Phase II Evaluation of Eribulin and Izorlisib Mesilate in Advanced PIK3CA/PTEN-Altered Triple Negative and HR-Positive/HER2-Negative Breast Cancer
- Trial ID
- 2024-512963-30-00
- Protocol
- MEDOPP437
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II study is to assess the **efficacy** of MEN1611 in combination with eribulin, as determined by the clinical benefit rate (CBR) in patients with locally advanced or unresectable PIK3CA and/or PTEN-altered metaplastic or non-metaplastic triple-negative breast cancer, as well as in those with locally advanced or unresectable PIK3CA and/or PTEN-altered metaplastic HR-positive/HER2-negative breast cancer. This evaluation is clinically relevant as it aims to determine the potential therapeutic benefit of this combination in a specific subset of breast cancer patients with limited treatment options.
Secondary objectives include:
- Assessing the efficacy of MEN1611 in combination with eribulin, measured by the objective response rate (ORR), time to response (TTR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).
- Evaluating the safety and tolerability of MEN1611 in combination with eribulin.
Participants
The clinical trial involves participants diagnosed with **locally advanced or unresectable PIK3CA and/or PTEN-altered metaplastic or non-metaplastic triple-negative breast cancer**, as well as those with HR-positive/HER2-negative breast cancer. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a life expectancy of at least 12 weeks and must demonstrate adequate hematologic and organ function. The trial does not include a vulnerable population. Participants were selected based on specific molecular alterations, and they must not have received prior treatment with PI3K/AKT/mTOR inhibitors or eribulin. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraceptive measures if applicable. The trial population was selected to ensure the presence of measurable or evaluable disease, and participants must have a confirmed PIK3CA mutation or PTEN loss. The study aims to assess the efficacy of MEN1611 in combination with eribulin, focusing on the clinical benefit rate in the specified cancer types.
Plans and Procedures
The clinical trial is a **Phase II** study designed to evaluate the efficacy of **MEN1611** in combination with **eribulin** for patients with advanced triple-negative or metaplastic HR-positive/HER2-negative, PIK3CA/PTEN-altered breast cancer. The trial employs a multicenter, two-cohort, non-comparative, open-label design. The primary objective is to assess the clinical benefit rate (CBR), defined as the percentage of patients achieving complete response, partial response, or stable disease for at least 12 weeks. Secondary endpoints include overall response rate (ORR), time to response (TTR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of adverse events (AEs) as per NCI-CTCAE v.5.0 criteria.
The trial is expected to last until December 2026, with participant recruitment having commenced in July 2023. Participants will be involved in the study for a maximum treatment period of 126 days. The study includes a pre-screening phase where patients must provide informed consent and tumor or blood samples for molecular determination. The screening phase requires participants to meet specific inclusion criteria, such as adequate hematologic and organ function, ECOG performance status of 0 or 1, and a life expectancy of at least 12 weeks. Women of childbearing potential must use effective contraceptive methods, and men must agree to refrain from donating sperm during the study period and for a specified duration afterward.
Study visits are structured to include an initial inclusion (screening) visit, where eligibility is confirmed, followed by regular follow-up visits to monitor treatment response and safety. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial aims to provide valuable insights into the treatment of specific breast cancer subtypes, contributing to the advancement of therapeutic options for these conditions.
Treatment
The clinical trial involves the administration of two experimental medications. The first medication is **HALAVEN**, which contains the active substance **eribulin**. It is provided as a 0.44 mg/ml **solution for injection**. The pharmaceutical form is a solution intended for **intravenous** administration. The maximum daily dose is 1.4 mg/m², and the treatment period can extend up to 126 days. The administration schedule is determined by the clinical protocol, and compliance is monitored through regular assessments. **Eribulin** is a chemically synthesized compound, and its use in this trial is to evaluate its efficacy in combination with another investigational drug.
The second investigational product is **MEN1611**, which contains the active substance **izorlisib mesilate**. This medication is formulated as a 16 mg **oral capsule**. The maximum daily dose is 96 mg, with a treatment duration of up to 126 days. **Izorlisib mesilate** is a selective Class I PI3K inhibitor, exhibiting strong inhibitory activity, particularly against PI3CA. The route of administration is oral, and dosing schedules are adhered to as per the study protocol. Participant compliance is monitored through pill counts and patient diaries. Both medications are used in combination to assess their efficacy in treating advanced triple-negative or metaplastic HR-positive/HER2-negative, PIK3CA/PTEN-altered breast cancer.
Efficacy
The efficacy of the combination treatment of MEN1611 and **eribulin** in patients with advanced triple-negative or metaplastic HR-positive/HER2-negative, PIK3CA/PTEN-altered breast cancer will be assessed primarily through the **Clinical Benefit Rate (CBR)**. CBR is defined as the percentage of patients who achieve a complete response (CR), partial response (PR), or stable disease (SD) for at least 12 weeks after the initiation of treatment. This assessment will be conducted locally by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.
Secondary efficacy endpoints include the **Objective Response Rate (ORR)**, which measures the proportion of patients with confirmed CR or PR, and the **Time to Response (TTR)**, defined as the time from the start of treatment to the first objective tumor response, characterized by a tumor shrinkage of at least 30%. Additionally, the **Duration of Response (DoR)** will be evaluated, which is the time from the first documented objective response to disease progression or death. **Progression-Free Survival (PFS)** and **Overall Survival (OS)** will also be assessed, with PFS being the time from the first dose of study drugs until objective tumor progression or death, and OS being the time from the first dose until death from any cause.
The incidence of adverse events (AEs) will be monitored as a secondary endpoint, with severity determined by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. These efficacy and safety parameters will be measured and analyzed throughout the trial duration, with specific timepoints and methods aligned with clinical trial standards.
Inclusion and Exclusion Criteria
Inclusion Criteria
- PRE-SCREENING PHASE: Patient must be able to sign written pre-screening informed consent form prior to any molecular determination during the pre-screening phase.
- SCREENING PHASE: Patient has a PIK3CA mutation confirmed by MEDSIR's designated central lab, determined in the pre-screening phase or patient has a pathology report confirming PIK3CA mutant status by a certified laboratory (using validated PIK3CA mutation assay) either from tissue or blood And/or Patient has evidence of PTEN loss by immunohistochemistry (IHC) confirmed by MEDSIR’s designated central lab in the pre-screening phase or patient has a pathology report confirming PTEN loss by a certified laboratory, preferably on the most recent available tumor sample. Note:. PI3KCA mutations should have been evaluated at least at hot spots, E542, E545 and H1047. PTEN staining should have been evaluated by assessing both intensity of staining and percentage of positive cells. Both nuclear and cytoplasmic staining should be evaluated. Staining of normal cells such as benign breast epithelium, stromal cells and/or endothelial cells should have been evaluated as an internal control. Any tumor nuclear or cytoplasmic staining showing similar intensity with internal control cells should have been considered positive staining (no PTEN loss). Complete lack of staining or faint staining (cytoplasmic or nuclear) in up to 50% of tumor cells should have been considered as PTEN loss. If there was no staining in internal control cells, the staining should have been considered inconclusive.
- SCREENING PHASE: Patients with clinically stable metastatic central nervous system (CNS) tumors are eligible if: a. Stereotactic radiotherapy ³ 7 days prior to initiation of study treatment. b. Whole-brain radiotherapy ³ 7 days prior to initiation of study treatment. c. Neurosurgical resection ³ 28 days prior to initiation of study treatment. d. Not receiving steroid therapy or anticonvulsant at Baseline
- PRE-SCREENING PHASE: - Histologically confirmed metaplastic or non-metaplastic TNBC as per local assessment. or - Histologically confirmed HR-positive/HER2-negative metaplastic breast cancer
- SCREENING PHASE: 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 (v.5.0). Note: Except for alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion
- SCREENING PHASE: Available archival tumor sample (FFPE tissue) of the most recent biopsy/surgery since last progression. Note: Subjects for whom the most recent tumor biopsy since last progression could not be obtained (e.g., inaccessible tumor or subject safety concern) may submit archival pathological material from either metastatic or primary sites.
- PRE-SCREENING PHASE: Being male or female aged ≥ 18 years
- PRE-SCREENING PHASE: Known HR status according to the updated American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2020 guidelines and HER2-negative breast cancer (BC) as per ASCO/CAP 2018 criteria based on local testing on the most recently analyzed biopsy.
- PRE-SCREENING PHASE: Prior treatment with at least one, but no more than four, prior lines of systemic therapy for advanced disease. Earlier adjuvant or neoadjuvant therapy for more limited disease will be considered as one of the required prior regimens if the development of unresectable locally advanced metastatic disease occurred within a 6-month period after completion of chemotherapy.
- PRE-SCREENING PHASE: No prior treatment with a PI3K/AKT/mTOR inhibitors, nor with eribulin.
- PRE-SCREENING PHASE: Patient must consent to give a tumor sample or/and a blood sample for testing of the prior mentioned alterations (or if needed and deemed safe by the investigator, able to provide a fresh tumor sample).
- SCREENING PHASE: 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 CSP, 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.
- PRE-SCREENING PHASE: Unknown PIK3CA mutational and PTEN loss status.
- SCREENING PHASE: Patient must be able to sign written main informed consent form (ICF) prior to participation in any Study-related activities.
- SCREENING PHASE: Adequate hematologic and organ function within 14 days before the first Study treatment on Day 1 of Cycle 1, defined by the following: a. 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). b. 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). Note: If total bilirubin is increased, assessment of direct bilirubin levels is recommended. c. Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min based on Cockcroft−Gault glomerular filtration rate estimation. d. Urinalysis: including dipstick (specific gravity, pH, glucose, protein, ketones, and blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial cells, and bacteria).
- SCREENING PHASE: 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
- SCREENING PHASE: Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 which the Investigator believes is stable at the time of screening.
- SCREENING PHASE: Patient must be accessible for treatment and follow-up.
- SCREENING PHASE: Measurable, or non-measurable but evaluable, disease as defined by the local site Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) criteria. Note: Patients with bone lesions as the only sites of metastatic disease are eligible.
- SCREENING PHASE: Life expectancy greater or equal to 12 weeks.
- SCREENING PHASE: Unresectable locally advanced/metastatic MpBC documented by computed tomography (CT) scan or magnetic resonance imaging (MRI), that is not amenable to resection with curative intent.
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. Note: For other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required.
- 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. Note: Patients who have DM adequately managed regardless FPG or HbA1c may be consider eligible as per the Medical Monitor assessment and criteria.
- 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 isoenzyme CYP3A as well as moderate or strong inducers of 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).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 18 Jul 2023 | 14 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MEN1611 oral capsule 16 mg | Test | CAPSULE | ORAL USE | 96 | 126 | PRD5731244 |
HALAVEN 0.44 mg/ml solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS | 1.4 | 126 | PRD525115 |