Clinical Trials Register

Summary
EudraCT Number:	2010-019554-41
Sponsor's Protocol Code Number:	16201
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:	2011-03-01
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Austria - BASG

A.2

EudraCT number

2010-019554-41

A.3

Full title of the trial

A Phase 1b/2 Open Label Study to Evaluate the Safety and Efficacy of TRU-016 in Combination with Bendamustine vs. Bendamustine Alone in Patients with Relapsed Chronic Lymphocytic Leukemia

A.3.1

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

Not applicable

A.4.1

Sponsor's protocol code number

16201

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	Emergent Product Development Seattle, LLC
B.1.3.4	Country	United States
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	Emergent Product Development Seattle, LLC
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	inVentiv Health Clinical (UK) Ltd
B.5.2	Functional name of contact point	Regulatory Operations Europe
B.5.3	Address:
B.5.3.1	Street Address	Thames House, 17 Marlow Road
B.5.3.2	Town/ city	Maidenhead, Berkshire
B.5.3.3	Post code	SL6 7AA
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	441628587 430
B.5.5	Fax number	441628408 428
B.5.6	E-mail	regopseurope@inventivhealth.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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	128.12
D.3 Description of the IMP
D.3.1	Product name	TRU-016
D.3.2	Product code	TRU-016
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not available
D.3.9.1	CAS number	1372645-37-8
D.3.9.2	Current sponsor code	TRU-016
D.3.9.3	Other descriptive name	Humanized Single-Chain Monoclonal Antibody to CD37
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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	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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Levact
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BENDAMUSTINE HYDROCHLORIDE
D.3.9.1	CAS number	3543757
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.25
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

Chronic lymphocytic leukemia

E.1.1.1

Medical condition in easily understood language

Not applicable

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10008976
E.1.2	Term	Chronic lymphocytic leukemia
E.1.2	System Organ Class	100000004864

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

The objective of the Phase 1b study is to determine a safe and tolerable dose of TRU-016 that can be used in combination with bendamustine in patients with relapsed CLL.
The objectives of the Phase 2 study are to compare the efficacy and safety of TRU-016 in combination with bendamustine to bendamustine alone in patients with relapsed CLL.

E.2.2

Secondary objectives of the trial

A secondary objective is to compare the PK and PD results of different doses of TRU-016 with bendamustine. Additional secondary objectives are exploratory and involve response by baseline disease and patient characteristics.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Blood and Tissue Samples for Genotyping and Biomarker Analysis of TRU 016 Clinical Activity

Blood samples will be collected to evaluate ex vivo response of CLL cells to TRU 016 treatment and to correlate the ex vivo and clinical activity of TRU-016 with biomarkers by genetic, RNA expression, and cell protein analysis.In patients who provided consent a biopsy from a lymph node will be obtained at screening and at V6.

E.3

Principal inclusion criteria

1. Previously treated patients with a diagnosis of CLL by the 2008 International Working Group Criteria with intermediate or high risk CLL.
2. Refractory or relapsed disease after at least one prior treatment and no more than 3 prior treatments. Patients with repeated treatment regimens of either single agent chlorambucil or single agent rituximab will count as only 1 prior treatment regimen for each drug. If a patient is discontinued from a treatment regimen or drug within 2 cycles secondary to toxicities then that regimen or drug will not count as a prior treatment regimen.
3. The presence of at least one of the following criteria for active disease requiring treatment:
• Progressive splenomegaly and/or lymphadenopathy.
• Anemia (hemoglobin <11 g/dL) or thrombocytopenia (platelets <100 x 109/L or <100,000/mm3) due to bone marrow involvement.
• Progressive lymphocytosis with an increase of >50% over a 2 month period or an anticipated doubling time of less than 6 months.
4. Age ≥18 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
6. Life expectancy greater than 6 months in the opinion of the Investigator.
7. Serum creatinine, total bilirubin, serum glutamic oxaloacetic transaminase (SGOT) or aspartate aminotransferase (AST), serum glutamate pyruvate transaminase (SGPT) or alanine aminotransferase (ALT) of ≤2.0 x upper limit of normal (ULN).
8. Creatinine clearance of >40 mL/min as calculated by the Cockgroft and Gault method23.
9. ANC ≥1,200/mm3 (≥1,200/µL)
10. Platelets ≥75,000/mm3 (≥75,000/µL). For patients receiving platelet transfusions, the most recent infusion must be at least 30 days prior to Screening.
11. Lymphocytes ≥5,000/mm3 (≥5,000/µL) for Phase 1b; no requirement for Phase 2.
12. Patient must be capable of understanding and providing written, voluntary informed consent.
13. Both women of child-bearing potential and male patients must use an acceptable form of birth control for the duration of their study participation and for 6 months after completing study drug dosing. Acceptable forms of birth control include, unless dictated otherwise by local regulatory authorities, consistent abstinence from heterosexual activity; consistent use of combined or progestogen oral contraceptives; injectable progestogen; implants of levonorgestrel; estrogenic vaginal ring; percutaneous contraceptive patches or intrauterine device (IUD); vasectomy with documented azoospermia >6 months of the sole male partner, hysterectomy, tubal ligation or double-barrier method (condom or occlusive cap plus spermicidal agent). Male subjects must not donate sperm during the study and for 6 months after completing study drug dosing.

E.4

Principal exclusion criteria

1. Received treatment with rituximab or other B cell depleting agent within 30 days before first study drug dose or alemtuzumab within 12 weeks before first study drug dose.
2. Received previous anticancer therapy within 30 days before first study drug dose and/or has not fully recovered from the toxic effects of that treatment.
3. Refractory to prior bendamustine, fludarabine or other purine analog therapy; either as single agent or in combination. Refractory is defined as failed to respond to therapy (did not achieve CR or PR) or relapsed <6 months after treatment completed. Patients who discontinued of prior bendamustine secondary to toxicities (i.e. prolonged neutropenia >4 weeks) are excluded.
4. Received prior TRU-016.
5. Received an investigational therapy within 30 days before first study drug dose or has not fully recovered from any toxic effect of that therapy.
6. Had major surgery within 30 days before first study drug dose.
7. Previous or concurrent additional malignancy except noninvasive, nonmelanomatous skin cancer, in situ carcinoma of the cervix, or other solid tumor treated curatively, or currently controlled (in remission or on hormonal therapy, e.g. prostate or breast cancer) with estimated survival in excess of 2 years. These cases must be discussed with the Medical Monitor before enrollment.
8. Any significant concurrent medical diseases or conditions, including:
• Clinically significant pulmonary dysfunction requiring oxygen therapy.
• Active infection (viral, bacterial, or fungal) requiring systemic therapy. Patients who are on prophylactic therapy are eligible.
• Prior allogeneic bone marrow transplant.
• Active autoimmune disease requiring immunosuppressive therapy. If the patient has an autoimmune complication secondary to CLL and it is controlled by immunosuppressive therapy then the patient may be enrolled. If the disease is active and uncontrolled with medication then they are to be excluded. If the patient has autoimmune disease not related to CLL they may not be enrolled if they are on any immunosuppressive therapy.
9. Positive serology for human immunodeficiency virus (HIV) or hepatitis C.
10. Hepatitis B surface antigen positive or hepatitis B core antibody positive. Patients positive for hepatitis B surface antibody may be enrolled if both hepatitis B surface antigen and hepatitis B core antibody are negative. If the hepatitis B core antibody is the only test positive and it is the result of immunoglobulin treatment, the patient may be enrolled if the HBV DNA is negative.
11. Pregnant or breast feeding; women of childbearing potential must have a negative pregnancy test prior to treatment.
12. Allergic to mannitol.
13. Known current drug or alcohol abuse.
14. Any severe, acute, or chronic medical or psychiatric condition, laboratory abnormality, or other condition, which in the judgement of the Investigator would place the subject at undue risk, interfere with the results of the study or make the patient otherwise unsuitable.
15. Any difficulty complying with protocol requirements that may increase the risk associated with study participation or study drug administration or may interfere with safety.
16. Any circumstance at the time of study entry that would preclude completion of the study

E.5 End points

E.5.1

Primary end point(s)

In the dose-escalation Phase 1b stage of the study, the primary endpoint is the incidence of dose limiting toxicities (DLT).
In the randomized Phase 2 stage of the study, the primary endpoint is the investigator-assessed overall response rate (ORR) for TRU-016 plus bendamustine and bendamustine alone.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the study the efficacy and safety between the two treatments will be compared

E.5.2

Secondary end point(s)

Secondary endpoints are:
• Complete response rate (CR)
• Progression-free survival (PFS)
• Overall survival (OS)
• Duration of response (DOR)
• Quality of Life – EORTC QLQ-C30 and CLL16
• Disease-related symptoms
• Occurrence of adverse events
• Changes in laboratory parameters, vital signs and physical examinations
The pharmacokinetics (PK) and pharmacodynamics (PD) of TRU-016 and the development of antibodies to TRU 016 will be evaluated in both phases of the study.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the study the efficacy and safety between the two treatments will be compared

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

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

Yes

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)

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

phase Ib

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

Yes

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

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

Germany

Austria

Poland

Spain

United States

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 completed when the last patient has completed their last visit

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