Phase Ib Evaluation of Ipatasertib with Pertuzumab and Trastuzumab in PIK3CA-Mutant, HER2-Positive Locally Advanced or Metastatic Breast Cancer
- Trial ID
- 2023-508826-92-00
- Protocol
- SOLTI-1507
- Sponsor
- Solti Group
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase Ib study is to define the **Recommended Phase 2 Dose (RP2D)** of ipatasertib when used in combination with pertuzumab and trastuzumab (HP), with or without endocrine therapy (ET), in patients with PIK3CA-mutant, HER2-positive locally advanced or metastatic breast cancer. Determining the RP2D is clinically relevant as it establishes the optimal dosing regimen for subsequent trials, ensuring both efficacy and safety in this patient population.
Secondary objectives include:
- Evaluating the safety and tolerability of the combination of ipatasertib with HP, with or without ET.
- Assessing the preliminary anti-tumor activity of the combination as maintenance therapy following first-line treatment for HER2-positive metastatic breast cancer with a taxane or vinorelbine plus HP.
Participants
The clinical trial involves participants diagnosed with **PIK3CA-mutant, HER2-positive locally advanced or metastatic breast cancer** who are candidates for maintenance therapy with trastuzumab plus pertuzumab (HP) following first-line treatment with a taxane or vinorelbine plus HP. The study population includes both female and male patients aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have adequate hematologic and organ function, a life expectancy of at least six months, and a baseline left ventricular ejection fraction (LVEF) of 50% or higher. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Participants' lifestyle factors such as diet, physical activity, or habits are not specified. Key inclusion criteria include confirmed HER2-positive invasive breast cancer and a PIK3CA mutation identified in tumor tissue or plasma ctDNA. The trial excludes individuals with baseline diarrhea or significant psychological, familial, sociological, or geographical conditions that could impede compliance with the study protocol.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **ipatasertib** in combination with **pertuzumab** and **trastuzumab** in patients with PIK3CA-mutant, HER2-positive locally advanced or metastatic breast cancer. This is a phase Ib, randomized, double-blind, controlled study aimed at determining the Recommended Phase 2 Dose (RP2D) of ipatasertib when used in combination with the aforementioned agents. The trial is expected to run from February 14, 2020, to December 16, 2025, with recruitment having commenced on March 4, 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including a confirmed PIK3CA mutation and adequate organ function. Following the screening, participants will receive treatment with ipatasertib plus HP (trastuzumab and pertuzumab) no later than nine weeks after their last dose of taxane or vinorelbine plus HP. The study will include regular follow-up visits to monitor safety, efficacy, and any adverse events, with a particular focus on the onset and severity of diarrhea. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is approximately 28 days for the dose-limiting toxicity assessment window, with the possibility of continuation based on individual response and tolerability. Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent. The primary endpoint is the determination of the Maximum Tolerated Dose (MTD) and RP2D, while secondary endpoints include the overall incidence and severity of adverse events, objective response rate, duration of response, clinical benefit rate, progression-free survival, and safety and tolerability assessments.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Herceptin** 600 mg is provided as a **solution for injection** in a vial. The active substance is **trastuzumab**, a protein-based therapeutic agent. The maximum daily and total dose is 600 mg, administered via injection. The treatment period is set for 21 days, with the administration frequency determined by the study protocol. Participant compliance is monitored through regular assessments and documentation of dosing schedules.
**Perjeta** 420 mg is formulated as a **concentrate for solution for infusion**. The active substance, **pertuzumab**, is also a protein-based therapeutic. The maximum daily and total dose is 420 mg, delivered through infusion. The treatment period is 21 days, with administration frequency as per the study protocol. Compliance is ensured through scheduled infusions and monitoring by clinical staff.
**Ipatasertib** is administered in the form of **film-coated tablets**. The active substance, **ipatasertib**, is a chemical compound. The maximum daily and total dose is 400 mg, taken orally. The treatment period extends to 28 days, with daily administration. Compliance is monitored through patient diaries and regular check-ins with the clinical team to ensure adherence to the dosing schedule.
Another formulation of **Herceptin** is available as a 150 mg **powder for concentrate for solution for infusion**. This formulation also contains **trastuzumab** as the active substance. The maximum daily and total dose is 150 mg, administered via infusion. The treatment period is 21 days, with administration frequency outlined in the study protocol. Compliance is monitored through infusion records and patient follow-up.
Throughout the trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The study focuses on the experimental medications, with compliance and administration closely monitored to ensure accurate data collection and participant safety.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the determination of the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of **ipatasertib** when used in combination with pertuzumab and trastuzumab. This will be evaluated by the Steering Committee, with the MTD defined as the highest dose level at which no more than 1 of 6 subjects experiences a Dose Limiting Toxicity (DLT) during the 28-day DLT assessment window.
Secondary endpoints include the Objective Response Rate (ORR), which is defined as the proportion of patients achieving a complete response (CR) or partial response (PR) as determined by the investigator using RECIST v1.1 criteria. The Duration of Response (DoR) will also be measured, defined as the time from the first documented Objective Response to disease progression or death. The Clinical Benefit Rate (CBR) will be assessed, representing the percentage of patients achieving CR, PR, or stable disease (SD) for at least 24 weeks. Progression-Free Survival (PFS) will be evaluated from the start of study treatment to disease progression or death. Safety and tolerability will be monitored through the incidence of adverse events, dose interruptions, reductions, and dose intensity.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written and signed informed consent for all study procedures according to local regulatory requirements prior to beginning of specific protocol procedures.
- Female (pre- or postmenopausal) or male patients.
- Age ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
- Confirmed HER2-positive invasive breast cancer by central determination defined by the current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) clinical practice guidelines.
- Known hormone receptor status, as assessed locally, defined by the current ASCO/CAP clinical practice guidelines. ER/PR positivity is defined as the presence of ≥ 1% of tumor cells with nuclear staining.
- Histologically confirmed, locally advanced or metastatic adenocarcinoma of the breast. Patients with unresectable locally advanced disease must have recurrent or progressive disease, which must not be amenable to resection with curative intent at the moment of taxane or vinorelbine + HP initiation. Patients with available standard curative options are not eligible. b. For patients with bilateral breast cancer, HER2-positivity must be demonstrated in both locations or in a metastatic biopsy.
- Patient must be a candidate to receive maintenance HP after first line treatment for metastatic disease with at least 4 cycles of taxane or vinorelbine plus HP.
- Prior taxane or vinorelbine must have been discontinued for a reason other than progressive disease.
- Patients may or may not have received neo/adjuvant therapy but must have a disease-free interval from completion of anti-HER2 therapy to metastatic diagnosis ≥6 months.
- PIK3CA mutation identified and confirmed in tumor tissue or plasma ctDNA by central determination. If prior approval has been granted by the Sponsor, centrally confirmed PIK3CA mutation result from a current or previous study identified by the sponsor can be used to determine eligibility for this study.
- Start of treatment with ipatasertib plus HP no later than 9 weeks after last dose of taxane or vinorelbine plus HP (i.e., maximum of 2 HP administrations with no taxane or vinorelbine).
- Willingness and ability to provide archived formalin fixed paraffin embedded (FFPE) tissue block.
- No baseline diarrhea or diarrhea grade ≤1 within the last 28 days.
- Adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of Cycle 1, defined by the following: a. Neutrophils (ANC ≥1500/μL) b. Hemoglobin ≥9 g/dL (with no need for transfusions in the last 14 days). c. Platelet count ≥75,000/μL d. Serum albumin ≥3 g/dL e. Total bilirubin ≤1.5x the upper limit of normal (ULN), with the exception: patients with known Gilbert syndrome who have serum bilirubin ≤3x ULN. f. AST and ALT ≤2.5x ULN, with the following exception: patients with documented liver or bone metastases who may have AST and ALT ≤5x ULN. g. ALP ≤2x ULN, with the following exceptions: - Patients with known liver involvement who may have ALP ≤5x ULN. - Patients with known bone involvement who may have ALP ≤7x ULN. h.PTT (or aPTT) and INR ≤1.5x ULN (except for patients receiving anticoagulation therapy). - Patients receiving heparin treatment should have a PTT (or aPTT) between 1.5 and 2.5x ULN. - Patients receiving coumarin derivatives should have an INR between 2.0 and 3.0 assessed in two consecutive measurements 1 to 4 days apart. i. Serum creatinine <1.5x ULN or creatinine clearance ≥50 mL/min based on Cockcroft−Gault glomerular filtration rate estimation: (140 − age) x (weight in Kg) x 0.85 (if female) 72 x (serum creatinine in mg/dL) j. Fasting total serum glucose ≤150mg/dL and glycosylated hemoglobin (HbA1C) ≤7.5%
- Life expectancy of at least 6 months.
- Baseline left ventricular ejection fraction (LVEF) ≥50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan.
- Negative β-HCG pregnancy test (serum) for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after the menopause. All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control from 2 weeks before administration of the first dose of investigational product until 28 days after the last dose of investigational product
- Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
Exclusion Criteria
- Last dose of taxane or vinorelbine plus HP given more than 9 weeks prior to C1D1.
- Prior malignancy within 3 years prior to randomization, except curatively treated non-melanoma skin, carcinoma in situ of the cervix or Stage I uterine cancer.
- Brain metastases that have not been treated previously, are progressive, or require any type of therapy (e.g., radiation, surgery, or steroids) to control symptoms within 30 days prior to the first study treatment dose.
- Radiotherapy for metastatic sites of disease outside of the brain performed within 14 days prior to study enrollment and/or radiation of >30% of marrow-bearing bone
- Symptomatic hypercalcemia requiring use of bisphosphonate or RANKL inhibitors therapy within 21 days prior to the first study treatment. Patients who receive bisphosphonate therapy specifically to prevent skeletal events are eligible if they have been initiated prior to the treatment to study.
- Cardiopulmonary dysfunction as defined by: a. Inadequately controlled angina or serious cardiac arrhythmia not controlled by adequate medication. b. Inadequate LVEF at baseline, as defined as LVEF <50% by either ECHO or MUGA scan. c. History of symptomatic congestive heart failure (CHF): Grade ≥3 per NCI CTCAE version 4.03 or Class ≥II New York Health Association (NYHA) criteria. d. History of a decrease in LVEF to <40% or symptomatic CHF with prior trastuzumab or HP treatment. e. History of myocardial infarction within 6 months prior to randomization. f. Current dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy.
- Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula (QTcF) > 480 milliseconds.
- Concurrent, serious, uncontrolled infections or current known infection with HIV (testing is not mandatory).
- History of intolerance, including Grade 3-4 infusion reaction or hypersensitivity, to trastuzumab or pertuzumab.
- Known hypersensitivity to any of the study drugs, including excipients.
- Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), current drug or alcohol abuse, or cirrhosis. - Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [HBcAg] antibody test) are eligible. -Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
- History of Type I or Type II diabetes mellitus requiring insulin. Patients who are on stable dose of oral diabetes medication > 2 weeks prior to initiation of study treatment are eligible for enrollment.
- Grade ≥2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia.
- History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis).
- Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (Pneumocystis pneumonia or Cytomegalovirus pneumonia).
- Need for chronic corticosteroid therapy of >10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids for a chronic disease.
- Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with indwelling catheters (e.g., PleurX®) are allowed.
- Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug.
- Prior treatment with an AKT inhibitor. Prior PI3K or mTOR inhibitors are allowed.
- Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures).
- Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 peripheral neuropathy.
- Major surgical procedure or significant traumatic injury within 28 days prior to enrollment
- Assessment by the investigator to be unable or unwilling to comply with the requirements of the protocol.
- History of significant comorbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with informed consent
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 16 Dec 2019 | 26 |
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 |
|---|---|---|---|---|---|---|
Herceptin 600 mg solution for injection in vial | Test | SOLUTION FOR INJECTION IN VIAL | SOLUTION FOR INJECTION | 600 | 21 | PRD938441 |
Perjeta 420 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 420 | 21 | PRD801541 |
Ipatasertib | Test | FILM-COATED TABLET | ORAL USE | 400 | 28 | PRD9859714 |
Ipatasertib | Test | FILM-COATED TABLET | ORAL | 400 | 28 | PRD9859715 |
Herceptin 150 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 150 | 21 | PRD389605 |