| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Breast Cancers Harboring Fibroblast Growth Factor Receptor (FGFR) Amplifications |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast Cancers harboring amplifications of a Fibroblast Growth Factor Receptor (FGFR) |
|
| 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 |
The primary objective of this study is to assess the anti-tumor activity of TAS-120 as mono-therapy or in combination with fulvestrant in the treatment of patients with metastatic breast cancer harboring Fibroblast Growth Factor Receptor (FGFR) amplifications, as measured by:
1. Objective response rate (ORR) in patients with centrally confirmed FGFR2 amplification and measurable disease (Cohorts 1, 2);
2. Clinical benefit rate (CBR) in patients with centrally confirmed FGFR2 amplification and non-measurable, evaluable disease (Cohort 3); and
3. 6-month progression-free survival (PFS) rate in patients with centrally confirmed high level FGFR1 amplification and measurable disease (Cohort 4) |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
1. To determine the complete response (CR) rate in Cohort 3, the ORR in Cohort 4, the CBR in Cohorts 1, 2, and 4, and the 6-month PFS rate in Cohorts 1-3.
2. To evaluate the duration of response (DOR) among patients with objective response in any cohort.
3. To evaluate the PFS and overall survival (OS) in all cohorts.
4. To investigate the safety of TAS-120 as monotherapy and in combination with fulvestrant.
Exploratory:
5. To investigate the downstream pharmacodynamic effects of treatment with TAS-120.
6. To explore markers of response and mechanisms of resistance in tumor tissue biopsies and/or blood
7. To explore PK of TAS-120 by population pharmacokinetics (PopPK) analysis and exposure-response analyses. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient provides written informed consent.
2. Patient is ¿18 years of age (or meets the country¿s regulatory definition for legal adult age, whichever is greater)
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
4. Histologically or cytologically confirmed recurrent locally advanced or metastatic breast cancer not amenable to treatment with curative intent, meeting all of the criteria for 1 of the following cohorts:
A. Cohort 1
i. HR+ HER2- breast cancer harboring an FGFR2 gene amplification. HR+ HER2- breast cancer is defined per the local pathology report as estrogen receptor (ER) >1% and/or progesterone receptor (PR) >1%, HER2-negative per American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines, 2018.
ii. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
iii. Has received 1-3 prior endocrine-containing therapies and up to 2 prior chemotherapy regimens for advanced/metastatic disease
iv. Has received prior treatment with a CDK4/6 inhibitor or is ineligible for such treatment (per Investigator decision)
v. Has experienced disease progression/recurrence within 1 month following the completion of any endocrine therapy for advanced/metastatic breast cancer
B. Cohort 2
i. TNBC harboring an FGFR2 gene amplification. TNBC is defined as negative for ER, PR and HER2. Negative for ER and PR includes the following: local pathology report classifies them as negative, Allred Score of 2 or below or <1% staining. HER2-negative per ASCO / CAP guidelines, 2018.
ii. Measurable disease per RECIST 1.1
iii. Has received at least 1 prior chemotherapy regimen for advanced/metastatic disease
iv. Has experienced disease progression/recurrence during or after the most recent prior chemotherapy for advanced/metastatic breast cancer
C. Cohort 3
i. TNBC or HR+ HER2- breast cancer (defined as above) harboring an FGFR2 gene amplification
ii. Non-measurable, evaluable disease per RECIST 1.1. Patients with bone-only disease must have lytic or mixed lytic-blastic lesions
iii. Other criteria for either HR+ HER2- breast cancer or TNBC should be met as described for Cohort 1 and 2, respectively
D. Cohort 4
i. HR+ HER2- breast cancer (defined as above) harboring an FGFR1 high-level gene amplification as defined in Section 6.1.1.1
ii. Measurable disease per RECIST 1.1
iii. Has received 1-2 prior endocrine-containing therapies and no more than 1 prior chemotherapy regimen for advanced/metastatic disease. Prior treatment with fulvestrant is not permitted.
iv. Has received prior treatment with a CDK4/6 inhibitor or is ineligible for such treatment (per Investigator decision)
v. Pre/peri-menopausal patients must be on goserelin. Patients must have commenced treatment with goserelin or an alternative GnRH agonist at least 4 weeks prior to the first dose of fulvestrant. If patients have received an alternative GnRH agonist prior to study entry, they must switch to goserelin for the duration of the trial. Postmenopausal is defined as at least one of the following criteria: age ¿60 years; age <60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle-stimulating hormone level within the laboratory¿s reference range for postmenopausal females; or documented bilateral oophorectomy.
vi. Has experienced disease progression/recurrence within 1 month following the completion of any endocrine therapy for advanced/metastatic breast cancer.
5. Archival or (preferably) fresh tumor tissue must be available for central laboratory confirmation of FGFR amplification.
6. The patient is able to take medications orally (a feeding tube is not permitted).
7. The patient has adequate organ function as defined by the following criteria:
a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ¿3.0 × the upper limit of normal (ULN); if liver function abnormalities are due to underlying liver metastases, AST and ALT ¿5 × ULN
b. Total bilirubin ¿1.5 × ULN or ¿3 × ULN in case of Gilbert¿s syndrome
c. Absolute neutrophil count (ANC) ¿1.0 × 109/L without hematopoietic growth factor support
d. Platelet count ¿75 × 109/L without transfusion support (that is, excluding measurements obtained within 3 days after transfusion of platelets)
e. Hemoglobin ¿9.0 g/dL without transfusion support (that is, excluding measurements within 7 days after transfusion of packed red blood cells or whole blood)
f. Serum phosphorus ¿ ULN
g. Creatinine clearance (calculated or measured value): ¿40 mL/min
(For more inclusion criteria's please refer to Section 4 of the Study Protocol TAS-120-201, version 2.0) |
|
| E.4 | Principal exclusion criteria |
1. History and/or current evidence of any of the following disorders:
a. Non-tumor related alteration of the calcium-phosphorus homeostasis that is considered clinically significant in the opinion of the Investigator
b. Ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, or myocardia and lung, considered clinically significant in the opinion of the Investigator
c. Retinal or corneal disorder confirmed by retinal/corneal examination and considered clinically significant in the opinion of the Investigator.
2. Corrected QT interval using Fridericia¿s formula (QTcF) >470 msec. Patients with an atrioventricular pacemaker or other condition (for example, right bundle branch block) that renders the QT measurement invalid are an exception and the criterion does not apply.
3. Treatment with any of the following within the specified time frame prior to the first dose of TAS-120:
a. Major surgery within 4 weeks (the surgical incision should be fully healed)
b. Radiotherapy for extended field within 4 weeks or limited field radiotherapy within 2 weeks
c. Any prior systemic therapy regardless of the stop date, but the patient must have recovered to eligibility levels from prior toxicity
d. Any investigational agent received within 30 days or 5 half-lives (whichever is shorter)
4. Prior treatment with an FGFR inhibitor
5. Cohort 4 only: Prior treatment with fulvestrant, or known hypersensitivity to fulvestrant.
6. A serious illness or medical condition(s) including but not limited to the following:
a. Known acute systemic infection
b. Myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure within the previous 6 months
c. History or current evidence of serious uncontrolled ventricular arrhythmia
d. Chronic diarrhea diseases considered to be clinically significant in the opinion of the Investigator
e. Congenital long QT syndrome, or any known history of torsade de pointes, or family history of unexplained sudden death
f. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or TAS-120 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
7. Brain metastases that are untreated or clinically or radiologically unstable (that is, have been stable for <1 month)
8. History of another primary malignancy that is currently clinically significant or currently requires active intervention
9. Pregnant or lactating female |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Objective response rate (ORR), defined as the proportion of patients with a confirmed response of either complete response (CR) or partial response (PR) per Investigator assessment.
2. Clinical benefit rate (CBR), defined as the proportion of patients with a confirmed response of CR, or stable disease (SD) lasting at least 24 weeks, per Investigator assessment.
3. 6-month progression-free survival (PFS) rate, defined as the proportion of patients who are alive and progression-free 6 months after the first dose of study therapy. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1,2&3) At baseline and at the end of every 8 weeks/2 cycles (±1 week) or as clinically indicated until disease progression, death, or withdrawal of consent, and at the end of therapy. |
|
| E.5.2 | Secondary end point(s) |
Secondary:
1) Objective response rate (ORR), Complete response (CR rate), Clinical benefit rate (CBR), and 6-month PFS rate,
2) Duration Of Response (DOR), defined as the time from first documentation of objective response to the date of death (any cause) or disease progression per Investigator assessment.
3) Progression-free survival (PFS), defined as the time from first dose of study therapy to the date of death (any cause) or disease progression per Investigator assessment. Overall survival (OS), defined as the time from first dose of study therapy to the date of death (any cause).
4) Adverse events, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Evaluation of dose-limiting toxicity (DLT) in Cohort 4 only.
Exploratory:
5) Changes in pharmacodynamic markers assessed in fresh tumor tissue biopsies.
6) Exploratory association of tissue and/or blood markers with tumor efficacy endpoints and/or tumor resistance to TAS-120.
7) Estimation of individual PK parameters such as area under the plasma concentration time curve (AUC) and exploratory association of the exposure with clinical parameters. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary:
1,2,3& 4) At baseline and at the end of every 8 weeks/2 cycles (±1 week) or as clinically indicated until disease progression, death, or withdrawal of consent, and at the end of therapy.
Exploratory:
5&6) prior to the first TAS-120 administration on Day 1 of Cycle 1, on Day 1 of each alternative uneven cycle (Cycle 3, 5, 7 and ongoing), at time of disease progression, and at the end of trial (EOT) visit.
7) Cycle 2, Day 1 (C2D1), within 1 hour prior to dosing and at 2 hours (±1 hour) and 5 hours (at least 3 hours apart from sampling at 2 hours) post dose. |
|
| 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 | No |
| 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 | 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 | Yes |
| E.8.1.1 | Randomised | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Canada |
| United States |
| France |
| Spain |
| Italy |
| Portugal |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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