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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GBG Forschungs GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Dec 2022 → ongoing

Decision date (initial)

2024-05-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

F. Hoffmann-La Roche Ltd, Switzerland

External identifiers

EU CT number

2022-501152-28-00

EudraCT number

2021-002323-38

ClinicalTrials.gov

NCT05306041

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

To compare pathological complete response (pCR=ypT0/is ypN0) rates between HER2-positive, HR-positive, PIK3CA mutant early breast cancer treated with inavolisib concurrently given to endocrine therapy, pertuzumab and trastuzumab vs. endocrine therapy, pertuzumab and trastuzumab alone.

Secondary objectives 8

1. To determine the rates of ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0
2. To assess the pCR rates per arm separately for the stratified subpopulations
3. To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests after study treatment in both arms
4. To determine the percentage of patients receiving additional neoadjuvant chemotherapy after residual disease was confirmed by core biopsy at the end of study treatment
5. To determine the breast conservation rate after each treatment
6. To assess early safety and tolerability after the first 20 and the first 40 have completed two cycles of therapy
7. To assess the overall safety and tolerability and treatment compliance in the two arms
8. Invasive disease-free survival (IDFS) and overall survival (OS) in both arms and according to stratified subpopulations.The timing for the time-to-event endpoints analysis will be defined in the statistical analysis plan.

Conditions and MedDRA coding

Breast Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
2. Untreated, unilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy is not allowed.
3. 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.
4. 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.
5. 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.
6. Age >= 18 years, female and male.
7. ECOG Performance status 0-1.
8. 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%.
9. Laboratory requirements: Hematology, Renal function, Hepatic function, Glucose Metabolism
10. Negative pregnancy test
11. 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.
12. Complete staging work-up within prior to randomization
13. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion criteria 23

1. Patients with HER2-negative breast cancer and/or HER2-positive, HR-negative breast cancer
2. Need of immediate neoadjuvant chemotherapy, e.g. inflammatory breast cancer
3. Patients with definitive clinical or radiologic evidence of Stage IV cancer.
4. 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).
5. Prior chemotherapy or endocrine therapy or radiation therapy prior to study entry.
6. 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).
7. 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.
8. BMI>30
9. Known hypersensitivity reaction to one of the compounds or substances, and/or murine proteins, and/or recombinant human hyaluronidase used in this protocol.
10. Patients with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on FPG and HbA1c.
11. Patients who are immunocompromised as the result of HIV or receiving immunosuppressive therapies.
12. Clinically significant and active liver disease, for example, sclerosing cholangitis, active viral hepatitis B or C infection, or autoimmune hepatic disorders.
13. Patients with inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, and active bowel inflammation (e.g., diverticulitis).
14. 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.
15. Patients with currently documented pneumonitis/interstitial lung disease.
16. 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.
17. Damaged skin at planned site of subcutaneous (SC) injections (thigh).
18. 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.
19. 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.
20. Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
21. Female patients: pregnancy or lactation at the time of randomization.
22. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
23. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Pathological complete response (ypT0/is ypN0) is defined as no microscopic evidence of residual invasive tumor cells in all resected specimens of the breast and axilla.

Secondary endpoints 5

1. ypT0 ypN0 is defined as no microscopic evidence of residual invasive or non-invasive viable tumor cells in all resected specimens of the breast and axilla; ypT0 ypN0/+ is defined as no microscopic evidence of residual invasive or non-invasive viable tumor cells in all resected specimens of the breast; ypT0/Tis ypN0/+ is defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast;
2. Clinical (c) and imaging (i) response will be assessed every 2nd cycle and before surgery by physical examination and imaging tests
3. Breast conservation is defined as tumorectomy, segmentectomy or quadrantectomy as a most radical surgery
4. Tolerability and safety analyses include assessment of patients whose treatment had to be dose reduced, delayed or permanently stopped
5. Survival endpoints are defined as the time period between randomization and first event and will be analyzed after the end of the study by referring to data from GBG´s registries.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GBG Forschungs GmbH

Sponsor organisation

GBG Forschungs GmbH

Address

Martin-Behaim-Strasse 12

City

Neu-Isenburg

Postcode

63263

Country

Germany

Scientific contact point

Organisation

GBG Forschungs GmbH

Contact name

Medicine and Research

Public contact point

Organisation

GBG Forschungs GmbH

Contact name

Project Management

Third parties 6

Locations

7 EU/EEA countries · 65 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 97 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

19 submissions — initial application plus substantial / non-substantial modifications