Clinical Trials /

Phase II Concurrent Durvalumab and Radiotherapy for for Stage III Non-Small Cell Lung Cancer

NCT04003246

Description:

Single arm, Phase II trial of concurrent Durvalumab (MEDI 4736) and radiotherapy followed by consolidative Durvalumb (MEDI 4736) for Stage III Non-Small Cell Lung Cancer (NSCLC)

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Concurrent Durvalumab and Radiotherapy for for Stage III Non-Small Cell Lung Cancer
  • Official Title: Phase II Concurrent Durvalumab (MEDI4736) and Radiotherapy Followed by Consolidative Durvalumab (MEDI4736) for Stage III Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: 2019-1082
  • NCT ID: NCT04003246

Conditions

  • Non Small Cell Lung Cancer
  • Lung Cancer Stage III

Interventions

DrugSynonymsArms
Consolidative DurvalumabSingle Arm: Therapeutic Intervention

Purpose

Single arm, Phase II trial of concurrent Durvalumab (MEDI 4736) and radiotherapy followed by consolidative Durvalumb (MEDI 4736) for Stage III Non-Small Cell Lung Cancer (NSCLC)

Detailed Description

      Immunotherapy has significantly improved the survival outcomes of patients with various
      cancer types including thoracic malignancies. In the PACIFIC study, patients with locally
      advanced NSCLC were randomized to the anti-PDL1 antibody durvalumab or placebo for up to 12
      months after completion of concurrent chemoradiation. While NSCLC is typically considered
      relatively non-immunogenic, RT is thought to augment tumor immunogenicity(Iyengar & Gerber,
      2013). The abscopal effect refers to the observation that the benefit seen in PACIFIC, along
      with the growing role of immunotherapy for the treatment advanced (stage IV) NSCLC, suggests
      that earlier exposure to durvalumab may improve outcomes and be well tolerated, thereby
      permitting de-escalation of therapy through removal of conventional chemotherapy from these
      regimens to a local area results in an antitumor effect distant to the radiation site.

      Durvalumab (Imfimzi; MEDI4736; AstraZeneca) is a human monoclonal antibody of the
      immunoglobulin (Ig) G1 kappa subclass that inhibits binding of PD-L1 (B7-H1, CD274) to PD-1
      (CD279) and CD80 (B7-1). MEDI4736 is composed of 2 identical heavy chains and 2 identical
      light chains, with an overall molecular weight of approximately 149 kDa. MEDI4736 contains a
      triple mutation in the constant domain of the Ig G1 heavy chain that reduces binding to
      complement protein C1q and the Fcγ receptors involved in triggering effector function.
      Durvlumab binds with high affinity and specificity to human PD-L1 and blocks its interaction
      with PD-1 and CD80
    

Trial Arms

NameTypeDescriptionInterventions
Single Arm: Therapeutic InterventionExperimental
  • Consolidative Durvalumab

Eligibility Criteria

        Inclusion Criteria:

        1.1 Pathologically (histologically or cytologically) proven diagnosis of NSCLC with,
        medically inoperable (or patients who refuse resection) stage IIIA or stage IIIB disease
        (AJCC 8th edition);

        1.1.1 Inoperable Stage IIIA disease is defined by multiple and/or bulky N2 mediastinal
        lymph nodes on computed tomography (CT) scan such that, in the opinion of the treating
        investigator, the patient was not a candidate for surgical resection.

        1.1.2 N2 disease must have been documented by biopsy, or at a minimum by fluorodeoxyglucose
        positron emission tomography (PET) or CT if nodes were more than 2 cm in short axis
        diameter.

        1.1.3 T4 disease is often considered resectable at the discretion of a thoracic surgeon.
        Patients with T4N0 or T4N1 disease can be enrolled if their case is reviewed by a thoracic
        surgeon and felt to be unresectable or if they are either medically inoperable or refuse
        surgery.

        1.1.4 Stage IIIB patients have N3 or T4N2 status. N3 status must have been documented by
        the presence of a contralateral (to the primary tumor) mediastinal lymph node or
        supraclavicular or scalene lymph node proven by biopsy, or at a minimum by
        fluorodeoxyglucose uptake on PET or more than 2 cm in short axis diameter on CT scan.
        Patients with disease extending into the cervical region (defined as disease extending
        above cricoid cartilage) are not eligible.

        1.2 Appropriate stage for study entry based on the following diagnostic workup:

        1.2.1 History/physical examination, including documentation of height, weight and vital
        signs, within 30 days prior to registration;

        1.2.2 CT scan with IV contrast (CT scan without contrast acceptable if IV contrast is
        medically contraindicated) of the lung and upper abdomen through the adrenal glands within
        60 days prior to registration (recommended within 30 days prior to registration);

        1.2.3 MRI of the brain with contrast (or CT with contrast if MRI is medically
        contraindicated) within 60 days prior to registration; note: the use of intravenous
        contrast is required for the MRI or CT (unless medically contra-indicated).

        1.2.4 Whole-body FDG-PET/CT within 60 days prior to registration;

        1.3 Age ≥ 18 years;

        1.4 Life expectancy ≥ 12 weeks

        1.5 Zubrod Performance Status of 0-1 within 30 days prior to registration;

        1.6 Adequate respiratory function within 180 days prior to registration defined as follows:
        FEV1 > 1.2 liters; DLCO ≥ 50% predicted;

        1.7 Patients with post-obstructive pneumonia are eligible provided they no longer require
        intravenous antibiotics at registration;

        1.8 Patients with a pleural effusion that is transudative, cytologically negative and
        non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed
        within a reasonable field of radiotherapy; if pleural fluid is too small a volume to
        effectively sample by thoracentesis and does not show increased metabolic activity on
        CT/PET imaging, the patient will be remain eligible.

        1.9 Allowable type and amount of prior therapy

        1.10 Adequate organ and marrow function as defined below

        1.10.1 Absolute neutrophil count >1.5 × 109/L

        1.10.2 Platelet count >100 × 109/L

        1.10.3 Baseline or post-transfusion Hemoglobin ≥9.0 g/dL

        1.10.4 Serum bilirubin≤ 1.5x upper limit of normal (ULN). This will not apply to patients
        with confirmed Gilbert's syndrome, who will be allowed in consultation with their
        physician.

        1.10.5 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x ULN.

        1.10.6 Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 mL/min as
        determined by Cockcroft-Gault (using actual body weight);

        Males:

        Creatinine CL = Weight (kg) × (140 - Age) (mL/min) 72 × serum creatinine (mg/dL)

        Females:

        Creatinine CL = Weight (kg) × (140 - Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL)

        1.11 Negative serum pregnancy test within three days prior to registration for women of
        childbearing potential.

        1.12 Women of child-bearing potential and men must agree to use adequate contraception
        (hormonal or barrier method of birth control; abstinence) prior to study entry, for the
        duration of study participation, and for 90 days following completion of therapy. Should a
        woman become pregnant or suspect she is pregnant while participating in this study, she
        should inform her treating physician immediately.

        1.12.1 A female of child-bearing potential is any woman (regardless of sexual orientation,
        having undergone a tubal ligation, or remaining celibate by choice) who meets the following
        criteria:

          -  Has not undergone a hysterectomy or bilateral oophorectomy; or

          -  Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has
             had menses at any time in the preceding 12 consecutive months).

        1.12.2 Evidence of post-menopausal status or negative urinary or serum pregnancy test for
        female pre-menopausal patients. Women will be considered post-menopausal if they have been
        amenorrheic for 12 months without an alternative medical cause. The following age-specific
        requirements apply:

          -  Women <50 years of age would be considered post-menopausal if they have been
             amenorrheic for 12 months or more following cessation of exogenous hormonal treatments
             and if they have luteinizing hormone and follicle-stimulating hormone levels in the
             post-menopausal range for the institution or underwent surgical sterilization
             (bilateral oophorectomy or hysterectomy).

          -  Women ≥50 years of age would be considered post-menopausal if they have been
             amenorrheic for 12 months or more following cessation of all exogenous hormonal
             treatments, had radiation-induced menopause with last menses >1 year ago, had
             chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical
             sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

        1.13 Ability to understand and the willingness to sign a written informed consent.

        Exclusion Criteria:

        2.1 Definitive clinical or radiologic evidence of metastatic disease;

        2.2 Subjects may not be receiving any other investigational agents for the treatment of the
        cancer under study.

        2.3 Current invasive malignancy (except non-melanomatous skin cancer, localized bladder and
        prostate cancer). Carcinoma in situ of the breast, oral cavity, or cervix are permissible
        regardless of timing;

        2.4 Prior radiotherapy to the region of the study cancer that would result in overlap of
        radiation therapy fields. For example, patients with prior breast radiotherapy treatments
        would likely be excluded;

        2.5 Prior systemic treatment with chemotherapy, targeted therapy or an anti-PD-1,
        anti-PD-L1 including durvalumab, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or
        drug specifically targeting T-cell costimulation or immune checkpoint pathways for NSCLC;

        2.6 A condition requiring systemic treatment with either corticosteroids (> 10 mg daily
        prednisone equivalents) or other immunosuppressive medications within 7 days of study drug
        administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily
        prednisone equivalents are permitted in the absence of active autoimmune disease;

        2.7 Severe, active co-morbidity defined as follows:

        2.7.1 Major surgical procedure (as defined by the Investigator) within 28 days prior to the
        first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
        acceptable.

        2.7.2 Active or prior documented autoimmune or inflammatory disorders (including
        inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the
        exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
        Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis,
        hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

          -  Patients with vitiligo or alopecia

          -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
             replacement

          -  Any chronic skin condition that does not require systemic therapy

          -  Patients without active disease in the last 5 years may be included but only after
             consultation with the study physician

          -  Patients with celiac disease controlled by diet alone

        2.7.3 Active infection including tuberculosis, hepatitis B, hepatitis C.

        2.7.4 History of allogenic organ transplantation.

        2.7.5 History of symptomatic or previously established interstitial lung disease;

        2.7.6 History of severe hypersensitivity reaction to any monoclonal antibody or allergy to
        study drug components;

        2.7.7 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
        Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
        30 days after the last dose of IP.

        2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active
        infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
        arrhythmia, or psychiatric illness/social situations that, in the opinion of the
        investigator, would limit compliance with study requirements.

        2.9 Pregnancy, nursing females, or women of childbearing potential and men who are sexually
        active and not willing/able to use medically acceptable forms of contraception; this
        exclusion is necessary because the treatment involved in this study may be significantly
        teratogenic.

        2.10 Patients whose radiation treatment plans are likely to encompass a volume of whole
        lung receiving ≥ 35% of lung volume. V20s up to 37% will be permitted and viewed as a minor
        deviation, provided that the treating radiation oncologist believes this level of exposure
        is within patient tolerance.

        2.11 Planned radiation cardiac dose V50 >25%.
      
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:Twelve months from the study enrollment
Safety Issue:
Description:To determine the PFS in these patients from the time of study enrollment to documented progressive disease or death due to any cause, whichever occurs first.

Secondary Outcome Measures

Measure:Local and regional control
Time Frame:From date of study enrollment until the date of first documented new local and regional lesion or date of death from any cause, whichever came first, assessed up to 100 months
Safety Issue:
Description:To determine the local and regional control in these patients
Measure:Distant metastases free survival
Time Frame:From date of study enrollment until the date of first documented new distant lesion or date of death from any cause, whichever came first, assessed up to 100 months
Safety Issue:
Description:To determine if patients will have a metastatic new lesion

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Texas Southwestern Medical Center

Trial Keywords

  • Lung

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