ABTL0812 in Combination With FOLFIRINOX for First-line Treatment of Metastatic Pancreatic Study

A Phase I Open Label Followed by a Phase II Randomized, Controlled Study to Assess the Efficacy and Safety of ABTL0812 in Combination With FOLFIRINOX for First-line Treatment of Metastatic Pancreatic

A Phase I open label followed by a Phase II randomized, controlled study to assess the efficacy and safety of ABTL0812 in combination with FOLFIRINOX for first-line treatment of metastatic pancreatic. Funded by: FDA OOPD (Grant #FD-R-006817-01), H2020 EIC Accelerator (Grant #954825) and Ability Pharmaceuticals SL.

Phase I: This is an open label Phase I to determine the RP2D of ABTL0812 in combination with FOLFIRINOX. All patients will receive ABTL0812 in combination with FOLFIRINOX.

A dose de-escalation phase will be performed in which up to 3 different ABTL0812 dose levels will be tested in combination with FOLFIRINOX. ABTL0812 doses are: 1300 mg tid (starting dose), followed (if necessary) by 975 mg tid and 650 mg tid. Patient intra-escalation is not allowed.

Phase II: This is a double blind, randomized, placebo-controlled Phase II multicenter study to evaluate ABTL0812 in combination with FOLFIRINOX for first-line treatment of metastatic pancreatic cancer. Patients will be randomized to one of two groups: arm A) receiving ABTL0812 in addition to FOLFIRINOX and arm B) receiving FOLFIRINOX plus placebo.

Arm A) ABTL0812 + FOLFIRINOX Arm B) PLACEBO + FOLFIRINOX

Inclusion Criteria:

1. Histologically or cytologically confirmed carcinoma, adenocarcinoma or ductal adenocarcinoma of the pancreas.

2. Confirmed metastatic disease

3. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 guidelines with at least one "target lesion" to be used to assess response. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.

5. Age, older than 18 years old

6. Adequate hematologic function, measured as:

   • absolute neutrophil count ≥ 1.5x109/L
   • platelet count ≥ 100x109/L without transfusion support
   • hemoglobin ≥ 10 g/dL

7. Total bilirubin ≤ 1.5 x ULN

8. Albumin ≥ 3.3 g/dL

9. AST (SGOT) and ALT (SGPT) ≤ 2.5 times x upper limit of normal (≤ 5 times the ULN in patients with evidence of liver metastases)

10. Alkaline phosphatase ≤ 2.5 times ULN (≤5 times the ULN in patients with evidence of liver metastases)

11. Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2

12. Only for Phase II patients. If available, a sample of tumor tissue or cytology (either archival or new tumor biopsy) for biomarker analyses. The most recently collected tumor tissue sample should be provided.

13. Contraception: All premenopausal female patients must use contraception. Male patients and their female partners (if fertile), must use contraception as well. In both cases, contraception means two forms of highly effective contraception during the study and for a period of 6 months following the last administration of the study drug.

14. Willing and able to provide informed consent

15. Ability and willingness to comply with study visits, treatment, testing, and to comply with the protocol.

Exclusion criteria

1. Patients with any histology other than carcinoma, adenocarcinoma or ductal adenocarcinoma (such as squamous cell, acinar cell, medullary, colloid, neuroendocrine, etc)
2. Patients has only locally advanced disease, resectable or borderline resectable.
3. The patient has received chemotherapy as adjuvant therapy for locally advanced disease, resectable or borderline resectable.
4. Patient has received previous abdominal radiotherapy, (with the exception of analgesic radiotherapy that was not performed on target lesions).
5. Patients previously treated with an inhibitor of the PI3K/Akt/mTOR pathway by a systemic route.
6. History of chronic diarrhea or inflammatory disease of the colon or rectum, or occlusion or sub-occlusion not resolved under symptomatic treatment
7. Patient is pregnant or in lactation period. High sensitivity pregnancy test (urine or serum) to be performed within 7 days before study treatment starts.
8. Patient had myocardial infarction within ≤ 6 months prior to study entry, LVEF <50%, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina pectoris, or unstable cardiac arrhythmia requiring medication.
9. 12-lead ECG with clinically relevant abnormality or showing a QTcF >450 ms, PR >210 ms, or QRS >120 ms at screening.
10. Patients with any other medical conditions (such as psychiatric illness, cardiovascular disease, infectious diseases, abnormal physical examination or laboratory findings) that in the opinion of the investigator may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.
11. Patient has active Hepatitis B or C, human immunodeficiency virus (HIV) or Covid-19 infection with non-controlled disease according to the treating physician.
12. Patients unable to provide informed consent like those under administrative or legal supervision