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

Pancreatic Cancer Clinical Trial

— PanC-ASAP  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04431258
• Other study ID #: ABT-C11-2020
• Secondary ID: 2020-002791-13FD
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 6, 2021
• Est. completion date: January 10, 2024

Study information

• Verified date: March 2024
• Source: Ability Pharmaceuticals SL
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: January 10, 2024
• Est. primary completion date: January 10, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Pancreatic Cancer

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
France	CGFL Dijon	Dijon
France	Institute Paoli-Calmettes	Marseille
France	Institut Gustave Roussy	Villejuif
Israel	Rabam MC	Haifa
Israel	Shaare Zedek MC	Jerusalem
Israel	Sheba MC	Ramat Gan
Spain	Centro Oncológico de Galicia	A Coruña	Galicia
Spain	Hospital General Universitario Dr. Balmis	Alicante
Spain	ICO Badalona	Badalona	Barcelona
Spain	Hospital Quiron Salud	Barcelona
Spain	Vall d'Hebron University Hospital	Barcelona
Spain	ICO Girona	Girona
Spain	Hospital Universitari Arnau de Vilanova	Lleida
Spain	Hospital Gregorio Marañón	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital General Universitario Morales Meseguer	Murcia
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Universitario de Toledo	Toledo
Spain	Hospital Universitario de Valencia	Valencia
Spain	Hospital Universitario Miguel Servet	Zaragoza
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Cincinnati	Cincinnati	Ohio
United States	Cedars Sinai	Los Angeles	California
United States	University of Kansas Cancer Center	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Ability Pharmaceuticals SL

Countries where clinical trial is conducted

United States,  France,  Israel,  Spain, 

References & Publications (7)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	PK - Cmax	Determination of peak plasma concentration	1 month
Other	PK - AUC	Determinatoin of Area under the plasma concentration versus time curve	1 month
Other	Quality of Life Questionnaire QLC-C30	Quality of life measured with questionnaires QLC-C30	1 year
Other	Quality of Life Questionnaire QLQ-PAN26	Quality of life measured with questionnaires QLQ-PAN26	1 year
Primary	Phase I - RP2D	Recommended Phase II Dose (RP2D) of ABTL0812 in combination with FOLFIRINOX	5 weeks
Primary	Phase II - PFS	PFS using RECIST v1.1 by central review	1 year
Secondary	PFS	PFS using RECIST v1.1 by investigator analysis	1 year
Secondary	ORR	Objective response rate	1 year
Secondary	PFS 6 m	PFS	6 months
Secondary	TTR	Time to response	1 year
Secondary	DOR	Duration of response	1 year
Secondary	OS	Overall survival	5 years
Secondary	OS 1y	Overall survival	1 year
Secondary	Adverse events	Number of participants with Adverse Events (AE). AEs classified according to CTCAE v5.0	1 year