| Study Objectives: |
Primary Objective and Corresponding Endpoint
To evaluate the efficacy of Phesgo plus giredestrant compared with Phesgo
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PFS, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
Secondary Objectives and Corresponding Endpoints
To evaluate the efficacy of Phesgo plus giredestrant compared with Phesgo
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OS, defined as the time from randomization to death from any cause
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ORR (following randomization), defined as the proportion of participants with a CR or PR on two consecutive occasions 4 weeks apart, as determined by the investigator according to RECIST v1.1
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DOR (following randomization), defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
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CBR (following randomization), defined as the proportion of participants with SD for 24 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1
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Mean and mean changes from baseline score in function (role, physical) and HRQoL by cycle and between treatment arms as assessed through the use of the Functional and GHS/QoL scales of the EORTC QLQ-C30
To evaluate the safety of Phesgo plus giredestrant compared with Phesgo
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Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0
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Change from baseline in targeted clinical laboratory test results
Exploratory Objectives and Corresponding Endpoints
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To evaluate the efficacy of Phesgo plus giredestrant compared with Phesgo
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Mean and mean changes from baseline score in disease/treatment-related symptoms by cycle and between treatment arms as assessed by all symptom items/scales of the EORTC QLQ-C30 and EORTC QLQ-BR23
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Proportion of participants reporting a clinically meaningful deterioration in pain severity, defined as a 2-point increase from baseline on the “worst pain” item score from the BPISF questionnaire
To evaluate effects of Phesgo plus giredestrant compared with Phesgo on work productivity and activity
-
Changes in patient-reported WPAI scores at specified timepoints
To evaluate health utility of participants treated with Phesgo plus giredestrant compared with Phesgo to generate utility scores for use in economic models
-
Utility scores of the EQ-5D-5L questionnaire
To evaluate the safety of Phesgo plus giredestrant compared with Phesgo from the participant's perspective
-
Presence, frequency of occurrence, severity, and/or degree of interference with daily function of symptomatic treatment toxicities (nausea, vomiting, diarrhea, rash, joint pain, fatigue, hot flashes), as assessed through use of the NCI PRO-CTCAE
-
Proportion of participants reporting each response option at each assessment timepoint by treatment arm for treatment side-effect bother single-item GP5 from the FACT-G
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Change from baseline in symptomatic treatment toxicities and treatment side-effect bother, as assessed through use of the PRO-CTCAE and the overall treatment side-effect bother item, respectively
To characterize the giredestrant, pertuzumab, and trastuzumab PK profile when given in combination
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Trough concentrations of pertuzumab and trastuzumab in serum at specified time points
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Cmax (maximum plasma concentration observed) and Cmin (minimum plasma concentration observed) of giredestrant concentrations in plasma at specified time points
To evaluate the potential relationships between Phesgo and giredestrant exposure and the safety, efficacy, immunogenicity, or biomarker endpoints.
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Relationship between pertuzumab PK and efficacy, safety, immunogenicity, or biomarker endpoints
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Relationship between trastuzumab PK and efficacy, safety, immunogenicity, or biomarker endpoints
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Relationship between giredestrant PK and efficacy, safety, immunogenicity, or biomarker endpoints
To evaluate the immune response to pertuzumab, trastuzumab, and rHuPH20
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Incidence of pertuzumab ADAs during the study relative to the prevalence of ADAs at baseline
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Incidence of trastuzumab ADAs during the study relative to the prevalence of ADAs at baseline
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Incidence of rHuPH20 ADAs during the study relative to the prevalence of ADAs at baseline
To evaluate potential effects of ADAs
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Relationship between pertuzumab ADA status and efficacy, safety, or PK endpoints
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Relationship between trastuzumab ADA status and efficacy, safety, or PK endpoints
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Relationship between rHuPH20 ADA status and efficacy, safety, or PK endpoints
To identify and/or evaluate biomarkers that are predictive of response to Phesgo and giredestrant (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with progression to a more severe disease state (i.e., prognostic biomarkers), are associated with acquired resistance to Phesgo and giredestrant, are associated with susceptibility to developing adverse events or can lead to improved adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence of Phesgo and giredestrant activity (i.e., pharmacodynamic biomarkers), or can increase the knowledge and understanding of disease biology and drug safety
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Relationship between biomarkers in blood, plasma and tumor tissue (listed in Section 8.7) and efficacy, safety, PK, immunogenicity, or other biomarker endpoints
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| Laymans Summary: |
The purpose of this study is to assess the efficacy and safety of giredestrant, a novel oral selective estrogen receptor degrader (SERD) in combination with Phesgo (pertuzumab, trastuzumab, and rHuPH20 injection, for SC use) in participants with previously untreated, locally-advanced unresectable, or metastatic, estrogen receptor (ER)-positive, HER2-positive breast cancer (BC), following four to six cycles of induction therapy with Phesgo + taxane (i.e., docetaxel or paclitaxel, as per the standard of care). Despite advances in early diagnosis and curative multimodality treatments, some patients may still experience a metastatic recurrence or present with “de novo” metastatic breast cancer (MBC). There continues to be a need for treatments with better benefit-risk profiles that prolong progression free survival (PFS) and other survival endpoints of patients with ER-positive, HER2-positive advanced breast cancer (ABC).
Study treatment is comprised of two phases: induction therapy followed by study maintenance therapy. Approximately 812 participants will be enrolled into the induction therapy phase, and approximately 730 participants will be randomized in the maintenance therapy phase. Participants who are still in the induction therapy phase after this target is reached will be also be allowed to enter the maintenance therapy phase, if they are deemed eligible by the investigator.
During the induction therapy phase, participants will receive four to six cycles of Phesgo in combination with a taxane (i.e., docetaxel or paclitaxel, as per the standard of care.) At the investigator’s discretion, participants who tolerate six cycles of induction therapy well and do not experience progressive disease (PD) may be given up to two additional cycles: up to a maximum of eight cycles as per the standard of care. Participants who have received one or two cycles of Phesgo (or trastuzumab SC with pertuzumab IV, or PH IV) with docetaxel or paclitaxel prior to enrollment are eligible and these additional cycles will count towards eligibility for the maintenance phase.
Following the induction therapy phase, eligible participants will be randomized into the maintenance therapy phase during which they will receive Phesgo plus giredestrant or Phesgo in 21-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end, whichever occurs first.
Participants will be followed for safety for 28 days after the final dose of study treatment, including a treatment discontinuation visit at 28 days (plus or minus 3 days) after the final dose of Phesgo. Thereafter, information on survival and new anti-cancer therapy will be collected every 3 months until death (unless the participant withdraws consent or the Sponsor terminates the study). The survival follow-up period for participants remaining in the study will conclude at the time of them final overall survival (OS) analysis.
The total duration of study participation for each individual is expected to range from 1 day to more 86 months.
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| Abstract of Study: |
A PHASE III, RANDOMIZED, OPEN-LABEL STUDY EVALUATING THE EFFICACY AND SAFETY OF GIREDESTRANT IN COMBINATION WITH PHESGO VERSUS PHESGO AFTER INDUCTION THERAPY WITH PHESGO+TAXANE IN PATIENTS WITH PREVIOUSLY UNTREATED HER2-POSITIVE, ESTROGEN RECEPTOR-POSITIVE LOCALLY-ADVANCED OR METASTATIC BREAST CANCER
PROTOCOL NUMBER: WO43571
STUDY NAME: heredERA
VERSION NUMBER: 1
TEST COMPOUND(S): Phesgo (pertuzumab, trastuzumab, and rHuPH20) (RO7198574) giredestrant (RO7197597)
Breast cancer is the most common cancer among women. In 2020, an estimated 2.26 million cases were diagnosed globally and approximately 685,000 deaths were attributed to this disease (Sung el al. 2021). Approximately 15%-20% of patients with primary invasive BCs overexpress HER2 (also known as HER2/neu or erbB2) (Burnstein et al. 2005). Prior to the availability of HER2-directed therapies, these patients had worse prognoses, including a greater risk of relapse and shortened survival time, compared with patients with HER2-negative BC (Slamon et al. 1987; Toikkanen et al. 1992; Andrulis et al. 1998).
The pivotal CLEOPATRA trial (Study WO20698) demonstrated the survival advantages and manageable toxicity profile of a dual HER2blockade with Herceptin® (trastuzumab) and Perjeta® (pertuzumab) combined with the cytotoxic agent docetaxel. Beginning in 2012, this regimen became widely accepted as the first-line treatment for patients diagnosed with HER2-positve advanced breast cancer (ABC) (Baselga et al. 2012; Swain et al. 2015; Denduluri et al. 2018; Giodarno et al. 2018; Cardoso et al. 2019, Cardoso et al. 2020).
ER expression in HER2-positive BC implies a rather distinct biology compared to that of ER-negative, HER2-positive BC: patients diagnosed with ER-positive, HER2-positive BC have tumors that are less proliferative, have lower HER2 gene amplification, and lower response rates to chemotherapy with anti-HER2 therapies (Baselga et al. 2012; Gianni et al. 2012; Schneeweiss et al. 2013; Loi et al. 2016).
A bi-directional cross-talk between the HER-family and ER has been fully characterized at cellular level, whereby suppression of either receptor alone is associated with upregulation of the other, ultimately leading to resistance to therapy (Cortés et al. 2011).PERTAIN (Study MO27775) also demonstrated the beneficial effect of a dual HER2 blockade with ET; an improvement in progression-free survival (PFS) alongside good tolerability was observed with the addition of pertuzumab to trastuzumab (PH) plus an aromatase inhibitor (AI), over trastuzumab plus AI alone (Rimawi et al. 2018).
Roche is developing giredestrant, a potent, orally bioavailable ER- alpha antagonist and inducer of ER- degradation that competes with estrogens for binding to the ER with low nanomolar potency. It is being developed as a new ET for the treatment of patients with ER-positive ABC, as well as early breast cancer (EBC) (Liang et al. 2021). Giredestrant antagonizes the effects of estrogens via competitive binding to the ligand-binding domain (LBD) of both wild-type and mutant ER with nanomolar potency. Upon binding, giredestrant induces an inactive conformation to the ER LBD, as measured by displacement of co-activator peptides. In addition to its direct antagonist properties, the mechanism of action of giredestrant includes reducing levels of ER protein through proteasome-mediated degradation. Degradation of ER is hypothesized to enable full suppression of ER signaling, which is not achieved by first-generation ER therapeutics such as tamoxifen that display partial agonism. Giredestrant potently inhibits the proliferation of multiple ER-positive BC cell lines in vitro, including cells engineered to express clinically relevant mutations in ER.
Despite advances in early diagnosis and curative multimodality treatments, some patients may still experience a metastatic recurrence or present with “de novo” metastatic breast cancer (MBC). In this setting, the main goals of treatment are to improve the quality of life and prolong patient survival as there still is not a cure (Cardoso et al. 2020). Thus there continues to be a need for treatments with better benefit-risk profiles that prolongs PFS and other survival endpoints of patients with ERpositive, HER2-positive ABC.
Primary Objective and Corresponding Endpoint
To evaluate the efficacy of Phesgo plus giredestrant compared with Phesgo
-
PFS, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
Secondary Objectives and Corresponding Endpoints
To evaluate the efficacy of Phesgo plus giredestrant compared with Phesgo
-
OS, defined as the time from randomization to death from any cause
-
ORR (following randomization), defined as the proportion of participants with a CR or PR on two consecutive occasions 4 weeks apart, as determined by the investigator according to RECIST v1.1
-
DOR (following randomization), defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
-
CBR (following randomization), defined as the proportion of participants with SD for 24 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1
-
Mean and mean changes from baseline score in function (role, physical) and HRQoL by cycle and between treatment arms as assessed through the use of the Functional and GHS/QoL scales of the EORTC QLQ-C30
To evaluate the safety of Phesgo plus giredestrant compared with Phesgo
-
Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0
-
Change from baseline in targeted clinical laboratory test results
Exploratory Objectives and Corresponding Endpoints
-
To evaluate the efficacy of Phesgo plus giredestrant compared with Phesgo
-
Mean and mean changes from baseline score in disease/treatment-related symptoms by cycle and between treatment arms as assessed by all symptom items/scales of the EORTC QLQ-C30 and EORTC QLQ-BR23
-
Proportion of participants reporting a clinically meaningful deterioration in pain severity, defined as a 2-point increase from baseline on the “worst pain” item score from the BPISF questionnaire
To evaluate effects of Phesgo plus giredestrant compared with Phesgo on work productivity and activity
-
Changes in patient-reported WPAI scores at specified timepoints
To evaluate health utility of participants treated with Phesgo plus giredestrant compared with Phesgo to generate utility scores for use in economic models
-
Utility scores of the EQ-5D-5L questionnaire
To evaluate the safety of Phesgo plus giredestrant compared with Phesgo from the participant's perspective
-
Presence, frequency of occurrence, severity, and/or degree of interference with daily function of symptomatic treatment toxicities (nausea, vomiting, diarrhea, rash, joint pain, fatigue, hot flashes), as assessed through use of the NCI PRO-CTCAE
-
Proportion of participants reporting each response option at each assessment timepoint by treatment arm for treatment side-effect bother single-item GP5 from the FACT-G
-
Change from baseline in symptomatic treatment toxicities and treatment side-effect bother, as assessed through use of the PRO-CTCAE and the overall treatment side-effect bother item, respectively
To characterize the giredestrant, pertuzumab, and trastuzumab PK profile when given in combination
-
Trough concentrations of pertuzumab and trastuzumab in serum at specified time points
-
Cmax (maximum plasma concentration observed) and Cmin (minimum plasma concentration observed) of giredestrant concentrations in plasma at specified time points
To evaluate the potential relationships between Phesgo and giredestrant exposure and the safety, efficacy, immunogenicity, or biomarker endpoints.
-
Relationship between pertuzumab PK and efficacy, safety, immunogenicity, or biomarker endpoints
-
Relationship between trastuzumab PK and efficacy, safety, immunogenicity, or biomarker endpoints
-
Relationship between giredestrant PK and efficacy, safety, immunogenicity, or biomarker endpoints
To evaluate the immune response to pertuzumab, trastuzumab, and rHuPH20
-
Incidence of pertuzumab ADAs during the study relative to the prevalence of ADAs at baseline
-
Incidence of trastuzumab ADAs during the study relative to the prevalence of ADAs at baseline
-
Incidence of rHuPH20 ADAs during the study relative to the prevalence of ADAs at baseline
To evaluate potential effects of ADAs
-
Relationship between pertuzumab ADA status and efficacy, safety, or PK endpoints
-
Relationship between trastuzumab ADA status and efficacy, safety, or PK endpoints
-
Relationship between rHuPH20 ADA status and efficacy, safety, or PK endpoints
To identify and/or evaluate biomarkers that are predictive of response to Phesgo and giredestrant (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with progression to a more severe disease state (i.e., prognostic biomarkers), are associated with acquired resistance to Phesgo and giredestrant, are associated with susceptibility to developing adverse events or can lead to improved adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence of Phesgo and giredestrant activity (i.e., pharmacodynamic biomarkers), or can increase the knowledge and understanding of disease biology and drug safety
-
Relationship between biomarkers in blood, plasma and tumor tissue (listed in Section 8.7) and efficacy, safety, PK, immunogenicity, or other biomarker endpoints
Inclusion Criteria:
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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
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At least one measurable lesion and/or non-measurable disease evaluable according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
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Disease-free interval from completion of adjuvant or neoadjuvant systemic non-hormonal treatment to recurrence of ≥6 months
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Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
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Left ventricular ejection fraction (LVEF) of at least (≥)50% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)
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Adequate hematologic and end-organ function
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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
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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
Maintenance Phase Inclusion Criteria
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Complete a minimum of four cycles of induction therapy
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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
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LVEF of ≥50% at the last assessment during the induction therapy phase
Exclusion Criteria:
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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.
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Prior treatment with a selective estrogen receptor degrader (SERD)
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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), ado-trastuzumab emtansine, lapatinib, and neratinib in the neoadjuvant or adjuvant setting
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Disease progression within 6 months of receiving trastuzumab, with or without pertuzumab, or ado-trastuzumab emtansine in the adjuvant setting
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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
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History of persistent Grade ≥2 (NCI-CTC, Version 5.0) hematological toxicity resulting from previous adjuvant or neo-adjuvant therapy
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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.
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Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease
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Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy
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Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the final dose of Phesgo
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Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of induction therapy
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Treated with investigational therapy within 28 days prior to initiation of induction therapy
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Treated with localized palliative radiotherapy within 14 days prior to initiation of induction therapy
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Concurrent participation in any other therapeutic clinical trial
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Known hypersensitivity to any of the study medications or to excipients of recombinant human or humanized antibodies
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Current chronic daily treatment (continuous for >3 months) with corticosteroids (dose of 10 mg/day methylprednisolone or equivalent)
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Poorly controlled hypertension
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Known clinically significant history of liver disease
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Active cardiac disease or history of cardiac dysfunction
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Major surgical procedure or significant traumatic injury within 14 days prior to enrollment or anticipation of need for major surgery during induction therapy
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Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery
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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, have a CD4 count ≥200 cells/uL, and have an undetectable viral load and no history of AIDS-defining opportunistic infections within 12 months prior to enrollment.
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Serious COVID-19 infection within 14 days prior to enrollment; however, no screening testing for SARS-CoV-2 is required
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Serious infection requiring oral or IV antibiotics within 7 days prior to screening
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Any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in the study
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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
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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
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