Chemoradiation Plus Durvalumab Followed by Surgery Followed by Adjuvant Durvalumab in Patients With Surgically Resectable Stage III (N2) Non-Small Cell Lung Cancer
Condition: Non Small Cell Lung Cancer; Stage III Non-small-cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Durvalumab; Paclitaxel; Carboplatin; Radiation; Surgical Resection
Intervention description: Neoadjuvant Durvalumab 750 mg IV on Days 1, 15 and 29
Adjuvant Durvalumab 12 weeks after undergoing surgical resection 1,500 mg IV on Day 1; Paclitaxel 45 mg/m2 IV Days 1, 8, 15, 22, 29 and +/- 36; Carboplatin AUC of 2 IV Days 1, 8, 15, 22, 29 +/- 36; 1.8-2.0 Gy per day (5 days/week) for a total of 45-61.2 Gy over 5-6 weeks. Treatment will be delivered using IMRT or 3DCRT using typically 6-10MV photons. Proton therapy is also allowed. 4D simulation and appropriate IGRT are encouraged. Radiation therapy must begin within one week of the first day of chemotherapy (or vice versa).; Patients will undergo repeat imaging between 4 and 12 weeks after completing neoadjuvant therapy. Those without evidence of progressive disease and found to be a surgical candidate by a thoracic surgeon will undergo surgical resection between 4 and 12 weeks after neoadjuvant therapy.
Intervention MeSH terms: Paclitaxel; Carboplatin; Durvalumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is an open label, multi-institutional, single arm Phase II trial. All patients will be
      treated with Carboplatin, Paclitaxel, Durvalumab and Radiation. All patients with non-PD
      after induction therapy who remain surgical candidates will undergo surgical resection 4-12
      weeks following induction therapy.

      After surgical resection, all patients who remain eligible will be treated with adjuvant
      Durvalumab every 4 weeks for 6 cycles beginning 4-12 weeks after surgical resection.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization for release of personal health
             information. NOTE: HIPAA authorization may be included in the informed consent or
             obtained separately.

          -  Age ≥ 18 years at the time of consent.

          -  ECOG Performance Status of 0 or 1 within 28 days prior to registration.

          -  Histological or cytological confirmation of NSCLC (Adenocarcinoma, Squamous Cell
             Carcinoma, Large Cell Carcinoma). A pathology report (from the last 6 months)
             confirming the diagnosis of NSCLC must be obtained and reviewed by the treating
             physician prior to registration to study.

          -  Must have resectable and medically operable stage III (N2) NSCLC with clinical or
             biopsy-proven N2 disease. If patients have clinical N2 disease they need to be
             biopsy-proven (with EBUS or mediastinoscopy) during screening and have confirmed prior
             to study enrollment). Subjects must be considered resectable and medically operable
             based on the judgment of the treating physician. Stage III (N2) defined as per the 7th
             edition of the TNM staging system (T1a, T1b, T1c, T2a, T2b, T3, or T4)N2M0.

          -  Individuals cannot have contralateral neck or contralateral mediastinum nodal
             involvement.

          -  Subjects must have a life expectancy of at least 12 weeks to qualify.

          -  Individuals must not have distant metastasis, defined as M0 in the TMN staging system.

          -  Demonstrate adequate organ function as defined in the table below; all screening labs
             to be obtained within 28 days prior to registration.

               -  Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3

               -  Hemoglobin (Hgb) ≥ 9 g/dL (may be transfused)

               -  Platelets ≥100,000/mcl

               -  Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be
                  used in place of creatinine or CrCl) ≤ 1.5 x upper limit of normal (ULN) OR ≥ 40
                  mL/min for subjects with creatinine levels >1.5 x institutional ULN

               -  Bilirubin ≤ 1.5 × ULN OR Direct bilirubin of ≤ ULN for subjects with total
                  bilirubin levels of >1.5x ULN

               -  Aspartate aminotransferase (AST) ≤ 2.5 × ULN if no liver metastases

                  ≤ 5 x ULN if liver metastases present

               -  Alanine aminotransferase (ALT) ≤ 2.5 × ULN if no liver metastases ≤ 5 x ULN if
                  liver metastases present

          -  All CT or PET imaging studies must be completed within 6 weeks (42 days) prior to
             registration.

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to
             registration. NOTE: Women are considered of childbearing potential unless they are
             surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or
             bilateral oophorectomy) or are postmenopausal. Menopause is defined clinically as 12
             months of amenorrhea in a woman over 45 in the absence of other biological or
             physiological causes. In addition, women under the age of 62 must have a documented
             serum follicle stimulating hormone (FSH) level greater than 40 mIU/mL.

          -  Women of childbearing potential must be willing to abstain from heterosexual activity
             or use an effective method of contraception from the time of informed consent until 90
             days after treatment discontinuation.

          -  Men who are sexually active with WOCBP must use any contraceptive method with a
             failure rate of less than 1% per year. Men receiving study drug and who are sexually
             active with WOCBP will be instructed to adhere to contraception for a period of 90
             days after the last dose of investigational product.

          -  As determined by the enrolling physician or protocol designee, ability of the subject
             to understand and comply with study procedures for the entire length of the study.

        Exclusion Criteria:

          -  History of a major surgical procedure (as defined by investigator) within 28 days
             prior to the first dose of study drug. NOTE: Local surgery for isolated lesions for
             palliative intent is acceptable.

          -  History of another primary malignancy except for a) malignancy treated with curative
             intent and with no known active disease ≥ 5 years before the first dose of study drug,
             b) adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
             disease, c) adequately treated carcinoma in situ without evidence of disease.

          -  History of leptomeningeal disease.

          -  Persons who have small cell carcinoma.

          -  Persons who do not meet the Stage IIIA NSCLC classification criteria outlined above.

          -  Presence of superior vena cava syndrome.

          -  Pregnant, breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 90 days after the last dose of trial treatment.

          -  Active central nervous system (CNS) metastases. Subjects must undergo a head computed
             tomography (CT) scan or brain MRI within 42 days prior to registration for protocol
             therapy to exclude brain metastases if symptomatic or without prior brain imaging.

          -  Treatment with any investigational agent within 28 days prior to registration for
             protocol therapy.

          -  Patients should not have received any prior therapy for the current diagnosis of
             NSCLC. Treatments done for previously diagnosed malignancies are permitted. Prior
             therapy with a PD-1, PD-L1 (including Durvalumab), PD-L2 or CTLA-4 inhibitor or a lung
             cancer-specific vaccine therapy are not permitted.

          -  Presence of metastatic disease (stage IV NSCLC) is not allowed. Subjects must be
             evaluated with a CT or PET scan prior to registration for protocol therapy to exclude
             metastatic disease.

          -  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

          -  Interstitial lung disease or history of pneumonitis requiring treatment with
             corticosteroids

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab. 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)

          -  History of psychiatric illness or social situations that would limit compliance with
             study requirements

          -  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 investigator.

               -  Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab may be included only after consultation with the
                  investigator.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the site investigator.

          -  Clinically significant acute infection requiring systemic antibacterial, antifungal,
             or antiviral therapy 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. Subjects with HIV/AIDS with adequate antiviral therapy to control viral
             load would be allowed. Subjects with viral hepatitis with controlled viral load would
             be allowed while on suppressive antiviral therapy. Testing not required.

          -  Has received a live vaccine within 30 days prior to planned start of study therapy.
             NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
             and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated vaccines, and are not allowed.

          -  History of allograft or allogeneic bone marrow transplant.