Clinical Trials Register

Summary
EudraCT Number:	2012-005657-24
Sponsor's Protocol Code Number:	PERMAD01
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-07-29
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

Austria - BASG

A.2

EudraCT number

2012-005657-24

A.3

Full title of the trial

Personalized marker-driven early switch to aflibercept in patients with metastatic colorectal cancer. A run in marker determination phase followed by a marker-driven randomized part - a multicenter, multinational, two-part, phase II trial.

A.3.1

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

A.4.1

Sponsor's protocol code number

PERMAD01

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	Universitätsklinikum Ulm
B.1.3.4	Country	Germany
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	Sanofi-Aventis Groupe
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinikum Ulm
B.5.2	Functional name of contact point	Coordinating Investigator
B.5.3	Address:
B.5.3.1	Street Address	Albert-Einstein-Allee 23
B.5.3.2	Town/ city	Ulm
B.5.3.3	Post code	89070
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049731 50044501
B.5.5	Fax number	004973150044502
B.5.6	E-mail	thomas.seufferlein@uniklinik-ulm.de

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	Zaltrap
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Aventis Groupe
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	Zaltrap
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous 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)	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.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

colorectal cancer

E.1.1.1

Medical condition in easily understood language

colon cancer

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10009944
E.1.2	Term	Colon cancer
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

evaluation of the impact of a personalized marker-driven treatment approach with early detection of progression and modification of treatment on cytokines and angiogenetic factors(CAF) and efficacy

E.2.2

Secondary objectives of the trial

prognostic and predictive value of CAF at baseline and the changes during treatment, efficacy, tolerability and patient related outcome.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients with histologically confirmed diagnosis of colorectal cancer presenting with unresectable stage IV (UICC) disease (primary tumor may be present)
2. Patients with at least one measurable lesion, with size > 1 cm (RECIST v1.1)
3. ECOG Performance status ≤ 1
4. Life expectancy > 3 months
5. Age ≥18 years.
6. Haematologic function: ANC ≥ 1.5 x 109/L, platelets ≥ 100 x109/L, hemoglobin ≥ 9 g/dl or 5.59 mmol/l
7. Patients not receiving therapeutic anticoagulation must have an INR < 1.5 ULN and aPTT < 1.5 ULN within 7 days prior to enrollment. The use of full dose anticoagulants is allowed as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least two weeks at the time of enrollment.
8. Adequate liver function as measured by serum transaminases (AST & ALT) ≤ 2.5 x ULN (in case of liver metastases < 5 x ULN) and total bilirubin ≤ 1.5 x ULN
9. Adequate renal function: Serum creatinine ≤ 1.5 x ULN
10. Signed, written informed consent
11. At least 6 months after completion of adjuvant chemotherapy.

E.4

Principal exclusion criteria

1. Treatment with any other investigational agent within 30 days prior to entering this study.
2. Prior systemic or local treatment of metastatic disease.
3. Prior adjuvant or neo-adjuvant chemotherapy/radiotherapy completed less than 6 months prior to study entry.
4. Pre History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) (unless adequately treated with standard medical therapy) e.g. uncontrolled seizures.
5. Fertile women (< 1 year after last menstruation) and men of childbearing potential unwilling or unable to use effective means of contraception (oral contraceptives, intrauterine device, barrier method in conjunction with spermicidal jelly, or surgically sterile) during treatment and for 6 months after the end of treatment.
6. Pregnancy or lactation.
7. Positive serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women < 1 year after the onset of menopause. Note: a negative test has to be reconfirmed by a urine test, should the 7-day window be exceeded.
8. Past or current history (within the last 2 years prior to treatment start) of other malignancies except metastatic colorectal cancer (patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).
9. Peripheral neuropathy NCI CTCAE-grade ≥ 1
10. Known DPD-insufficiency.
11. Active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as > 4 loose stools per day)
12. History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) haemoptoe or evidence of interstitial lung disease on baseline chest X-ray or CT scan.
13. Serious, non-healing wound, ulcer or bone fracture.
14. Thrombosis or severe bleeding within 6 months prior to entry into the study (except for bleeding of the tumor before its surgical resection) and no evidence of bleeding diathesis or coagulopathy.
15. Urine dipstick for proteinuria ≥ 2+. If urine dipstick is ≥ 2+, 24-hour urine must demonstrate ≤ 1 g of protein in 24 hours for patient to be eligible.
16. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment.
17. Clinically significant cardiovascular disease, for example CVA, myocardial infarction (≤ 12 months before treatment start), unstable angina, NYHA Class II CHF, arrhythmia requiring medication, or uncontrolled hypertension.
18. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications.
19. Known hypersensitivity or contraindication to the drugs used in the trial (eg: aflibercept, 5-FU, folinic acid/ leucovorin, oxaliplatin, bevacizumab, irinotecan).
20. Concomitant treatment with ASS > 325 mg or NSAIDs, known to inhibit platelet function, sorivudin or analog compounds or preparations of St. John’s wort.
21. Inability or unwillingness to comply with the protocol.

E.5 End points

E.5.1

Primary end point(s)

Progression free survival (PFS1) of first line treatment
The primary endpoint of the randomized part with marker-driven switch of antiangiogenic
agent and maintenance of chemotherapy is:
Progression free survival rate at 6 months (PFSR@6) after randomization.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after randomization

E.5.2

Secondary end point(s)

- Predictive value of cytokines and angiogenic factor (CAF) for early detection of progression during treatment with chemotherapy and bevacizumab
- Determination and validation of a CAF profile predicting tumor progression before radiologic progression
- PFS1, after randomization (PFSr) and of second line treatment (PFS2)
- Time to randomization (TTR)
- Overall survival (OS)
- Overall response rate (RR) according to RECIST v1.1
- Secondary resection rate (sRR)
- Toxicity (Safety assessments will include physical examinations (blood pressure, heart rate, respiratory rate), vital signs, ECOG, clinical laboratory profile and monitoring of adverse events, according to NCI CTCAE v4.03)
- Quality of life using the EORTC QLQ-C30 and the modules CR29
- Changes in CAF during early marker-driven switch and conventional treatment approach
- Prognostic value of CAF at baseline and/or during treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

1. After all patients had first progression
2. After completion of run-in phase and after all patients had first progression
3. After all patients had second progression
4. after all patients in randomization part changed treatment
5. at end of study
6. After all patients had second progression
7. at end of study
8. End of study
9. End of treatment
10. after all patients in randomization part changed treatment
11. End of treatment

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

Yes

E.6.13.1

Other scope of the trial description

Secondary objectives of both parts are prognostic and predictive value of CAF at baseline and the changes during treatment, efficacy, tolerability and patient related outcome.

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

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

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Run-in phase of the study with at least 30 patients followed by a randomized part

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

Yes

E.8.2.3.1

Comparator description

Bevacizumab

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

Australia

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

The study will be considered complete when all patients have exited the study following progression during or after second line, or all patients have discontinued treatment.
Overall survival post study completion will be assessed by clinical visit and/or telephone follow-up for a maximum of two years after last patient out.

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

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:

130

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

144

F.4.2.2

In the whole clinical trial

200

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 patients will be treated according to the current therapeutic standard. Decisions for further therapies will be done by the treating physician in agreement with patient.

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

2015-09-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-08-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-08-17

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