A randomized, open-label, phase II trial comparing neoadjuvant endocrine therapy in combination with trastuzumab, pertuzumab +/- the PI3K inhibitor inavolisib in patients with HER2-positive, HR-positive, PIK3CA mutant early breast cancer - GeparPiPPa
- Trial ID
- 2022-501152-28-00
- Protocol
- GBG 105
- Sponsor
- GBG Forschungs GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **pathological complete response** (pCR=ypT0/is ypN0) rates between patients with HER2-positive, HR-positive, PIK3CA mutant early **breast cancer** treated with inavolisib in combination with endocrine therapy, pertuzumab, and trastuzumab versus those treated with endocrine therapy, pertuzumab, and trastuzumab alone. This comparison is clinically relevant as it aims to evaluate the efficacy of adding inavolisib, a PI3K inhibitor, to the standard neoadjuvant treatment regimen, potentially improving treatment outcomes for this specific patient population.
Secondary objectives include: - Determining the rates of ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0. - Assessing the pCR rates per arm separately for stratified subpopulations. - Determining the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests after study treatment in both arms. - Determining the percentage of patients receiving additional neoadjuvant chemotherapy after residual disease confirmation by core biopsy at the end of study treatment. - Determining the breast conservation rate after each treatment. - Assessing early safety and tolerability after the first 20 and the first 40 patients have completed two cycles of therapy. - Assessing the overall safety, tolerability, and treatment compliance in the two arms. - Evaluating invasive disease-free survival (IDFS) and overall survival (OS) in both arms and according to stratified subpopulations, with the timing for the time-to-event endpoints analysis defined in the statistical analysis plan.
Participants
The clinical trial focuses on participants diagnosed with **breast cancer**, specifically targeting HER2-positive, HR-positive, PIK3CA mutant early breast cancer. The study population includes both female and male subjects aged 18 years and older, with an **ECOG Performance status** of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have normal cardiac function, confirmed by ECG and cardiac ultrasound, with LVEF results above 55%. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include untreated, unilateral primary carcinoma of the breast, confirmed histologically by core biopsy, with measurable tumor lesions. Participants must meet adequate laboratory requirements, including hematology, hepatic function, and glucose metabolism. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is a **randomized**, open-label, phase II study designed to evaluate the efficacy of neoadjuvant endocrine therapy in combination with **trastuzumab**, **pertuzumab**, and the PI3K inhibitor **inavolisib** in patients with HER2-positive, HR-positive, PIK3CA mutant early **breast cancer**. The primary objective is to compare the pathological complete response (pCR) rates between the treatment groups. The trial is expected to run until March 31, 2026, with recruitment having started on May 16, 2022.
Participants will be randomly assigned to receive either the combination therapy including inavolisib or the standard therapy without inavolisib. The trial involves several key study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed untreated, unilateral primary carcinoma of the breast, and specific tumor characteristics. Follow-up visits will occur every second cycle to assess clinical and imaging responses, with a final end-of-study visit to evaluate the primary and secondary endpoints, including safety and tolerability.
The expected duration of participant involvement is up to 18 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events necessitating discontinuation, or withdrawal of consent. The study aims to provide valuable insights into the potential benefits of adding inavolisib to the treatment regimen for this specific breast cancer subtype.
Treatment
The clinical trial involves the administration of **Phesgo**, a combination of **trastuzumab** and **pertuzumab**, formulated as a solution for injection. Two dosage forms are utilized: Phesgo 600 mg/600 mg and Phesgo 1200 mg/600 mg. Both formulations are administered via **intravenous use**. The maximum daily dose for the 600 mg/600 mg formulation is 600 mg, while the 1200 mg/600 mg formulation has a maximum daily dose of 1200 mg. The treatment period for both formulations is up to 18 months. Phesgo is classified as a Her2 antibody and is produced by Roche Registration GmbH.
**Inavolisib**, also known by its product code RO 711-3755, is another experimental medication used in this trial. It is provided in the form of a **film-coated tablet** and is administered **orally**. Two dosage regimens are included: one with a maximum daily dose of 3 mg and another with a maximum daily dose of 9 mg. The treatment duration for inavolisib is also up to 18 months. Inavolisib functions as a PI3K Alpha Inhibitor and is manufactured by F. Hoffmann-La Roche Ltd.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to evaluate the efficacy of these treatments in patients with HER2-positive, HR-positive, PIK3CA mutant early breast cancer.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of **pathological complete response (pCR)**, defined as the absence of microscopic evidence of residual invasive tumor cells in all resected specimens of the breast and axilla (ypT0/is ypN0). This endpoint will be used to compare the efficacy of neoadjuvant endocrine therapy in combination with trastuzumab, pertuzumab, and the PI3K inhibitor inavolisib against the combination of endocrine therapy, trastuzumab, and pertuzumab alone in patients with HER2-positive, HR-positive, PIK3CA mutant early breast cancer.
Secondary efficacy endpoints include various measures of tumor response and patient outcomes. These include the assessment of ypT0 ypN0, ypT0 ypN0/+, and ypT0/Tis ypN0/+ statuses, which evaluate the presence of residual invasive or non-invasive viable tumor cells. Clinical and imaging responses will be assessed every second cycle and before surgery through physical examination and imaging tests. Breast conservation, defined as tumorectomy, segmentectomy, or quadrantectomy, will also be evaluated. Additionally, tolerability and safety analyses will be conducted, focusing on patients whose treatment required dose reduction, delay, or permanent cessation. Survival endpoints will be analyzed post-study, using data from GBG's registries to determine the time period between randomization and the first event.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
- Untreated, unilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy is not allowed.
- Tumor lesion in the breast with a palpable size of ≥ 2 cm or a sonographical size of ≥ 1 cm in maximum diameter. The lesion has to be measurable in two dimensions, preferably by sonography.
- Patients must be in the following stages of disease: cT1b – cT3 regardless of nodal status In patients with multifocal or multicentric breast cancer the largest lesion (target lesion) should be measured.
- HR+/HER2+ disease with centrally confirmed ER-status, PR-status, HER2- status, PIK3CA mutation (tumor), Ki-67 value and TILs on core biopsy (target lesion). ER/PgR positive and HER2-positive is defined according to current ASCO/CAP guidelines. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy of target lesion has therefore to be sent to the GBG central pathology laboratory prior to randomization. In patients with multifocal or multicentric breast cancer, all non-target lesions must also be HR+/HER2+, as confirmed by local testing.
- Age >= 18 years, female and male.
- ECOG Performance status 0-1.
- Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. Results for LVEF must be ≥ 55%.
- Laboratory requirements: Hematology, Renal function, Hepatic function, Glucose Metabolism
- Negative pregnancy test
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% per year during the treatment period and for least 7 months after the last dose of PH-FDC SC. Examples of non-hormonal contraceptive methods with a failure rate of 1% per year include: bilateral tubal ligation; male partner sterilization; intrauterine devices. For men: men must remain abstinent or use a condom with a spermicidal product during the treatment period and for 7 months after the last dose of PH-FDC therapy to avoid exposing the embryo. Men and women must refrain from donating sperm/eggs during this same period.
- Complete staging work-up within prior to randomization
- Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Exclusion Criteria
- Patients with HER2-negative breast cancer and/or HER2-positive, HR-negative breast cancer
- Need of immediate neoadjuvant chemotherapy, e.g. inflammatory breast cancer
- Patients with definitive clinical or radiologic evidence of Stage IV cancer.
- Excisional biopsy or lumpectomy and /or axillary lymph node dissection and/or sentinel lymph node biopsy performed prior to study entry (biopsy of clinical involved LN is warranted).
- Prior chemotherapy or endocrine therapy or radiation therapy prior to study entry.
- Patients with a history of breast cancer are ineligible with the following exceptions: Patient has been disease-free for more than 5 years and is at low risk for recurrence (at the investigator’s discretion).
- Patients with a history of any treated malignancy are ineligible in case of high risk of recurrence (at the investigator’s discretion) and/or ongoing oncological treatment. This also applies to patients who are at high risk that oncological treatment is indicated during study therapy.
- BMI>30
- Known hypersensitivity reaction to one of the compounds or substances, and/or murine proteins, and/or recombinant human hyaluronidase used in this protocol.
- Patients with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on FPG and HbA1c.
- Patients who are immunocompromised as the result of HIV or receiving immunosuppressive therapies.
- Clinically significant and active liver disease, for example, sclerosing cholangitis, active viral hepatitis B or C infection, or autoimmune hepatic disorders.
- Patients with inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, and active bowel inflammation (e.g., diverticulitis).
- Patients with any concurrent ocular or intraocular condition, such as cataract or diabetic retinopathy, that would require medical or surgical intervention during the study period to prevent or treat vision loss. In addition, patients with active uveitis or vitritis, history of uveitis, or active infectious process in the eye.
- Patients with currently documented pneumonitis/interstitial lung disease.
- Known or suspected congestive heart failure (>NYHA I) and / or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP >160 / 90 mm Hg under treatment with three antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
- Damaged skin at planned site of subcutaneous (SC) injections (thigh).
- Patients who may have had a recent episode of thromboembolism and are still trying to optimize the anticoagulation dose and/or have not normalized their INR.
- Concurrent treatment with: • Chronic corticosteroids unless initiated > 6 months prior to study entry and at low dose (10 mg or less methylprednisolone or equivalent). • Sex hormones. Prior treatment must be stopped before study entry. (GnRH a is allowed) • Other experimental drugs or any other anti-cancer therapy.
- Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
- Female patients: pregnancy or lactation at the time of randomization.
- History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 16 May 2022 | 25 |
 Germany | Recruiting | 16 May 2022 | 65 |
 Italy | Recruiting | 16 May 2022 | 28 |
 Poland | Recruiting | 16 May 2022 | 6 |
 Romania | Recruiting | 16 May 2022 | 18 |
 Slovakia | Recruiting | 16 May 2022 | 8 |
 Spain | Recruiting | 16 May 2022 | 45 |
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 |
|---|---|---|---|---|---|---|
INAVOLISIB | Test | FILM-COATED TABLET | ORAL USE | 9 | 18 | PRD9793810 |
Phesgo 600 mg/600 mg solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS USE | 600 | 18 | PRD8601830 |
INAVOLISIB | Test | FILM-COATED TABLET | ORAL USE | 3 | 18 | PRD9793131 |
Phesgo 1200 mg/600 mg solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS USE | 1200 | 18 | PRD8600161 |