| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Patients with Breast Cancer | |
| E.1.1.1 | Medical condition in easily understood language | | Patients with Breast Cancer | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 compare the efficacy of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in patients with HER2 negative, HR positive LA/MBC previously treated with a taxane in the neoadjuvant or adjuvant setting
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| E.2.2 | Secondary objectives of the trial | •To assess the safety and tolerability of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in patients with HER2 negative, HR positive LA/MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. Patient-reported outcomes (PROs) will also be assessed
Pharmacokinetic:
•To investigate the relationship between the pharmacokinetics (PK) of tesetaxel and efficacy and safety endpoints in patients with HER2 negative, HR positive LA/MBC previously treated with a taxane in the neoadjuvant or adjuvant setting
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | All of the following criteria must be met:
1. Female or male patients at least 18 years of age
2. Histologically or cytologically confirmed breast cancer
3. HER2 negative disease based on local testing: American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines should be utilized for assessing HER2 status.
4. HR (Estrogen Receptor (ER) and/or Progesteron Receptor (PgR)) positive disease based on local testing: ASCO/CAP guidelines should be utilized for assessing HR status.
5. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST)
•Patients with bone-only metastatic cancer must have a lytic or mixed lytic-blastic lesion that can be accurately assessed by computerized tomography (CT) or magnetic resonance imaging (MRI). Patients with bone-only disease without a lytic component (ie, blastic-only metastasis) are not eligible.
•Known metastases to the central nervous system (CNS) are permitted but not required. The following criteria apply:
•Patients must be neurologically stable and either off corticosteroids or currently treated with a maximum daily dose of 4 mg of dexamethasone (or equivalent), with no increase in corticosteroid dose within 7 days prior to Randomization
•Patients with a history of CNS metastases but with no current evidence of CNS lesions following local therapy are eligible
•Patients may have CNS metastases that are stable or progressing radiologically
•Patients with current evidence of leptomeningeal disease are not eligible
•Patients may have untreated brain metastases or previously treated brain metastases, as long as no immediate local CNS-directed therapy is indicated
•Any prior whole brain radiation therapy must have been completed > 14 days prior to the date of Randomization
•Prior stereotactic brain radiosurgery is permitted
•CNS surgical resection must have been completed > 28 days prior to the date of Randomization; patient must have complete recovery from surgery
6. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
(Oken Am J Clin Oncol. 1982 Dec;5(6):649-55)
7. Prior therapy (at least one completed dose) with a taxane-containing regimen in the neoadjuvant or adjuvant setting
8. Prior therapy with an anthracycline-containing regimen in the neoadjuvant, adjuvant, or metastatic setting, where indicated by local regulation or Investigator judgment
9. Prior endocrine therapy with or without a Cyclin dependant kinase (CDK) 4/6 inhibitor unless endocrine therapy is not indicated (ie, short relapse-free interval while on adjuvant endocrine therapy [endocrine resistance]; rapidly progressing disease/visceral crisis; or endocrine intolerance). Any targeted therapies approved for HER2 negative, HR positive LA/MBC, including everolimus, are permitted as prior therapy. There is no limit to the number of prior endocrine therapies.
10. Documented disease recurrence or disease progression of: (a) locally advanced disease that is not considered curable by surgery and/or radiation; or (b) metastatic disease
11. Adequate hematologic, hepatic, and renal function, as evidenced by:
Absolute neutrophil count (ANC) ≥ 1,500/μL without colony-stimulating factor
support
Platelet count ≥ 100,000/μL
Hemoglobin ≥ 10 g/dL without need for hematopoietic growth factor or transfusion support
Total bilirubin < 1.5 × upper limit of normal (ULN); does not apply to patients with Gilbert’s syndrome
Alanine aminotransferase (ALT) < 3 × ULN unless hepatic metastases are present then < 5 × ULN
Aspartate aminotransferase (AST) < 3 × ULN unless hepatic metastases are present then < 5 × ULN
Alkaline phosphatase < 2.5 × ULN unless hepatic metastases are present then
< 5 × ULN
Calculated creatinine clearance ≥ 50 mL/min (by Cockroft-Gault formula or local standard)
Serum albumin ≥ 3.0 g/dL
Prothrombin time (PT) < 1.5 × ULN or international normalized ratio (INR) < 1.3 and partial thromboplastin time (PTT) < 1.5 × ULN; unless the patient is on a therapeutic anticoagulant
12. Complete recovery to baseline or Grade 1 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 from adverse effects of prior surgery, radiotherapy, endocrine therapy, and other therapy, as applicable with the exception of Grade 2 alopecia from prior chemotherapy
13. Ability to swallow an oral solid-dosage form of medication
14. A negative serum pregnancy test within 7 days prior to the first dose of Study treatment in women of childbearing potential (ie, all women except those who are post menopause for ≥ 1 year or who have a history of hysterectomy or surgical sterilization)
please, refer to protocol for further inclusion criteria
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| E.4 | Principal exclusion criteria | 1. Two or more prior chemotherapy regimens for advanced disease
2. Prior treatment with a taxane in the metastatic setting
3. Prior treatment with capecitabine at any dose
4. Current evidence of leptomeningeal disease
5. Other cancer that required therapy within the preceding 5 years other than adequately: (a) non melanoma skin cancer or in situ cancer; or (b) following approval by the Medical Monitor, other cancer that has a very low risk of interfering with the safety or efficacy endpoints of the Study
6. Known human immunodeficiency virus infection unless well controlled. Patients who are on an adequate antiviral regimen with no evidence of active infection are considered well controlled
7. Active hepatitis B or active hepatitis C infection
8. 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.
9. Presence of neuropathy > Grade 1 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0
10. History of hypersensitivity to taxanes; hypersensitivity to the solvent does not preclude patient participation in this Study
11. Anticancer treatment, including endocrine therapy, radiotherapy (except stereotactic brain radiosurgery), chemotherapy, or biologic therapy, or therapy in an investigational clinical study, ≤ 14 days prior to the date of Randomization
12. Major surgery ≤ 28 days prior to the date of Randomization; patient must have complete recovery from surgery
13. Less than 2 weeks or 5 plasma half-lives (whichever is greater) since last use of a medication or ingestion of an agent, beverage, or food that is a known clinically relevant strong inhibitor or known clinically relevant inducer of the cytochrome P450 (CYP) 3A pathway (patients should discontinue taking any regularly-taken medication that is a strong inhibitor or inducer of the CYP3A pathway)
14. History of hypersensitivity or unexpected reactions to capecitabine, other fluoropyrimidine agents, or any of their ingredients
15. Known dihydropyrimidine dehydrogenase (DPD) deficiency. Testing for DPD deficiency must be performed where required by local regulations, using a validated method that is approved by local health authorities.
16. Pregnant or breastfeeding
17. If, in the opinion of the Investigator, the patient is deemed unwilling or unable to comply with the requirements of the Study
18. Patients considered by the Investigator to be suitable candidates to receive fulvestrant are excluded; patients who have previously received fulvestrant, or for whom fulvestrant is not recommended or refused, may be enrolled
19.Treatment with brivudine, sorivudine, or its chemically-related analogs ≤ 28 days prior to the date of Randomization
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| E.5 End points |
| E.5.1 | Primary end point(s) | | The primary endpoint is Progression Free Survival (PFS) adjudicated by the Independent Radiologic Review Committee (IRC). | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | Progression Free Survival is defined as the time from randomization to the date of Disease Progression as adjudicated by IRC. | |
| E.5.2 | Secondary end point(s) | Secondary efficacy endpoints (in order of importance):
Overall Survival (OS)
Objective Response Rate (ORR) as assessed by the Independent Radiologic Review Committee (IRC)
Disease control rate (DCR) as assessed by the IRC
The secondary endpoints of OS, ORR, and DCR will be analyzed by using a hierarchical procedure to control a family-wise error rate of 0.05. The secondary endpoints will only be tested if the primary efficacy endpoint analysis demonstrates the statistical superiority of Arm A at a 2-sided 0.05 (1-sided 0.025) alpha level. Each of these secondary endpoints will be analyzed sequentially in the following order:
OS
ORR as assessed by the IRC
DCR as assessed by the IRC
Only when the analysis of an endpoint is statistically significant all prior primary and secondary sequential endpoints demonstrate the statistical superiority of Arm A at a 2-sided 0.05 (1-sided 0.025) alpha level will
the statistical inference be determined based on the analysis of the next endpoint.
CNS Metastases Efficacy Endpoints:
• CNS ORR as assessed by the CNS IRC in patients with CNS metastases at baseline
• CNS PFS as assessed by the CNS IRC in patients with CNS metastases at baseline or a history of CNS metastases and in the intent-to-treat (ITT) population
• CNS OS in patients with CNS metastases at baseline or a history of CNS metastases
Patient-reported outcome endpoints:
EORTC Quality of Life Questionnaire (QLQ)-C30 Global Health Status/QoL
EORTC QLQ-C30 Functional Scales and Symptom Scales/Items
Pharmacokinetic Endpoints:
•Tesetaxel PK and its association with efficacy and safety endpoints | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | OS is defined as time from randomization to death due to any cause. ORR and DCR are defined from time of randomization to time of response or disease control as adjudicated by IRC. Timepoint for QLQ: Adverse event
(AE) collection is from Randomization through 30 days after last administration of Study treatment. SAEs and AEs thought to be
attributable to Screening procedures are reported from consent onward.
Any SAEs experienced after this period will be reported to Sponsor if Investigator suspects a causal and 15 of Cycle 1, on Day 1 of each
subsequent Cycle and at end of treatment.
CNS metastases efficacy endpoints include CNS ORR and CNS PFS as assessed by the CNS IRC, and CNS OS.
Safety endpoints: AEs including deaths and other SAEs, Clinical laboratory abnormalities
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| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 72 |
| 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 | | Austria | | Belgium | | Czech Republic | | France | | Germany | | Hungary | | Italy | | Korea, Republic of | | Netherlands | | Poland | | Russian Federation | | Singapore | | Spain | | Taiwan | | Thailand | | Ukraine | | 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
