Clinical Trials Register

Summary
EudraCT Number:	2006-006152-34
Sponsor's Protocol Code Number:	EFC6663
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-02-24
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

Germany - BfArM

A.2

EudraCT number

2006-006152-34

A.3

Full title of the trial

A Multicenter, Open-Label, Single Arm Study of Weekly Alvocidib in Patients with Previously Treated B-Cell Chronic Lymphocytic Leukemia (CLL) or Prolymphocytic Leukemia (PLL) Arising from CLL

A.4.1

Sponsor's protocol code number

EFC6663

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	sanofi-aventis recherche & développement
B.1.3.4	Country	France
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	Sanofi-aventis recherche et développement
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	Sanofi-Aventis Deutschland GmbH
B.5.2	Functional name of contact point
B.5.3.4	Country	Germany
B.5.6	E-mail	medinfo.de@sanofi-aventis.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Alvocidib
D.3.2	Product code	HMR1275
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	alvocidib
D.3.9.1	CAS number	131740-09-5
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	50 mg base /5ml
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)	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	Information not present in EudraCT

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

B-Cell Chronic Lymphocytic Leukemia (CLL) or Prolymphocytic Leukemia (PLL) arising from CLL

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10009310
E.1.2	Term	CLL
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 determine the objective overall response rate (CR+PR including nPR) of alvocidib administered as a 30 minute infusion followed by a 4 hour continuous infusion in previously treated CLL patients or Prolymphotic Leukemia (PLL ) arising from CLL.

E.2.2

Secondary objectives of the trial

To assess the objective overall safety profile of this treatment.

To assess the response duration, progression free survival (PFS) and overall survival (OS) following this treatment.

To assess the clinical benefit by assessing:
- Reduction in incidence and severity of B-symptoms and time to relief of B-symptoms;
- Reduction in the frequency and amount of blood and platelet transfusions;
- Reduction in incidence of cytomegalovirus (CMV) reactivation and other opportunistic infections.

To assess the pharmacokinetics of this schedule of administration.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient must have documentation of histologically confirmed CLL, or PLL arising from CLL as established by the NCI Working Group Response Criteria (NCI 96 criteria) for diagnosis of CLL.

2. Patient must have symptomatic Rai Stage III or IV, or Binet Stage B or C. (Patient will also be eligible if presented with Rai stage I, II or Binet Stage A, accompanied by rapid doubling time of peripheral lymphocyte count, or symptomatic splenomegaly/hepatomegaly or symptomatic or progressive lymphadenopathy or B-symptoms).

3. Patient must have progressive or symptomatic disease as defined by any of the following conditions:
- Progressive lymphocytosis with a lymphocyte count increased > 50% over last 2 month period or an anticipation of the doubling time in less than 6 months;.
- symptomatic splenomegaly/hepatomegaly
- symptomatic or progressive lymphadenopathy
- Anemia (hemoglobin < 11 g/dl) or thrombocytopenia (platelets < 100 x 10 9/L) within past 6 months.
- Presence of any B-symptoms:
Weight loss ≥ 10% within the previous 6 months; extreme fatigue or inability to perform work or usual activities; Fevers > 100.5 °F (38 °C) for ≥ 2 weeks without evidence of infection; night sweats without evidence of infection.
4.Patient must have received one or more prior therapies for CLL or PLL arising from CLL. All patients:
- must have received prior alkylating agent(s) and be fludarabine refractory either as a single agent or in combination with other chemotherapy agents. Examples of prior chemotherapy regimen(s) include:
-chlorambucil (pulse or continuous) ± prednisone
-cyclophosphamide ± prednisone
-CVP (cyclophosphamide, vincristine, prednisone)
-FC (fludarabine, cyclophosphamide) ± rituximab
-fludarabine ± rituximab
-Fludarabine refractory CLL is defined as:
Stable disease (lack of an objective PR or CR) after at least 2 cycles of fludarabine-based therapy;
Progressive disease on therapy or ≤ 6 months following completion of fludarabine-based therapy.
-Patient may have received any of the following prior treatment regimens, or be intolerant, or not an appropriate candidate for such treatment:
(alemtuzumab single agent or in combination,rituximab or pentostatin incombinations)
5.Patients must have the adequate organ functions
- White Blood Cells (WBC) ≤ 150 x 10 exp9/L,
- Serum Creatinine ≤ 2 mg/dl, or Creatinine clearance ≥ 70 mL/min
- AST and/or ALT ≤ 2.5 x ULN (higher values due to hemolysis or disease infiltration of the liver are allowed)
- Normal serum potassium levels according to institutional limits
6..Patient’s age must be ≥ 18 years.
7.Patient’s ECOG performance status must be 0-2
8.Women of child bearing potential must have a negative serum pregnancy test 14 days prior to administration of the study drug. Men and women who are fertile and are of child bearing potential and their partner must use highly effective contraception (highly effective method of birth control is defined as those which result in low failure rate (<1% per year )when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IDUs, sexual abstinence, or vasectomized partner )

E.4

Principal exclusion criteria

1. Patient with de novo PLL.
2. Patient with secondary malignancy that will limit survival to less than 5 years.
3. Patient received prior alvocidib treatment.
4. Patient with prior allogenic or autologous bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT) less than 12 months. (Patients with chronic GVHD and/or currently receiving immunosuppresants must be excluded)
5. Patient receiving an investigational agent or an approved agent for an investigational purpose within last 4 weeks prior to study registration.
6. Patient receiving any anticancer agents (chemotherapy, immunotherapy, or targeted agents) within last 4 weeks prior to study registration. (Non-chemotherapeutic treatment for the progressive disease or side effects from the prior treatment is allowed at the discretion of the investigator)
7. Patient receiving chronic steroids (topical or inhaled steroid to treat concomitant conditions are allowed)
8. Patient with known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency of or history of hemolysis indicative of G6PD deficiency. (G6PD deficiency is a contraindication for rasburicase. Patient at high risk (e.g. African or Mediterranean ancestry) with no known history of G6PD deficiency may be screened prior to rasburicase administration at the discretion of the investigator)
9. Patient with autoimmune hemolytic anemia.
10. Patient who underwent any major surgery within last 30 days prior to study registration.
11. Patient with known CNS involvement.
12. Patient with uncontrolled or poorly controlled high blood pressure, unstable angina pectoris, symptomatic congestive heart failure (New York Heart Association Classification III or IV), severe cardiac arrhythmia or myocardial infarction within the last 6 months. In addition, any patient with a personal history of unexplained syncopal episodes or long QT syndrome, or known family history of unexplained syncopal episodes, long QT syndrome, or unexplained sudden death.
13. Patient with active, uncontrolled serious bacterial, viral or fungal infections.
14. Patient with intercurrent illness such as uncontrolled diabetes, uncontrolled seizure disorders requiring anti-convulsant therapy or severe chronic obstructive pulmonary disease.
15. Patient with active hepatitis or HIV positive and/or receiving anti-retroviral therapy.
16. Life expectancy of less than 3 months.
17. Patient not willing to sign informed consent form.
18. Patient who is pregnant or breast feeding.
19. QTc interval ≥450 milliseconds on the ECG performed at the screening visit

E.5 End points

E.5.1

Primary end point(s)

Overall objective response rate (CR + PR including nPR) will be assessed using “hybrid” criteria (CT scan for assessment of nodal disease in combination with NCI 96 criteria for assessment of liver and spleen, constitutional symptoms, peripheral blood +/- bone marrow.)

E.5.1.1

Timepoint(s) of evaluation of this end point

when all patients have completed at least 6 months of follow-up or died

E.5.2

Secondary end point(s)

• In addition, overall objective response rate, (CR + PR
including nPR) will also be assessed using NCI 96 criteria only
• Objective response duration will be assessed using NCI-96
criteria only
• Progression-free survival (PFS) will be assessed using NCI-
96 criteria only.
• Overall survival will be assessed
• Overall safety profile as determined by the incidence of
clinically significant adverse events (AE’s) including serious
adverse events (SAE’s) and laboratory abnormalities while on
treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

when all patients have completed at least 6 months of follow-up or died

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

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)

E.7.1.1

First administration to humans

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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

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

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

Each patient may receive a maximum of 6 cycles of the study drug (36 weeks). Post treatment follow up of the patients will
be continued for 6 months (3 to 6 month follow-up can be phone call only), so the total duration of the study participation for patient will be about 15 months.

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 months

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.1.2.1	Number of subjects for this age range:	102
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	63
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	Information not present in EudraCT
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	Information not present in EudraCT
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	20
F.4.2	For a multinational trial
F.4.2.1	In the EEA	65
F.4.2.2	In the whole clinical trial	165

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

2007-11-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-11-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-01-16

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