Clinical Trials Register

Summary
EudraCT Number:	2017-000364-15
Sponsor's Protocol Code Number:	SUNRISE-CRC
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-09-11
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

Netherlands - Competent Authority

A.2

EudraCT number

2017-000364-15

A.3

Full title of the trial

A randomized phase II/III study of pulsatile high-dose sunitinib versus TAS-102 in patients with metastatic colorectal carcinoma (mCRC).

Gerandomiseerde fase II-III studie tussen sunitinib versus TAS-102 bij patiënten met gemetastaseerd colorectaalcarcinoom.

A.3.1

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

A trial testing TAS-102 therapy versus an alternative high-dose, intermittent scheduling for sunitinib in patients with metastatic colorectal carcinoma.

Een onderzoek bij patiënten met uitgezaaid dikke darm en/of endeldarm kanker die een indicatie hebben voor behandeling met TAS-102 waarbij de behandeling met TAS-102 wordt vergeleken met een behandeling met hoge dosis, intermitterend, sunitinib.

A.3.2

Name or abbreviated title of the trial where available

SUNRISE-CRC

A.4.1

Sponsor's protocol code number

SUNRISE-CRC

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	VU University Medical Center, Department of Medical
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	VU University Medical Center, Department of Medical
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	VU University Medical Center
B.5.2	Functional name of contact point	Department of Medical Oncology
B.5.3	Address:
B.5.3.1	Street Address	De Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081HV
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031204444321
B.5.6	E-mail	s.gerritse@vumc.nl

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.2.1.1.1	Trade name	Sutent
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Ltd
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	sunitinib
D.3.2	Product code	L01XE04
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.3.11 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	Yes
D.3.11.13.1	Other medicinal product type	tyrosine kinase inhibitor

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 colorectal tumors

Gemetastaseerd colorectaal carcinoom

E.1.1.1

Medical condition in easily understood language

Metastasized (spread) or inoperable colorectal cancer

Uitgezaaid (verspreid) of inoperabel colorectaal carcinoom

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to improve progression free survival (PFS), of patients with metastatic colorectal carcinoma (mCRC) treated with high-dose sunitinib once every 2 weeks to 5 months, compared to the reported 2 months for TAS-102 monotherapy

E.2.2

Secondary objectives of the trial

Secondary objectives are:
1: Overall Survival (OS), counting from the date of study inclusion to the date of death of the patient (from any cause) or to the last day of follow-up.
2: To determine quality of life (QoL) of patients in the study.
3: To determine safety and tolerability of the two drugs.
4. Liquid biopsies for circulating blood biomarker analysis including microRNA and platelets containing tumor-derived RNA.
5. A cost effectiveness (utility) analysis will be performed from a health care perspective.
6. Phosphoproteomics profiling on tumor biopsy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

To be eligible for this trial, patients will need to meet all of the following inclusion criteria. Screening must be performed no more than 14 days prior to the first study drug dose.
1: Signed (by the patient or legally acceptable representative) and dated Informed Consent Form (ICF).
2: Histological or cytological confirmed, documentation of incurable locally advanced or metastatic, colorectal adenocarcinoma, not amenable for potentially curative treatment (i.e. inoperable).
3: Indication for treatment with TAS-102; progressive on (or intolerant to) therapy including fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy and anti-EGFR therapy (for tumours with wild-type KRAS)).
4: Evaluable disease by RECIST version 1.1 criteria (see appendix III).
6: Age ≥ 18 years.
7: Eastern Cooperative Oncology Group (ECOG) Performance Status of < 3.
8: Normal 12-lead ECG (clinically insignificant abnormalities permitted).
9: No signs of clinical thyroid abnormalities (suppletion or blocking drugs permitted).
10: Adequate bone marrow function; hemoglobin > 5.6 mmol/l, absolute neutrophil count (ANC) >1,5 x 10*9/l, Platelet count  100 x 10*9/l,
11: Adequate liver function; total bilirubin < 1.5 times the upper limit of normal (ULN), ALT and AST < 2.5 x ULN (In case of liver metastases: < 5 x ULN).
12: Albumin higher than 25 g/L
13: Serum creatinine <1.5 x ULN or creatinine clearance  50 ml/min/1.73m2 (based on MDRD).
14: Pregnant or breast-feeding subjects: Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. For fertile men or women of childbearing potential: documented willingness to use a highly effective means of contraception (e.g., hormonal methods [implants, injectables, or combined oral contraceptives], intrauterine devices, sexual abstinence, or vasectomized or surgically sterilized partner). Contraception is necessary for at least 6 months after receiving the study medication.

E.4

Principal exclusion criteria

The following criteria exclude the patient from enrollment in this trial
1: Previous treatment with sunitinib and/or TAS-102 for mCRC.
2: Evidence of significant uncontrolled concomitant disease, such as cardiovascular disease (including stroke, New York Heart Association Class III or IV cardiac disease or myocardial infarction within 6 months prior to screening, unstable arrhythmia, clinically significant valvular heart disease and unstable angina); pulmonary disease (including obstructive pulmonary disease > GOLD 2 and inadequately treated symptomatic bronchospasm), and uncontrolled central nervous system, renal, hepatic, endocrine, or gastrointestinal disorders; or a serious non-healing wound or fracture.
3: Extensive prior radiotherapy in the rectum, pelvis or in more than 3 vertebrae in the spine (less than 3 vertebrae are considered a small radiation field and eligibility will be decided on an individual basis from the PI).
4: Poorly controlled hypertension despite adequate blood pressure medication. Blood pressure must be ≤160/95 mmHg at the time of screening on a stable antihypertensive regimen. Blood pressure must be stable on at least 2 separate measurements.
5: Instable seizure disorders requiring anticonvulsant therapy.
6: Major surgery, other than diagnostic surgery, within 4 weeks prior to day 1, without complete recovery.
7: Uncontrolled bleeding disorders, and/or active bleeding.
8: Known active bacterial, viral, fungal, mycobacterial, or other infection. (including HIV and atypical mycobacterial disease, but excluding fungal infection of the nail beds.)
9: Known hypersensitivity to sunitinib, TAS-102, or to its excipients.
10: Presence of any significant psychiatric disorder(s) that would interfere with the patient’s compliance.
11: Chemotherapy, radiotherapy, or other anti-cancer therapy within the previous 4 weeks; no nitrosoureas or mitomycin C within the previous 6 weeks; no investigational agents within the previous 4 weeks.
12: Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis.
13: Untreated or active central nervous system (CNS) metastases.
14: Predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline of > 3 loose stools daily despite medication.
15: Unresolved bowel obstruction
16: Any evidence of a disease or condition that might affect compliance with the protocol or interpretation of the study results or render the patient at high risk from treatment complications.

E.5 End points

E.5.1

Primary end point(s)

The primary objective of this study is to improve PFS of patients with stage IV colorectal carcinoma, who progressed on (or are intolerant to) 5-FU, oxaliplatin, irinotecan, anti-VEGF (and/or anti-EGFR) containing therapy, treated with high-dose sunitinib (once every 2 weeks) to 5 months, compared to 2 months for patients treated with TAS-102 monotherapy. Progression free survival is defined as the time from randomization to the date of the first documented tumor progression as determined by the investigator using RECIST 1.1 criteria or death due to any cause. PFS between patients included in the two different study arms will be compared.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 9-10 weeks of treatment by CT-scan (RECIST 1.1) and every 2 weeks by physical exam en laboratory exam.

E.5.2

Secondary end point(s)

Secondary objectives are:
1: Overall Survival (OS), counting from the date of study inclusion (and randomization) to the date of death of the patient (from any cause) or to the last day of follow-up.
2: To determine quality of life (QoL) of patients in the study. The difference in quality of life between two treatment arms will be assessed. Patients will complete the European Organisation for Research and Treatment of Cancer Quality of Life questionnaires (EORTC QoL) to evaluate this objective. A total of 2 questionnaires will be included; EORTC QlQ-C30 Version 3.0 to assess QoL of cancer patients in general and EORTC-QLQ-CR29 to asses QoL of CRC cancer patients.
3: To determine safety and tolerability of the two drugs. In this study two therapeutic drugs are compared in an attempt to improve survival of patients with CRC. TAS-102 had been previously safely used in patients with mCRC. Sunitinib is already registered for various cancer types with acceptable toxicity, but not at this dosing regimen and for mCRC. Safety and tolerability will be studied by analysis of adverse events, physical examinations, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, and laboratory-abnormality assessments (complete blood count with differential count, serum electrolyte measurements, and electro cardiogram). Severity of adverse events will be rated by investigators by use of the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.27. CTCAE (2006)
4. Liquid biopsies for circulating blood biomarker analysis including microRNA and platelets containing tumor-derived RNA. Evaluation of potentially predictive circulating biomarkers could help in identifying patients, rather easily by venepuncture, who will not benefit from treatment and thereby may provide a potential selection tool to avoid unnecessary treatment and its associated toxicity. The potential value of blood markers for molecular diagnostics, disease and response monitoring will be assessed.
5. A cost effectiveness (utility) analysis will be performed from a health care perspective, using a 3-year time horizon. The median overall survival in this patient population is 7 months, so all health effects and costs will be covered within a 3-year time horizon. The direct-medical and total costs will be included. Direct medical costs taken into account will include treatment costs, cost of hospitalization, medication, imaging, laboratory testing and pathology. Within the trial, resource use will be monitored and this will be linked to integral cost prices or Dutch tariffs, using the CVZ guideline on costing studies as our basis. Health-care costs incurred outside the hospital, such as the attendance of a general practitioner will be assessed using the Health Resource Usage Assessments questionnaire.
The primary health outcome measure in this economic evaluations will be the total quality adjusted life years (QALY) per trial arm. QALYS will be calculated by using the utility scores linked to the various health states of the EQ-5D (Appendix VIII); in essence the length of time a patient spends in a particular health condition is weighed by the corresponding utility. Missing data on costs and utilities will be imputed using multiple imputation. The difference in total costs and total QALYs in both arms will be used to calculate the incremental cost-effectiveness ratio (ICER): the cost per QALY gained (or cost-savings per QALY gained or lost), using the formula: ICUR = (Cintervention - Ccontrol) / (QALYintervention - QALYcontrol).
Using the non-parametric bootstrap, a probabilistic sensitivity analysis will be performed to examine the uncertainty around the base-case cost-effectiveness estimate. Furthermore, as the expiration date of the patent for sunitinib approaches, we foresee that the cost for this treatment will decrease significantly.
6. Phosphoproteomics profiling on tumor biopsy. Development of agents blocking kinases has established the use of molecularly targeted therapy for patients with metastatic cancer. It is unclear which patient will respond to targeted therapy. It is assumed that responses to targeted agents depend on specific receptor and protein signalling activities in tumor tissue. Therefore, protein phosphorylation profiling with phosphoproteomics will be explored as a potential clinical diagnostic tool to predict for tumor response to targeted therapy in a subgroup of the patients that are willing to undergo a tumor biopsy from a metastasis (not mandatory for participation).

E.5.2.1

Timepoint(s) of evaluation of this end point

1: Until death survival follow-up will take place every 12 weeks.
2: After study inclusion, and every 9 weeks (with a possibility to extend with 1 week) until progression of disease, patients will be asked to complete The European Organisation for Research and treatment of Cancer Quality of Life questionnaires (EORTC QoL).
3: Every hospital visit using CTCAE version 4.0
4: By Screening and every 2 weeks (hospital visit) after 8 weeks this wil be extended to every 4 weeks.
5: Every hospital visit
6: Screening and day 17 (in case of extra informed consent)

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

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)

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

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

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

TAS-102 monotherapy

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

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

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:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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)

Treatment with sunitinib or TAS-102 will be continued until disease progression or until any other medical or patient-related reason for discontinuation. Follow up will end when death of the patient, or upon patient request. In the case of progressive disease, the choice of subsequent therapy is at the discretion of the treating physician.

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

2019-09-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-11

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-01-24

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