Pharmacy and Poisons Board: Applications

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Protocol No:

ECCT/21/11/07

Date of Protocol:

30-06-2021

Study Title:

A PHASE III, RANDOMIZED, OPEN-LABEL, MULTICENTER STUDY EVALUATING THE EFFICACY AND SAFETY OF ADJUVANT GIREDESTRANT COMPARED WITH PHYSICIAN'S CHOICE OF ADJUVANT ENDOCRINE MONOTHERAPY IN PATIENTS WITH ESTROGEN RECEPTORPOSITIVE, HER2-NEGATIVE EARLY BREAST CANCER

Study Objectives:

This study will evaluate the efficacy and safety of giredestrant compared with Endocrine Therapy of Physician's Choice (TPC) in participants with ER HER2 EBC who have completed (neo)adjuvant chemotherapy and have had surgery. Specific objectives and corresponding endpoints for the study are outlined below

Primary Objective

Corresponding Endpoint

To demonstrate superiority of giredestrant over the control treatment.

IDFS is defined as the time from randomization to first occurrence of one of the following IDFS events

Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion)

Ipsilateral locoregional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast)

Distant recurrence (i.e., evidence of breast cancer in any anatomic site other than the two sites mentioned above that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer)

Contralateral invasive breast cancer

Death from any cause, including breast cancer, non-‑breast cancer, or unknown cause (but the cause of death should be specified, if possible)

All second primary non-breast cancers and in situ carcinomas (including DCIS and LCIS) and non‑melanoma skin cancers will be excluded as an event for this endpoint

The primary estimand per the estimand framework introduced in the ICH-E9 addendum (2020) is defined as follows:

Population: participants with ER+ HER2- EBC who have completed (neo)adjuvant chemotherapy and have had surgery, as defined by the inclusion/exclusion criteria

Variable: primary IDFS

Treatment: participants will be randomized in 1:1 ratio to receive either giredestrant or TPC. During the conduct of the study, participants may also receive concomitant medications as detailed in the study protocol

Intercurrent events: – events of second primary non-breast cancers – events of in situ carcinomas, and non-melanoma skin cancers – use of any new anti-cancer treatment – discontinuation of study treatment due to adverse events

Population-level summary: hazard ratio

DCIS = ductal carcinoma in situ; EBC = early breast cancer; ER+ = estrogen receptor positive; HER2- = HER2 negative; ICH-E9 = International Council for Harmonisation = E9; IDFS = invasive disease-free survival; LCIS = lobular carcinoma in situ; TPC = Endocrine Therapy of Physician’s Choice

Secondary Objectives

Corresponding Endpoints

To evaluate the efficacy of giredestrant compared with TPC

Overall survival, defined as the time from randomization to death from any cause

IDFS (per STEEP), including second primary non-breast cancer, defined in the same way as the primary IDFS, but including second primary non-breast invasive cancer as an event (with the exception of non-melanoma skin cancers and in situ carcinomas of any site)

DFS, defined as the time from randomization to first occurrence of an IDFS (per STEEP) event, including second primary non-breast cancer event or contralateral or ipsilateral DCIS

DRFI, defined as the time from randomization to first occurrence of a DRFI event

LRRFI, defined as the time from randomization to first occurrence of an LRRFI event

Mean and mean change from baseline in physical functioning, role functioning, and global health status/QoL at relevant timepoints as assessed through use of the EORTC QLQ‑C30 respective scale scores

To evaluate the safety of giredestrant compared with TPC

Incidence and severity of adverse events, with severity determined according to NCI CTCAE 5.0

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results

To characterize giredestrant PK

Plasma concentrations of giredestrant at specified timepoints

To evaluate health status utility scores of participants treated with giredestrant compared with TPC

Change from baseline in EQ 5D-5L index-based and visual analogue scale scores at relevant timepoint

Refer to protocol Section 9.4.2 for description of relevant secondary estimand framework.

DCIS = ductal carcinoma in situ; DFS = disease-free survival; DRFI = distant recurrence = free interval; EORTC = European Organisation for the Research and Treatment of Cancer; EQ-5D-5L = EuroQol 5-Dimension, 5-Level Questionnaire; IDFS = invasive disease-free survival; LRRFI = locoregional recurrence-free interval; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PK = pharmacokinetic; QLQ-C30 = Quality of Life = Core 30 Questionnaire; QoL = Quality of Life; STEEP = Standardized Definitions for Efficacy End Points; TPC = Endocrine Therapy of Physician’s Choice.

The primary estimand per the estimand framework introduced in the ICH-E9 addendum (2020) is defined as follows: • Population: participants with ER HER2 EBC who have completed (neo)adjuvant chemotherapy and have had surgery, as defined by the inclusion/exclusion criteria (see Section 5) • Variable: primary IDFS • Treatment: participants will be randomized in 1:1 ratio to receive either giredestrant or TPC. During the conduct of the study, participants may also receive concomitant medications as detailed in Section 6.8. • Intercurrent events: – events of second primary non-breast cancers – events of in situ carcinomas, and non-melanoma skin cancers – use of any new anti-cancer treatment (as defined in Section 6.8.3) – Breast surgery for secondary prevention of cancer – discontinuation of study treatment due to adverse events • Population-level summary: hazard ratio

Laymans Summary:

Breast cancer is the second most common cancer worldwide, and cause of cancer-related deaths in women and men. Despite the availability and effectiveness of current treatment options, many patients have experienced disease recurrence, discontinued treatments, and developed resistance besides having treatment-associated toxicities. Consequently, this hinders the use of currently available breast cancer treatment options. As such, this study aims to evaluate the efficacy and safety of giredestrant (the study drug) compared with physician's choice standard of care among patients with a history of surgery of the breast, and completion of the treatment.

Treatment with the study drug is expected to provide a meaningful improvement and has the potential to be better tolerated than the existing drugs currently in use. We are therefore comparing whether the study drug is stronger and/or safer against the physician’s current choice of care in reducing treatment-associated toxicities, treatment discontinuation, disease recurrence and in the overall improvement of health outcomes among women and men who are diagnosed with breast cancer disease in stages I to III (early breast cancer).

This study will take place at International Cancer Institute (ICI) Research and Care Clinic in Eldoret town, along Nandi Road. The site is expected to enroll patients from the Western Kenya region who are routinely receiving care at the facility and those that will be referred to the study site from other facilities.

Although enrolment to the study is competitive globally, International cancer institute is expected to recruit approximately 80-100 participants for this study. 4000 other participants will be recruited in other participating sites worldwide.

Breast cancer patients attending the outpatient clinic will be recruited. The study will enrol men and women aged 18 years and above who have history of breast surgery for breast cancer and are eligible for treatment with the physician’s current choice of standard treatment. Additionally, the patients must have completed the physician’s new current choice of treatment at the time of enrolment to the study.

We will ask the study participants to come to the clinic every month during the study period. The medical doctor together with a team of nurses and clinicians will do medical check-ups and collect samples (blood, urine and breast tissue) to aid in conducting tests and monitor treatment outcomes within the scheduled visits. Moreover, participants will be randomized to either get the study medication or the physician’s current treatment option for breast cancer.

Risks.

Participants may experience some side effects from the study medicine. Overall, the likely risks of the study drug are anticipated to include nausea, vomiting, diarrhea, renal problems, menopausal symptoms, infertility among other

Benefits.

There may or may not be any benefit from being in the study. It is possible that participant with early breast cancer may get better, stay the same, or get worse. Considering effectiveness data from earlier studies, the safety profile for the study drug, and the risk reduction measures for the study, the benefit-risk ratio is expected to be acceptable for the drug.

The study may benefit the community, scientists, and doctors who work in breast cancer care by providing increased knowledge and information about the treatment of the disease.

The total duration of study participation for each individual is expected to be approximately 10 years - 5 years of treatment followed by 5 years of follow up.

The findings of the study will be disseminated through conferences and seminars as abstracts, policy briefs and publications in refereed journals. The study findings will also be shared by the study participants after data analysis.

Abstract of Study:

Breast cancer is the second most commonly diagnosed cancer in the world and the most commonly diagnosed cancer among women with 2.26 million new cases and approximately 684,000 deaths in 2020 (IARC Breast Cancer 2020). Approximately 80% of all breast cancers express the estrogen receptors and are dependent on estrogen for tumor growth and progression, hence endocrine therapy is the cornerstone of treatment of estrogen receptor positive breast cancer. Tamoxifen and Aromatase Inhibitors are currently the main endocrine treatment options for estrogen receptor positive early breast cancer. Despite the effectiveness of these therapies, many patients ultimately experience disease relapse or resistance to these agents. There is a high unmet need for more optimal adjuvant therapies in patients with estrogen receptor positive early breast cancer, especially those with an increased likelihood of recurrence. The purpose of this study is to evaluate the efficacy and safety of giredestrant, a potent,

orally bioavailable, Selective Estrogen Receptor Degrader (SERD), compared with endocrine therapy of physician's choice in participants with Estrogen receptor positive, Her-2 negative early breast cancer who have completed (neo)adjuvant chemotherapy and have had surgery. Selective estrogen receptor degraders (SERD) are recognized as a therapeutic approach in patients with estrogen receptor positive metastatic breast cancer. Fulvestrant, a first-generation approved SERD, has shown statistically significant improvement in PFS compared with anastrozole in frontline patients, as demonstrated in the FALCON study. However, unfavorable pharmacokinetic properties and a requirement for intramuscular injection have hindered further development of this drug in early breast cancer. Oral SERDs may provide a more tolerable treatment option that enables better adherence and thus maximizes therapeutic benefit and compliance. Giredestrant is a potent, orally bioavailable, SERD, which parallels fulvestrant’s mechanism of action. On the basis of its mechanism of action, giredestrant has the potential to be an important new drug for the treatment of patients with estrogen receptor positive breast cancer and support development of giredestrant in early breast cancer in addition to the ongoing development in metastatic breast cancer. This is a Phase III, global, randomized, open-label, multicenter, study evaluating the efficacy and safety of adjuvant giredestrant compared with endocrine therapy of physician’s choice in participants with medium- and high-risk Stage I to III histologically confirmed estrogen receptor positive and Her-2 negative early breast cancer. Approximately 4700 participants will be screened to achieve random assignment in 1:1 ratio to study treatment of 4100 randomized participants for an estimated total of 2050 randomized participants per treatment group. Eligible participants will be randomly assigned to one of the following treatment arms: 1^st arm- giredestrant 30 mg once a day; second arm- endocrine treatment of physician choice (tamoxifen or aromatase inhibitor). The primary efficacy endpoint of the study is the invasive disease-free survival which is defined as the time from randomization to first occurrence of one of the following events:

Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion)
Ipsilateral locoregional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast)
Distant recurrence (i.e., evidence of breast cancer in any anatomic site other than the two sites mentioned above that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer)
Contralateral invasive breast cancer
Death from any cause, including breast cancer, non-breast cancer, or unknown cause (but the cause of death should be specified, if possible).

Once completed, the findings of the study will be disseminated through conferences and seminars as abstracts, policy briefs and publications in refereed journals. The study findings will also be shared by the study participants after analysis.

Substantive changes to the protocol, along with a rationale for each change, are summarized below:

Following the results of drug-drug interaction study (GP44001), which showed that giredestrant is a moderately sensitive CYP3A substrate, exclusion criteria for patients receiving or having recently received treatment with strong CYP3A inhibitors or inducers has been added (Section 5.2).

In addition, Section 6.8.2.3 (Moderate CYP3A inducers) has been added to cautionary therapy, language added to prohibited therapy (Section 6.8.2) and language added to prohibited food (Section 6.8.4).

The color of the giredestrant capsules has been added for clarification (Section 6.1.1)

Clarification has been provided for the urine pregnancy test, which must be performed 24 hours prior to study treatment initiation (Section 1.3)

For patients who discontinue study treatment and start new endocrine therapy, AE reporting period of 28 days and AE requirements have been added, to ensure adequate safety follow up (Sections 1.3, 8.3.1, and A3-6).

Language has been added to reiterate that discordance between local and central Ki67 results does not require sample re-testing or sample resubmission. Central pathology laboratory results will be used to determine eligibility (Sections 4.1, 5.4, and 8.7).

In alignment with the In Vitro Diagnostic Medical Devices Regulation, the Clinical Investigation Identification Number (CIV ID) has been added to the title page of the protocol. Text has also been added to indicate that the VENTANA CONFIRM anti-Ki-67 IHC assay is investigational and reference to the associated clinical performance study protocol has been included (Section 8.7).

The clinic visit time window has been amended and for the first three cycles must be scheduled within ±2 days of the day specified and within ±6 days from Cycle 4 onward. This is a logistic change as the IMP is provided in bottles of 30 tablets/capsules (Section 1.3).

Requirement for serial measurements of estradiol and FSH has been added upon withdrawal of LHRH agonist, for patients who are potentially considered post-menopausal, to ensure their post-menopausal status (Section 6.1.3).

Text has been added to clarify that serial measurements of estradiol and FSH apply for patients with unilateral oophorectomy (Schedule of Activities Section 1.3)

A description of the technical and organizational security measures taken to protect personal data has been added to align with CTR requirements (Section A1-4 Data Protection).

Due to local process change from December 2019, the term “NMPA-recognized” is not valid and is removed throughout.

The Sponsor record retention policy has been clarified (Section A1-7).

Due to certain local requirements and an alignment of Sponsor process, it has been clarified that summaries of clinical study results may be available in health authority databases for public access in addition to redacted Clinical Study Reports (Section A1-6).

Personal identifiable information (i.e., name and telephone number) for the Medical Monitors has been removed from the protocol (front matter and Section 8.3.9). Medical Monitor contact information has been replaced with a sentence indicating that this information will be provided separately to sites.