| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HR+ / HER2- metastatic breast cancer and non-visceral disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hormone receptor positive and HER2-negative breast cancer that has spread |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To show efficacy of xentuzumab in combination with everolimus and exemestane over everolimus and exemestane in this patient population. |
|
| E.2.2 | Secondary objectives of the trial |
| To determine further efficacy and safety of xentuzumab in combination with exemestane and everolimus in HR+/HER2- advanced or metastatic breast cancer patients with non-visceral disease. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed breast cancer with documented ER-positive and/or PgR-positive and HER2-negative status if there are at least 1% positive tumour nuclei in the sample as defined in the relevant American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guidelines
2. Locally advanced or mBC not deemed amenable to curative surgery or curative radiation therapy
3. Archival tumour sample available at the time of informed consent and provided to the central laboratory around the time of randomisation. Patients must provide a formalin-fixed paraffin embedded (FFPE) tissue biopsy sample preferably taken at the time of presentation with recurrent or metastatic disease (provision of a biopsy sample taken from the bone is not acceptable).If archival tissue is not available, provision of detailed information from the original histology report may be agreed with the sponsor on a case by case basis.
4. Patients must satisfy the following criteria for prior therapy:
Disease progression during treatment or within 12 months of completion of endocrine adjuvant therapy
OR
Disease progression while on or within 1 month after the end of prior endocrine therapy for advanced/metastatic breast cancer (Note: the endocrine therapy does not have to be the treatment immediately prior to trial entry)
5. Inclusion criteria 5 is now obsolete
6 Inclusion criteria 6 is now obsolete
7.Female patients ≥18 years old or over the legal age of consent in countries where that is greater than 18 years at the time of informed consent. Patients must be either:
Premenopausal on ovarian suppression with a gonadotropin-releasing hormone (GnRH) agonist with FSH and estradiol in postmenopausal range (initiated at least 28 days prior screening ) OR
Post-menopausal, defined as one of the following:
Age ≥ 60 years
Age < 60 years and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression, and FSH and estradiol in the postmenopausal range.
If taking tamoxifen or toremifene, and age <60 years, then FSH and estradiol in post-menopausal range.
Surgical menopause with bilateral oophorectomy
8. Patients must have an indication for combination treatment with everolimus and exemestane.
9. Patients must have
At least one measurable non-visceral lesion according to RECIST version 1.1 in either lymph nodes, soft tissue, skin
AND/OR
At least one measurable non-visceral lesion according to RECIST version 1.1 as lytic or mixed (lytic + blastic) in bone
AND/OR
At least one non-measurable (lytic, mixed lytic + blastic, or blastic bone lesion according to RECIST version 1.1
10. Eastern Cooperative Oncology Group (ECOG) performance score 0 or1
11. Fasting glucose <8.9 mmol/L (<160 mg/dL) and HbA1c <8.0%
12. Adequate organ function, defined as all of the following:
a) Absolute neutrophil count (ANC) ≥1500/mm3
b) Platelet count ≥100,000/mm3
c) International Normalised Ratio (INR)1 ≤2.0
d) Serum creatinine ≤1.5 times upper limit of institutional normal (ULN) or creatinine clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault formula).
e) Total Bilirubin ≤1.5 times ULN (patients with Gilbert syndrome total bilirubin must be <4 times ULN)
f) Aspartate amino transferase (AST) and alanine amino transferase (ALT) ≤2.5 times the ULN
g) Fasting triglycerides ≤300 mg/dL or 3.42 mmol/L
h) Haemoglobin (Hgb) ≥9.0 g/dL
13. Recovered from any previous therapy related toxicity to ≤Grade 1 at study entry (except for stable sensory neuropathy ≤Grade 2 and alopecia) |
|
| E.4 | Principal exclusion criteria |
1. Previous treatment with agents targeting the IGF pathway, AKT, or mTOR pathways (sirolimus, temsirolimus, etc.)
2. Prior treatment with exemestane (except adjuvant exemestane stopped >12 months prior to start of study treatment as long as the patient did not recur during or within 12 months after the end of adjuvant exemestane)
3. Evidence of visceral metastasis/es (i.e. liver, lung, peritoneal, pleural metastases, malignant pleural effusions, malignant peritoneal effusions)at screening. NOTE: Patients with a past history of visceral metastases are eligible if visceral metastases have completely resolved at least 3 months prior to screening.
4. History or evidence of metastatic disease to the brain
5. Leptomeningeal carcinomatosis
6. Known hypersensitivity to any of the study drugs or their excipients
7. Any contraindication to treatment with everolimus or exemestane
8. More than 1 prior line of chemotherapy for HR+ HER2- metastatic breast cancer
9. Radiotherapy within 4 weeks prior to the start of study treatment, except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to study treatment
10. Major surgery (major according to the investigator’s assessment) performed within 4 weeks prior to randomisation or planned after screening
11. Use of concomitant systemic sex hormone therapy (e.g. Megace) within 2 weeks prior to start of trial treatment. NOTE: Ovarian suppression with GnRH agonists is permitted in premenopausal patients.
12. History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of ≥3, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator. Myocardial infarction within 6 months prior to randomisation.
13. Any history of or concomitant condition that, in the opinion of the Investigator, would compromise the patient’s ability to comply with the study or interfere with the evaluation of the efficacy and safety of the study medications.
14. Previous or concomitant malignancies at other sites, except effectively treated
a) Non-melanoma skin cancers
b) Carcinoma in situ of the Cervix
c) Ductal carcinoma in situ
d) Other malignancy that has been in remission for more than 3 years and is considered to be cured.
15. Known pre-existing interstitial lung disease (ILD).
16. Known active hepatitis B infection (defined as presence of Hep B sAg and/or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known Human immunodeficiency virus (HIV) carrier
17. Active infectious disease which puts the patient at increased risk in the opinion of the investigator
18. Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the study drug (e.g. nausea, uncontrolled vomiting, Crohn’s disease, ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the investigator
19. Previous randomisation in this trial
20. Concurrent participation in another clinical trial with an investigational device or drug.
21. Patients receiving concomitant immunosuppressive agents or chronic corticosteroid use except in cases outlined below:
Topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways diseases), eye drops, mouth washes or local injections (e.g. intra-articular) are allowed
Patients on stable low dose of corticosteroids for at least two weeks before study entry are allowed
22. Patients who have taken or wish to continue the intake of restricted medications (see Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial must have stopped them at least 2 weeks before C1V1 Treatment with denosumab/bisphosphonates is allowed.
23. Growth hormones or growth hormone inhibitors
24. More than 1 prior treatment line with a CDK4/6 inhibitor
25. Pregnant or nursing (lactating) women.
26. Women of child-bearing potential* unless they are using highly effective nonhormonal methods of contraception that achieve a failure rate of less than 1% per year when used consistently and correctly during dosing of study treatment and for at least 1 month after the last dose of exemestane, 8 weeks after the last dose of everolimus and 6 months after the last dose of xentuzumab /placebo (whichever is the longest). Highly effective contraception methods
are listed in the exclusion criteria in protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint to determine efficacy of xentuzumab is progression-free survival (PFS) which is defined as time from randomisation until disease progression according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) or death from any cause, whichever occurs earlier. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The timepoint of primary evaluation of PFS will take place when 40 PFS events have occurred |
|
| E.5.2 | Secondary end point(s) |
1) Overall survival (OS)
2) Disease control (DC)
3) Duration of DC
4) Objective response (OR)
5) Time to pain progression or intensification of pain palliation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) The timepoint of primary evaluation of OS will take place when all patients have completed treatment and attended FU1
2) Same timepoint as PFS analysis
3) Same timepoint as PFS analysis
4) Same timepoint as PFS analysis
5) Same timepoint as PFS analysis |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| France |
| Germany |
| Greece |
| Ireland |
| Italy |
| Portugal |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
Print
