of NSCLC; for non-squamous NSCLC: no known sensitizing
                        EGFR-mutation, no known EML4-ALK translocation. When a patient with non-squamous
                        NSCLC has a KRAS mutation, further testing for EGFR and EML4-ALK is not
                        necessary. For squamous NSCLC, EGFR and EML4-ALK testing is not necessary.
      
                     -  Availability of adequate in quality and quantity archived tumor material for IHC
                        PD-L1 testing; (Preferably 15 but 8 mandatory slides or block of tumor tissue
                        will be collected);
      
                     -  Stage IIIB or IIIC not eligible for radical treatment or stage IV according to
                        TNM8 (Ref. 6);
      
                     -  Brain metastases should be treated with local therapy (stereotactic radiotherapy
                        or whole brain radiotherapy), and patients should be asymptomatic, without
                        treatment with steroids for four weeks before enrollment. Before enrollment, new
                        brain imaging (contrast-CT or gadolinium-MRI) is needed to demonstrate that there
                        is no progression in the brain when the last brain imaging is more than four
                        weeks earlier. Screening for brain metastases is not necessary in patients that
                        were previously not diagnosed with brain metastases and that are without signs
                        indicative of brain metastases.
      
                     -  ≥ 18 years of age at time of study entry;
      
                     -  WHO performance status 0 or 1; at enrollment
      
                     -  Body weight > 30 kg at enrollment
      
                     -  Evaluable disease with CT or MRI according to RECIST 1.1 (except for patients
                        with a CR after 4 cycles of platinum-based doublet chemotherapy, these patients
                        are also eligible);
      
                     -  Stable disease or response by RECIST criteria response after 4 cycles of
                        platinum-based doublet chemotherapy;
      
                     -  Adequate normal organ and marrow function:
      
                     -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)
      
                     -  Platelet count ≥ 100 x 109/L (>100,000 per mm3)
      
                     -  Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not
                        apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent
                        hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
                        or hepatic pathology)AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of
                        normal; for patients with liver metastases ≤ 5 x institutional upper limit of
                        normal
      
                     -  Measured or calculated creatinine clearance ≥45 mL/min by the Cockcroft-Gault
                        formula (Appendix E)
      
                     -  Haemoglobin ≥ 9.0 g/dL
      
                     -  Patient with following autoimmune or inflammatory disorders are eligible:
      
                     -  Vitiligo or alopecia
      
                     -  Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
      
                     -  Any chronic skin condition that does not require systemic therapy
      
                     -  Active disease in the last 5 years may be included but only after consultation
                        with the study investigator
      
                     -  Celiac disease controlled by diet alone
      
                     -  Patient with history of another primary malignancy are eligible in the following
                        cases:
      
                     -  Malignancy treated with curative intent and with no known active disease ≥5 years
                        before the first dose of IP and of low potential risk for recurrence
      
                     -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                        of disease
      
                     -  Adequately treated carcinoma in situ without evidence of disease
      
                     -  Women of child bearing potential (WOCBP) must have a negative serum pregnancy
                        test within 72 hours prior to the first dose of study treatment.
      
              Note: women of childbearing potential are defined as premenopausal females capable of
              becoming pregnant (i.e. females who have had any evidence of menses in the past 12 months,
              with the exception of those who had prior hysterectomy). However, women who have been
              amenorrheic for 12 or more months are still considered to be of childbearing potential if
              the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight,
              ovarian suppression or other reasons.
      
                -  Patients of childbearing / reproductive potential should use adequate birth control
                   measures, as defined by the investigator, during the study treatment period and from
                   screening to 90 days after the last dose of durvalumab monotherapy or 180 days after
                   the last dose of durvalumab + tremelimumab combination. A highly effective method of
                   birth control is defined as a method which results in a low failure rate (i.e. less
                   than 1% per year) when used consistently and correctly. Such methods include:
      
                -  Combined (estrogen and progestogen containing) hormonal contraception associated with
                   inhibition of ovulation (oral, intravaginal, transdermal)
      
                -  Progestogen-only hormonal contraception associated with inhibition of ovulation (oral,
                   injectable, implantable)
      
                -  Intrauterine device (IUD)
      
                -  Intrauterine hormone-releasing system (IUS)
      
                -  Bilateral tubal occlusion
      
                -  Vasectomized partner
      
                -  Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in
                   relation to the duration of the clinical trial and the preferred and usual lifestyle
                   of the patient)
      
                -  Female subjects who are breast feeding should discontinue nursing prior to the first
                   dose of study treatment, from screening to 90 days after the last dose of durvalumab
                   monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination
                   therapy or pemetrexed.
      
                -  Subject is willing and able to comply with the protocol for the duration of the study
                   including undergoing treatment and scheduled visits and examinations including follow
                   up;
      
                -  Before patient registration, written informed consent must be given according to
                   ICH/GCP, and national/local regulations.
      
              Exclusion Criteria:
      
                -  Patients should not enter the study if any of the following exclusion criteria is
                   fulfilled
      
                     -  Concurrent enrollment in another clinical study, unless it is an observational
                        (non-interventional) clinical study or the follow-up period of an interventional
                        study
      
                     -  Mixed small-cell lung cancer and NSCLC histology, sarcomatoid variant or large
                        cell neuro-endocrine variant
      
                     -  Patients with known history of leptomeningeal carcinomatosis
      
                     -  Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with
                        the exception of alopecia, vitiligo, and the laboratory values defined in the
                        inclusion criteria
      
                     -  Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
                        consultation with the study investigator
      
                     -  Patients with irreversible toxicity not reasonably expected to be exacerbated by
                        treatment with durvalumab or tremelimumab may be included only after consultation
                        with the study investigator
      
                     -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, a
                        CTLA-4 including tremelimumab or other checkpoint inhibitors or other immune
                        therapy during the last 12 months
      
                     -  Current or prior use of immunosuppressive medication within 14 days before the
                        first dose of durvalumab and tremelimumab, with the exceptions of intranasal and
                        inhaled corticosteroids or systemic corticosteroids at physiological doses, which
                        are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid, or
                        steroids as premedication for hypersensitivity reactions (eg, CT scan
                        premedication)
      
                     -  Radiotherapy treatment to more than 30% of the bone marrow or with a wide field
                        of radiation within 4 weeks of the first dose of study drug. Note: Local
                        treatment of isolated lesions, excluding target lesions, for palliative intent is
                        acceptable when it is not within 7 days of the first dose of study drug.
      
                     -  Major surgical procedure (as defined by the study investigator) within 28 days
                        prior to the first dose of IP. Note: Local surgery of isolated lesions for
                        palliative intent is acceptable
      
                     -  History of allogenic organ transplantation
      
                     -  Receipt of live attenuated vaccination within 30 days prior to enrollement
      
                     -  Active or prior documented autoimmune or inflammatory disorders (including
                        inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with
                        the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis
                        syndrome, or Wegener syndrome [granulomatosis with polyangitis, Graves' disease,
                        rheumatoid arthritis, hypophysitis, uveitis, etc]).
      
                     -  History of hypersensitivity to durvalumab, tremelimumab or any excipient
      
                     -  Uncontrolled intercurrent illness including, but not limited to:
      
                     -  Active infection including tuberculosis (clinical evaluation that includes
                        clinical history, physical examination and radiographic findings, and TB testing
                        in line with local practice), hepatitis B (known positive HBV surface antigen
                        (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2
                        antibodies). Patients with a past or resolved HBV infection (defined as the
                        presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are
                        eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if
                        polymerase chain reaction is negative for HCV RNA.
      
                     -  Symptomatic congestive heart failure, uncontrolled hypertension (defined as blood
                        pressure above 160/90 mm Hg despite medication), unstable angina pectoris,
                        cardiac arrhythmia
      
                     -  Active peptic ulcer disease or gastritis
      
                     -  Liver cirrhosis CHILD B+, C (Appendix J)
      
                     -  Active bleeding diatheses
      
                     -  History of primary immunodeficiency
      
                     -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
                        electrocardiograms (ECGs) using Frediricia's Correction
      
                     -  Female patients who are pregnant or male or female patients of reproductive
                        potential who are not willing to employ effective birth control from screening to
                        90 days after the last dose of durvalumab monotherapy or 180 days after the last
                        dose of durvalumab + tremelimumab combination therapy or pemetrexed.
      
                     -  Any psychological, familial, sociological or geographical condition potentially
                        hampering compliance with the study protocol and follow-up schedule; those
                        conditions should be discussed with the patient before registration in the trial
      
                     -  History of another primary malignancy
      
                     -  For non-squamous: unable to interrupt aspirin or other nonsteroidal
                        anti-inflammatory agents, other than an aspirin dose <1.3 grams per day, for a
                        5-day period (8-day period for long-acting agents, such as piroxicam). Unable or
                        unwilling to take folic acid, vitamin B12 supplementation.
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Progression free survival (PFS)
      Time Frame:4.3 years from FPI
      Safety Issue:
      Description:The time interval between the date of randomization and the date of disease progression or death, whichever comes first.

      Secondary Outcome Measures

      Measure:Overall Survival (OS)
      Time Frame:5 years from FPI
      Safety Issue:
      Description:Overall Survival (OS) is defined as the time interval between the date of randomization and the date of death from any cause.
      Measure:Objective response rate according to RECIST 1.1;
      Time Frame:5 years from FPI
      Safety Issue:
      Description:Patients with response categories progression, early death and unknown will be considered as failing to respond to treatment. The response rates in each arm and their 95% confidence intervals will be provided.
      Measure:Progression-free survival -2
      Time Frame:5 years from FPI
      Safety Issue:
      Description:PFS-2 calculated as the time between randomization and the 2nd PD or death, not of the maintenance treatment/observation but the PD after the subsequent treatment thus taking into account the influence of the treatment under investigation on the following treatment line.
      Measure:Time to failure of 2nd treatment
      Time Frame:5 years from FPI
      Safety Issue:
      Description:Defined as the time between randomization and the permanent treatment interruption of the subsequent/second treatment (treatment received after progression of the first treatment) due to progressive disease, PS worsening, unacceptable toxicity that does not allow continuing the treatment according to the investigator.
      Measure:Safety
      Time Frame:5 years from FPI
      Safety Issue:
      Description:All adverse events will be recorded according to CTCAE version 4.
      Measure:Quality of life
      Time Frame:5 years from FPI
      Safety Issue:
      Description:The hypothesis to test is whether the possible benefit with respect to PFS/OS of the intense maintenance treatment will also translate in a better QoL or will the higher risk of Adverse events cause a reduction in QoL. (methodology: quality of life questionnaires)

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Not yet recruiting
      Lead Sponsor:European Organisation for Research and Treatment of Cancer - EORTC

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