Clinical Trials Register

Summary
EudraCT Number:	2018-004568-72
Sponsor's Protocol Code Number:	ASTX029-01
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-01-11
Trial 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

France - ANSM

A.2

EudraCT number

2018-004568-72

A.3

Full title of the trial

A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 in Subjects with Advanced Solid Tumors

A.3.1

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

A Phase 1-2 Study of the Safety and Activity of ASTX029 in Patients with Advanced Solid Tumors

A.4.1

Sponsor's protocol code number

ASTX029-01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03520075

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	Astex Pharmaceuticals, 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	Astex Pharmaceuticals, 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	Astex Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	ASTX029-01 Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	4420 Rosewood Drive, Suite 200
B.5.3.2	Town/ city	Pleasanton, CA
B.5.3.3	Post code	94588
B.5.3.4	Country	United States
B.5.4	Telephone number	+1925-560-0100
B.5.5	Fax number	+1925-560-0101
B.5.6	E-mail	ASTX029-01@astx.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	ASTX029
D.3.4	Pharmaceutical form	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	ASTX029
D.3.9.2	Current sponsor code	ASTX029
D.3.9.3	Other descriptive name	AT35029, AT35029X free base, AT35029W for the hydrate, AP-0000055, AP-055
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.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	ASTX029
D.3.4	Pharmaceutical form	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	ASTX029
D.3.9.2	Current sponsor code	ASTX029
D.3.9.3	Other descriptive name	AT35029, AT35029X free base, AT35029W for the hydrate, AP-0000055, AP-055
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	120
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

E.1.1.1

Medical condition in easily understood language

Advanced Solid Tumors

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.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10065252
E.1.2	Term	Solid tumor
E.1.2	System Organ Class	100000004864

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	10053571
E.1.2	Term	Melanoma
E.1.2	System Organ Class	100000004864

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	10029514
E.1.2	Term	Non-small cell lung cancer NOS
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• Phase 1 (Parts A and B): To assess safety and to identify the MTD, the RP2D, and the
recommended dosing regimen of ASTX029.
• Phase 2: To assess preliminary clinical activity, as determined by ORR in tumors characterized
by gene aberrations in the MAPK signal pathway that may confer sensitivity to ASTX029

E.2.2

Secondary objectives of the trial

• To determine the PK profile of ASTX029 including the food effect on PK parameters.
• To evaluate other clinical activity parameters, such as duration of response (DOR), disease
control rate (DCR), progression-free survival (PFS), and overall survival (OS).
• To evaluate relevant pharmacodynamic markers and target engagement (ie, phosphorylated
ribosomal s6 kinase [pRSK] inhibition) in tumor biopsies.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed.
2) Men or women 18 years of age or older.
3) Subjects with histologically or cytologically confirmed advanced solid tumors that are metastatic or unresectable, who are refractory or have relapsed after treatment with available therapies or for whom standard life-prolonging measures or approved therapies are not available. In Phase 1 Part B and in the Phase 2 portion of the protocol, subjects must also have documented gene alterations in the MAPK pathway as detailed in Section 4.1.2 and Table 2.
4) In Phase 1 Part B of the protocol, subjects must have disease lesions that are amenable to biopsy.
5) In the Phase 2 portion of the protocol, subjects must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
6) Eastern Cooperative Oncology Group performance status 0 to 2.
7) Acceptable organ function, as evidenced by the following laboratory data:
a) AST and alanine aminotransferase (ALT) ≤2×upper limit of normal (ULN) or ≤3 ULN in
the presence of liver metastases.
b) Total serum bilirubin ≤1.5×ULN.
c) Absolute neutrophil count (ANC) ≥1500 cells/mm3 .
d) Platelet count ≥100,000 cells/mm3 .
e) Calculated creatinine clearance (by the standard Cockcroft-Gault formula) of ≥50 mL/min or glomerular filtration rate of ≥50 mL/min.
8) Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]; see protocol for details) must not be pregnant or breastfeeding and must have a negative pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study treatment. Women of child-bearing potential must agree to the following during the treatment period and for 5 half-lives of ASTX029 or metabolite plus 30 days after receipt of the last dose of study treatment:
a) Refrain from donating eggs (ova, oocytes) for the purpose of reproduction.
b) Use a contraceptive method that is highly effective with a failure rate of <1% per year, with low user dependency. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk of inclusion of a woman with an early unexpected pregnancy.
9. Men must agree to the following during the treatment period and for 5 half-lives of ASTX029 or metabolite plus 90 days after receipt of last dose of study treatment:
a) Refrain from donating sperm.
b) Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and to remain abstinent OR to use a male condom when having sexual intercourse with a woman of childbearing potential (according to recommendations of the CTFG; see protocol for details) who is not currently pregnant, and the female partner should be advised of the benefit of using an additional highly effective contraceptive method with a failure rate of <1% per year as a condom may break or leak. The investigator should evaluate the effectiveness of the contraceptive method before the first dose of study treatment.

E.4

Principal exclusion criteria

1) Hypersensitivity to ASTX029 or excipients of the drug product.
2) Poor medical risk in the investigator’s opinion because of systemic diseases in addition to the cancer under study, for example, uncontrolled infections.
3) Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, could compromise subject safety or the integrity of study outcomes or interfere with the absorption or metabolism of ASTX029.
4) Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX029), as follows:
a) Cytotoxic chemotherapy or radiotherapy within 3 weeks prior. Palliative radiotherapy to a single lesion within 2 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) not stabilized or resolved to ≤Grade 1.
b) Monoclonal antibodies or biologics within 4 weeks prior. Any encountered treatment related toxicities not stabilized or resolved to ≤Grade 1.
c) Molecularly targeted drug or other investigational drugs, without the potential for delayed toxicity, within 4 weeks of the first dose of study treatment or 5 half-lives (minimum
14 days), whichever is shorter. Any encountered treatment-related toxicities (excepting alopecia) not stabilized or resolved to ≤Grade 1.
5) Prior treatment with ERK inhibitors.
6) History of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions:
a) Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.
b) Congestive cardiac failure of ≥Grade 3 severity according to New York Heart Association (NYHA) functional classification defined as patients with marked limitation of activity and who are comfortable only at rest.
c) Unstable cardiac disease including unstable angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days).
d) History or evidence of long QT interval corrected for heart rate (QTc), ventricular arrhythmias including ventricular bigeminy, complete left bundle branch block, clinically significant bradyarrhythmias such as sick sinus syndrome, second- and third-degree atrioventricular (AV) block, presence of cardiac pacemaker or defibrillator, or other significant arrhythmias.
e) Screening 12-lead ECG with measurable QTc interval of ≥470 msec. (Fridericia's formula should be used to calculate the QTc interval throughout the study.)
7) Known history of human immunodeficiency virus (HIV) infection or seropositive results consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
8) Known brain metastases, unless previously treated and stable for at least 3 months with or without steroids.
9) Known significant mental illness or other conditions, such as active alcohol or other substance abuse that, in the opinion of the investigator, predispose the subject to high risk of noncompliance with the protocol treatment or assessments.
10) History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including:
a) Presence of predisposing factors to RVO or CSR (eg, uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus) or
b) Visible retinal pathology as assessed by ophthalmic examination at screening that is considered a risk factor for RVO or CSR such as:
• Evidence of optic disc cupping or
• Evidence of new visual field defects on automated perimetry or
• Intraocular pressure >21 mmHg as measured by tonography.

E.5 End points

E.5.1

Primary end point(s)

• Phase 1: Incidences of DLTs and AEs to determine the MTD of up to 2 dosing regimens of ASTX029 and the RP2D and regimen to be taken to Phase 2.
• Phase 2: Clinical activity assessed by ORR according to RECIST v1.1 criteria.

E.5.1.1

Timepoint(s) of evaluation of this end point

REGIMEN 1
Incidence of DLTs and AES:
Cycle 1 and 2: Days 1, 2, 8 and 15, >/=Cycle 3: Day 1, at treatment termination and at 30-day Safety Follow-up visit
Clinical activity:
At screening, at the end of every 2 cycles (±7 days) for the first 4 cycles and then every 4 cycles (±1 cycle) thereafter

REGIMEN 2
Incidence of DLTs and AES:
Cycle 1: Days 1, 2, 8, 14 and 15, Cycle 2: Days 1, 8 and 15 >/=Cycle 3: Day 1, at treatment termination and at 30-day Safety Follow-up visit

E.5.2

Secondary end point(s)

REGIMEN 1
• PK parameters of ASTX029, including AUC, Cmax, minimum concentration (Cmin), time to reach maximum concentration (Tmax), elimination half-life (t½), food effect on ASTX029 PK parameters, and other secondary PK parameters of ASTX029 if data permit; analysis of ASTX029 metabolites if applicable.
• Inhibition of pRSK protein in response to ASTX029 treatment in tumor biopsies.
• PFS.
• OS.
• DCR.
• DOR.

E.5.2.1

Timepoint(s) of evaluation of this end point

REGIMEN 1-
Pharmacokinetics: Cycle 1 and 2: Days 1, and 2, >/=Cycle 3: Day 1
- tumor biopsies: during screening and on Day 8 of cycle 2
- PFS, OS, DCR, DOR: At screening, at the end of every 2 cycles (±7 days) for the first 4 cycles and then every 4 cycles (±1 cycle) thereafter
REGIMEN 2
Pharmacokinetics: Cycle 1: Days 1, 2, 14 and 15 - >/=Cycle 3: Day 1
- tumor biopsies: during screening and on Day 8 of cycle 2
- PFS, OS, DCR, DOR: At screening, at the end of every 2 cycles (±7 days) for the first 4 cycles and then every 4 cycles (±1 cycle) thereafter

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

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

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.8.3

The trial involves single site in the Member State concerned

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

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

United States

France

Spain

United Kingdom

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

6 months from last subject treatment visit

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

250

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

300

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

2021-04-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-05-27

P. End of Trial
P.	End of Trial Status	Completed

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