TTFields and Chemotherapy in Metastatic Pancreatic Adenocarcinoma (mPDAC)

Phase Ib-II, Non-randomized, Open-label Study of Tumor Treating Fields (TTFields, 150 kHz) Concomitant With modFOLFIRINOX for Front-line Treatment of Metastatic Pancreatic Adenocarcinoma (NOVOFFOX)

The purpose of this clinical trial is to assess the safety and tolerability of TTFields in combination with chemotherapy in adults with metastatic pancreatic adenocarcinoma based on treatment-emergent adverse events of chemotherapy (modFOLFIRINOX) or device (TTFields).

The main questions it aims to answer are:

• Is TTFields treatment safe for the patients in combination with modFOLFIRINOX?
• Are participants compliant with the treatment?
• Is Is TTFields treatment effective in combination with modFOLFIRINOX against metastatic pancreatic adenocarcinoma?

This is a phase Ib-II, non-randomized, open-label, one arm, multi-center study of the combination of NovoTTF-200T system with modFOLFIRINOX for the evaluation of the safety of the treatment in patients with metastatic pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the eight cause of cancer mortality in men and ninth in women worldwide. Nearly 50,000 patients are diagnosed annually and almost all of them are expected to die from the disease without any challenges in survival in the last decade. Unfortunately, in most of the cases the disease is already disseminated when tumor related symptoms appear, with 5-year survival rate of less than 8 percent in this population (Siegel et al, 2020).

Tumor Treating Fields (TTFields) are a non-invasive regional antimitotic treatment with minimal toxicity. TTFields act by delivering alternate low-intensity electric fields (1-3 V/cm), intermediate frequency (100-300 kHz), and alternating electric fields to the tumor using non-invasive transducer arrays placed on the skin around the region of the body containing the tumor. TTFields act predominantly during two phases of mitosis: 1) during metaphase, by disrupting the formation of the mitotic spindle; and 2) during cytokinesis, by dielectrophoretic dislocation of intracellular constituents, leading apoptosis.

There is an increasing interest in the addition of immunotherapy to treatment pancreatic adenocarcinoma. Thus, combining TTFields with immunotherapy represents an interest for future clinical trials. However, the combination of TTFields with FOLFIRINOX chemotherapy scheme has not been evaluated yet. In this trial, it is proposed to evaluate the combination of TTFields with modFOLFIRINOX chemotherapy in metastatic PDAC patients with liver metastases. The aim is to analyze both the safety of combining TTFields with modFOLFIRINOX chemotherapy scheme, and to study the potential effect of TTFields and chemotherapy on the TME of liver metastasis.

Each patient shall participate in the trial for a maximum of 24 months. The trial will consist in two consecutive parts:

• A first part (Phase Ib) consisting of a safety run-in cohort: This first part will include 6 patients that will be treated with standard dose of modFOLFIRINOX scheme combined with TTFields.
• A second part (Phase II) consisting of an expansion cohort in which the rest of accorded patients will be included.

Inclusion Criteria:

All the patients should comply with the following criteria for inclusion:

1. Histological/cytological diagnosis of pancreatic adenocarcinoma.

2. The patient should be 18 years of age and older.

3. The patient has given consent to participate in the study.

4. The patient should be able to comply with all the requirements of the clinical trial.

5. Life expectancy of at least 3 months.

6. Metastatic disease with, at least, one hepatic lesion that must be accessible for biopsy.

7. Measurable disease as defined by Response Evaluation Criteria in Solid Tumor v1.1 (RECIST 1.1) apart from the liver lesion to be biopsied.

8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

9. Amenable and assigned by the investigator to receive therapy with modFOLFIRINOX.

10. Prior chemotherapy or radiotherapy on the neoadjuvant or adjuvant setting is allowed as long as at least six months have elapsed since last chemotherapy treatment.

11. Able to operate the Novo TTF-200T System independently or with the help of a caregiver.

12. Adequate hematologic and organ function, defined by the following laboratory test results, obtained during the screening period and before C1D1.

    1. WBC higher than or equal to 2.5 x 10^9/L.
    2. ANC higher than or equal to 1.5 x 10^9/L without granulocyte colony-stimulating factor support.
    3. Platelet count higher than or equal to 100 x 10^9/L without transfusion.
    4. Hemoglobin higher than or equal to 9 g/dL. Patients may be transfused to meet this criterion.
    5. Albumin higher than or equal to 2.5 g/dL.
    6. Serum bilirubin lower than or equal to 1.5 times the upper limit of normal (ULN); patients with known Gilbert´s disease may have a bilirubin value lower than or equal to 3 x ULN.
    7. INR and aPTT lower than or equal to 1.5 x ULN.
    8. AST, ALT, lower than or equal to 5 x ULN.
    9. Serum creatinine lower than or equal to 1.5 x ULN or Creatinine Clearance higher than or equal to 30ml/min (calculated using Cockcroft-Gault formula).

13. For women of childbearing potential: Negative serum pregnancy test within 14 days prior to C1D1. Agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of lower than or equal to 1 percentage per year during the treatment period (combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal o transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable o implantable); intrauterine device (IUD) or intrauterine hormone-releasing system (IUS); bilateral tubal occlusion or vasectomized partner) and for at least 180 days after the last study treatment. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (higher than or equal to 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).

Exclusion Criteria:

Patients who present any of the following criteria for exclusion cannot be included in the clinical trial:

1. Malignancies other than pancreatic cancer within 3 years prior to Cycle 1 Day 1 (C1D1) with the exceptions of those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival higher than 90 percentage), treated with expected curative outcome (such as but not limited to: adequately treated in situ carcinoma of the cervix, basal squamous or melanomatous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ of the breast treated surgically with curative intent).

2. Previous treatment with chemotherapy for metastatic pancreatic ductal adenocarcinoma.

3. Untreated CNS metastases. Treatment of brain metastases, either by surgical or radiation techniques, must have been completed at least 4 weeks prior to study entry.

4. Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene polymorphism predisposing the patient for 5-fluorouracil (5-FU) toxicity.

5. Previous radiation therapy within 14 days prior to C1D1 and/or persistence of radiation-related adverse effects.

6. Implantable electronic medical devices in the torso, such as pacemakers.

7. Known severe hypersensitivities to medical adhesives or hydrogel, or history of severe allergic, anaphylactic, or other hypersensitivity reactions to any of the study treatments used.

8. Spinal cord compression not definitively treated with surgery and/or radiation.

9. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.

10. Pregnant and lactating women

11. Patients who have received brivudine, sorivudine or analogues 4 weeks prior to Fluoracile administration.

12. Serious co-morbidities, including but not limited to:

    1. History of significant cardiovascular disease unless the disease is well controlled. Significant cardiac disease includes second/third degree hart block; significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of the New York Heart Association (NYHA) Class II or worse.
    2. History of cerebrovascular accident (CVA) within 3 months prior to randomization or that is not stable.
    3. Active infection or serious underlying medical condition that would impair the ability of the patient to receive protocol therapy.
    4. History of any psychiatric condition that might impair patient´s ability to understand or comply with the requirements of the study or to provide consent.