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 |
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E.1.1.1 | Medical condition in easily understood language |
Diffuse large B-cell lymphoma |
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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 |
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E.1.3 | Condition being studied is a rare disease | No |
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. |
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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. |
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E.2.3 | Trial contains a sub-study | No |
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) |
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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). |
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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. |
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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. |
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E.5.2 | Secondary end point(s) |
Part I: Stem cell mobilization
Part II: PFS, OS and Toxicity |
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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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |