Clinical Trials Register

Summary
EudraCT Number:	2011-001491-20
Sponsor's Protocol Code Number:	STORM-2011
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:	2012-07-05
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

2011-001491-20

A.3

Full title of the trial

A phase II trial to evaluate the safety, feasibility and efficacy of a salvage therapy consisting of the mTOR inhibitor Temsirolimus (Torisel™) added to the standard therapy of Rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma – the STORM trial

A.3.1

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

Temsirolimus, Rituximab and DHAP for relapsed and refractory diffuse large B-cell lymphoma

A.3.2

Name or abbreviated title of the trial where available

STORM

A.4.1

Sponsor's protocol code number

STORM-2011

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	Ruprecht-Karls University Heidelberg, Medical Faculty
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	Pfizer
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ruprecht-Karls University Heidelberg, Medical Faculty
B.5.2	Functional name of contact point	Julia Meißner
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 410
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	D-69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	00496221568001
B.5.5	Fax number	00496221565813
B.5.6	E-mail	julia.meissner@med.uni-heidelberg.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	Torisel® 30 mg Konzentrat und Verdünnungsmittel zur Herstellung einer Infusionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ
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	Torisel®
D.3.4	Pharmaceutical form	Concentrate and solvent 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	TEMSIROLIMUS
D.3.9.1	CAS number	162635-04-3
D.3.9.4	EV Substance Code	SUB21308
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	30
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.IMP: 2
D.1.2 and D.1.3	IMP Role
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.2.1.2	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
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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)	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

Diffuse large B-cell lymphoma with documented relapse or progression following at least one but a maximum of two prior treatments, aged older than 18 years

E.1.1.1

Medical condition in easily understood language

Diffuse large B-cell lymphoma

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	HLT
E.1.2	Classification code	10012819
E.1.2	Term	Diffuse large B-cell lymphomas
E.1.2	System Organ Class	100000004943

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 STORM-trial consists of two parts.

In the part I (dose escalation of Temsirolimus) the primary objective is to establish a maximum tolerated dose of Temsirolimus in combination with Rituximab and DHAP.

In the part II (full target dose) the primary objective is to evaluate the ORR in patients with relapsed DLBCL.

E.2.2

Secondary objectives of the trial

The STORM-trial consists of two parts.

In the part I (dose escalation of Temsirolimus) the secondary objective is to prove ability to mobilize stem cells in patients scheduled to high dose therapy.

In the part II (full target dose) the secondary objective is to evaluate PFS, OS and Toxicity.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

· Patients with histologically proven diagnosis of diffuse large cell B-cell lymphoma (DLBCL) according to the World Health Organization classification
· Documented relapse or progression following at least one treatment but a maximum of 2 prior treatments. Prior treatment must have included at least 3 cycles of anthracycline containing chemotherapy (e.g. CHOP-like).
· Any of the following: at least 1 measurable tumor mass (>1.5 cm x >1.0 cm), involvement of any organ or bone marrow infiltration
· Subjects 18 years or older
· Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study
· Adequate bone marrow reserve: Platelets of at least 75000/μl, absolute neutrophil count at least 1500/μl, Hemoglobin of at least 10g/dl
· Alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN); Aspartate aminotransferase (AST) < 2.5 x ULN
· Total bilirubin < 1.5 x ULN except chronic hepatic conditions leading to bilirubin increase but not interfering therapy, e. g. Gilbert´s Syndrom
· Calculated creatinine clearance (according to CKD-EPI, if possible) > 70 mL/min
· Eastern Cooperative Oncology Group [ECOG] performance Status < 3
· Female subject must be postmenopausal (for at least 6 months), surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner
sterilization) before entry and throughout the study; and have a negative serum ß-hCG pregnancy test at screening
· Male subject, if sexual active and with a sexual partner of childbearing age must be practicing an effective method of contraception throughout the study (e.g. surgical sterilization or double-barrier method. Prescription oral contraceptives,
contraceptive injections, intrauterine device, surgically sterilization or contraceptive patch in female sexual partners)

E.4

Principal exclusion criteria

· Active central nervous System lymphoma. Brain MRI is required only if clinically indicated
· Pregnancy or breast feeding women
· Lymphoma other than DLBCL
· Severe concomitant disease (e.g. uncontrolled arterial hypertension, heart failure (NYHA III-IV), uncontrolled diabetes mellitus, pulmonary fibrosis, uncontrolled hyperlipoproteinemia)
· Active uncontrolled infections including HIV-positivity, active Hep B or C
· Mental status precluding patient’s compliance
· Prior treatment with Temsirolimus
· Known CD20 negativity
· Patients refractory to DHAP in a prior treatment line
· Prior autologous or allogeneic stem cell or bone marrow transplantation
· Peripheral neuropathy or neuropathic pain of Grade 2 or worse
· Diagnosed or treated for a malignancy other than NHL except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, DCIS of the breast, or other solid tumors curatively treated with no evidence of disease for >5 years
· Concurrent treatment with another investigational agent during the conduct of the trial. Concurrent participation in non-treatment studies is not excluded.
· Known intolerance to Dexamethasone, Sirolimus or derivates, Cytarabine, Cisplatine or Rituximab.
Known intolerance to any other ingredients contained in the trial therapy. Known intolerance to pre-treatment or premedication in this trial (e.g. Prednisolone, Allopurinol, H1-Blocker, Paracetamole).

E.5 End points

E.5.1

Primary end point(s)

Part I (dose escalation of Temsirolimus): establish a maximum tolerated dose of Temsirolimus in combination with Rituximab and DHAP.

part II (full target dose): ORR in patients with relapsed DLBCL.

E.5.1.1

Timepoint(s) of evaluation of this end point

Part I: 4 cohorts, 6 patients will be included in each dose level, administering up to a maximum of 4 cycles 25 mg, 50 mg, 75mg or 100mg Temsirolimus in combination with Rituximab and DHAP.

Part II: Active treatment with Temsirolimus in combination with R-DHAP for 2 to 4 cycles will last approximately to a maximum of 12 weeks. Patients will be followed for disease progression and or death and initiation of subsequent therapy for DLBCL for at least 2 years (if no event occurs) up to a maximum of 5 years.

E.5.2

Secondary end point(s)

Part I: Stem cell mobilization

Part II: PFS, OS and Toxicity

E.5.2.1

Timepoint(s) of evaluation of this end point

Part I: Stem cell mobilization is recommended after the second treatment cycle with G-CSF starting on day 5.

Part II: Active treatment with Temsirolimus in combination with R-DHAP for 2 to 4 cycles will last approximately to a maximum of 12 weeks. Patients will be followed for disease progression and or death and initiation of subsequent therapy for DLBCL for at least 2 years (if no event occurs) up to a maximum of 5 years.

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)

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.8.2.4

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

see protocol chapter 13

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

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.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)

see protocol chapter 13

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

2012-10-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-11-01

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