A Study of ABTL0812 in Pancreatic Cancer

A Randomized Phase I/II Open Label Study to Assess the Efficacy and Safety of ABTL0812 in Combination With Gemcitabine and Nab-paclitaxel in Patients With Advanced Metastatic Pancreatic Cancer at First Line Therapy.

This is an open-label, randomized phase I/II multicenter study to evaluate ABTL0812 in combination with gemcitabine and nab-paclitaxel at first line therapy. Patients will be assigned to the following groups during the study conduct:

* GROUP A: You will receive the standard treatment of chemotherapy and the investigational drug ABTL0812.
* GROUP B: You will receive the standard treatment of chemotherapy.

For GROUP A:

Phase I: A 3+3 de-escalation design followed by an expansion phase will be performed

* ABTL0812 will be administered chronically daily. Potential dose levels are 1300 mg tid, 1000 mg tid, 650 mg tid and 500 mg tid. Intrapatient escalation or de-escalation is not permitted. A run-in period of one week for ABTL0812 is planned before starting the first cycle of chemotherapy.
* Chemotherapy will be administered on 28-day cycles: gemcitabine 1000 mg/m2 + nab-paclitaxel 125 mg/m2 on days 1, 8 and 15.
* If any, or all, the components of the chemotherapeutic regimen must be interrupted for any reason (excluding disease progression), ABTL0812 will be administered as maintenance therapy until disease progression, onset of unacceptable drug toxicities, or patient/physician's request to discontinue.

Phase II:

* ABTL0812 will be administered chronically daily at the Recommended Phase 2 Dose (RP2D). A run-in period of one week for ABTL0812 is planned before starting the first cycle of chemotherapy.
* Chemotherapy will be administered on 28-day cycles: gemcitabine 1000 mg/m2 IV + nab-paclitaxel 125 mg/m2 IV on days 1, 8 and 15
* If any, or all, the components of the chemotherapeutic regimen must be interrupted for any reason (excluding disease progression), ABTL0812 will be administered as maintenance therapy until disease progression, onset of unacceptable drug toxicities, or patient/physician's request to discontinue.

Eligibility Criteria:
Inclusion Criteria:

* Patients ≥18 years of age
* Willing and able to provide informed consent
* Ability and willingness to comply with study visits, treatment, testing, and to comply with the protocol
* Patient has histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. The definitive diagnosis of metastatic pancreatic adenocarcinoma will be made by integrating the histopathological data within the context of the clinical and radiographic data. Patients with islet cell neoplasms are excluded. Initial diagnosis of metastatic disease must have occurred ≤6 weeks prior to inclusion in the study.
* Patient has one or more metastatic tumors measurable by CT scan (or MRI, if patient is allergic to CT contrast media).
* Patient has not received previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease. Prior treatment with 5-FU or gemcitabine administered as a radiation sensitizer in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present.
* Patient has not received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
* Adequate hematologic function, measured as:

  * absolute neutrophil count ≥ 1.5x109/L
  * platelet count ≥ 100x109/L
  * hemoglobin ≥ 9.0 g/dL
* Total bilirubin ≤ 1.5 x ULN
* Albumin ≤ 1.5 x ULN AST (SGOT) ≤ 2.5 times x upper limit of normal (ULN) 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)
* Serum creatinine ≤1.5 ULN
* Have adequate tumor tissue available (either archival or new tumor biopsy) for biomarker analyses. The most recently collected tumor tissue sample should be provided, if available.
* Life expectancy ≥ 12 weeks in the opinion of the investigator
* 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
* Contraception: All female patients will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months' consecutive amenorrhea, in the appropriate age group and without other known or suspected cause), or have been sterilized surgically. Female patients of childbearing potential must agree to use two forms of highly effective contraception methods during the study and for a period of 6 months following the last administration of the study drug. Male patients and their female partners, who are of childbearing potential and are not practicing total abstinence, must agree to use two forms of highly effective contraception during the study and for a period of 6 months following the last administration of the study drug.
* Toxicities incurred as a result of previous anticancer therapy (radiation therapy, chemotherapy, or surgery) must be resolved to ≤ grade 1 (as defined by Common Terminology Criteria for Adverse Events version 4.03).

Exclusion Criteria:

Inclusion criteria:

Patients fulfilling the following criteria are eligible for participation in the study:

* Patients ≥18 years of age
* Willing and able to provide informed consent
* Ability and willingness to comply with study visits, treatment, testing, and to comply with the protocol
* Patient has histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. The definitive diagnosis of metastatic pancreatic adenocarcinoma will be made by integrating the histopathological data within the context of the clinical and radiographic data. Patients with islet cell neoplasms are excluded. Initial diagnosis of metastatic disease must have occurred ≤6 weeks prior to inclusion in the study.
* Patient has one or more metastatic tumors measurable by CT scan (or MRI, if patient is allergic to CT contrast media).
* Patient has not received previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease. Prior treatment with 5-FU or gemcitabine administered as a radiation sensitizer in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present.
* Patient has not received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
* Adequate hematologic function, measured as:

  * absolute neutrophil count ≥ 1.5x109/L
  * platelet count ≥ 100x109/L
  * hemoglobin ≥ 9.0 g/dL
* Total bilirubin ≤ 1.5 x ULN
* Albumin ≤ 1.5 x ULN AST (SGOT) ≤ 2.5 times x upper limit of normal (ULN) 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)
* Serum creatinine ≤1.5 ULN
* Have adequate tumor tissue available (either archival or new tumor biopsy) for biomarker analyses. The most recently collected tumor tissue sample should be provided, if available.
* Life expectancy ≥ 12 weeks in the opinion of the investigator
* 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
* Contraception: All female patients will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months' consecutive amenorrhea, in the appropriate age group and without other known or suspected cause), or have been sterilized surgically. Female patients of childbearing potential must agree to use two forms of highly effective contraception methods during the study and for a period of 6 months following the last administration of the study drug. Male patients and their female partners, who are of childbearing potential and are not practicing total abstinence, must agree to use two forms of highly effective contraception during the study and for a period of 6 months following the last administration of the study drug.
* Toxicities incurred as a result of previous anticancer therapy (radiation therapy, chemotherapy, or surgery) must be resolved to ≤ grade 1 (as defined by Common Terminology Criteria for Adverse Events version 4.03).

Exclusion criteria:

Patients who meet one of more of the following criteria are not eligible:

* Patients with neuroendocrine tumors or cystic neoplasms are excluded
* Patient has received previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease. Prior treatment with 5-FU or gemcitabine administered as a radiation sensitizer in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present. Patients having received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting are not eligible for this study
* Patient has only locally advanced disease.
* Patients has symptomatic brain metastases. Patients with asymptomatic brain metastases can be included in the study if they are kept on stable doses of steroids for a period of 1 month prior to study entry provided they don't have peripheric neuropathy grade 2 or superior.
* Patients previously treated with an inhibitor of the PI3K/Akt/mTOR pathway
* Patients has gastrointestinal abnormalities including inability to take oral medications, malabsorption syndromes or other clinically significant gastrointestinal abnormalities that may impair the absorption of the investigational medicinal product.
* Pregnancy or lactation. Serum pregnancy test to be performed within 7 days prior to study treatment start.
* Patients had myocardial infarction within ≤ 12 months prior to study entry, symptomatic congestive heart failure (New York Heart Association \> class II), unstable angina pectoris, or unstable cardiac arrhythmia requiring medication.
* Evidence of pre-existing uncontrolled hypertension. Patients whose hypertension is controlled by antihypertensive therapies are eligible.
* Patients has active Hepatitis B or C or human immunodeficiency virus (HIV) infection with non-controlled disease according to the treating physician.
* Patients with any other medical conditions (such as psychiatric illness, 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.