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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: ABTL0812
* Drug: Folfirinox
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed carcinoma, adenocarcinoma or ductal adenocarcinoma of the pancreas. Confirmed metastatic disease 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. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. Age, older than 18 years old Adequate hematologic function, measured as: absolute neutrophil count ≥ 1.5x109/L platelet count ≥ 100x109/L without transfusion support hemoglobin ≥ 10 g/dL Total bilirubin ≤ 1.5 x ULN Albumin ≥ 3.3 g/dL AST (SGOT) and ALT (SGPT) ≤ 2.5 times x upper limit of normal (≤ 5 times the ULN in patients with evidence of liver metastases) Alkaline phosphatase ≤ 2.5 times ULN (≤5 times the ULN in patients with evidence of liver metastases) Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 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. 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. Willing and able to provide informed consent Ability and willingness to comply with study visits, treatment, testing, and to comply with the protocol. Exclusion criteria Patients with any histology other than carcinoma, adenocarcinoma or ductal adenocarcinoma (such as squamous cell, acinar cell, medullary, colloid, neuroendocrine, etc) Patients has only locally advanced disease, resectable or borderline resectable. The patient has received chemotherapy as adjuvant therapy for locally advanced disease, resectable or borderline resectable. Patient has received previous abdominal radiotherapy, (with the exception of analgesic radiotherapy that was not performed on target lesions). Patients previously treated with an inhibitor of the PI3K/Akt/mTOR pathway by a systemic route. History of chronic diarrhea or inflammatory disease of the colon or rectum, or occlusion or sub-occlusion not resolved under symptomatic treatment Patient is pregnant or in lactation period. High sensitivity pregnancy test (urine or serum) to be performed within 7 days before study treatment starts. 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. 12-lead ECG with clinically relevant abnormality or showing a QTcF >450 ms, PR >210 ms, or QRS >120 ms at screening. 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. Patient has active Hepatitis B or C, human immunodeficiency virus (HIV) or Covid-19 infection with non-controlled disease according to the treating physician. Patients unable to provide informed consent like those under administrative or legal supervision

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blind, randomized, placebo-controlled, multicenter study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A) ABTL0812 + FOLFIRINOX<br>FOLFIRINOX will be dosed according to the standard following regimen: oxaliplatin 85 mg/m2, administered as 2-hour iv infusion leucovorin 400 mg/m2, administered as 2-hour iv infusion irinotecan 180 mg/m2, administered as 1.5-hour iv infusion fluorouracil 2400 mg/m2, administered as 46-hour iv infusion every 2 weeks (=1 cycle) until disease progression or unacceptable toxicities. ABTL0812 will be administered daily at its RP2D. ABTL0812 will be administered as single agent during a run-in period of one week before starting the first cycle of FOLFIRINOX, then daily during chemotherapy cycles. Also, ABTL0812 will be maintained once chemotherapy is discontinued, if ABTL0812 is tolerated and if the patient is in response or stable disease. | Drug: ABTL0812<br>* ABTL0812 will be administered daily at its RP2D. ABTL0812 will be administered as single agent during a run-in period of one week before starting the first cycle of FOLFIRINOX, then daily during chemotherapy cycles. Also, ABTL0812 will be maintained once chemotherapy is discontinued, if ABTL0812 is tolerated and if the patient is in response or stable disease.<br>Drug: Folfirinox<br>* FOLFIRINOX will be dosed according to the standard following regimen: oxaliplatin 85 mg/m2, administered as 2-hour iv infusion leucovorin 400 mg/m2, administered as 2-hour iv infusion irinotecan 180 mg/m2, administered as 1.5-hour iv infusion fluorouracil 2400 mg/m2, administered as 46-hour iv infusionevery 2 weeks (=1 cycle) until disease progression or unacceptable toxicities.<br>* Other names: Chemotherapy;|
| Experimental: Arm B) PLACEBO + FOLFIRINOX<br>FOLFIRINOX will be dosed according to the standard following regimen: oxaliplatin 85 mg/m2, administered as 2-hour iv infusion leucovorin 400 mg/m2, administered as 2-hour iv infusion irinotecan 180 mg/m2, administered as 1.5-hour iv infusion fluorouracil 2400 mg/m2, administered as 46-hour iv infusion every 2 weeks (=1 cycle) until disease progression or unacceptable toxicities. Placebo will be administered at the same volume than ABTL0812 in arm A) FOLFIRINOX, then daily during chemotherapy cycles. Also, placebo will be maintained once chemotherapy is discontinued. | Drug: ABTL0812<br>* ABTL0812 will be administered daily at its RP2D. ABTL0812 will be administered as single agent during a run-in period of one week before starting the first cycle of FOLFIRINOX, then daily during chemotherapy cycles. Also, ABTL0812 will be maintained once chemotherapy is discontinued, if ABTL0812 is tolerated and if the patient is in response or stable disease.<br>Drug: Placebo<br>* Placebo will be administered daily at the same regim as ABTL0812. Placebo will be administered as single agent during a run-in period of one week before starting the first cycle of FOLFIRINOX, then daily during chemotherapy cycles. Also, placebo will be maintained once chemotherapy is discontinued, if the patient is in response or stable disease.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - RP2D | Recommended Phase II Dose (RP2D) of ABTL0812 in combination with FOLFIRINOX | 5 weeks | 
| Phase II - PFS | PFS using RECIST v1.1 by central review | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | PFS using RECIST v1.1 by investigator analysis | 1 year | 
| ORR | Objective response rate | 1 year | 
| PFS 6 m | PFS | 6 months | 
| TTR | Time to response | 1 year | 
| DOR | Duration of response | 1 year | 
| OS | Overall survival | 5 years | 
| OS 1y | Overall survival | 1 year | 
| Adverse events | Number of participants with Adverse Events (AE). AEs classified according to CTCAE v5.0 | 1 year |