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

NCT04431258 | Completed Phase 1 FDA Drug

• 3 other identifiers: ABT-C11-20202020-002791-13FD-R-006817-01
• Study Type: interventional
• Target: 150
• Locations: 4 countries
• Sites: 24

Brief Summary

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.

Conditions

Pancreatic Cancer

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (8)

• PFS

  1 year

• ORR

  1 year

• PFS 6 m

  6 months

• TTR

  1 year

• DOR

  1 year

Other Outcomes (4)

• PK - Cmax

  1 month

• PK - AUC

  1 month

• Quality of Life Questionnaire QLC-C30

  1 year

Study Arms (2)

Arm A) ABTL0812 + FOLFIRINOX

EXPERIMENTAL

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; Drug: Folfirinox

Arm B) PLACEBO + FOLFIRINOX

EXPERIMENTAL

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; Drug: Placebo

Interventions

ABTL0812 DRUG

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.

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

Folfirinox DRUG

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.

Also known as: Chemotherapy

Arm A) ABTL0812 + FOLFIRINOX

Placebo DRUG

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.

Arm B) PLACEBO + FOLFIRINOX

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Ability Pharmaceuticals SL: lead

Study Sites (24)

Cedars Sinai

Los Angeles, California, 90048, United States

Location

University of Kansas Cancer Center

Westwood, Kansas, 66205-0000, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45267, United States

Location

CGFL Dijon

Dijon, 21000, France

Location

Institute Paoli-Calmettes

Marseille, 13009, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

Rabam MC

Haifa, Israel

Location

Shaare Zedek MC

Jerusalem, Israel

Location

Sheba MC

Ramat Gan, Israel

Location

ICO Badalona

Badalona, Barcelona, 08916, Spain

Location

Centro Oncológico de Galicia

A Coruña, Galicia, 15009, Spain

Location

Hospital General Universitario Dr. Balmis

Alicante, 03010, Spain

Location

Hospital Quiron Salud

Barcelona, 08023, Spain

Location

Vall d'Hebron University Hospital

Barcelona, 08035, Spain

Location

ICO Girona

Girona, 17007, Spain

Location

Hospital Universitari Arnau de Vilanova

Lleida, 25198, Spain

Location

Hospital Gregorio Marañón

Madrid, 28009, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital General Universitario Morales Meseguer

Murcia, 30008, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

Hospital Universitario de Toledo

Toledo, 45007, Spain

Location

Hospital Universitario de Valencia

Valencia, 46010, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, 50009, Spain

Location

Related Publications (8)

• 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.

  PMID: 26671995 BACKGROUND

• 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.

  PMID: 32397857 BACKGROUND

• 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.

  PMID: 30853360 BACKGROUND

• 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.

  PMID: 31943158 BACKGROUND

• 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.

  PMID: 33588149 BACKGROUND

• 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.

  PMID: 32943619 BACKGROUND

• 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.

  PMID: 36408162 BACKGROUND

• 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.

  PMID: 35293148 DERIVED

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

ABTL0812; folfirinox; Drug Therapy

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Marc Cortal

  Ability Pharmaceuticals SL

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Double blind, randomized, placebo-controlled, multicenter study

Study Record Dates

• First Submitted: May 27, 2020
• First Posted: June 16, 2020
• Study Start: May 6, 2021
• Primary Completion: January 10, 2024
• Study Completion: January 10, 2024
• Last Updated: March 18, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (3); IL (3); US (4); ES (14)