Clinical Trials Register

Summary
EudraCT Number:	2008-005180-33
Sponsor's Protocol Code Number:	CNTO328STM2001
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-12-09
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
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

Spain - AEMPS

A.2

EudraCT number

2008-005180-33

A.3

Full title of the trial

Estudio Fase 1/2, de dosis múltiples y escalada de dosis para valorar la seguridad, eficacia y farmacocinética de CNTO328 intravenoso, un anticuerpo monoclonal anti-interleucina 6 (IL-6), en sujetos con tumores sólidos

A.4.1

Sponsor's protocol code number

CNTO328STM2001

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Centocor B.V.
B.1.3.4	Country	Netherlands
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	CNTO328
D.3.2	Product code	CNTO328
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	CNTO328
D.3.9.3	Other descriptive name	chimeric murine-human monoclonal antibody against IL-6.
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Monoclonal antibody

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

Tumores sólidos

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10065147
E.1.2	Term	Malignant solid tumor

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 the Phase 1 portion of the study is to determine a recommended dose for Phase 2 (RP2D) of CNTO 328 monotherapy.

The primary objective of the Phase 2 portion of the study is to estimate the clinical benefit rate (CR + PR + SD > 6 weeks) of CNTO 328 monotherapy in subjects with ovarian cancer and with K-Ras mutant tumors.

E.2.2

Secondary objectives of the trial

Secondary objectives:
The secondary objectives of the Phase 1 portion of the study are to assess:
• Safety profile, including the AE profile and dose limiting toxicities (DLTs)
• Pharmacokinetic profile
• Immune response
• Pharmacodynamic effects associated with IL-6 pathway and mechanisms of anemia
• Clinical effects of CNTO 328

The secondary objectives of the Phase 2 portion of the study are to assess:
• Safety profile of CNTO 328
• Pharmacodynamic effects on biomarkers of IL-6, mechanisms of anemia and correlation with K-Ras mutations
• Pharmacokinetics
• Immune response
• Patient-reported outcomes (PRO) for ovarian cancer subjects

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

To be eligible for the study, subjects must meet all of the following criteria:

1. Age ≥ 18 years old.

2. Have capacity to understand and provide signed and dated informed consent prior to any study specific-procedures and agree to comply with all protocol-specified procedures.

3. Histologic or cytologic documentation of malignancy as follows:

a. Phase 1 Pharmacokinetic (Cohort 1) and dose-escalation (Cohorts 2 through 4): Subjects with malignant solid tumors that have progressed on or after standard therapy, or for which there is no effective therapy.

b. Phase 1 expansion Cohort 5: Subjects with solid tumors of the subtypes
described.

1) Epithelial ovarian cancer subject who progressed on or after standard therapy. Subjects should be platinum resistant and taxane resistant, defined as, progression on or within 6 months of completing therapy with taxane and platinum either alone or in combination (unless contraindications for taxane or platinum exist), and for which there is no effective therapy.

2) Subjects with known K-Ras mutant tumors or pancreatic cancer, or NSCLC, CRC or head and neck (H&N) cancer that are refractory or resistant to anti-EGFR therapy. All subjects must have received at least 1 line of standard chemotherapy.

c. Phase 2 ovarian cancer cohort: Subjects with epithelial ovarian cancer, who progressed on or after standard therapy. Subjects should be platinum resistant and taxane resistant, defined as progression on or within 6 months of completing therapy with taxane and platinum either alone or in combination (unless contraindications for taxane or platinum exist), and for which there is no effective therapy.

d. Phase 2 K-Ras mutant cohort: Subjects with known K-Ras mutant tumors or subjects with pancreatic cancer, or subjects with NSCLC, CRC or head and neck (H&N) cancer that are refractory or resistant to anti-EGFR therapy. All subjects must have received at least 1 line of standard chemotherapy.

4. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2.

5. Subjects must have recovered from reversible toxicity of previous treatment to ≤ Grade 1 or an acceptable baseline.

6. Subjects of childbearing potential must use adequate birth control measures. Negative pregnancy test (urinary beta human chorionic gonadotropin [β-HCG]) at screening (applicable to women of child bearing potential who are sexually active).

7. Adequate bone marrow, liver, and renal function:

a. Hb ≥ 9.0 g/dL (5.6 mmol/L; 90 g/L)

b. Absolute neutrophil count ≥ 1.5 x 109/L (1500/mm3)

c. Platelets ≥ 75 x 109/L

d. CrCL > 20 mL/min estimated by formula

e. Liver function tests:

1) Aspartate transaminase [AST], alanine transaminase [ALT]): ≤ 2.5 x upper limit of normal [ULN] if no liver metastasis; ≤ 5 x ULN with liver metastasis
2) Total bilirubin ≤ 1.5 x ULN or ≤ 3x ULN if due to tumor obstruction
3) Alkaline phosphatase ≤ 3 x ULN if no liver metastasis or bone involvement, and ≤ 5 x ULN with liver metastasis or bone involvement

f. Coagulation prothrombin time/international normalized ratio (PT/INR) and
activated partial thromboplastin time (aPTT) within 1.5 x ULN

8. For the expansion Cohort 5 and Phase 2 ovarian cancer and K-Ras mutant tumor cohorts: evaluable or measurable disease (defined by RECIST, as applicable)

E.4

Principal exclusion criteria

Subjects meeting any of the following criteria may not be enrolled in the study:

1. Received any prior systemic therapy or had major surgery for the cancer under study within 4 weeks (in the case of nitrosoureas and mitomycin C within 6 weeks) prior to the first CNTO 328 administration. Concomitant use of immunotherapy, biotherapy, radiotherapy, chemotherapy, investigative therapy, immunosuppressive therapy, or IL-6 modulating agents is prohibited during the study except for stable low-dose steroids or luteinizing hormone-releasing hormone (LHRH) agonists in prostate cancer subjects.

2. Previous anti IL-6 targeted therapy.

3. Serious concurrent illness or history of uncontrolled heart disease such as: unstable angina, congestive heart failure, myocardial infarction within preceding 12 months, clinically significant rhythm or conduction abnormality.

4. Subjects with known allergies or clinically significant reactions to murine,
chimeric, or human proteins.

5. For the dose expansion Cohort 5, ovarian cancer and K-Ras mutant tumor cohorts: Prior malignancy (other than the 1 under study) except adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or other cancer for which the subject has been disease-free for ≥ 5 years).

6. Clinically significant active infection within 2 weeks prior to the first CNTO 328
administration.

7. Evidence of bleeding disorder.

8. Pregnant or lactating women.

9. Any uncontrolled medical condition, including the presence of laboratory abnormalities, that places the subject at unacceptable risk by participating in the study or confounds the ability to interpret data from the study.

10. Known central nervous system (CNS) metastases.

11. Known infection with human immunodeficiency virus (HIV), known hepatitis C infection or known to be hepatitis B surface antigen positive.

12. Subjects cannot be vaccinated with live, attenuated vaccines during the following time period: Within 4 weeks of the first administration of CNTO 328 and from the first administration of study agent to 12 weeks after the last administration of CNTO 328.

E.5 End points

E.5.1

Primary end point(s)

The primary safety endpoints include:
Dose-limiting Toxicity: A DLT is defined as any of the following events occurring up to 3 weeks after the first administration of CNTO 328:

• Grade 3 or greater nonhematologic AEs with the exception of:
− Nausea and vomiting, which is controllable with antiemetics
− Diarrhea, which is controllable with adequate anti-diarrheal treatment
− Grade 3 hypertension, which is controllable with medication
− Hypersensitivity reactions unless there are 2 or more occurrences of ≥ Grade 3
hypersensitivity reactions within a cohort.
• Clinically relevant hematologic toxicity such as Grade 4 neutropenia lasting > 1 week, febrile neutropenia, Grade 4 thrombocytopenia lasting more than 1 week or associated with hemorrhage.
• Any other CNTO 328-related toxicity that in the judgment of the SET is considered to be dose limiting.

A toxicity that is determined to be clearly unrelated to the investigational agent (eg, injury from motor vehicle accident in which the subject is a passenger) will not be considered a DLT. In such cases, confirmation by the SET is required at the next scheduled meeting.

The safety endpoints include:
• Incidence of DLT
• Incidence of all AEs and reasonably related AEs
• Incidence of all Grade 3 or higher AEs and reasonably related Grade 3 or higher AEs
• Incidence of all SAEs and reasonably related SAEs
• Incidence of infusion reactions, including ≥ Grade 3 allergic reactions/hypersensitivity (including drug fever) and ≥ Grade 3 cytokine release syndrome/acute infusion reaction
• Incidence of clinically significant abnormal safety-related laboratory parameters
• Incidence of antibodies to CNTO 328

The primary efficacy endpoint is the clinical benefit rate. The major secondary efficacy endpoints include overall response rate, tumor marker response, and changes in hemoglobin. Additional efficacy endpoints include progression-free survival (PFS), and overall survival (OS).

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

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Patient Reported Outcomes

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Dose Escalation

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Information not present in EudraCT

E.7.4

Therapeutic use (Phase IV)

Information not present in EudraCT

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Information not present in EudraCT

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

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

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	No
F.1.1.1	In Utero	Information not present in EudraCT
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	Information not present in EudraCT
F.1.1.3	Newborns (0-27 days)	Information not present in EudraCT
F.1.1.4	Infants and toddlers (28 days-23 months)	Information not present in EudraCT
F.1.1.5	Children (2-11years)	Information not present in EudraCT
F.1.1.6	Adolescents (12-17 years)	Information not present in EudraCT
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	15
F.4.2	For a multinational trial
F.4.2.1	In the EEA	60
F.4.2.2	In the whole clinical trial	90

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

2009-02-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-12-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2011-04-11

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