A Study to Assess the Efficacy and Safety of ABTL0812

Study Overview
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Brief Summary
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A phase I/ II, open label study to assess the efficacy and safety of ABTL0812 in combination with paclitaxel and carboplatin in patients with advanced endometrial cancer or squamous NSCLC.

Detailed Description
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This is a phase I/II multicenter divided in two phases. Phase I: Safety and dose escalation This study is not randomized, and all included patients will receive ABTL0812 in addition to paclitaxel + carboplatin (SOC). In this phase, patients can be selected from both indications, regardless of the number of each indication. This phase will be divided in 2 periods: Period 1: A dose de-escalation phase will be performed with a 3 + 3 design, in which up to four different ABTL0812 dose levels will be tested in combination with SOC. Then, 12 patients will be included in an expansion phase. All patients will receive one week of ABTL0812 alone followed by ABTL0812 + SOC (up to 8 SOC cycles) as combined treatment. Period 2: After the finalization of the SOC cycles, ABTL0812 will be taken as single therapy, at 1300 mg tid, up to 12 months from initiation of period 1. This is the Recommended Phase 2 Dose (RP2D) as monotherapy for ABTL0812 determined in the previous phase I clinical trial. Phase II: Efficacy and safety This phase of the study will include up to 33 patients per indication (up to 66 patients overall). The final number will depend on the number of patients included in the phase I. The number of patients selected per indication will depend on the number already selected in phase I, as it is necessary to compensate both indications to have a final number of 40 patients per indication approximately.

Official Title
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A Phase I/II, Open Label Study to Assess the Efficacy and Safety of ABTL0812 in Combination With Paclitaxel and Carboplatin in Patients With Advanced Endometrial Cancer or Squamous NSCLC

Conditions
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Endometrial Cancer, Squamous Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: ABTL0812 in combination with paclitaxel and carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥18 years of age Willing and able to provide informed consent For endometrial cancer: Patients with advanced, metastatic or recurrent endometrial cancer, from all histological types except carcinosarcoma and leiomyosarcoma. For squamous NSCLC: Patients with histologically or radiological/cytologically confirmed diagnosis (non-irradiance IIIb stage or stage IV), excluding mixed tumors, neuroendocrine or adenocarcinoma. Have adequate tumor tissue available (either archival not older than 6 months 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. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 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. Adequate bone marrow function defined as: absolute neutrophil count ≥ 1.5x109/L platelet count ≥ 100x109/L hemoglobin ≥ 10.0 g/dL Total bilirubin ≤ 1.5 x upper limit of normal Aspartate transaminase (AST) ≤ 2.5 times upper limit of normal (ULN) (≤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 ≥ 50 mL/min Serum creatinine ≤1.5 ULN 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 4.02). Ability and willingness to comply with study visits, treatment, testing, and to comply with the protocol Exclusion Criteria: Patients previously treated with an inhibitor of the Phosphoinositide 3-kinase/Protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway. Patients previously treated with adjuvant or co-adjuvant chemotherapy administered 6 months or less in advance of patient inclusion Patients with symptomatic brain metastases. Patients with asymptomatic and treated 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 with 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 with 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 with 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.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Endometrial cancer<br>ABTL0812 (starting 1,300 mg tid orally) in combination with paclitaxel and carboplatin will be given to patients with advanced endometrial cancer, up to 12 months from initiation. | Drug: ABTL0812 in combination with paclitaxel and carboplatin<br>* ABTL0812 in combination with paclitaxel and carboplatin.<br>|
| Experimental: Squamous non-small cell lung cancer<br>ABTL0812 (starting 1,300 mg tid orally) in combination with paclitaxel and carboplatin will be given to patients with squamous NSCLC, up to 12 months from initiation. | Drug: ABTL0812 in combination with paclitaxel and carboplatin<br>* ABTL0812 in combination with paclitaxel and carboplatin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Emergent Adverse Events | Related Adverse Events as Assessed by CTCAE v4.03 | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Objective response rate (ORR) based on tumor assessment by CT-Scan according to RECIST criteria version 1.1. performed at baseline and at every other treatment visit, starting at 3rd SOC cycle | 2 years | 
| Progression Free Survival (PFS) | Progression Free Survival (PFS) based on tumor assessment by CT-Scan according to RECIST criteria version 1.1. performed at baseline and at every other treatment visit, starting at 3rd SOC cycle | 2 years | 
| Time to Progression (TP) | Time to Progression (TP) based on tumor assessment by CT-Scan according to RECIST criteria version 1.1. performed at baseline and at every other treatment visit, starting at 3rd SOC cycle | 2 years | 
| Duration of Response (DR) | Duration of Response (DR), based on tumor assessment by CT-Scan according to RECIST criteria version 1.1. performed at baseline and at every other treatment visit, starting at 3rd SOC cycle | 2 years |