Tumor Treating Fields for Locally Advanced NSCLC

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 Criteria:
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, or IIIC 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 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.