Clinical Trials /

Neoadjuvant Immunoradiation for Resectable Non-Small Cell Lung Cancer

NCT03237377

Description:

This is a pilot study of neoadjuvant 'immunoradiation' (durvalumab or durvalumab plus tremelimumab) administered every 4 weeks for 2 doses, concurrently with standard thoracic radiation (RT) (45Gy in 25 fractions), with one dose of immunotherapy alone delivered in the pre-surgical window, prior to surgical resection, for patients with stage IIIA NSCLC that is deemed resectable with a lobectomy by a thoracic surgeon. If preliminary safety of the durvalumab/thoracic RT combination is established, a second cohort investigating the combination of durvalumab/tremelimumab/thoracic RT prior to surgical resection will be opened. After surgical resection, patients may receive standard adjuvant chemotherapy, as deemed appropriate by the treating investigator.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Immunoradiation for Resectable Non-Small Cell Lung Cancer
  • Official Title: Neoadjuvant Immunoradiation for Stage III Resectable Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: J1772
  • SECONDARY ID: IRB00127418
  • SECONDARY ID: ESR-16-12244
  • NCT ID: NCT03237377

Conditions

  • Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
DurvalumabDurvalumab with Radiation
TremelimumabDurvalumab and Trememlimumab with Radiation

Purpose

This is a pilot study of neoadjuvant 'immunoradiation' (durvalumab or durvalumab plus tremelimumab) administered every 4 weeks for 2 doses, concurrently with standard thoracic radiation (RT) (45Gy in 25 fractions), with one dose of immunotherapy alone delivered in the pre-surgical window, prior to surgical resection, for patients with stage IIIA NSCLC that is deemed resectable with a lobectomy by a thoracic surgeon. If preliminary safety of the durvalumab/thoracic RT combination is established, a second cohort investigating the combination of durvalumab/tremelimumab/thoracic RT prior to surgical resection will be opened. After surgical resection, patients may receive standard adjuvant chemotherapy, as deemed appropriate by the treating investigator.

Trial Arms

NameTypeDescriptionInterventions
Durvalumab with RadiationExperimental
  • Durvalumab
Durvalumab and Trememlimumab with RadiationExperimental
  • Durvalumab
  • Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent and any locally-required authorization obtained.

          -  Histologically-confirmed diagnosis of stage III non-small cell lung cancer (NSCLC)

          -  Age≥18 years

          -  Life expectancy >6 months

          -  Body weight >30kg

          -  Subjects with non-small cell lung cancer deemed surgically resectable by an attending
             thoracic surgeon with lobectomy

          -  ECOG Performance Status 0-1

          -  Normal bone marrow and organ function on routine laboratory tests, as defined in
             section 4.1

          -  Evidence of post-menopausal status or negative urinary/serum pregnancy test for female
             pre-menopausal subjects. Women will be considered post-menopausal if they have been
             amenorrheic for 12 months without an alternative medical cause.

          -  Ability to understand and willingness of sign consent form

          -  Willingness to comply with the protocol for the duration of the study

        Exclusion Criteria:

          -  Involvement in the planning and/or conduct of the study (includes AstraZeneca staff
             and staff at the study site)

          -  Prior investigational therapy within 28 days/at least 5 half-lives before study drug
             administration

          -  Prior chest radiation

          -  Prior history of interstitial lung disease or pneumonitis requiring corticosteroids,
             or active non-infectious pneumonitis

          -  Patients only suitable for surgical management with pneumonectomy, deemed by an
             attending thoracic surgeon

          -  Prior therapy with PD-1, PD-L1, CTLA-4 or anti-cancer vaccines, including durvalumab
             and tremelimumab

          -  Participation in another clinical study with an investigational product in the last 4
             weeks or equivalent of 5 half-lives of the first dose of study treatment, whichever is
             shorter

          -  History of another primary malignancy except for: malignancy treated with curative
             intent and with no known active disease for the last 5 years, adequately treated
             non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately
             treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

          -  Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy

          -  Subjects with irreversible toxicity that is not reasonably expected to be exacerbated
             by the investigational product may be included (e.g., hearing loss, peripherally
             neuropathy)

          -  Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
             Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
             replacement therapy) is acceptable

          -  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.

          -  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

          -  History of allogenic organ transplantation.

          -  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 (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 physician; celiac disease controlled by diet alone.)

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
             bleeding diatheses including any subject known to have evidence of acute or chronic
             hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
             illness/social situations that would limit compliance with study requirements or
             compromise the ability of the subject to give written informed consent

          -  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). Subjects
             with a past or resolved HBV infection (defined as the presence of hepatitis B core
             antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for
             hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
             for HCV RNA.

          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of receiving durvalumab or tremelimumab

          -  Female subjects who are pregnant, breast-feeding or male or female patients of
             reproductive potential who are not employing an effective method of birth control.

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study result.

          -  Known allergy or hypersensitivity to IP or any excipient

          -  Uncontrolled psychiatric illness/social situations that would limit compliance with
             study requirements or compromise the ability of the subject to give written consent

          -  Any condition that, in the opinion of the investigator would interfere with evaluation
             of study treatment or interpretation of patient safety or study results.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Toxicities as measured by number of participants experiencing adverse events
Time Frame:Up to 100 days
Safety Issue:
Description:Number of participants experiencing adverse events as defined by CTCAE v4.0.

Secondary Outcome Measures

Measure:Surgical Morbidity and Mortality
Time Frame:Up to 3 years
Safety Issue:
Description:Number of participants who experience post-operative death. Calculated through log-rank test and Cox proportional hazards (PH) model.
Measure:Percentage of Participants with Pathologic Response
Time Frame:Up to 3 years
Safety Issue:
Description:Percentage of participants with major pathologic response (MPR), partial response (PR) or no response (NR), where MPR is >90% reduction in tumor cells, PR = 10-90% or NR = 0-10%. The percentage of patients whose tumor samples achieve MPR, PR and NR will be tabulated.
Measure:Percentage of Participants with Radiologic Response
Time Frame:Up to 3 years
Safety Issue:
Description:Percentage of participants with complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) as defined by RECIST 1.1 and immune-related RECIST criteria when treated with preoperative immunoradiation followed by surgery. CR = disappearance of all target lesions, PR is =>30% decrease in sum of diameters of target lesions, PD is >20% increase in sum of diameters of target lesions, SD is <30% decrease or <20% increase in sum of diameters of target lesions.
Measure:Duration of Response as measured by recurrence-free survival
Time Frame:Up to 3 years
Safety Issue:
Description:Time from first evidence of response until recurrence when treated with preoperative immunoradiation followed by surgery. Calculated through log-rank test and Cox proportional hazards (PH) model.
Measure:Overall Survival
Time Frame:Up to 3 years
Safety Issue:
Description:Number of months alive after treatment with preoperative immunoradiation followed by surgery. Calculated through log-rank test and Cox proportional hazards (PH) model.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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