Clinical Trials Register

Summary
EudraCT Number:	2015-004134-95
Sponsor's Protocol Code Number:	M15PAS/DSSG02
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-06-10
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

UK - MHRA

A.2

EudraCT number

2015-004134-95

A.3

Full title of the trial

Phase II clinical study of concurrent PAzopanib for non-metastatic SArcoma patients to be treated with RadioTherapy, localized in the extremities, trunk and chest wall or the head and neck region.

A.3.1

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

PASART 2

A.3.2

Name or abbreviated title of the trial where available

PASART 2

A.4.1

Sponsor's protocol code number

M15PAS/DSSG02

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	The Netherlands Cancer Institute
B.1.3.4	Country	Netherlands
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	The Netherlands Cancer Institute
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The Royal Marsden NHS Fundation Trust
B.5.2	Functional name of contact point	Galina Petrikova
B.5.3	Address:
B.5.3.1	Street Address	Fulham Road
B.5.3.2	Town/ city	London
B.5.3.3	Post code	SW3 6JJ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02078118090
B.5.5	Fax number	02073490701
B.5.6	E-mail	galina.petrikova@rmh.nhs.uk

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.2.5	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	Pazopanib
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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)	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

soft tissue sarcoma

E.1.1.1

Medical condition in easily understood language

sarcoma/cancer

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	HLT
E.1.2	Classification code	10041298
E.1.2	Term	Soft tissue sarcomas histology unspecified
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10024627
E.1.2	Term	Liposarcoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10016632
E.1.2	Term	Fibrosarcoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10049067
E.1.2	Term	Spindle cell sarcoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10024189
E.1.2	Term	Leiomyosarcoma
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate the proportion of patients following pre-operative radiotherapy with pazopanib with resection specimens demonstrating induction of a pathological (near) complete remission (≥ 95% tumor regression)

E.2.2

Secondary objectives of the trial

Secondary Objectives
 To assess tolerability and toxicity profile in the pre‐operative setting.
 To assess acute toxicities and late toxicities of combination of radiotherapy and pazopanib
 To determine tumour response using the RECIST 1.1 criteria
 To describe any pathological evidence of tumour regression after pre‐operative pazopanib and radiotherapy
 To determine local control rates
 To determine the rate of R0 resection
 To determine the rate of R1 resection
 Incidence of post‐operative wound complications
 Recurrence rate at 5 years (local and/or distant disease).

Exploratory Objectives
 Correlation between diffusion weighted MRI characteristics and histopathological response evaluation
 To study tumour changes measured by dynamic contrast enhanced MRI (DCE‐MRI), diffusionweighted MRI (DW‐MRI) and blood‐oxygenation‐level‐dependent (BOLD) MR imaging
 Correlation between pazopanib PK plasma and pazopanib PK tumour tissue
 PK/PD correlations:
 Correlat

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Histologically confirmed newly diagnosed intermediate to high grade soft tissue sarcoma localized to the extremities, trunk and chest wall or the head and neck area, for which the standard treatment is a combination of and radiotherapy and surgery(deep seated, > 5cm according to the RECIST 1.1 criteria and/or an anticipated close resection margin, grade II/III according to the FNLCC definition)
•Age ≥ 18 years
•WHO performance status of ≤ 1
•Able and willing to undergo blood sampling for PK and PD analysis
•Able to swallow and retain oral medication
•Able and willing to undergo MRI scanning
•Able and willing to undergo tumor biopsies
•Adequate organ functions as described by the laboratory findings in the table 1. For thyroid function, the T4 and TSH values must be within normal values of the range of the participating centers
•Written informed consent prior to performance of study-specific procedures or assessments and must be willing to comply with treatment and follow up.

E.4

Principal exclusion criteria

•Prior malignancies; except another malignancy and disease-free for ≥ 5 years, or completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma.
•Patients with recurrent sarcomas (even without prior radiotherapy)
•Ewing sarcoma and other PNET family tumors, rhabdomyosarcomas (both pediatric and adult), osteosarcomas
•Clinically significant gastrointestinal abnormalities which might interfere with oral dosing diagnosed as:
Active peptic ulcer disease
Inflammatory bowel disease, ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment
Major resection of the stomach or small bowel
•Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Following antihypertensive medication initiation or adjustment, blood pressure (BP) must be re-assessed three times at approximately 2-minute intervals. At least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement. These three values should be averaged to obtain the mean diastolic blood pressure and the mean systolic blood pressure. The mean SBP / DBP ratio must be <140/90 mmHg (or 150/90 mm Hg, if this criterion is approved by the Principal Investigator) in order for a subject to be eligible for the study.
•Unstable or serious concurrent condition (e.g., active infection requiring systemic therapy)
•Prolongation of corrected QT interval (QTc) > 480 msecs on ECG
•History of any of more of the following cardiovascular conditions within the past 6 months:
Cardiac angioplasty or stenting
Myocardial infarction
Unstable angina
Symptomatic peripheral vascular disease
Coronary artery by-pass graft surgery
Class II, III or IV congestive heart failure as defined by the New York Heart Association (NYHA)
History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months
•Macroscopic hematuria
•Hemoptysis that is clinically relevant within 4 weeks of first dose of pazopanib
•Evidence of active bleeding or bleeding diathesis
•Prior major surgery or trauma within 28 days prior to first dose of study medication and/or presence of any non-healing wound, fracture, or ulcer
•Chemotherapy or radiation therapy within 2 weeks prior to the first dose of study medication
•Biological therapy or treatment with an investigational agent within 28 days or five half-lives, whichever is longer prior to the first dose of study medication
•Prohibited medications listed in the protocol for 14 days or five half-lives of a drug (whichever is longer) prior to visit 1 and for the duration of the study
•Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib
•Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
•Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth

E.5 End points

E.5.1

Primary end point(s)

The resection specimen of each patient will evaluated for the individual percentage of tumor regression. For the analysis of this primary endpoint, a patient is either a “success” (a pathological (near) complete remission being ≥ 95% tumor regression) or a “failure” (< 95% tumor regression). The proportion of patients with resection specimens demonstrating a pathological (near) complete remission will be calculated. The percentage tumor regression is the proportion of the tumor mass replaced with other tissue where the tumor has regressed, usually fibrous or fibro- inflammatory tissue, necrosis, calcifications or acellular mucin pools.

E.5.1.1

Timepoint(s) of evaluation of this end point

Following 6 weeks of Pazopanib with radiotherapy for 5 weeks of this schedule, participants will have an imaging assessment for resoinse at 4 weeks after completing radiotherapy and pazopanib with surgery at 6-8 weeks after completing radiotherapy and pazopanib. This will provide the tumor resection speciment from which to evaluate histological response

E.5.2

Secondary end point(s)

• Proportion of patients completed radiotherapy without delay (By definition for this protocol, any lengthening of the overall treatment time by ≤ 3 days is not a delay. Any increase in the overall treatment time of ≥ 4 days will be registered as a delay, including the reason for delay (e.g. machine down-time, public holidays, toxicity etc.)
• Incidence of acute and late toxicities measured by NCI-CTCAE v4.0 and EORTC/RTOG scoring systems respectively (radiotherapy alone, pazopanib alone or both).
• Rate of response as measured by RECIST v 1.1 at 4 weeks after completing radiotherapy
• Incidence of acute post-operative wound complications up to 3 weeks (+/- 1 week) after surgery as defined in section 6.1.3 and reference 29
• Local control rate at 2 years , defined as the absence of sarcoma at the original site, counted from day of surgery
• Rate of R0 resections
• Rate of R1 resections
• Disease free survival at 2 and 5 years
• Overall survival at 2 and 5 years

E.5.2.1

Timepoint(s) of evaluation of this end point

as listed above

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

Yes

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

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

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

Netherlands

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

Last visit of the last subject undergoing the trial

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