PIK3CA/PTEN-altered Advanced Breast Cancer Treated With MEN1611 Monotherapy or in Combination With Eribulin

Study Overview
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Brief Summary
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The multicenter, two-cohort, non-comparative, open-label, phase II clinical trial SABINA aims to analyze the safety and efficacy of MEN1611 in monotherapy and in combination with eribulin, a non-taxane chemotherapy agent, in Hormone Receptor (HR)-known/Human Epidermial Growth Factor Receptor 2 (HER2)-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)/ Phosphatase and Tensin Homolog (PTEN)-altered, unresectable locally advanced or metastatic metaplastic breast carcinoma (MpBC) patients. A run-in phase for safety and tolerability of MEN1611 in combination with standard doses of eribulin will be conducted as an initial step of the cohort A. This first step aims at evaluating the dosing schedule of MEN1611, by analyzing the toxicity profile of the combined regimen. With the background of the first-in-human study (PA-001EU), the safe dose of MEN1611 has been established as 48 mg orally BID (two intakes of 3 capsules of 16 mg each, for a total daily dose of 96 mg MEN1611 free-base).

Detailed Description
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This is a multicenter, two-cohort, non-comparative, open-label, phase II clinical trial to assess: the efficacy of MEN1611 in combination with eribulin as determined by the clinical benefit rate (CBR) in unresectable locally advanced or metastatic HR-known/HER2-negative, PIK3CA/ PTEN-altered MpBC patients (Cohort A), and the efficacy of MEN1611 as monotherapy as determined by the objective response rate (ORR) at 6 weeks in unresectable locally advanced or metastatic HR-known/HER2-negative, PIK3CA/ PTEN-altered MpBC patients (Cohort B). Upon meeting all selection criteria, 28 patients will be enrolled as follows: - Cohort A: A run-in phase for safety and tolerability of MEN1611 in combination with eribulin will be conducted in this patient population (N=3). A Steering Committee decision/agreement is needed, after reviewing all toxicities, to expand this cohort with 11 additional patients (up to N=14). Cohort B will be run only if positive finding in Cohort A, defined as ≥ 6 patients (42.9%) with achieved clinical benefit (CB) among 14 first recruited patients. - Cohort B: Simon's two-stage minimax design. Stage I (N=7) will be initiated with MEN1611 monotherapy. This cohort will be stopped for futility if no responders (no complete response [CR] or partial response [PR]) are observed after 2 cycles among the first 7 patients included. Otherwise, Cohort B will be expanded with 7 additional patients for Stage II (up to N=14).

Official Title
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Phase II Study for PIK3CA/PTEN-altered Advanced Metaplastic Breast Cancer Treated With MEN1611 Monotherapy or in Combination With Eribulin

Conditions
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Breast Cancer, Advanced Breast Cancer, Metastatic Breast Cancer

Intervention / Treatment
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* Drug: MEN1611
* Drug: Eribulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form (ICF) prior to beginning specific protocol procedures. Age ≥18 years at time of signing ICF. Histological confirmed MpBC as per local assessment. Known HR status Prior treatment with at least one, but no more than four, prior lines of systemic therapy for advanced disease. No prior treatment with a PI3K/AKT/mTOR inhibitor. Patient has a PIK3CA mutation or evidence of PTEN loss by immunohistochemistry (IHC) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Life expectancy greater or equal to 12 weeks. Unresectable locally advanced/metastatic MpBC documented by computed tomography (CT) scan or magnetic resonance imaging (MRI) Patients with clinically stable metastatic central nervous system (CNS) tumors who are not receiving steroid therapy or anticonvulsant at baseline are not eligible if stereotactic radiotherapy within 7 days prior to initiation of study treatment; whole-brain radiotherapy within 14 days prior to initiation of study treatment; or neurosurgical resection within 28 days prior to initiation of study treatment. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Available archival tumor sample (FFPE tissue) of the most recent biopsy/surgery since last progression. No prior treatment with eribulin. Adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of Cycle 1, defined by the following: Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within 7 days before first study treatment dose): White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 9.0 g/dL (≥ 5.6 mmol/L). Hepatic: Serum albumin ≥ 3 g/dL; total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (≤ 3 x ULN in the case of Gilbert's disease); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (in the case of liver metastases ≤ 5 × ULN); alkaline phosphatase (ALP) ≤ 2 × ULN (≤ 5 × ULN in the case of liver and/or bone metastases). Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min based on Cockcroft-Gault glomerular filtration rate estimation. Urinalysis: including dipstick (specific gravity, pH, glucose, protein, ketones, and blood) and microscopic examination (sediment, red blood cells [RBC], white blood cells [WBC], casts, crystals, epithelial cells, and bacteria). For women of childbearing potential: agreement to remain abstinent (must refrain from heterosexual intercourse) or use highly effective contraceptive methods, or two effective contraceptive methods, as defined in the protocol, during the treatment period and for at least 7 months after the last dose of study treatment, whichever is longer. Women of childbearing potential must have a negative serum pregnancy test within 7 days before study treatment initiation, and must agree to refrain from donating eggs during the entire study treatment period and for 3 months after the last administration of the study drug. Being male subjects, surgically sterile or having agreed with true abstinence (must refrain from heterosexual intercourse), or whose female partners are willing to agree with true abstinence or use barrier contraceptive measures mentioned above during the entire study treatment period and for 7 months after the last administration of the study drug. Males must agree to refrain from donating sperm during the entire study treatment period and for 3 months after the last administration of the study drug. Patient must be accessible for treatment and follow-up. Measurable, or non-measurable but evaluable, disease (in case of cohort A) and measurable disease (in case of cohort B) as defined by the local site Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) criteria. Exclusion Criteria: Current participation in another therapeutic clinical trial. Extra-cranial radiotherapy or limited-field palliative radiotherapy within 7 days prior to study enrolment, or patients who have not recovered from radiotherapy-related toxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously irradiated. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 21 days of start of study drug, or patients who have not recovered from the side effects of any major surgery. Patient with a concurrent malignancy or malignancy within 5 years of study enrollment except for carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage I uterine cancer. Treatment with approved chemotherapy/immunotherapy/ targeted agents within 21 days prior to initiation of study, or treatment with an investigational cancer therapy for 21 days or 5 half-lives (whichever is longer) prior to initiation of any study treatment. Patient with cerebrovascular accident or transient ischemic attack within 6 months prior to the start of any study treatment. Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula (QTcF) > 480 milliseconds. Patient with an active cardiac disease or a history of cardiac dysfunction or conduction abnormalities including any of the following: Unstable angina pectoris or documented myocardial infarction within 6 months prior to study entry. Symptomatic pericarditis. Documented congestive heart failure (New York Heart Association functional classification III- IV). Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO). Ventricular arrhythmias except for benign premature ventricular contractions. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication. Conduction abnormality requiring a pacemaker. Other cardiac arrhythmia not controlled with medication. Patient with uncontrolled hypertension. Uncontrolled diabetes mellitus (glycated haemoglobin [HbA1c] >7%) and/or fasting plasma glucose (FPG) >120 mg/dL or 6.7 mmol/L. Known concurrent severe and/or uncontrolled concomitant medical conditions (i.e. influenza or any other active infections) that could cause unacceptable safety risks or compromise compliance with the protocol. Known active or uncontrolled pulmonary dysfunction. Current known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antibody [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances. Patient with serious and/or unstable pre-existing psychiatric or neurologic illness or other conditions that could interfere with subject safety. History of significant gastrointestinal disease, including but not limited to abdominal fistula, gastrointestinal perforation or other malabsorption syndromes that would impact on drug absorption. Grade ≥ 2 diarrhea should resolve at least 7 days prior to the start of any study treatment. Subject receiving chronic treatment with steroids, as immunosuppressant, or another immunosuppressive agent. Subject receiving treatment with drugs known to be moderate and strong inhibitors or inducers of cytochrome P450 3A isoenzyme (CYP3A) as well as moderate or strong inducers of cytochrome P450 1A2 (CYP1A2) within 2 weeks of the first administration of MEN1611. Breastfeeding or pregnancy as determined by a serum pregnancy test (β-HCG) at screening, prior to the administration of MEN1611 either in monotherapy or in combination with eribulin. Since β-HCG over expression can be also elevated in some tumor types, a positive result should be confirmed with a validated alternative test (e.g., ultrasound).

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
Interventional Model Description: Multicenter, two-cohort, non-comparative, open-label, phase II clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>MEN1611 orally (PO) 48 mg twice daily (BID) (2 intakes of 3x16 mg capsules, for a total daily dose of 96 mg MEN1611 free-base) during each 21-day cycle combined with eribulin mesylate 1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2 when expressed as a free base) administered intravenously (IV) over 2 to 5 minutes on days 1 and 8 of every 21-day cycle (CXD1 and CXD8). A run-in phase for safety and tolerability of MEN1611 in combination with eribulin will be conducted after the first 2 cycles on the first 3 patients. Upon Steering Committee agreement the cohort A will be expanded up to N=14 (11 additional patients). Patients will receive treatment until disease progression, unacceptable toxicity, death, discontinuation from the study treatment for any other reason, withdrawal of consent, or study termination. Cohort B will be run only if there will be positive finding in Cohort A, defined as ≥ 6 patients (42.9%) with CB (CR or PR) among 14 recruited patients. | Drug: MEN1611<br>* MEN1611 is a potent, orally bioavailable selective inhibitor of the class I phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) with a novel structure which exhibits a strong inhibitory activity especially against the PI3K catalytic subunit alpha (PIK3CA), with potential antineoplastic activity. PI3K alpha inhibitor MEN1611 selectively binds to and inhibits PIK3CA and its mutated forms in the PI3K/Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway.<br>Drug: Eribulin<br>* Eribulin mesylate (eribulin), a non-taxane inhibitor of microtubule dynamics of the halichondrin class of antineoplastics, suppresses microtubule growth and sequesters tubulin into nonfunctional aggregates, preventing mitotic spindle formation with subsequent G2-M stop and apoptosis.<br>* Other names: HALAVEN, Eribulin mesylate;|
| Experimental: Cohort B<br>Stage I (N =7): MEN1611 monotherapy 48 mg PO BID (2 intakes of 3x16 mg capsules, for a total daily dose of 96 mg MEN1611 free-base) during each 21-day cycle. After 2 cycles, ORR will be determined per RECIST v1.1 criteria: Patients experiencing CR or PR will continue with MEN1611 monotherapy. Patients experiencing stable disease (SD) will continue with MEN1611 monotherapy or will be treated with MEN1611 plus eribulin mesylate 1.4 mg/m2 (1.23 mg/m2 eribulin free base), IV on CXD1 and CXD8, under investigator's decision. An interim analysis will assess the viability of this part of the trial. Cohort B will be stopped for futility if no responders (no CR or PR) are observed among the 7 patients included. Stage II: same as stage I with 7 additional patients (total N=14). Patients will receive treatment until disease progression, unacceptable toxicity, death, discontinuation from the study treatment for any other reason, withdrawal of consent, or study termination. | Drug: MEN1611<br>* MEN1611 is a potent, orally bioavailable selective inhibitor of the class I phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) with a novel structure which exhibits a strong inhibitory activity especially against the PI3K catalytic subunit alpha (PIK3CA), with potential antineoplastic activity. PI3K alpha inhibitor MEN1611 selectively binds to and inhibits PIK3CA and its mutated forms in the PI3K/Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway.<br>Drug: Eribulin<br>* Eribulin mesylate (eribulin), a non-taxane inhibitor of microtubule dynamics of the halichondrin class of antineoplastics, suppresses microtubule growth and sequesters tubulin into nonfunctional aggregates, preventing mitotic spindle formation with subsequent G2-M stop and apoptosis.<br>* Other names: HALAVEN, Eribulin mesylate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A: To assess the efficacy of MEN1611 in combination with eribulin as determined by the clinical benefit rate (CBR). | CBR, defined as the percentage of patients who experience a complete response (CR), partial response (PR) or stable disease (SD) in cohort A for at least 12 weeks after the start of MEN1611 in combination with eribulin treatment, as determined locally by the investigator per RECIST v1.1 criteria. | Baseline up to at least 12 weeks | 
| Cohort B: To assess the efficacy of MEN1611 as monotherapy defined as objective response rate (ORR). | ORR, defined as the percentage of patients in cohort B with confirmed CR or PR at 6 weeks after the start of MEN1611 treatment, as determined per RECIST v1.1 criteria. | Baseline up to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A: To determine the efficacy of MEN1611 in combination with eribulin defined as ORR of patients. | ORR, defined as the proportion of patients with confirmed CR or PR who received MEN1611 in combination with eribulin treatment in Cohort A, as determined per RECIST v1.1 criteria. | Baseline up to 24 months | 
| Cohort A: To determine the efficacy of MEN1611 in combination with eribulin defined as Time To Response (TTR). | TTR, defined as the time from the start of MEN1611 in combination with eribulin treatment to the first objective tumor response (tumor shrinkage of ≥ 30%) of patients in Cohort A, as determined per RECIST v1.1 criteria. | Baseline up to 24 months | 
| Cohort A: To determine the efficacy of MEN1611 in combination with eribulin defined as Duration of Response (DoR) of patients. | DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, of patients in Cohort A who received MEN1611 in combination with eribulin treatment, as determined per RECIST v1.1 criteria. | Baseline up to 24 months | 
| Cohort A: To determine the efficacy of MEN1611 in combination with eribulin defined as Progression-Free Survival (PFS). | PFS, defined as the time from the first dose of study drugs until objective tumor progression or death, whichever occurs first, of patients in Cohort A who received MEN1611 in combination with eribulin treatment, as determined per RECIST v1.1 criteria. | Baseline up to 24 months | 
| Cohort A: To determine the efficacy of MEN1611 in combination with eribulin defined as Overall Survival (OS). | OS, defined as the time from the first dose of study drugs until death from any cause of patients in Cohort A who received MEN1611 in combination with eribulin treatment. | Baseline up to 24 months | 
| Cohort B: To assess the efficacy of MEN1611 as monotherapy defined as ORR. | ORR, defined as the proportion of patients with confirmed CR or PR, of patients in Cohort B who received MEN1611 in monotherapy treatment, as determined per RECIST v1.1 criteria. | Baseline up to 24 months | 
| Cohort B: To assess the efficacy of MEN1611 as monotherapy defined as CBR. | CBR, defined as the percentage of patients who experience a CR, PR or SD, of patients in the Cohort B who received MEN1611 in monotherapy treatment, as determined per RECIST v1.1 criteria. | Baseline up to 24 months | 
| Cohort B: To assess the efficacy of MEN1611 as monotherapy defined as TTR. | TTR, defined as the time from the start of treatment to the first objective tumor response (tumor shrinkage of ≥ 30%), of patients in Cohort B who received MEN1611 in monotherapy treatment, as determined per RECIST v1.1 criteria. | Baseline up to 24 months | 
| Cohort B: To assess the efficacy of MEN1611 as monotherapy defined as DoR. | DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, of patients in Cohort B who received MEN1611 in monotherapy treatment, as determined per RECIST v1.1 criteria. | Baseline up to 24 months | 
| Cohort B: To assess the efficacy of MEN1611 as monotherapy defined as PFS. | PFS, defined as the time from the first dose of study drugs until objective tumor progression or death, whichever occurs first, of patients in the Cohort B who received MEN1611 in monotherapy treatment, as determined per RECIST v1.1 criteria. | Baseline up to 24 months | 
| Cohort B: To assess the efficacy of MEN1611 as monotherapy defined as OS. | OS, defined as the time from the first dose of study drugs until death from any cause of patients in Cohort B who received MEN1611 in monotherapy treatment. | Baseline up to 24 months | 
| Cohort A: To assess the safety and tolerability of MEN1611 in combination with eribulin defined as incidence and severity of adverse events. | To evaluate the incidence and severity of adverse events of MEN1611 in combination with eribulin treatment of patients in cohort A, in accordance to NCI-CTCAE v.5.0. | Baseline up to 24 months | 
| Cohort B: To assess the safety and tolerability of MEN1611 as monotherapy defined as incidence and severity of adverse events. | To evaluate the incidence and severity of adverse events of MEN1611 as monotherapy treatment of patients in Cohort B, in accordance to NCI-CTCAE v.5.0. | Baseline up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, MEN1611, Eribulin