Clinical Trials Register

Summary
EudraCT Number:	2021-000293-28
Sponsor's Protocol Code Number:	AVB500-OC-004
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-07-13
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

Czechia - SUKL

A.2

EudraCT number

2021-000293-28

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind, Adaptive, Placebo/Paclitaxel-Controlled Study of AVB S6 500 in Combination with Paclitaxel in Patients with Platinum-Resistant Recurrent Ovarian Cancer

3. fáze, randomizovaná, dvojitě zaslepená, adaptivní, placebo/paklitaxel kontrolovaný výzkum AVB S6 500 v kombinaci s paklitaxelem u pacientů s platina rezistentní rekurencí ovariálního karcinomu

A.3.1

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

clinical trial to evaluate the safety and efficacy of a drug under investigation called AVB S6 500 in combination with Paclitaxel in women with ovarian cancer which comes back after a platinum therapy.

A.4.1

Sponsor's protocol code number

AVB500-OC-004

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04729608

A.5.4

Other Identifiers

Name:

IND

Number:

135920

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	Aravive, 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	Aravive, 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	InnoPharma srl
B.5.2	Functional name of contact point	clinical department
B.5.3	Address:
B.5.3.1	Street Address	via Lavoratori Autobianchi nr. 1
B.5.3.2	Town/ city	Desio (MB)
B.5.3.3	Post code	20832
B.5.3.4	Country	Italy
B.5.4	Telephone number	0039362573128
B.5.5	Fax number	0039362544211
B.5.6	E-mail	a.bertani@innopharma.it

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	AVB-S6-500
D.3.2	Product code	AVB-S6-500
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Batiraxcept
D.3.9.1	CAS number	2268717-61-7
D.3.9.2	Current sponsor code	AVB-S6-500
D.3.9.3	Other descriptive name	GAS6 decoy receptor
D.3.9.4	EV Substance Code	SUB219261
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Yes
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.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Paclitaxel
D.3.9.1	CAS number	33069-62-4
D.3.9.4	EV Substance Code	SUB09583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Platinum-Resistant Recurrent Ovarian Cancer

E.1.1.1

Medical condition in easily understood language

Ovarian cancer which comes back after a platinum therapy

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	10066697
E.1.2	Term	Ovarian cancer recurrent
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the effect of AVB-S6-500 plus Paclitaxel (PAC) (AVB-S6-500 + PAC) versus Placebo and PAC (Placebo + PAC) on progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria, in subjects with platinum-resistant recurrent ovarian cancer.

E.2.2

Secondary objectives of the trial

- To evaluate the effect of AVB-S6-500 + PAC versus Placebo + PAC on overall survival (OS)
- To evaluate the effect of AVB-S6-500 + PAC versus Placebo + PAC on objective response rate (ORR) based on RECIST v1.1 criteria
- To evaluate the effect of AVB-S6-500 + PAC versus Placebo + PAC on duration of response (DOR) based on RECIST v1.1 criteria
- To evaluate the effect of AVB-S6-500 + PAC versus Placebo + PAC on quality of life (QOL) as assessed by the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) questionnaire
- To evaluate the effect of AVB-S6-500 + PAC versus Placebo + PAC on clinical benefit rate (CBR) based on RECIST v1.1 criteria
- To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of AVB-S6-500

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically confirmed and documented recurrent ovarian, fallopian tube, or peritoneal cancer. Only patients with high-grade serous adenocarcinoma histology are eligible.
2. Aged 18 years or older
3. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1
4. Ability to understand the nature of this clinical study and willingness to give written informed consent, comply with scheduled visits, the treatment plan, laboratory tests, and follow up visits
5. Platinum resistant disease (defined as progression within ≤6 months from completion of most recent platinum-containing regimen and calculated from the date of the last administered dose of platinum therapy). Subject may have been treated with additional regimen(s) subsequent to determination of platinum resistance.
6. Available archived tumor tissue (a paraffin-embedded tissue block with sufficient tumor tissue for biomarker testing or unstained slides with sufficient tumor tissue may be substituted) or if archived tissue is not available, a fresh tumor biopsy is required.
7. Radiologic imaging with a computerized tomography (CT) scan or magnetic resonance imaging (MRI) (if cannot tolerate a CT scan) within 21 days of randomization. (If a site can document the CT performed as part of the positron emission tomography [PET]-CT is of identical diagnostic quality to a diagnostic CT [with IV and oral contrast], then the CT portion of a PET-CT can be used.)
8. Received at least 1 but not more than 4 prior therapy regimens since ovarian cancer diagnosis.
Note: maintenance therapy OR hormonal therapies should not be counted as a separate therapy.
9. Ovarian cancer that is measurable according to RECIST v1.1
10. Normal gastrointestinal (GI) function. This includes no GI obstruction, NG tube, or bleeding or signs/symptoms thereof within 3 months prior to randomization. If nausea or vomiting is present due to prior treatment, symptoms must be recovered to Grade 1 or less. Subjects with a history of abdominal fistula will be considered eligible if the fistula was surgically repaired or has healed, there has been no evidence of fistula for at least 6 months, and the subject is deemed to be at low risk of recurrent fistula.
11. Life expectancy >3 months
12. Negative serum pregnancy test within 7 days of randomization for females of childbearing potential (premenopausal and not surgically sterilized)
13. Adequate bone marrow function:
a. Absolute neutrophil count ≥1500/µL
b. Platelet count ≥100,000/ µL
c. Hemoglobin ≥9.0 g/dL
14. Adequate hepatic function:
a. Total bilirubin ≤1.5×upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≤3.0×ULN*
c. Alanine aminotransferase (ALT) ≤3.0×ULN*
*Unless liver metastases are present, in which case AST/ALT must be ≤5×ULN
15. Adequate renal function as determined by calculated or measured creatinine clearance ≥30 mL/min (using Cockcroft-Gault equation).
16. International normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (aPTT) ≤1.5 ULN for subjects not on anticoagulation treatment. If subjects are on anticoagulation treatment, the corresponding laboratory values should be in therapeutic range for the respective agent.
17. Full recovery from all recent surgery on date of randomization; at least 1 week must have elapsed from the time of a minor surgery (port placement at any time is acceptable); from the date of randomization at least 21 days must have elapsed from the time of a major surgery. Must have fully recovered from all surgery-related toxicities to Grade 1 or less
18. At least 28 days between termination of prior anticancer or hormonal therapy and first administration of AVB-S6-500
19. Full recovery from all treatment-related toxicities to Grade 1 or less, except alopecia

E.4

Principal exclusion criteria

1. Tumors in the breast or bone
2. Untreated central nervous system (CNS) metastases (surgery and/or radiotherapy). Subjects requiring corticosteroid therapy for the management of their treated CNS metastases may not be on >10 mg/day prednisone or equivalent OR have demonstrated signs or symptoms of neurologic instability for 28 days or less prior to randomization.
3. Primary platinum-refractory disease (defined as progression during or within 4 weeks after completion of the first platinum regimen)
4. Is being treated with concurrent anticancer therapy or other interventional treatments administered for their underlying ovarian cancer.
5. Received prior therapy with PAC in the recurrent setting
6. Clinically significant cardiac disease history including the following:
a. cardiac arrhythmia uncontrolled on medication
b. unstable angina or clinically and/or electrocardiographically documented myocardial infarction within 6 months before randomization
c. clinically significant valvular disease
d. uncontrolled congestive heart failure
e. QT (QTc) prolongation >470 msec
f. clinically significant pericardial effusion.
7. History of a prior malignancy that was active (not indolent) within the previous 3 years, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, endometrial stage 1 cancer, or carcinoma in situ of the cervix or breast
8. History of or present CNS disease unrelated to cancer, unless adequately treated with standard medical therapy (eg, uncontrolled seizures)
9. Nonhealing wound, ulcer, or bone fracture
10. Paracentesis for ascites within 3 months prior to the first dose of Study Treatment or has clinically significant active pleural effusion, anasarca, or other evidence of third spacing
11. Serious active infection requiring IV antibiotics and/or hospitalization within 7 days of randomization.
12. Known severe hypersensitivity to any of the study drugs or excipients, including history of allergic, anaphylactic, or other severe hypersensitivity reactions to fusion proteins, products containing Cremophor EL (eg, cyclosporin for injection concentrate and teniposide for injection concentrate), or known hypersensitivity or allergy to Chinese hamster ovary cell products
13. History of or evidence of any other medical conditions (such as psychiatric illness, etc.), therapy, physical examination or laboratory findings that may interfere with the subject’s participation for the full duration of the Study Treatment, affect subject compliance, place the subject at high risk from treatment-related complications, confound the results of the study, or is not in the best interest of the subject to participate
14. Known previous or current human immune deficiency (HIV) syndrome, hepatitis B, or hepatitis C, or any other known active viral illness such as COVID-19
15. Ever participated in a study with AVB-S6-500

E.5 End points

E.5.1

Primary end point(s)

PFS based on investigator-assessed RECIST v1.1 criteria

E.5.1.1

Timepoint(s) of evaluation of this end point

During all study duration

E.5.2

Secondary end point(s)

- OS
- ORR based on investigator-assessed RECIST v1.1
- DOR based on investigator-assessed RECIST v1.1
- FACT-O score
- CBR based on investigator-assessed RECIST v1.1
- Multiple PK endpoints, including Cycle 1 Day 15 trough level
Exploratory analyses include the following additional assessments:
- CA-125 per Gynecologic Cancer Intergroup guidelines
- Expression/activity of AXL pathway biomarkers (eg, AXL, sAXL, and GAS6)
Efficacy endpoints in biomarker-defined subgroups will be based on expression/activation of these biomarkers in serum.
Safety endpoints:
- Adverse events by system organ class and preferred terms using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
- Clinical laboratory results (serum chemistry, hematology etc.)
- Vital signs (blood pressure, heart rate, body temperature etc.)
- 12-lead electrocardiogram measurements
- Physical examination
- Pregnancy test results
Immunogenicity endpoint:
- Anti-drug antibodies to AVB-S6-500

E.5.2.1

Timepoint(s) of evaluation of this end point

During all study duration

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

E.6.8

Bioequivalence

E.6.9

Dose response

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)

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

adaptive

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

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

Canada

Georgia

Ukraine

United States

Belgium

France

Germany

Greece

Ireland

Italy

Poland

Spain

United Kingdom

Czechia

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

End of survival follow-up (up to 5 years after the end of treatment)

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

E.8.9.2

In all countries concerned by the trial days

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:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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

100

F.4.2.2

In the whole clinical trial

400

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)

All subjects will be followed for OS until withdrawal of informed consent or until the end of the Survival Follow-up period up to 5 years, as indicated in the Schedule of Events

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

2021-10-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-08-16

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