| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061020 |
| E.1.2 | Term | Breast cancer male |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057654 |
| E.1.2 | Term | Breast cancer female |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006201 |
| E.1.2 | Term | Breast cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006202 |
| E.1.2 | Term | Breast cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Primary:
Cohort 1: To assess the antitumor activity of tesetaxel in combination with one of three different programmed cell death protein 1 or programmed death-ligand 1 (PD-(L)1) inhibitors (including a randomized comparison of the antitumor activity with nivolumab, pembrolizumab, or atezolizumab) in patients with previously untreated, triple-negative MBC with PD-L1 positive disease as assessed by objective response rate (ORR) and progression free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Cohort 2: To assess the antitumor activity of tesetaxel monotherapy in elderly patients with HER2 negative, HR positive MBC previously untreated with chemotherapy in the MBC setting as assessed by ORR and PFS by RECIST 1.1
Cohort 3: To assess the antitumor activity of tesetaxel monotherapy in non-elderly adult patients with HER2 negative, HR positive MBC
previously untreated with chemotherapy in the MBC setting as assessed by ORR and PFS by RECIST 1.1 |
|
| E.2.2 | Secondary objectives of the trial |
Cohort 1: To assess the antitumor activity of tesetaxel in combination
with one of three different PD-(L)1 inhibitors (including a randomized
comparison of the antitumor activity with nivolumab, pembrolizumab, or atezolizumab) in patients with previously untreated, triple-negative MBC as assessed by ORR and PFS by RECIST 1.1; To assess the safety and tolerability of tesetaxel in combination with one of three different PD-(L)1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) in patients
with previously untreated, triple-negative MBC
Cohort 2: To assess the antitumor activity of tesetaxel monotherapy in elderly patients with triple-negative MBC previously untreated with chemotherapy in the MBC setting as assessed by ORR and PFS by RECIST 1.1; To assess the safety and tolerability of tesetaxel monotherapy in elderly patients with HER2 negative MBC previously untreated with chemotherapy in the MBC setting
Cohort 3: "Please refer to the Study Protocol for remainder." |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female or male patients aged:
Cohort 1: ≥ 18 years old
Cohort 2: ≥ 65 years old
Cohort 3: ≥ 18 to < 65 years old
2. Histologically or cytologically confirmed breast cancer
3. Most recent biopsy must be HER2 negative based on local testing: American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines should be utilized for assessing HER2 status
4. Cohort 1 only: Most recent biopsy must be hormone receptor (HR) (estrogen receptor and progesterone receptor) negative based on local testing per ASCO/CAP guidelines
5. Measurable disease per RECIST 1.1.
Patients with bone-only metastatic cancer must have a measurable 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 CNS are permitted but not required. The following criteria apply:
Patients must be neurologically stable and off corticosteroids for ≥7 days
Patients with a history of CNS metastases who have completed local therapy with surgical resection and/or radiation therapy are eligible
Patients may have CNS metastases that are stable or progressing radiologically. If patients have progressive brain metastases, they should be asymptomatic from their CNS disease
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 Enrollment
Prior stereotactic brain radiosurgery is permitted at any time prior to Enrollment
CNS surgical resection must have been completed >28 days prior to the date of Enrollment; patient must have complete recovery from surgery
6. Documented (including de novo): a) locally advanced breast cancer that is not considered curable by surgery and/or radiation; or b) metastatic breast cancer (MBC)
7. Disease-free interval of at least 12 months after the completion of systemic neoadjuvant or adjuvant chemotherapy for patients previously treated with systemic chemotherapy for a tumor surgically resected with curative intent
8. Cohort 2 and 3: Prior endocrine therapy with or without a cyclin-dependent 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 prior targeted therapies are permitted. There is no limit to the number of prior endocrine therapies. Patients must not be, in the judgment of the Investigator, candidates for combination chemotherapy, combination chemotherapy with immunotherapy, or additional HR-directed therapy
9. Cohort 1 only: At Screening, patients must have documented evidence of positive PD-L1 expression as assessed via immunohistochemistry (IHC) scoring by local, regional, or central laboratory testing. In addition to any tissue used for PD-L1 testing to determine eligibility, a tumor block or 15 slides from a newly obtained or archival core or excisional biopsy of a not-previously-irradiated tumor lesion obtained since completion of any systemic therapy (metastatic tumor lesion preferred) must be submitted for central PD-L1 testing. If tumor block or 15 slides are unavailable or if
biopsy is thought to be unsafe, discuss with Sponsor whether patient can be enrolled
10. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
11. Adequate bone marrow, 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 ≥9g/dL without need for hematopoietic growth factor or transfusion support in the preceding 3 weeks
Total bilirubin < 1.5 × upper limit of normal (ULN); does not apply to patients with Gilbert’s syndrome
ALT<3×ULN unless hepatic metastases are present, then <5×ULN
AST<3×ULN unless hepatic metastases are present, then <5×ULN
Calculated creatinine clearance ≥50mL/min (by Cockcroft-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; does not apply to patients on a stable dose of 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 or radiotherapy
13. Ability to swallow an oral solid-dosage form of medication
Please refer to the Study Protocol for further inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
1. Prior chemotherapy for locally advanced or metastatic disease
2. Cohort 1 only: prior treatment with pembrolizumab, nivolumab, atezolizumab, any other PD-(L)1/PD-L2 inhibitor, or a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor
3. Current evidence or history of leptomeningeal disease
4. Other cancer that required therapy within the preceding 5 years other than adequately treated: (a) non-melanoma skin cancer or in situ cancer; or (b) following approval by the Sponsor medical team, other cancer that has a very low risk of interfering with the safety or efficacy endpoints of the Study
5. 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.
6. Hepatitis B or hepatitis C infection
7. 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
8. Presence of neuropathy Grade > 1 per NCI CTCAE version 5.0
9. History of hypersensitivity to any of the Study drugs or any of their ingredients, as applicable
10. Cohort 1 only:
Chronic autoimmune disease
Evidence of active, non-infectious pneumonia (eg, pneumonia due to autoimmune or connective tissue disease)
Treatment with a live vaccine within 30 days prior to the first dose of nivolumab, pembrolizumab, or atezolizumab
History of active tuberculosis
Prior organ transplantation including allogeneic stem cell transplantation
Active infection requiring systemic therapy
Current or prior use of immunosuppressive medication within 7 days prior to
Cycle 1, Day 1; the following are exceptions to this exclusion criterion:
o Intranasal, inhaled, or topical steroids, or local steroid injections (eg, intraarticular injection)
o Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent
o Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent; patients with Type 1 diabetes, vitiligo, psoriasis, hypothyroid disease, celiac disease or hyperthyroid disease not requiring immunosuppressive treatment are eligible
11. Anticancer treatment, including endocrine therapy, radiotherapy (except stereotactic brain radiosurgery), chemotherapy or biologic therapy, ≤ 14 days prior to Enrollment
12. Major surgery ≤ 28 days prior to Enrollment; 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. Pregnant or breastfeeding
15. If, in the opinion of the Investigator, the patient is deemed unwilling or unable to comply with the requirements of the Study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints:
Cohort 1 only: Objective response rate (ORR) as assessed by the
Investigators using RECIST 1.1 criteria in patients with PD-L1 positive
disease
Cohort 1 only: Progression-free survival (PFS) as assessed by the
Investigators using RECIST 1.1 criteria in patients with PD-L1 positive
disease
Cohorts 2 and 3 only: ORR as assessed by the Investigators using
RECIST 1.1 criteria in patients with HER2 negative, HR positive disease
Cohorts 2 and 3 only: PFS as assessed by the Investigators using RECIST
1.1 criteria in patients with HER2 negative, HR positive disease |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohort 1 only, in pts with PD-L1 positive disease: ORR [approx. 2-3 yrs];
PFS [approx. 2-3 yrs]
Cohort 2 only, in pts with HER2 negative, HR positive disease: ORR
[approx. 1.5-2.5 yrs]; PFS [approx. 1.5-2.5 yrs]
Cohort 3 only, in pts with HER2 negative, HR positive disease: ORR
[approx. 2-3 yrs]; PFS [approx. 2-3 yrs] |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
Cohort 1 only: ORR as assessed by the Investigators using RECIST 1.1
criteria in all patients
Cohort 1 only: PFS as assessed by the Investigators using RECIST 1.1
criteria in all patients
Cohorts 2 and 3 only: ORR as assessed by the Investigators using
RECIST 1.1 criteria in patients with triple-negative disease
Cohorts 2 and 3 only: PFS as assessed by the Investigators using RECIST
1.1 criteria in patients with triple-negative disease
Duration of response (DoR) as assessed by the Investigators using
RECIST 1.1 criteria
Overall survival (OS)
Exploratory Efficacy Endpoints:
Cohort 1 only: ORR by level of PD-L1 expression as determined by
central PD-L1 testing, where tumor response status is assessed by the
Investigators using RECIST 1.1 criteria
Cohort 1 only: PFS by level of PD-L1 expression as determined by
central PD-L1 testing, where tumor response status is assessed by the
Investigators using RECIST 1.1 criteria
CNS ORR as assessed by the Investigators in patients with CNS
metastases at baseline
CNS DoR as assessed by the Investigators in patients with CNS
metastases at baseline
Safety Endpoints:
Treatment-emergent adverse events (TEAEs), including deaths and
other serious adverse events (SAEs)
Immune-related adverse events (AEs)
Clinical laboratory abnormalities |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary:
Cohort1 only, all pts: ORR [approx. 2-3yrs]; PFS [approx. 2-3yrs]
Cohort2 only, pts with triple-negative disease: ORR [approx.1.5-2.5yrs]; PFS [approx.1.5-2.5yrs]
Cohort3 only, pts with triple-negative disease: ORR [approx.2-3yrs];
PFS [approx.2-3yrs]
All pts: DoR [approx.2-3yrs]; OS [approx.4-5yrs]
Exploratory:
Cohort1 only: by PD-L1 expression ORR [approx.2-3yrs] and PFS
[approx.2-3yrs]; in pts with CNS metastases at baseline CNS ORR
[approx. 2-3yrs] and CNS DoR [approx. 2-3yrs]
All pts: CNS ORR in pts with CNS metastases at baseline [approx. 2-
3yrs]; CNS DoR in pts with CNS metastases at baseline [approx. 2-3yrs]
Safety:A DSMC will conduct periodic reviews of safety data, including
interim analysis of first 6 pts who have completed 1st cycle of therapy in Cohort1 |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Singapore |
| Spain |
| Taiwan |
| Ukraine |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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