Clinical Trials Register

Summary
EudraCT Number:	2019-001238-32
Sponsor's Protocol Code Number:	ADVL1622
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-09-26
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
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2019-001238-32

A.3

Full title of the trial

Phase 2 Trial of XL184 (Cabozantinib) an Oral Small-Molecule Inhibitor of Multiple Kinases, in Children and Young Adults with Refractory Sarcomas, Wilms Tumor, and Other Rare Tumors

A.3.1

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

Cabozantinib in Children and Young Adults with Refractory Sarcomas, Wilms Tumor and Other Rare Tumors

A.4.1

Sponsor's protocol code number

ADVL1622

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/331/2019

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	National Cancer Institute Cancer Therapy Evaluation
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	NCI/CTEP
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	Ipsen
B.5.2	Functional name of contact point	Ipsen Medical Director
B.5.3	Address:
B.5.3.1	Street Address	5 avenue du Canada
B.5.3.2	Town/ city	Les Ulis
B.5.3.3	Post code	91940
B.5.3.4	Country	France
B.5.6	E-mail	clinical.trials@ipsen.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	Yes
D.2.1.1.2	Name of the Marketing Authorisation holder	Ipsen Pharma
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Cabozantinib
D.3.2	Product code	XL184
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	CABOZANTINIB
D.3.9.1	CAS number	1140909-48-3
D.3.9.4	EV Substance Code	SUB93452
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(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

Ewing sarcoma, Rhabdomyosarcoma, Non rhabdomyosarcoma, Wilms Tumor, Osteosarcoma and Other Rare Tumors

E.1.1.1

Medical condition in easily understood language

Sarcomas, Wilms tumor or other rare tumors that have come back or have not responded to other treatments

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

• To determine the objective response rate (complete response +
partial response) of XL184 in children and young adults with Refractory Sarcomas, Wilms Tumor, and Other Rare
Tumors.
• To estimate whether XL184 therapy either improves the disease
control rate at 4 months in patients with recurrent measurable osteosarcoma as compared to a historical COG experience or produces an objective response rate.

E.2.2

Secondary objectives of the trial

• To further define XL184 related toxicities in pediatric, adolescent and young adult patients.
• To further define XL184 pharmacokinetics in the pediatric and adolescent patients.
• To estimate 1-year time to progression, progression free survival (PFS) and overall survival for each stratum, and if feasible to compare to historical controls.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients must be ≥ 2 and ≤ 30 years of age at the time of study entry for all strata except upper age limit of ≤ 18 years of age for medullary thyroid carcinoma (MTC), renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC)
• Patients must have a body surface area >= 0.35 m^2
• Patients must have recurrent or refractory disease, or newly diagnosed disease with no known curative therapy or therapy proven to prolong survival with an acceptable quality of life; patients must have had histologic verification of one of the malignancies listed at original diagnosis or at relapse: Ewing sarcoma; Rhabdomyosarcoma (RMS); Non-rhabdomyosarcoma soft tissue sarcomas (STS) including microphthalmia transcription factor associated STS (alveolar soft part sarcoma [ASPS] and clear cell sarcoma [CCS]); Osteosarcoma; Wilms tumor; Rare tumors: Medullary thyroid carcinoma (MTC), Renal cell carcinoma (RCC), Hepatocellular carcinoma (HCC), Hepatoblastoma, Adrenocortical carcinoma, Pediatric solid tumors (including central nervous system [CNS] tumors) with known molecular alterations in the targets of XL184
• Patients must have radiographically measurable disease; measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 10 mm in at least one dimension (CT scan slice thickness no greater than 5 mm)
• Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
• Patients with solid tumors must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea)
• At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim
• Anti-cancer agents not known to be myelosuppressive >= 7 days after the last dose of agent
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• >= 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of M-Iodobenzylguanidine (MIBG); >= 3 months must have elapsed if prior craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if total-body irradiation (TBI) was received; >= 6 weeks must have elapsed if other substantial bone marrow irradiation was given
• Subjects should not have any clinically relevant ongoing complications from prior radiation therapy
• No evidence of active graft versus (vs.) host disease and >= 2 months must have elapsed since transplant
• Not previously received XL184 or another MET/HGF inhibitor (tivantinib or crizotinib);
• For patients with solid tumors without bone marrow involvement: Peripheral absolute neutrophil count (ANC) >= 1000/uL; Platelet count >= 100,000/uL; Hemoglobin >= 8.0 g/dL;
• For patients with solid tumors and known bone marrow metastatic disease: Peripheral absolute neutrophil count (ANC) >= 750/uL; Platelet count >= 50,000/uL; Hemoglobin >= 8.0 g/dL;
• Adequate renal function: Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or a serum creatinine based on age/gender; Urine protein: =< 30 mg/dl in urinalysis or =< 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour (h) urine sample
• Adequate Liver Function: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age; Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3 x ULN) (for the purpose of this study, the ULN for SGPT is 45 U/L); Serum albumin >= 2.8 g/dL
• Adequate Cardiac Function: No history of congenital prolonged corrected QT (QTc) syndrome, New York Heart Association (NYHA) class III or IV congestive heart failure (CHF); No clinically significant cardiac arrhythmias, stroke or myocardial infarction within 6 months prior to enrollment; QTc =< 480 msec
• Central Nervous System Function Defined as: Patients with a known seizure disorder who are receiving non-enzyme inducing anticonvulsants and have well-controlled seizures; CNS toxicity =< grade 2 with the exception of decreased tendon reflex (DTR); any grade of DTR is eligible;
• Adequate Blood Pressure Control: A blood pressure (BP) =< the 95th percentile for age, height, and gender for pediatric patients < 18 years old and =< 140/90 mmHg for patients >= 18 years old; Adequate Coagulation Defined as International normalized ratio (INR) =< 1.5
• Adequate Pancreatic Function Defined as: Serum amylase =< 1.5 ULN; Serum lipase =< 1.5 ULN

E.4

Principal exclusion criteria

• Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use two methods of birth control
• Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment (14 days if pegfilgrastim)
• Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Previous treatment with XL184 (cabozantinib) or another MET/HGF inhibitor (tivantinib, crizotinib)
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anti-cancer agents are not eligible
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial
• Patients must not be receiving any of the following potent CYP3A4 inducers or inhibitors: erythromycin, clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St. John's wort
• Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin, and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel) are prohibited
• Patients must not have received enzyme-inducing anticonvulsants within 14 days prior to enrollment
• Patients who are receiving drugs that prolong QTc are not eligible
• Patients who are unable to swallow intact tablets are not eligible
• Patients who have an uncontrolled infection are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
• Patients with active bleeding are not eligible
• Patients who have had or are planning to have invasive procedures are not eligible.
• Patients who have had significant traumatic injury within 28 days prior to enrollment are not eligible
• Patients with any medical or surgical conditions that would interfere with gastrointestinal absorption of the study drug are not eligible

E.5 End points

E.5.1

Primary end point(s)

Objective response assessed by Response Evaluation Criteria in Solid Tumors version 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 1 year

E.5.2

Secondary end point(s)

• Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0
• Pharmacokinetics (PK) parameters of cabozantinib s-malate

E.5.2.1

Timepoint(s) of evaluation of this end point

• Up to 1 year
• Prior to dose, 2, 4, 8 and 20-28 hours after dose on day 1, and prior to dose and 2-4 hours after dose on day 22 of course 1, prior to dose on day 1 of courses 2 and 3

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

Yes

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)

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

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

United States

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.8.9.2

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

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

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)

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.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

146

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

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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