Clinical Trials Register

Summary
EudraCT Number:	2020-004770-22
Sponsor's Protocol Code Number:	TAS-117-201
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-02-08
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Austria - BASG

A.2

EudraCT number

2020-004770-22

A.3

Full title of the trial

A Phase 2 Study of TAS-117 in Patients with Advanced Solid Tumors Harboring Germline PTEN Inactivating Mutations

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Phase 2 Study of TAS-117 in Patients with Advanced Solid Tumors Harboring Germline PTEN Inactivating Mutations

A.4.1

Sponsor's protocol code number

TAS-117-201

A.5.4

Other Identifiers

Name:

IND

Number:

148650

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Taiho Oncology, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Taiho Oncology Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Taiho Oncology, Inc
B.5.2	Functional name of contact point	Medical Monitor
B.5.3	Address:
B.5.3.1	Street Address	101 Carnegie Center, Suite 101
B.5.3.2	Town/ city	Princeton
B.5.3.3	Post code	NJ 08540
B.5.3.4	Country	United States
B.5.6	E-mail	kbenhadji@taihooncology.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TAS-117
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not Assigned
D.3.9.1	CAS number	1402602-94-1
D.3.9.2	Current sponsor code	TAS-117
D.3.9.3	Other descriptive name	Trans-3-Amino-1-methyl-3-(4-(3-phenyl-5H-imidazo(1,2-c)pyrido(3,4-e)(1,3)oxazin-2-yl)phenyl)cyclobutanol
D.3.9.4	EV Substance Code	SUB218115
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TAS-117
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not Assigned
D.3.9.1	CAS number	1402602-94-1
D.3.9.2	Current sponsor code	TAS-117
D.3.9.3	Other descriptive name	Trans-3-Amino-1-methyl-3-(4-(3-phenyl-5H-imidazo(1,2-c)pyrido(3,4-e)(1,3)oxazin-2-yl)phenyl)cyclobutanol
D.3.9.4	EV Substance Code	SUB218115
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced Solid Tumors Harboring Germline PTEN Inactivating Mutations

E.1.1.1

Medical condition in easily understood language

Advanced Solid Tumors Harboring Germline PTEN Inactivating Mutations

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	23.0
E.1.2	Level	PT
E.1.2	Classification code	10071986
E.1.2	Term	PTEN gene mutation
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part A: To investigate the safety and tolerability and determine the MTD and the RP2D of TAS-117

Part B: To evaluate the ORR in patients with solid tumors harboring germline PTEN inactivating mutations (including patients in Dose and Regimen Confirmation portion in Part A) based on the independent central review (ICR).

E.2.2

Secondary objectives of the trial

Part A:
• To characterize the PK profile of TAS-117.
• To characterize the pharmacodynamic profile of TAS-117.

Part B:
• To evaluate the safety profile of TAS-117.

Parts A and B:
• To evaluate ORR based on investigator assessment.
• To evaluate DCR, DOR, and PFS based on Investigator assessments (ICR assessment will be also performed in Dose and Regimen Confirmation portion in Part A and Part B).
• To evaluate OS.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

PGx

E.3

Principal inclusion criteria

1. Provide written informed consent.
2. Life expectancy of at least 12 weeks.
3. Dose Escalation in Part A:
a. ≥18 years of age
b. ECOG performance status 0 or 1
c. Histologically or cytologically confirmed advanced or metastatic solid tumors (patients with primary brain tumors are not eligible).
d. Has progressed after all standard treatment for advanced or metastatic disease known to provide clinical benefit, or was intolerant to ineligible for such available standard therapies.
e. Patients with solid tumors irrespective of gene alterations.
f. Patients with at least one measurable or non-measurable lesion per RECIST 1.1.
4. Dose and Regimen Confirmation in Part A and Phase 2 (Part B):
a. ≥12 years of age. Patients age ≥12 and <18 years must have a body weight of ≥40 kg.
b. ECOG performance status 0 or 1 (for patients ≥18 years of age) or KPS of ≥70% (for patients age ≥12 and <18 years of age). Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing KPS.
c. Histologically confirmed advanced or metastatic solid tumors (patients with primary brain tumors are not eligible).
d. Has progressed after standard treatment for advanced or metastatic disease or was intolerant or ineligible to available standard therapies.
e. Patients with locally confirmed germline PTEN inactivating mutations determined from a blood sample (in case that germline PTEN mutation is predicted by local tumor tissue sample testing, it must be confirmed by blood sample germline testing at a local laboratory or a laboratory designated by the Sponsor).
f. Patients with at least one measurable lesion per RECIST 1.1.
5. Has cancerous tumor tissue available from archival tumor tissue samples or newly obtained core or excisional biopsy (preferably a tumor lesion not previously irradiated).
Formalin-fixed, paraffin-embedded tissue blocks are preferable to slides. Newly obtained biopsies are preferable to archived tissue.
6. Adequate organ function as defined by the following criteria:
a. ANC ≥1.5 × 109/L (At least a 7-day washout is required if G-CSF is
administered).
b. Platelet count ≥75,000/mm3 (≥75 × 109/L) (At least a 14-day washout is required if platelet transfusion is performed).
c. Hemoglobin ≥8.5 g/dL (At least a 14-day washout is required if blood transfusion is performed).
d. ALT and AST ≤3.0 × ULN; if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤5.0 × ULN.
e. Total bilirubin ≤1.5 × ULN, or ≤3.0 × ULN for patients with Gilbert’s syndrome.
f. Glycosylated hemoglobin (HbA1c) ≤7.0%.
g. Creatinine clearance (CrCl) (calculated or measured value): ≥50 mL/min. For calculated CrCl, use the Cockcroft-Gault formula.
7. WOCBP must have a negative serum pregnancy test prior to administration of the first dose of study treatment. Female patients are not considered to be of child-bearing potential if they are post-menopausal (no menses for 12 months without an alternative medical cause) or permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
8. Both males and females of reproductive potential must agree to use effective birth control (prior to the first dose, during the study, for 180 days after the last dose of study treatment, or longer) based on local requirements.
9. Patients are willing and able to comply with scheduled visits and study procedures.

E.4

Principal exclusion criteria

1. Currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study.
2. History of or current evidence of active interstitial lung disease or pneumonitis.
3. Current evidence of diabetes mellitus that requires insulin therapy.
4. Prior treatment with PI3K/AKT/mTOR pathway inhibitors.
5. Patients with primary brain tumor.
6. Corrected QT interval using Fridericia’s formula (QTcF) >470 msec.
7. Any unresolved acute toxicity CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, skin pigmentation, and the laboratory values defined in the inclusion criteria (for example, anemia).
Note: Patients with Grade ≥2 neuropathy may be included on a case-by-case basis after consultation with the Sponsor.
8. Prior treatment with any of the following within the specific time frame prior to the first dose of study treatment:
a. Major surgery/surgical therapy for any cause within 4 weeks; the patient must have recovered adequately from the toxicity and/or complications of the intervention prior to starting study treatment.
b. Any non-investigational anticancer therapy (chemotherapy, biologic therapy, targeted therapy, or immunotherapy) within 5 half-lives or within 3 weeks (whichever is shorter) prior to the first dose of study treatment.
c. Any investigational agent within 5 half-lives or within 4 weeks (whichever is shorter) prior to the first dose of study treatment.
d. Radiotherapy within 4 weeks prior to the first dose of study treatment. A 2-week washout is permitted for palliative radiation (≤4 weeks of radiotherapy) to non-CNS disease.
9. Patients with prior active malignancies must be excluded unless a complete remission was achieved prior to enrollment and no additional therapy is required or anticipated to be required during the study. Patients with nonmelanoma skin cancers or carcinoma in situ (for example, bladder, prostate, cervical, breast cancers) who have undergone potentially curative therapy are not excluded.
10. Patients with meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or symptomatic or unstable brain metastasis.
11. Currently receiving chronic corticosteroid therapy of ≥10 mg/day of prednisone or its equivalent.
12. Patients unable to swallow orally administered medication (feeding tube is not permitted).
13. Pregnant or breastfeeding women.
14. History of Stevens-Johnson syndrome or toxic epidermal necrolysis.
15. A serious illness or medical condition(s) including (but not limited to) the following:
a. Known acute systemic infection.
b. History of severe myocardial infarction within 6 months of screening.
c. Any New York Heart Association Classification of Heart Failure ≥ Class II.
d. History or current evidence of uncontrolled ventricular arrhythmia.
e. Congenital long QT syndrome, or any known history of torsade de pointes, or family history of unexplained sudden death.
f. Other clinically significant acute or chronic medical or psychiatric condition that may increase the risk associated with study drug administration, or may interfere with the interpretation of study results (based on Investigator decision). This may include (but is not limited to) chronic nausea, vomiting, or diarrhea considered to be clinically significant (≥ Grade 2).

E.5 End points

E.5.1

Primary end point(s)

Part A:
• AE profile, clinical laboratory tests, vital signs, and 12-lead ECG.
• Dose-limiting toxicities (DLTs) graded according to CTCAE v5.0 during Cycle 1.

Part B:
• ORR, defined as the proportion of patients experiencing a best overall response of CR or PR per RECIST 1.1.

E.5.1.1

Timepoint(s) of evaluation of this end point

Refer to protocol for details

E.5.2

Secondary end point(s)

Part A:
• TAS-117 PK parameters, including Cmax, Tmax, AUC, T½.
• Total and phosphorylated AKT and PRAS40.

Part B:
• AE profile, clinical laboratory tests, vital signs, and 12-lead ECG.

Parts A and B:
• ORR, defined as the proportion of patients experiencing a best overall response of PR or CR per RECIST 1.1.
• DCR, defined as the proportion of patients experiencing a best overall response of SD, PR, or CR per RECIST 1.1.
• DOR, defined as the time from the first documentation of response per RECIST 1.1 to the first documentation of objective tumor progression or death due to any cause, whichever occurs first.
• PFS, defined as the time from date of the first dose of study treatment to the date of disease progression based on Investigator assessment of radiographic images or death, whichever occurs first.
• OS, measured from the date of the first dose of study treatment until the date of death due to any cause.

E.5.2.1

Timepoint(s) of evaluation of this end point

Refer to protocol for details

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability and antitumor activity

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Brazil

Japan

Korea, Republic of

Singapore

Taiwan

United States

Austria

France

Sweden

Spain

Switzerland

Germany

Italy

Denmark

Portugal

United Kingdom

E.8.7

Trial has a data monitoring committee

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

100

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-05-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-08-04

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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