ABTL0812 in Combination With FOLFIRINOX for First-line Treatment of Metastatic Pancreatic Study (PanC-ASAP)

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.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: ABTL0812; Drug: Folfirinox; Drug: Placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Marc Cortal; Phone Number: +34603141706; Email: contact@abilitypharma.com

Study Locations

• France
  • Dijon, France, 21000
    • CGFL Dijon
  • Marseille, France, 13009
    • Institute Paoli-Calmettes
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Israel
  • Haifa, Israel
    • Rabam MC
  • Jerusalem, Israel
    • Shaare Zedek Mc
  • Ramat Gan, Israel
    • Sheba MC
• Spain
  • Alicante, Spain, 03010
    • Hospital General Universitario Dr. Balmis
  • Barcelona, Spain, 08035
    • Vall d'Hebron University Hospital
  • Barcelona, Spain, 08023
    • Hospital Quiron Salud
  • Girona, Spain, 17007
    • Ico Girona
  • Lleida, Spain, 25198
    • Hospital Universitari Arnau de Vilanova
  • Madrid, Spain, 28009
    • Hospital Gregorio Marañón
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Murcia, Spain, 30008
    • Hospital General Universitario Morales Meseguer
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocío
  • Toledo, Spain, 45007
    • Hospital Universitario de Toledo
  • Valencia, Spain, 46010
    • Hospital Universitario de Valencia
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Ico Badalona
  • Galicia
    • A Coruña, Galicia, Spain, 15009
      • Centro Oncológico de Galicia
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai
  • Kansas
    • Westwood, Kansas, United States, 66205-0000
      • University of Kansas Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A) ABTL0812 + FOLFIRINOX; 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; 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: Folfirinox; 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.; Other Names: Chemotherapy
Experimental: Arm B) PLACEBO + FOLFIRINOX; 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; 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: Placebo; 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.

What is the study measuring?

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
OS	Overall survival	5 years
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 1y	Overall survival	1 year
Adverse events	Number of participants with Adverse Events (AE). AEs classified according to CTCAE v5.0	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK - Cmax	Determination of peak plasma concentration	1 month
PK - AUC	Determinatoin of Area under the plasma concentration versus time curve	1 month
Quality of Life Questionnaire QLC-C30	Quality of life measured with questionnaires QLC-C30	1 year
Quality of Life Questionnaire QLQ-PAN26	Quality of life measured with questionnaires QLQ-PAN26	1 year

Collaborators and Investigators

• Sponsor: Ability Pharmaceuticals SL
• Investigators: Study Director: Marc Cortal, Ability Pharmaceuticals SL

Publications and helpful links

General Publications

• Erazo T, Lorente M, Lopez-Plana A, Munoz-Guardiola P, Fernandez-Nogueira P, Garcia-Martinez JA, Bragado P, Fuster G, Salazar M, Espadaler J, Hernandez-Losa J, Bayascas JR, Cortal M, Vidal L, Gascon P, Gomez-Ferreria M, Alfon J, Velasco G, Domenech C, Lizcano JM. The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase. Clin Cancer Res. 2016 May 15;22(10):2508-19. doi: 10.1158/1078-0432.CCR-15-1808. Epub 2015 Dec 15.
• Munoz-Guardiola P, Casas J, Megias-Roda E, Sole S, Perez-Montoyo H, Yeste-Velasco M, Erazo T, Dieguez-Martinez N, Espinosa-Gil S, Munoz-Pinedo C, Yoldi G, Abad JL, Segura MF, Moran T, Romeo M, Bosch-Barrera J, Oaknin A, Alfon J, Domenech C, Fabrias G, Velasco G, Lizcano JM. The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells. Autophagy. 2021 Jun;17(6):1349-1366. doi: 10.1080/15548627.2020.1761651. Epub 2020 May 25.
• Felip I, Moiola CP, Megino-Luque C, Lopez-Gil C, Cabrera S, Sole-Sanchez S, Munoz-Guardiola P, Megias-Roda E, Perez-Montoyo H, Alfon J, Yeste-Velasco M, Santacana M, Dolcet X, Reques A, Oaknin A, Rodriguez-Freixinos V, Lizcano JM, Domenech C, Gil-Moreno A, Matias-Guiu X, Colas E, Eritja N. Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer. Gynecol Oncol. 2019 May;153(2):425-435. doi: 10.1016/j.ygyno.2019.03.002. Epub 2019 Mar 7.
• Lopez-Plana A, Fernandez-Nogueira P, Munoz-Guardiola P, Sole-Sanchez S, Megias-Roda E, Perez-Montoyo H, Jauregui P, Yeste-Velasco M, Gomez-Ferreria M, Erazo T, Ametller E, Recalde-Percaz L, Moragas-Garcia N, Noguera-Castells A, Mancino M, Moran T, Nadal E, Alfon J, Domenech C, Gascon P, Lizcano JM, Fuster G, Bragado P. The novel proautophagy anticancer drug ABTL0812 potentiates chemotherapy in adenocarcinoma and squamous nonsmall cell lung cancer. Int J Cancer. 2020 Aug 15;147(4):1163-1179. doi: 10.1002/ijc.32865. Epub 2020 Feb 6.
• Vidal L, Victoria I, Gaba L, Martin MG, Brunet M, Colom H, Cortal M, Gomez-Ferreria M, Yeste-Velasco M, Perez A, Rodon J, Sohal DPS, Lizcano JM, Domenech C, Alfon J, Gascon P. A first-in-human phase I/Ib dose-escalation clinical trial of the autophagy inducer ABTL0812 in patients with advanced solid tumours. Eur J Cancer. 2021 Mar;146:87-94. doi: 10.1016/j.ejca.2020.12.019. Epub 2021 Feb 12.
• Paris-Coderch L, Soriano A, Jimenez C, Erazo T, Munoz-Guardiola P, Masanas M, Antonelli R, Boloix A, Alfon J, Perez-Montoyo H, Yeste-Velasco M, Domenech C, Roma J, Sanchez de Toledo J, Moreno L, Lizcano JM, Gallego S, Segura MF. The antitumour drug ABTL0812 impairs neuroblastoma growth through endoplasmic reticulum stress-mediated autophagy and apoptosis. Cell Death Dis. 2020 Sep 17;11(9):773. doi: 10.1038/s41419-020-02986-w.
• Mancini A, Colapietro A, Cristiano L, Rossetti A, Mattei V, Gravina GL, Perez-Montoyo H, Yeste-Velasco M, Alfon J, Domenech C, Festuccia C. Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models. Front Oncol. 2022 Nov 2;12:943064. doi: 10.3389/fonc.2022.943064. eCollection 2022.
• Polonio-Alcala E, Sole-Sanchez S, Munoz-Guardiola P, Megias-Roda E, Perez-Montoyo H, Yeste-Velasco M, Alfon J, Lizcano JM, Domenech C, Ruiz-Martinez S, Puig T. ABTL0812 enhances antitumor effect of paclitaxel and reverts chemoresistance in triple-negative breast cancer models. Cancer Commun (Lond). 2022 Jun;42(6):567-571. doi: 10.1002/cac2.12282. Epub 2022 Mar 16. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2021
• Primary Completion (Actual): January 10, 2024
• Study Completion (Actual): January 10, 2024

Study Registration Dates

• First Submitted: May 27, 2020
• First Submitted That Met QC Criteria: June 12, 2020
• First Posted (Actual): June 16, 2020

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Antineoplastic Agents; Folfirinox
• Other Study ID Numbers: ABT-C11-2020; 2020-002791-13 (EudraCT Number); FD-R-006817-01 (Other Grant/Funding Number: FDA OOPD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No