A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Giredestrant Plus Palbociclib Compared With Anastrozole Plus Palbociclib for Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Untreated Early Breast Cancer (coopERA Breast Cancer)

Early Breast Cancer Clinical Trial

Official title:

A Randomized, Multicenter, Open-Label, Two-Arm, Phase II, Neoadjuvant Study Evaluating the Efficacy, Safety, and Pharmacokinetics of GDC-9545 Plus Palbociclib Compared With Anastrozole Plus Palbociclib for Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Untreated Early Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04436744
• Other study ID #: WO42133
• Secondary ID: 2020-001007-16
• Status: Completed
• Phase: Phase 2
• Start date: September 4, 2020
• Est. completion date: November 24, 2021

Study information

• Verified date: January 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, multicenter, open-label, two-arm, Phase II study to evaluate the efficacy, safety, and pharmacokinetics of giredestrant versus anastrozole (in the window-of-opportunity phase) and giredestrant plus palbociclib compared with anastrozole plus palbociclib (in the neoadjuvant phase) in postmenopausal women with untreated, estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative, early breast cancer.

The study consists of a screening period of up to 28 days, a window-of-opportunity phase for 14 days, followed by a neoadjuvant treatment phase for 16 weeks (four 28-day cycles), surgery, and an end of study visit (28 days after the final dose of study treatment).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 221
• Est. completion date: November 24, 2021
• Est. primary completion date: July 6, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Postmenopausal women age =18 years

• Histologically confirmed operable or inoperable invasive breast carcinoma

• Candidate for neoadjuvant treatment and considered appropriate for endocrine therapy

• Willingness to undergo breast surgery after neoadjuvant treatment and to provide three mandatory tumor samples

• Documented estrogen receptor (ER)-positive tumor in accordance to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (Allison et al.2020), assessed locally and defined as =1% of tumor cells stained positive on the basis of the most recent tumor biopsy

• Documented progesterone receptor status (positive or negative) as per local assessment

• Documented human epidermal growth factor receptor-2 (HER2)-negative tumor in accordance to 2018 ASCO/CAP guidelines (Wolff et al. 2018), assessed locally on the most recent tumor biopsy

• Ki67 score =5% analyzed centrally or locally

• Eastern Cooperative Oncology Group Performance Status 0-1

• Adequate organ function

Exclusion Criteria:

• Stage IV (metastatic) breast cancer

• Inflammatory breast cancer (cT4d)

• Bilateral invasive breast cancer

• History of invasive breast cancer, ductal carcinoma in situ or lobular carcinoma in situ and other malignancy within 5 years prior to screening

• Previous systemic or local treatment for the primary breast cancer currently under investigation

• History of any prior treatment with aromatase inhibitors (AIs), tamoxifen, selective estrogen receptor down regulator, or cyclin-dependent kinase 4 and 6 inhibitors

• Major surgery within 4 weeks prior to randomization

• Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including hepatitis

• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study

• History of allergy to anastrozole, or palbociclib or any of its excipients

• Known issues with swallowing oral medication

• History of documented hemorrhagic diathesis, coagulopathy, or thromboembolism

• Active cardiac disease or history of cardiac dysfunction

• Current treatment with medications that are well known to prolong the QT interval

• Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery including gastric resection

• Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination half-lives prior to randomization

• Known HIV infection

• Serious infection requiring oral or IV antibiotics, or other clinically significant infection within 14 days prior to screening

• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study

Related Conditions & MeSH terms

• Breast Neoplasms
• Early Breast Cancer

Intervention

Drug:
• Giredestrant
During the window-of-opportunity phase (first 2 weeks) giredestrant will be taken orally once per day (QD) as a single agent. During the neoadjuvant treatment phase, giredestrant will be taken orally QD on Days 1-28 of each 28-day cycle for a total of 4 cycles, in combination with palbociclib.
• Anastrozole
During the window-of-opportunity phase (first 2 weeks), anastrozole 1 mg will be taken orally QD as a single agent. During the neoadjuvant treatment phase, anastrozole 1 mg will be taken orally QD on Days 1-28 of each 28-day cycle for a total of 4 cycles, in combination with palbociclib.
• Palbociclib
During the neoadjuvant treatment phase, palbociclib 125 mg will be taken orally QD on Days 1-21 of a 28-day cycle for a total of 4 cycles.

Procedure:
• Surgery
Surgery must be performed within a maximum of 14 days after the final cycle in the neoadjuvant treatment phase and ideally should occur as soon as possible after the last dose of study treatment.

Locations

Country	Name	City	State
Australia	Macquarie University Hospital	Macquarie Park	New South Wales
Australia	Westmead Hospital; Medical Oncology and Pallative Care	Westmead	New South Wales
Brazil	Santa Casa de Misericordia de Porto Alegre	Porto Alegre	RS
Brazil	Hospital do Cancer de Pernambuco - HCP	Recife	PE
Brazil	Clinica de Pesquisa e Centro de Estudos em Oncologia Ginecologica e Mamaria Ltda	Sao Paulo	SP
Brazil	Núcleo de Pesquisa São Camilo; ONCOLOGIA CLINICA / QUIMIOTERAPIA	Sao Paulo	SP
Germany	Universitätsklinikum Dresden	Dresden
Germany	LUISENKRANKENHAUS; Senological Oncology	Düsseldorf
Germany	UNIVERSITATSKLINIKUM ERLANGEN; Department of Gynecology and Obstetrics	Erlangen
Hungary	Bacs-Kiskun Megyei Korhaz, SZTE AOK Oktato Korhaza, Onkoradiologiai Kozpont; Onkoradiologiai Kozpont	Kecskemet
Hungary	Tolna Megyei Kórház, Onkológia	Szekszárd
Korea, Republic of	National Cancer Center; Medical Oncology	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital; Internal Medicine	Seoul
Korea, Republic of	The Catholic University of Korea Seoul St. Mary's Hospital	Seoul
Poland	Szpital Morski Im. Pck; Oncology & Radiotherapy Dept	Gdynia
Poland	COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej	Lublin
Poland	Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Oncology	Warszawa
Poland	DOLNOSLASKIE CENTRUM ONKOLOGII; Oddzial Chirurgii Piersi	Wroclaw
Russian Federation	Republican Clinical Oncology Dispensary of Ministry of Healthcare of Tatarstan Republic	Kazan	Tatarstan
Russian Federation	Moscow City Oncology Hospital #62	Moscovskaya Oblast	Moskovskaja Oblast
Russian Federation	Filial #1 Regional Oncology Dispensary of Nizhniy Novgorod	Nizhny Novgorod
Russian Federation	S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)	Saint-Petersburg
Russian Federation	FSI "SRC of Oncology n. a. N.N.Petrov of Rosmedtekhnologiy"	St. Petersburg
Russian Federation	Private Healthcare Institution Clinical Hospital RZhD Medicine	St. Petersburg	Sankt Petersburg
Spain	Institutio Catalan De Oncologia	Badalona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario Quirón Dexeus	Barcelona
Spain	Hospital Clinico San Cecilio	Granada
Spain	Hospital Universitario Virgen de las Nieves : Hospital General	Granada
Spain	Hospital de Jerez de la Frontera; Servicio de Oncologia	Jerez de La Frontera	Cadiz
Spain	Hospital Universitario de Canarias;servicio de Oncologia	La Laguna	Tenerife
Spain	Hospital Universitari Arnau de Vilanova	Lleida	Lerida
Spain	Hospital Universitario Lucus Augusti	Lugo
Spain	Fundación Jimenez Díaz	Madrid
Spain	Hosp Univ Fundacion Alcorcon	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda	Madrid
Spain	Complejo Hospitalario de Althaia; Servicio de Oncologia	Manresa	Barcelona
Spain	Hospital Universitario Virgen de La Arrixaca	Murcia
Spain	Hospital de Navarra; Servicio de Oncologia	Navarra
Spain	Hospital Universitari Sant Joan de Reus; Planta baja, color lila	Reus	Tarragona
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital General Universitario de Valencia	Valencia
Taiwan	National Cheng Kung Uni Hospital; Surgery	Tainan
Taiwan	National Taiwan Uni Hospital; General Surgery	Taipei
Ukraine	Municipal institution Dnipropetrovsk City Multifield Clinical Hospital #4; dept. of Chemotherapy	Dnipropetrovsk
Ukraine	Regional Oncology Center of Kharkiv Regional Council; Department of Soft Tissues and Breast Cancer	Kharkiv	Kharkiv Governorate
Ukraine	Khmelnytsky Regional Antitumor Center; Department of Breast, Skin, Soft Tissues and Bones Tumors	Khmelnytskyi	Podolia Governorate
Ukraine	ME Kryviy Rih Oncology Dispensary of Dnipropetrovs'k Regional Council; Chemotherapy Department	Kryvyi Rih
Ukraine	Kyiv Regional Oncological Dispensary	Kyiv
Ukraine	Odesa Regional Clinical Hospital; Department of Thoracic Surgery	Odesa	Kharkiv Governorate
United States	UCLA - Burbank	Burbank	California
United States	UCLA - Laguna Hills	Laguna Hills	California
United States	Saint Barnabas Medical Center Cancer Center	Livingston	New Jersey
United States	Univ of Wisconsin-Madison; Clinical Science Center	Madison	Wisconsin
United States	Tennessee Oncology; Sarah Cannon Research Institute	Nashville	Tennessee
United States	Orlando Health Inc.	Orlando	Florida
United States	UCLA Hematology/Oncology-San Luis Obispo	San Luis Obispo	California
United States	UCLA Hematology Oncology-Santa Monica	Santa Monica	California
United States	Torrance Memorial Physician Network/Cancer Care	Torrance	California
United States	SCRI Florida Cancer Specialists East	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Germany,  Hungary,  Korea, Republic of,  Poland,  Russian Federation,  Spain,  Taiwan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relative Percent Change in Ki67 Scores From Baseline to Week 2	Ki67 is a proliferation biomarker with prognostic value in ER-positive breast cancer. Ki67 scores were centrally assessed with immunohistochemistry and defined as a percentage of positively stained tumor cell nuclei among the total number of tumor cells assessed, with a potential range of 0-100%. A score of 0% indicates no tumor cell nuclei with Ki67 staining and a score of 100% indicates all tumor cell nuclei are positively stained with Ki67. The relative percentage change was calculated using Ki67 scores at Baseline and Week 2. Relative Percent Change was defined as Week 2 Ki67 percentage score/Baseline Ki67 percentage score*100. A smaller value of relative percentage change indicates improvement.	Baseline, Week 2
Secondary	Overall Response Rate (ORR) by Ultrasound as Determined by the Investigator	ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR), as determined by the investigator according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST). Ultrasound and clinical exam were used to assess response. CR per mRECIST was defined as the disappearance of all target lesions. PR per mRECIST was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. An estimate of ORR and its 95% confidence interval (CI) was calculated using the Clopper-Pearson method.	Baseline up to Cycle 4 Day 1 (each cycle is 28 days)
Secondary	Complete Cell Cycle Arrest (CCCA) Rate at Week 2	CCCA was defined as the percentage of participants with centrally assessed Ki67 scores =2.7%. The CCCA rate at Week 2 was summarized.	Week 2
Secondary	Number of Participants With Adverse Events (AEs) With Severity Determined in Accordance With National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)	AE is any untoward medical occurrence in clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable & unintended sign, symptom/disease temporally associated with use of a medicinal product, whether or not related to medicinal product. Preexisting conditions which worsen during a study also considered as AEs. Severity of AEs was determined per NCI CTCAE v5.0. Grade 1: Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2: Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living; Grade 3: Severe/medically significant, but not immediately life-threatening: hospitalization/prolongation of hospitalization indicated; disabling/limiting self-care activities of daily living; Grade 4: Life-threatening consequences/urgent intervention indicated; Grade 5: Death related to AE.	From baseline up to 28 days after the last dose (up to approximately 24 weeks)
Secondary	Change From Baseline in Respiratory Rate Over Time	Respiratory rate was measured while the participant was in a seated position.	Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery (up to 2 weeks after the final dose of study treatment [approximately Week 18]) and end of study (up to approximately 24 weeks)
Secondary	Change From Baseline in Pulse Rate Over Time	Pulse rate was measured while the participant was in a seated position.	Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery (up to 2 weeks after the final dose of study treatment [approximately Week 18]) and end of study (up to approximately 24 weeks)
Secondary	Change From Baseline in Systolic Blood Pressure Over Time	Systolic blood pressure was measured while the participant was in a seated position.	Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery (up to 2 weeks after the final dose of study treatment [approximately Week 18]) and end of study (up to approximately 24 weeks)
Secondary	Change From Baseline in Diastolic Blood Pressure Over Time	Diastolic blood pressure was measured while the participant was in a seated position.	Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery (up to 2 weeks after the final dose of study treatment [approximately Week 18]) and end of study (up to approximately 24 weeks)
Secondary	Change From Baseline in Body Temperature Over Time		Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery (up to 2 weeks after the final dose of study treatment [approximately Week 18]) and end of study (up to approximately 24 weeks)
Secondary	Number of Participants With Shifts in Hematology Test Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline	Hematology test parameters were measured per NCI CTCAE v5.0. Grade 0 is normal, and Grades 1 to 4 represent worsening levels of the parameter outside of the normal range in the specified direction of the abnormality (high and low are above and below the range, respectively). Number of participants with shift in the hematology values from grade 0-2 at baseline to grade 3-4 at post-baseline were reported. A marked reference range for hemoglobin 12.3-15.3 grams per deciliter (g/dL), lymphocytes absolute (Abs) 1.0-4.8 10^3/microliters (uL), neutrophils total, Abs, 1.8-8.5 10^3/uL, platelet 100-450 10^9/liter (L), total leukocyte 4.4-11 10^9/L.	From baseline up to 28 days after the last dose (up to approximately 24 weeks)
Secondary	Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline	Blood chemistry parameters were measured per NCI CTCAE v5.0. Grade 0=normal, and Grades 1 to 4 represent worsening levels of parameter outside of normal range in the specified direction of abnormality (high & low are above & below the range, respectively). Number of participants with shift in blood chemistry values from grade 0-2 at baseline to grade 3-4 at post-baseline were reported. Marked reference range for albumin 32-45 grams per liter (g/L), alkaline phosphatase 20-130 units per liter (U/L), serum glutamic pyruvic transaminase (SGPT)/ alanine transaminase (ALT) 4-36 U/L, serum glutamic oxaloacetic transaminase (SGOT)/ aspartate transaminase (AST) 8-33 U/L, calcium 2.3-2.74 millimoles per liter (mmol/L), cholesterol 3.88-6.47mmol/L, creatinine 6-12 milligrams per liter (mg/L), glucose 3.9-6.1 mmol/L, potassium 3.5-5.0 mmol/L, sodium 135-147 mmol/L, bilirubin 2-21 micromoles per liter (µmol/L), triglycerides 0.11-2.15 mmol/L, & uric acid 2.7-7.3 milligrams per deciliter (mg/dL).	From baseline up to 28 days after the last dose (up to approximately 24 weeks)
Secondary	Plasma Concentration of Giredestrant at Specified Timepoints		Window of Opportunity Phase: Day 1 (3 hours Postdose) and Day 15 (Predose) during Cycle 0 (the 15-day period in Window of Opportunity Phase is called Cycle 0 for PK analysis); Neoadjuvant Phase: Cycle 2 Day 1, Predose