Resumen

Este estudio de fase III, aleatorizado, de dos brazos, abierto y multicéntrico evaluará la eficacia y seguridad de giredestrant más Phesgo en comparación con Phesgo tras terapia de inducción con Phesgo más taxano en participantes con cáncer de mama avanzado (metastásico o localmente avanzado no susceptible de tratamiento curativo) HER2-positivo y receptor de estrógenos (RE) positivo, que no hayan recibido previamente tratamiento sistémico no hormonal contra el cáncer en el contexto avanzado.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Histologically or cytologically confirmed and documented human epidermal growth factor receptor 2 (HER2)-positive/estrogen receptor (ER)-positive adenocarcinoma of the breast with metastatic or locally-advanced disease not amenable to curative resection
At least one measurable lesion and/or non-measurable disease evaluable according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Disease-free interval from completion of adjuvant or neoadjuvant systemic non-hormonal treatment to recurrence of ≥6 months
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
Left ventricular ejection fraction (LVEF) of at least (≥)50% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)
Adequate hematologic and end-organ function
For women of childbearing potential: Participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agree to refrain from donating eggs, during the treatment period and for 7 months after the final dose of Phesgo
For men: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, during the treatment period and for 7 months after the final dose of Phesgo to avoid exposing the embryo
Complete a minimum of four cycles to a maximum of eight cycles of induction therapy; the minimum cycles are defined as either: Phesgo injections + 4 docetaxel infusions, or Phesgo injections + 12 paclitaxel infusions
Achieve a minimum of stable disease (SD) (or Non-complete response \[CR\]/Non-progressive disease \[PD\] for participants with non-measurable disease) (i.e., did not experience PD) according to RECIST v1.1 at the last tumor assessment during the induction therapy phase
LVEF of ≥50% at the last assessment during the induction therapy phase

Criterios de exclusión

Previous systemic non-hormonal anti-cancer therapy in the metastatic breast cancer (MBC) or advanced breast cancer (ABC) setting. Note: Up to one line of single-agent endocrine therapy given in the metastatic or locally advanced setting will be allowed.
Prior treatment with a selective estrogen receptor degrader (SERD)
Previous treatment with approved or investigative anti-HER2 agents in any breast cancer treatment setting, except Phesgo (or trastuzumab SC with pertuzumab IV, or pertuzumab and trastuzumab IV), single-agent trastuzumab IV or SC, ado-trastuzumab emtansine, lapatinib, and neratinib in the neoadjuvant or adjuvant setting
Disease progression within 6 months of receiving adjuvant anti-HER2 therapy (such as trastuzumab, with or without pertuzumab \[IV, SC, or fixed-dose combination\], or ado-trastuzumab emtansine, or neratinib)
Non-resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) Grade 1 or better
History of persistent Grade ≥2 (NCI-CTC, Version 5.0) hematological toxicity resulting from previous adjuvant or neo-adjuvant therapy
History of exposure to the following cumulative doses of anthracyclines; Doxorubicin \>360 mg/m2; Liposomal doxorubicin \>500 mg/m2; Epirubucin \>720 mg/m2; Mitoxantrone \>120 mg/m2; Idarubicin \>90 mg/m2.
Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease
Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy
Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the final dose of Phesgo (Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of induction therapy).
Treated with investigational therapy within 28 days prior to initiation of induction therapy
Treated with localized palliative radiotherapy within 14 days prior to initiation of induction therapy
Concurrent participation in any other therapeutic clinical trial
Known hypersensitivity to any of the study medications or to excipients of recombinant human or humanized antibodies
Current chronic daily treatment (continuous for \>3 months) with corticosteroids (dose of 10 mg/day methylprednisolone or equivalent)
Poorly controlled hypertension
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, active liver disease including active viral or other hepatitis virus, autoimmune hepatic disorders, or sclerosing cholangitis, current alcohol abuse, or cirrhosis
Active cardiac disease or history of cardiac dysfunction
Major surgical procedure or significant traumatic injury within 14 days prior to enrollment or anticipation of need for major surgery during induction therapy
Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery
Concurrent, serious, uncontrolled infections, or known infection with HIV with the following exception: Individuals who are HIV positive are eligible provided they are stable on anti-retroviral therapy for ≥4 weeks, have a CD4 count ≥350 cells/uL, and have an undetectable viral load and no history of AIDS-defining opportunistic infections within 12 months prior to enrollment.
Serious COVID-19 infection within 14 days prior to enrollment; however, no screening testing for SARS-CoV-2 is required
Serious infection requiring oral or IV antibiotics within 7 days prior to screening
Any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in the study
History of malignancy within 5 years prior to screening with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death
For pre- and perimenopausal women, and men: Known hypersensitivity to luteinizing hormone-releasing hormone agonist (LHRHa); Not willing to undergo and maintain treatment with approved LHRHa therapy for the duration of endocrine therapy that requires gonadal function suppression
Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of giredestrant treatment in Arm B
A documented history of hemorrhagic diathesis, coagulopathy, or thromboembolism, including deep vein thrombosis, unless the condition is adequately treated and under control

Intervenciones

drug

Phesgo

Phesgo will be administered subcutaneously (SC) at a fixed non-weight-based dose. In the induction therapy phase, a loading dose (1200 milligram (mg) pertuzumab, 600 mg trastuzumab, and 30,000 units of recombinant human PH20 hyaluronidase \[rHuPH20\]) will be administered in the first cycle (1 cycle is 21 days). In subsequent cycles, maintenance doses (600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units rHuPH20) will be administered once every 3 weeks (Q3W).

drug

Giredestrant

A 30 milligram (mg) capsule of giredestrant will be taken orally once a day on Days 1 to 21 of each 21-day cycle.

drug

Docetaxel

During the induction therapy phase, the investigator's choice of taxane-based chemotherapy (i.e., docetaxel or paclitaxel) will be administered after Phesgo. Docetaxel will be administered at 75 milligrams per metre squared of body surface area (mg/m2) intravenously over 60 (±10) minutes on Day 1 of each cycle for 4 to 8 cycles (a cycle is 21 days); this dose may be escalated to 100 mg/m2 if the initial dose was well tolerated.

drug

Paclitaxel

During the induction therapy phase, the investigator's choice of taxane-based chemotherapy (i.e., docetaxel or paclitaxel) will be administered after Phesgo. Paclitaxel will be administered at 80 milligrams per metre squared of body surface area (mg/m2) intravenously over a minimum of 1 hour on Days 1, 8, and 15 of each cycle for 4 to 8 cycles (a cycle is 21 days); this weekly regimen is considered as one complete cycle whenever 3 weekly doses are given.

drug

LHRH Agonist

A luteinizing hormone-releasing hormone (LHRH) agonist will be administered every 28 days to pre- and peri-menopausal women and all male participants while receiving giredestrant in Arm B. An LHRH agonist may be administered to male participants and pre- and peri-menopausal female participants receiving tamoxifen in Arm A, and should be administered to those receiving an aromatase inhibitor in Arm A. The investigator will determine and supply the appropriate LHRH agonist locally approved for use in breast cancer. The LHRH agonist will be administered according to local prescribing information.

drug

Optional Endocrine Therapy of Investigator's Choice

For participants in Arm A, optional endocrine therapy of investigator's choice is allowed based on the standard of care, and it can include an aromatase inhibitor or tamoxifen with or without an LHRH agonist, or gonadal ablation. The decision to include or exclude this option must be made prior to randomization.

Ubicaciones

Centro de Investigaciones Médicas y Desarrollo LC S.R.L

Buenos Aires, Ciudad Autónoma de BuenosAires, Argentina

Centro Oncologico Korben

Ciudad Autonoma Buenos Aires, Argentina

Centro Oncologico Riojano Integral (CORI)

La Rioja, Argentina

Fundacion Centro Oncologico de Integracion Regional (COIR)

Mendoza, Argentina

Instituto de Oncología de Rosario

Rosario, Argentina

Hospital Provincial del Centenario

Rosario, Argentina

CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica

San Juan, Argentina

Resumen

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Phesgo

Giredestrant

Docetaxel

Paclitaxel

LHRH Agonist

Optional Endocrine Therapy of Investigator's Choice

Ubicaciones

Centro de Investigaciones Médicas y Desarrollo LC S.R.L

Centro Oncologico Korben

Centro Oncologico Riojano Integral (CORI)

Fundacion Centro Oncologico de Integracion Regional (COIR)

Instituto de Oncología de Rosario

Hospital Provincial del Centenario

CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica

Patrocinadores