HeredERA

• Participants who are capable of giving signed informed consent

• Participants who are age ³ 18 years at the time of signing Informed Consent Form

• Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally advanced disease not amenable to curative resection

• HER2-positive advanced breast cancer confirmed by a central laboratory prior to study enrollment. HER2-positive status will be determined based on primary or metastatic lesion and defined as 3+ by IHC and/or positive by HER2 amplification by in situ hybridization (ISH) with a ratio of ³ 2 for the number of HER2 gene copies to the number of signals for chromosome 17 copies

• Estrogen receptor-positive (ER) advanced breast cancer, confirmed by a central laboratory according to the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines, prior to study enrolment. ER positive status will be determined on the same lesion that was used to determine HER2 positivity, and will be defined as primary or metastatic tumor with ≥1% of tumor cells staining positive for the ER. Availability of the most recently collected and representative tumor tissue specimen (i.e., archived formalin-fixed, paraffin-embedded [FFPE] tissue block [preferred] or at least 20 slides containing unstained, freshly cut, serial sections), with associated de-identified pathology report, and whenever possible, from a metastatic site of disease (see Section 4.5.7 and the laboratory manual). A minimum of 20 slides is required, but 14-19 slides are acceptable only in exceptional cases provided that other eligibility requirements are met and after consultation with the Medical Monitor. Fine-needle aspiration (defined as samples that do not preserve tissue architecture and yield cell suspension and/or smears), is not acceptable.

• 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 neo-adjuvant systemic non-hormonal treatment to recurrence of ≥ 6 month

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

• Left ventricular ejection fraction (LVEF) of at least 50%

• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 7 days prior to randomization:

– ANC ³ 1.5 x 109/L (1500 cells/μL) without granulocyte colony-stimulating factor (G-CSF) support

• Participants who have an ANC >1.5 x 109/L (1500/mL) for individuals of non-African descent or > 1.3 x 109/L (1300/mL) for individuals of African descent

– Platelet count ³ 100,000 cells/μL

– Hemoglobin ³ 9.0 g/dL

• Patients may receive red blood cell transfusions to obtain this level

– Serum creatinine <1.5 x upper limit of normal (ULN) or estimated creatinine clearance ³ 60ml/min as calculated per institutional guidelines

– INR and aPTT £ 1.5 ´ ULN (except for patients receiving anticoagulation therapy)

• For patients receiving warfarin, a stable INR between 2 and 3 is required. For patients receiving heparin, PTT (or aPTT) between 1.5 and 2.5´ ULN (or patient's value before starting heparin treatment) is required. If anticoagulation therapy is required for a prosthetic heart valve, stable INR between 2.5 and 3.5 is permitted.

– Serum AST and ALT £ 3 ´ ULN

– For patients with documented liver metastasis: AST and ALT £ 5 ´ ULN

– Serum total bilirubin (TBILI) £ 1.5 ´ ULN, except for patients with Gilbert’s syndrome (£3 x ULN), for whom direct bilirubin should be within the normal range

– Serum albumin ³ 25 g/L (2.5 g/dL)

• Participants who have a negative HIV test at screening, with the following exception: individuals with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ³ 200/mL, and have an undetectable viral load and provided that they have not had a history of AIDS-defining opportunistic infections within 12 months prior to randomization.

• Participants who have a negative hepatitis B surface antigen (HBsAg) test at screening

• Participants who have a positive hepatitis B surface antibody (HBsAb) test at screening, or a negative HBsAb at screening accompanied by either of the following:

– Negative hepatitis B core antibody (HBcAb)

– Positive HBcAb test followed by a negative (per local laboratory definition) hepatitis B virus (HBV) DNA test

• The HBV DNA test must be performed for individuals who have a negative HBsAg test, a negative HBsAb test, and a positive HBcAb test.

• Participants who have a negative hepatitis C virus (HCV) antibody test at screening, or a positive HCV antibody test followed by a negative HCV RNA test at screening.

• The HCV RNA test must be performed for individuals who have a positive HCV antibody test.

• 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 , as defined below:

• Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate of < 1% per year during the treatment period and for 7 months after the final dose of. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (³ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.

• Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices.

• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

• For men: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, as defined below:

• With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 7 months after the final dose of Phesgo to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.

• Participants who are willing and able to use the electronic Patient Reported Outcome (ePRO) device. 

• Previous systemic non-hormonal anticancer therapy in the metastatic or locally advanced breast cancer setting. Up to one line of single agent endocrine therapy may have been given in the advanced setting.

• Prior treatment with a SERD, with the exception of fulvestrant, if fulvestrant treatment was terminated at least 28 days prior to study treatment initiation.

• Previous treatment with approved or investigative anti-HER2 agents in any breast cancer treatment setting, except trastuzumab, pertuzumab, ado-trastuzumab emtamsine, and neratinib in the neoadjuvant or adjuvant setting. Disease progression while/ within 6 months of receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine in the adjuvant setting.

• Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE v5.0 Grade ≤ 1 (except alopecia, Grade ≤ 2 peripheral neuropathy, or other toxicities not considered a safety risk for the patient per investigator's judgment).

• History of persistent grade 2 or higher (NCI-CTC, Version 4.0) haematological toxicity resulting from previous adjuvant or neo-adjuvant therapy.

• Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, surgery), are clinically stable, and have not been treated with anticonvulsants or corticosteroids within 2 weeks prior to randomization.

• Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy

• Participants who are 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 study treatment.

• Participants who have received treatment with investigational therapy within 28 days prior to initiation of study treatment

• 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 equivalent), excluding inhaled steroids

• Poorly controlled hypertension (e.g., systolic > 180 mm Hg or diastolic > 100 mmHg)

• Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis virus (e.g., hepatitis B or hepatitis C), current alcohol abuse, or cirrhosis

• Active cardiac disease or history of cardiac dysfunction, including any of the following:

– History or presence of symptomatic bradycardia or resting heart rate < 50 bpm at screening. Patients on stable dose of a b-blocker or calcium channel antagonist for pre-existing baseline conditions (e.g., hypertension) may be eligible if resting heart rate is at least 50 bpm

– History of angina pectoris or myocardial infarction within 12 months prior to study entry

– History of NCI CTCAE (v4) Grade ³ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) Class ³ II or cardiomyopathy

– Left ventricular ejection fraction < 50% as determined by multiple-gated acquisition scan or echocardiogram

– QT interval corrected through use of Fridericia's formula (QTcF) >470 ms, history of long or short QT syndrome, Brugada syndrome or known history of corrected QT interval prolongation, or torsades de pointes

– History or presence of an abnormal ECG that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree heart block, sick sinus syndrome, long QT syndrome, or evidence of prior myocardial infarction

– History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcaemia), or family history of long QT syndrome

– High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate ³ 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade atrioventricular [AV]-block, such as second degree AV-block Type 2 [Mobitz 2] or third-degree AV-block)

– Serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality

– Clinically significant valvular heart disease

– Evidence of transmural infarction on ECG

• Major surgical procedure or significant traumatic injury within 14 days prior to enrollment or anticipation of need for major surgery during the course of study treatment. Note: Should surgery be necessary during the course of the study, patients should be allowed to recover for a minimum of 14 days prior to subsequent PHESGO treatment, regardless of the phase of the study (chemo-induction or maintenance). Implantable central venous access (e.g., Porth-a-cath) placement is not considered a major surgery.

• Active inflammatory bowel disease, chronic diarrhoea, short bowel syndrome, or major upper gastrointestinal (GI) surgery, including gastric resection, potentially affecting enteral absorption

• Participants who have had a serious infection requiring oral or IV antibiotics within 7 days prior to screening

• Participants who have had any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in and completion of the study

• Participants who have 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 (e.g., 5-year OS rate > 90%), such as

• adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer

• For premenopausal/perimenopausal women: known hypersensitivity to LHRH agonists, unless willing to undergo bilateral oophorectomy prior to endocrine therapy initiation requiring ovarian suppression (i.e., experimental arm and aromatase inhibitor use in the control arm); for all men: know hypersensitivity to LHRH agonist.

• For premenopausal/perimenopausal women and men: not willing to undergo and maintain treatment with approved LHRH-agonist therapy for the duration of endocrine therapy requiring gonadal function suppression (i.e., experimental arm, and aromatase inhibitor use in the control arm). 

Research Nurse: Huang Haiyan (Nolly) (x3766) Haiyan.Huang@lthtr.nhs.uk

Administrator: Bethany Webster (x8475)