Overview

The goal of this open-label, Phase 1 clinical trial is to determine the safety of TTFields started concurrently with SOC chemoradiation and during consolidation durvalumab in locally advanced, unresectable stage III non-small cell lung cancer (NSCLC). The main question it aims to answer is, "What is the rate of dose-limiting toxicities (DLTs) with TTFields in addition to concurrent chemoradiation and consolidation durvalumab?"

Step 1

• All participants will be screened and enrolled in Step 1 prior to SOC concurrent chemoradiation.
• The purpose of the Step 1 Registration is to ensure that eligible participants are candidate for concurrent chemoradiation and do not have contraindications to TTF therapy or immunotherapy.
• Starting Level: Participants in Device Duration Level 1 will receive standard of care concurrent chemoradiation following Step 1 Registration.
• Escalation Level : Participants in Device Duration Level 2 will begin standard of care chemoradiation and treatment with TTFields following Step 1 Registration.

Step 2

• All participants will complete Step 2 screening and enrollment prior to receiving treatment with durvalumab consolidation therapy and TTFields.
• The purpose of the Step 2 registration is to ensure that eligible patients meet criteria for consolidation durvalumab after completion of CRT and do not have contraindications to TTF. therapy or immunotherapy.

Eligibility

Inclusion Criteria:

Step 1: Pre-Chemoradiation Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC).
• Clinical AJCC (AJCC, 8th ed.) stage IIIA or IIIB NSCLC with unresectable disease. Staging FDG-PET/CT and MRI brain (preferred) or CT head with contrast scan must have been completed within 60 days prior to initiation of concurrent CRT. Unresectable disease must be determined by a multi-disciplinary team unless, in the opinion of the the treating investigator, the subject's disease is clearly unresectable. Subjects who refuse surgery will be considered to have unresectable disease.
• Able to operate the NovoTTF-200T System independently or with the help of a caregiver.
• Eligible to receive standard of care chemoradiation per institutional standards.
• Subject must have measurable disease by RECIST 1.1 criteria by CT.
• ECOG Performance Status ≤ 1.
• Adequate organ function as defined as:
• Hematologic:
  • Absolute neutrophil count (ANC) ≥ 1500/mm3
  • Platelet count ≥ 100,000/mm3
  • Hemoglobin ≥ 10 g/dL (transfusions are allowed for Device Duration Level 2 only if anemia is due to prior therapy.)
• Hepatic:
  • Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) or direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN.
  • AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
  • Subjects with liver metastases will be allowed to enroll with AST and ALT levels ≤ 5 x ULN.
• Renal:
  • Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula:
• Males:
  • ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72)
• Females:
  • (((140-age)×weight[kg])/(serum creatinine [mg/dL]×72))×0.85
• For subjects of childbearing potential:
  • Negative pregnancy test or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements

    apply

• Subjects < 50 years of age:
  • Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
  • Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or
  • Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Subjects ≥ 50 years of age:
  • Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
  • Had radiation-induced menopause with last menses >1 year ago; or
  • Had chemotherapy-induced menopause with last menses >1 year ago; or
  • Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
• Subjects of childbearing potential and subjects with a sexual partner of childbearing

  potential must agree to use a highly effective method of contraception as described in Section 4.6.

• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Step 2: Pre-Consolidative Immunotherapy Phase Inclusion Criteria

• The subject must have previously completed and been eligible for Step 1 registration.
• Completion of post-chemoradiation CT scan and RECIST 1.1 assessment.
• Eligible to receive consolidation immunotherapy per institutional standards and Investigator judgement.
• Able to operate the NovoTTF-200T System independently or with the help of a caregiver.
• ECOG Performance Status ≤ 1.
• Adequate organ function as defined as:
• Hematologic:
  • Absolute neutrophil count (ANC) ≥ 1500/mm3
  • Platelet count ≥ 100,000/mm3
  • Hemoglobin ≥ 10 g/dL (transfusions are allowed for Device Duration Level 2 only if anemia is due to prior therapy with concurrent chemoradiation.)
• Hepatic:
  • Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) or direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN.
  • AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
  • Subjects with liver metastases will be allowed to enroll with AST and ALT levels ≤ 5 x ULN.
• Renal:
  • Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula:
• Males:
  • ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72)
• Females:
  • (((140-age)×weight[kg])/(serum creatinine [mg/dL]×72))×0.85
• Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior

  cancer therapy (except for alopecia or fatigue) unless considered clinically not significant and/or stable by the treating investigator.

• Resolution of any pneumonitis from prior radiation therapy to < grade 1 per the treating investigator.

Exclusion Criteria:

Step 1: Pre-Chemoradiation Phase Exclusion Criteria

• Prior thoracic radiation, including breatbreast radiation.
• Prior exposure to TTFields.
• Prior systemic immunotherapy or radiotherapy for NSCLC.
• nown underlying skin hypersensitivity or known allergy to skin adhesives or hydrogel.
• Known hypersensitivity to radiation due to genetic susceptibility, connective tissue disease, or any other cause.
• Receiving other investigational agents.
• Major surgery (per treating investigator) within 4 weeks prior to starting study drug or who have not fully recovered from major surgery. Note: Biopsies without significant complications will not be considered major surgery.
• The diagnosis of another malignancy within ≤ 2 years before study enrollment, except for those considered to be adequately treated with no evidence of disease or symptoms and/or will not require therapy during the study duration (i.e., basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix, or low-grade prostate cancer with Gleason Score ≤ 6).
• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:
  • Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious or clinically significant cardiac arrhythmias.
  • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 3 months before the first dose.
  • QTc prolongation defined as a QTcF > 500 ms.
  • Known congenital long QT.
  • Left ventricular ejection fraction < 50%.
  • Uncontrolled hypertension defined as persistent blood pressure of ≥ 160/90 as assessed from the mean of three consecutive blood pressure measurements taken over 10 minutes.
  • Implanted pacemaker, defibrillator or other electrical medical devices;
  • Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [subjects may not receive the drug through a feeding tube], social/ psychological issues, etc.)
• Known HIV infection with a detectable viral load within 6 months of the anticipated

  start of treatment. Note: Subjects on effective antiretroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.

• Active known infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C. Note: 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.
• Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.
• History of allogenic stem cell or solid organ transplantation
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, uveitis, etc.]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia
  • Patients with endocrine disorders with controlled disease on hormone replacement therapy (e.g. adrenal, thyroid, or pituitary replacement therapy)
  • 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 principal investigator.
  • Patients with celiac disease controlled by diet alone
• Current or prior use of immunosuppressive medication within 14 days of cycle one day

  one, EXCEPT for the following permitted steroids:

  • Intranasal, inhaled, topical steroids, eye drops, or local steroid injection (e.g., intra-articular injection);
  • Systemic corticosteroids at physiologic doses ≤ 10mg/day of prednisone or equivalent;
  • Steroids as premedication for hypersensitivity reactions (e.g., computed tomography (CT) scan premedication).
• Subjects taking prohibited medications as described in Section 5.11. A washout period

  of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment.

• History of exudative pleural effusions, regardless of cytology.
• Peripheral neuropathy > grade 1 for patients receiving concurrent carboplatin and paclitaxel with radiation.

Step 2 Pre-Consolidative Immunotherapy Phase Exclusion Criteria

• Subjects who in the investigators opinion had disease progression following concurrent chemoradiation.
• Known underlying skin hypersensitivity or known allergy to skin adhesives or hydrogel.
• Major surgery (per treating investigator) 4 weeks prior to starting study drug or who have not fully recovered from major surgery.
• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:
  • Congestive heart failure New York Heart Association Class III or IV, unstable angina pectoris, serious or clinically significant cardiac arrhythmias.
  • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 3 months before the first dose.
  • QTc prolongation defined as a QTcF > 500 ms.
  • Known congenital long QT.
  • Left ventricular ejection fraction < 50%.
  • Uncontrolled hypertension defined as persistent blood pressure of ≥ 160/90 as assessed from the mean of three consecutive blood pressure measurements taken over 10 minutes.
  • Implanted pacemaker, defibrillator or other electrical medical devices;
  • Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [subjects may not receive the drug through a feeding tube], social/ psychological issues, etc.)
• Medical, psychiatric, cognitive, or other conditions that may compromise the subject's

  ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.

• History of allogenic stem cell or solid organ transplantation
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, uveitis, etc.]).
• The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia
  • Patients with endocrine disorders with controlled disease on hormone replacement therapy (e.g. adrenal, thyroid, or pituitary replacement therapy)
  • 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 principal investigator
  • Patients with celiac disease controlled by diet alone.
• Current or prior use of immunosuppressive medication within 14 days of cycle one day

  one, EXCEPT for the following permitted steroids:

  • Intranasal, inhaled, topical steroids, eye drops, or local steroid injection (e.g., intra-articular injection)
  • Systemic corticosteroids at physiologic doses ≤ 10mg/day of prednisone or equivalent
• History of exudative pleural effusions, regardless of cytology.