STORM: Temsirolimus, Rituximab and DHAP for Relapsed and Refractory Diffuse Large B-cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
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. 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 primary objective is to evaluate the ORR in patients with relapsed diffuse large B cell lymphoma (DLBCL). The secondary objective is to evaluate progression free survival (PFS), overall survival (OS) and Toxicity.

Detailed Description
-----------------
This is a multicenter, open label, single arm, phase II study. There will be no placebo usage within this trial. In the part I, dose escalation part, of this trial 6 patients will be included in each dose level. There will be 4 cohorts, administering up to a maximum of 4 cycles 25 mg, 50 mg, 75mg or 100mg Temsirolimus in combination with Rituximab and DHAP. Treatment regimen part I: Part I - Cohort A, B, C, D, X Temsirolimus 25 (A), 50 (B), 75 (C),100 (D) or 15 (X) mg, Day 1, 8, Rituximab (375 mg/m² day 2) Dexamethasone 40mg day 3-6 Cisplatine 100 mg/m² day 3 Cytarabine 2x2 g/m² day 4 ...repeat day 22, up to a maximum of 4 cycles In part I, after inclusion of 6 patients, each patient has to receive at least 1 complete cycle w/o dose limiting toxicity until the enrollment into the next cohort can be initiated. In the part II of the trial 40 patients will be included to receive the full target dose, established within the part I of the study.

Official Title
-----------------
A Phase II Trial to Evaluate the Safety, Feasibility and Efficacy of a Salvage Therapy Consisting of Temsirolimus Added to the Standard Therapy R-DHAP for the Treatment of Patients With Relapsed or Refractory DLBCL - the STORM Trial

Conditions
-----------------
Diffuse Large B-Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: Rituximab, Temsirolimus, DHAP, intravenous


Participation Criteria
=================
Eligibility Criteria
-----------------
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 Alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN); Aspartate aminotransferase (AST) < 2.5 x ULN, Total bilirubin < 1.5 x ULN Calculated creatinine clearance (MDRD) > 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 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 Sirolimus or derivates, Cytarabine, Cisplatine or Rituximab.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab, Temsirolimus, DHAP, intravenous<br>This is a multicenter, open label, single arm, phase II study. There will be no placebo usage within this trial. In the part I, dose escalation part, of this trial 6 patients will be included in each dose level. There will be 4 cohorts, administering up to a maximum of 4 cycles 25 mg, 50 mg, 75mg or 100mg Temsirolimus in combination with Rituximab and DHAP. Treatment regimen part I: Part I - Cohort A, B, C, D, X Temsirolimus 25 (A), 50 (B), 75 (C),100 (D) or 15 (X) mg, Day 1, 8, Rituximab (375 mg/m² day 2) Dexamethasone 40mg day 3-6 Cisplatine 100 mg/m² day 3 Cytarabine 2x2 g/m² day 4 ...repeat day 22, up to a maximum of 4 cycles In the part II of the trial 40 patients will be included to receive the full target dose, established within the part I of the study. | Drug: Rituximab, Temsirolimus, DHAP, intravenous<br>* Maximum tolerated dose of Temsirolimus Rituximab (375 mg/m²) Dexamethasone (120 mg) Cisplatin (100mg/m²) Cytarabine (2x2g/m²))<br>* Other names: Temsirolimus-Rituximab-DHAP;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, Tolerability and Efficacy of a combination therapy of Temsirolimus added to the standard therapy, Rituximab and DHAP (Cytarabine, Cisplatine, Dexamethasone) | 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. | 09-2012 to 06-2018 (up to six years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, Tolerability and Efficacy of a combination therapy of Temsirolimus added to the standard therapy, Rituximab and DHAP (Cytarabine, Cisplatine, Dexamethasone) | In the part I (dose escalation of Temsirolimus) secondary objective is to prove ability to mobilize stem cells in patients scheduled to high dose therapy. | 09-2012 to 06-2018 (up to six years) | 
| Safety, Tolerability and Efficacy of a combination therapy of Temsirolimus added to the standard therapy, Rituximab and DHAP (Cytarabine, Cisplatine, Dexamethasone) | In the part II (full target dose) the secondary objective is to evaluate Progression Free Survival | 09-2012 to 06-2018 (up to six years) | 
| Safety, Tolerability and Efficacy of a combination therapy of Temsirolimus added to the standard therapy, Rituximab and DHAP (Cytarabine, Cisplatine, Dexamethasone) | In the part II (full target dose) the secondary objective is to evaluate Overall Survival | 09-2012 to 06-2018 (up to six years) | 
| Safety, Tolerability and Efficacy of a combination therapy of Temsirolimus added to the standard therapy, Rituximab and DHAP (Cytarabine, Cisplatine, Dexamethasone) | In the part II (full target dose) the secondary objective is to evaluate Toxicity | 09-2012 to 06-2018 (up to six years) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
aggressive NHL, Non Hodgkin´s Lymphoma, Diffuse Large B-Cell Lymphoma, Aggressive Lymphoma, Aggressive Non Hodgkin´s Lymphoma, NHL, aNHL, Temsirolimus, Torisel, Relapsed Non Hodgkin´s Lymphoma, Relapsed Diffuse Large B-Cell Lymphoma, B-NHL, aggressive B-NHL