Effect of Tumor Treating Fields (TTFields, 150 kHz) as Front-Line Treatment of Locally-advanced Pancreatic Adenocarcinoma Concomitant With Gemcitabine and Nab-paclitaxel (PANOVA-3)

Brief Summary: The study is a prospective, randomized controlled phase III trial aimed to test the efficacy and safety of Tumor Treating Fields (TTFields) in combination with gemcitabine and nab-paclitaxel, for front line treatment of locally-advanced pancreatic adenocarcinoma.The device is an experimental, portable, battery operated device for chronic administration of alternating electric fields (termed TTFields or TTF) to the region of the malignant tumor, by means of surface, insulated electrode arrays.

PAST PRE-CLINICAL AND CLINICAL EXPERIENCE: The effect of the electric fields (TTFields, TTF) has demonstrated significant activity in in vitro and in vivo pancreatic adenocarcinoma pre-clinical models both as a single modality treatment and in combination with chemotherapies. TTFields have been demonstrated to act synergistically with taxanes and have been shown to be additive when combined with other chemotherapies including gemcitabine. In addition, TTFields have shown to inhibit metastatic spread of malignant melanoma in in vivo experiment. In a pilot study, 40 patients with locally advanced or metastatic pancreatic adenocarcinoma received gemcitabine together with TTFields (150 kHz) or gemcitabine and nab-paclitaxel together with TTFields (150 kHz) applied to the abdomen until disease progression. The combination was well tolerated and the only device-related adverse event was contact dermatitis. In addition, a phase III trial of Optune® (200 kHz) as monotherapy compared to active chemotherapy in recurrent glioblastoma patients showed TTFields to be equivalent to active chemotherapy in extending survival, associated with minimal toxicity, good quality of life, and activity within the brain (14% response rate) (Stupp R., et al., EJC 2012). Finally, a phase III trial of Optune® combined with maintenance temozolomide compared to maintenance temozolomide alone has shown that combined therapy led to a significant improvement in both progression free survival and overall survival in patients with newly diagnosed glioblastoma without the addition of high grade toxicity and without decline in quality of life (Stupp R., et al., JAMA 2017). DESCRIPTION OF THE TRIAL: All patients included in this trial are patients with locally advanced pancreatic adenocarcinoma. In addition, all patients must meet all eligibility criteria. Eligible patients will be randomly assigned to one of two groups: 1. Patients receive gemcitabine and nab-paclitaxel in combination with TTFields using the NovoTTF-200T System. 2. Patients receive gemcitabine and nab-paclitaxel without TTFields. Patients will be randomized at a 1:1 ratio. Baseline tests will be performed in patients enrolled in both arms. If assigned to the NovoTTF-200T group, the patients will be treated continuously with the device until progression in the abdomen. On both arms, patients who have progression outside the abdomen will switch to a second line treatment according to local practice. SCIENTIFIC BACKGROUND: …

Device: NovoTTF-200T. Patients receive continuous TTFields treatment using the NovoTTF-200T device. TTFields treatment will consist of wearing four electrically insulated electrode arrays on the torso. The treatment enables the patient to maintain regular daily routine.

Drug: Gemcitabine. Gemcitabine 1000 mg/m\^2 over 30 minute infusion will be administered immediately after nab-paclitaxel on Days 1, 8 and 15 of each 28-day cycle.

Drug: nab paclitaxel. nab-paclitaxel 125 mg/m\^2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle.

NovoTTF-200T (experimental): Patients receive TTFields using the NovoTTF-200T System together with gemcitabine and nab-Paclitaxel

Best Standard of Care (active comparator): Patients receive best standard of care with gemcitabine and nab-Paclitaxel

Overall Survival of Subjects Treated With TTFields Concomitant With Gemcitabine and Nab-paclitaxel vs Chemotherapy Alone. Overall survival of subjects treated with TTFields concomitant with gemcitabine and nab-paclitaxel in the first line treatment of unresectable, locally advanced pancreatic cancer subjects, compared to overall survival of subjects treated with chemotherapy alone, measured as the period between the time of randomization and the time of death. Time frame: From randomization until death from any cause or last known alive..

Progression-free Survival of Subjects Treated With TTFields Concomitant With Gemcitabine and Nab-paclitaxel vs Chemotherapy Alone. Time frame: From randomization until radiologic disease progression per RECIST v1.1 or death, whichever occurs first..

Local Progression-free Survival of Subjects Treated With TTFields Concomitant With Gemcitabine and Nab-paclitaxel vs Chemotherapy Alone. Time frame: From randomization until local disease progression per RECIST v1.1 (in the absence of distant metastasis) or death, whichever occurs first..

Objective Response Rate of Subjects Treated With TTFields Concomitant With Gemcitabine and Nab-paclitaxel vs Chemotherapy Alone. Time frame: From randomization until radiologic disease progression per RECIST v1.1 or end of tumor assessment follow-up..

One-year Survival Rate of Subjects Treated With TTFields Concomitant With Gemcitabine and Nab-paclitaxel vs Chemotherapy Alone. Time frame: From randomization through 12 months after randomization..

Quality of Life of Subjects Treated With TTFields Concomitant With Gemcitabine and Nab-paclitaxel vs Chemotherapy Alone. Time frame: From randomization until the first ≥10-point deterioration without subsequent improvement, or death, assessed for the duration of study follow-up..

Pain-free Survival of Subjects Treated With TTFields Concomitant With Gemcitabine and Nab-paclitaxel vs Chemotherapy Alone. Time frame: From randomization until a ≥20-point increase from baseline in pain on the patient-reported visual analogue scale (0-100) or death, whichever occurs first..

Inclusion Criteria: 1. 18 years of age and older 2. Life expectancy of ≥ 3 months 3. Histological/cytological diagnosis of de novo adenocarcinoma of the pancreas 4. Unresectable, locally advanced stage disease according to the following criteria: * Head/uncinate process: 1. Solid tumor contact with SMA\>180° 2. Solid tumor contact with the CA\>180° 3. Solid tumor contact with the first jejunal SMA branch 4. Unreconstructible SMV/PV due to tumor involvement or occlusion (can be d/t tumor or bland thrombus) 5. Contact with most proximal draining jejunal branch into SMV * Body and tail 1. Solid tumor contact of \>180° with the SMA or CA 2. Solid tumor contact with the CA and aortic involvement 3. Unreconstructible SMV/PV due to tumor involvement or occlusion (can be d/t tumor or bland thrombus) * No distant metastasis, including non-regional lymph node metastasis * No borderline resectable (per Al-Hawary MM, et al., Radiology 201414) 5. ECOG score 0-2 6. Amenable and assigned by the investigator to receive therapy with gemcitabine and nab-paclitaxel 7. Able to operate the NovoTTF-200T System independently or with the help of a caregiver 8. Signed informed consent form for the study protocol Exclusion Criteria: 1. Prior palliative treatment (e.g. surgery, radiation) to the tumor 2. Cancer requiring anti-tumor treatment within the 5 years before inclusion, excluding treated stage I prostate cancer, in situ cervical or uterus cancer, in situ breast cancer and non-melanomatous skin cancer. 3. Serious co-morbidities: 1. Clinically significant (as determined by the investigator) hematological, hepatic and renal dysfunction, defined as: Neutrophil count \< 1.5 x 10\^9/L and platelet count \< 100 x 10\^9/L; bilirubin \> 1.5 x Upper Limit of Normal (ULN); AST and/or ALT \> 2.5 x ULN; and serum creatinine \> 1.5 x ULN. 2. History of significant cardiovascular disease unless the disease is well controlled. Significant cardiac disease includes second/third degree heart block; significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of the New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary activity results in fatigue, palpitation or dyspnea). 3. History of arrhythmia that is symptomatic or requires treatment. Patients with atrial fibrillation or flutter controlled by medication are not excluded from participation in the trial. 4. History of cerebrovascular …

Enrollment: 571 participants (actual).