| 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 | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| 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 |
Phase 1 Dose Escalation: completed.
Phase 1 Expansion
• To evaluate ORR in cholangiocarcinoma patients with tumors harboring
FGFR2 gene fusions or other FGFR abnormalities.
• To evaluate ORR and EPR (defined as progression-free rate at the end of Cycle 2) in patients with primary CNS tumors harboring FGFR gene fusions or FGFR1 activating mutations.
• To evaluate ORR in a basket of tumor types with tumors harboring
FGFR2 amplifications
• To evaluate ORR in a basket of tumor types with tumors harboring any FGFR gene fusions or activating mutations.
Phase 2:
• To confirm ORR in iCCA patients with FGFR2 gene fusions or other FGFR2 rearrangements based on independent central radiology
review. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1 Dose Escalation: completed.
Phase 1 Expansion
• To investigate the safety of TAS-120.
• To evaluate disease control rate (DCR), DOR, PFS and OS in each treatment group.
Phase 2:
Key secondary
•T o evaluate DOR
Other secondary
• To evaluate the safety and tolerability of TAS-120
• To evaluate DCR, PFS, and OS
• To evaluate Patient-Reported Outcomes (PROs) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide written informed consent.
2. Is ≥ 18 years .
3. Has histologically or cytologically confirmed, locally advanced, metastatic cancer meeting the following criteria:
a. Phase 1 Expansion
I. Patient has failed all standard therapies or standard therapy does not exist or is not tolerated.
ii. Patient is eligible for 1 of the following enrollment groups, based on diagnosis, prior therapy, and FGF/FGFR aberrations as shown:
Group 1 (Enrollment Suspended as of Amendment 7): Patient has
intrahepatic or extrahepatic cholangiocarcinoma harboring FGFR2 gene
fusions.
Group 2: Patient has intrahepatic or extrahepatic cholangiocarcinoma harboring FGFR2 gene fusions, and has not received or received less
than 1 cycle of prior chemotherapy (due to intolerance or patient refusal).
Group 3 (Enrollment Suspended as of Amendment 7): Patient has
intrahepatic or extrahepatic cholangiocarcinoma harboring FGFR2 gene
fusions and has received prior treatment with FGFR inhibitors.
Group 4 (Enrollment suspended as of Amendment 7): Patient has
intrahepatic or extrahepatic cholangiocarcinoma harboring FGFR
abnormalities other than FGFR2 gene fusions.
Group 5: Patient has a primary CNS tumor harboring FGFR gene fusion or
FGFR1 activating mutation and fulfills the criteria (i and ii).
Group 6 (Enrollment Suspended as of Amendment 7): Patient has
advanced urothelial carcinoma harboring FGFR3 fusions or FGFR3
activating mutations.
Group 7: Patient has any tumor type not included in one of the prior
groups, harboring FGFR2 amplification (no minimum number of copies).
Group 8 (Enrollment Suspended as of Amendment 7): Patient has any
tumor type not included in one of the prior groups, harboring FGFR gene
fusions or activating mutations.
b. Phase 2
i. Patient has histologically or cytologically confirmed, locally advanced,
metastatic, unresectable iCCA harboring FGFR2 gene fusions or other
FGFR2 rearrangements based on results from either of the following
a. Testing by Foundation Medicine:
i. As part of study pre-screening; or
ii. Previously tested by Foundation Medicine; in this case, it is requested
that tumor tissue should be provided to Foundation Medicine if available.
b. Local laboratory testing using next generation sequencing [NGS], fluorescence in situ hybridization [FISH], or other assays that can determine FGFR2 gene fusions or other FGFR2 rearrangements on tumor tissues or from ctDNA. It is requested that patients enrolled on this basis provide tumor tissues to Foundation Medicine, if available from either archival samples or fresh tumor biopsy.
ii. Patient has been treated with at least one prior systemic gemcitabine
and platinum-based chemotherapy. Patients with prior adjuvant
gemcitabine-platinum chemotherapy are eligible if the patient had
recurrence within 6 months of the last dose of the regimen.
iii. Patient has documentation of radiographic disease progression on
the most recent prior therapy
4. Patient has measurable disease as defined by Response Evaluation
Criteria in Solid Tumors (RECIST) guidelines (version 1.1, 2009) for
advanced solid tumors or RANO criteria (2010) for brain tumors.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or
1 on Day 1 of Cycle 1
6. Able to take medications orally
7. Adequate organ function as defined by the following criteria:
a. Aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) ≤ 3.0 ×upper limit of normal (ULN); if liver function abnormalities
are due to underlying liver metastasis, AST and ALT ≤ 5 × ULN.
b. Total bilirubin ≤ 1.5 × ULN, or ≤ 3.0 mg/dL for patients with Gilbert's
syndrome.
c. International normalized ratio (INR) <1.3 (or < 3.0 on
anticoagulants)
d. Absolute neutrophil count ≥ 1000/mm3 (i.e., ≥ 1.0 × 109/L by
International Units [IU])
e. Platelet count ≥ 75,000/mm3 (IU: ≥ 75 × 109/L)
f. Hemoglobin ≥ 9.0 g/dL
g. Phosphorus ≤ ULN.
8. Creatinine clearance (calculated* or measured value**): ≥ 40
mL/min
9. Women of child-bearing potential (WOCBP) must have a negative
pregnancy test (urine or serum) within 7 days prior to administration of
the first dose of TAS 120. Female patients are not considered to be of
child bearing potential if they have a history of hysterectomy or are post
menopausal defined as no menses for 12 months without an alternative
medical cause. Both males and females of reproductive potential must
agree to use effective birth control during the study prior to the first
dose and for 6 months after the last dose.
10. Willing and able to comply with scheduled visits and study
procedures |
|
| E.4 | Principal exclusion criteria |
1. History and/or current evidence of clinically significant non-tumor
related alteration of calcium-phosphorus homeostasis.
2. History and/or current evidence of clinically significant ectopic
mineralization/calcification.
3. History and/or current evidence of clinically significant retinal
disorder confirmed by retinal examination.
4. History or current evidence of serious uncontrolled ventricular
arrhythmias
5. Fridericia's corrected QT interval (QTcF) > 470 ms on ECG conducted
during Screening.
6. Treatment with any of the following within the specified time frame
prior to the first dose of TAS-120:
a. Major surgery within the previous 4 weeks (the surgical incision
should be fully healed prior to the first dose of TAS 120).
b. Radiotherapy for extended field within 4 weeks or limited field
radiotherapy within 2 weeks.
c. Patients with locoregional therapy, e.g., transarterial
chemoembolization (TACE), selective internal radiotherapy (SIRT) or
ablation within 4 weeks.
d. Any noninvestigational anticancer therapy within 3 weeks or have
not recovered from side effects of such therapy prior to TAS 120
administration (mitomycin within prior 5 weeks).
• Targeted therapy or immunotherapy within 3 weeks or within 5 halflives
(whichever is shorter)
e. Any investigational agent received within 5 half-lives of the drug or 4
weeks, whichever is shorter. Concurrent participation in an
observational study may be allowed after review by the Sponsor's
Medical Monitor.
f. Patients with prior FGFR-directed therapy.
7. A serious illness or medical condition(s) including, but not limited to,
the following:
a. Known brain metastasis (not including primary brain tumors) unless patient is clinically stable for ≥ 1 month.
b. Known acute systemic infection.
c. Myocardial infarction, severe/unstable angina, symptomatic
congestive heart failure (New York Heart Association [NYHA] Class III
or IV (see Appendix D, New York Heart Association [NYHA]
Classification) within the previous 2 months; if > 2 months, cardiac
function must be within normal limits and the patient must be free of
cardiac-related symptoms.
d. Chronic nausea, vomiting, or diarrhea 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 in the judgment of the investigator would
make the patient inappropriate for entry into this study.
8. Patients with a history of another primary malignancy that is
currently clinically significant, and has potential for metastases or
currently requires active intervention (except for gonadotropin-releasing
hormone (GnRH) or luteinizing hormone-releasing hormone (LH-RH)
agonists in prostate cancer or adjuvant hormonal therapy in breast
cancer).
9. Pregnant or lactating female. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
For Phase 1 Expansion, the primary endpoint is ORR (and EPR for primary CNS tumors).
For Phase 2, the primary endpoint is ORR.
Primary endpoints will be based on the independent review of images by the Core Imaging Laboratory. In addition, for the Phase 2 part of the study, sensitivity analyses for some key efficacy endpoints (e.g., ORR, and PFS) will be performed based on investigators or local radiologist assessments. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The endpoint is based on Overall response rate (ORR).
|
|
| E.5.2 | Secondary end point(s) |
For Phase 1 Expansion, secondary endpoints of DOR, DCR, PFS, and OS
in each treatment group.
For Phase 2, secondary endpoints of DOR, DCR, PFS, PROs and OS.
Primary endpoints will be based on the independent review of images by
the Core Imaging Laboratory. In addition, for the Phase 2 part of the
study, sensitivity analyses for some key efficacy endpoints (e.g., ORR,
and PFS) will be performed based on investigators or local radiologist
assessments. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The assessment of DCR will parallel that of ORR, with DCR defined as the proportion of patients with objective evidence of CR, PR, or SD, except that there is no requirement for a confirmation of an SD response, if it is maintained for at least 6 weeks post treatment initiation.
Disease control rate will be analyzed using the same methodology as ORR. |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| dose-escalation and dose-expansion |
|
| 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 | 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) | 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
| 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 | 25 |
| 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 |
| Canada |
| France |
| Germany |
| Hong Kong |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Portugal |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
For the Phase 1 Expansion part of the study, patients in each treatment
group should be followed for survival for up to 12 months after the last
patient enrolled in that group.
For Phase 2, patients should be followed for survival for up to 18
months after the last patient enrolled in this phase of the study. |
|
| 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 | 8 |
| 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 |
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