Ro Plus CHOEP as First Line Treatment Before HSCT in Young Patients With Nodal Peripheral T-cell Lymphomas

Study Overview
=================
Brief Summary
-----------------
This is a multicenter study that includes two phases: A phase I study to define the maximum tolerated dose (MTD) of Romidepsin in addition to CHOEP-21 and to test the safety and feasibility of CHOEP-21 in combination with dose escalation of Romidepsin (8, 10, 12, 14 mg). The dose level defined as MTD of Romidepsin will be used for the subsequent phase II study. A phase II study to evaluate the efficacy (response rate, progression free survival and overall survival) and safety of Ro-CHOEP-21 incorporated into a treatment strategy including SCT.

Detailed Description
-----------------
PHASE I A1) Induction phase Ro-CHOEP-21 x 3 cycles Romidepsin (dose escalation) starting dose: 12mg/ms iv day +1 and +8. Dose modification according to toxicity (14mg/ms day +1 and +8; 10mg/ms day +1 and +8; 8mg/ms day +1 and +8); CHOEP-21 (Doxorubicin 50 mg/ms iv day +1; Vincristin 1.4 mg/ms (maximum 2.0 mg total dose) iv day+1; Cyclophosphamide 750 mg/ms iv day +1; Etoposide 100mg/ms iv from day +1 to +3; Prednisone100 mg orally from days +1 to +5). According to the response achieved after the first 3 Ro-CHOEP-21 cycles: PR or CR: Ro-CHOEP-21 for 3 additional cycles followed by phase A2 SD or PD: Treatment failures, proceed to salvage according to each institutional policy. A2) Stem cell mobilization and transplantation phase Response evaluation and one DHAP course followed by peripheral stem cell harvesting. According to response achieved after 6 Ro-CHOEP-21 cycles: CR: BEAM or FEAM or CEAM followed by auto-SCT PR Allogeneic SCT with HLA-identical (A, B, C, DR, DQ loci) or one antigen mismatched (class I) sibling donors. Donor selection is based on molecular high-resolution typing (4 digits) of the HLA gene loci class I (HLA-A, B, and C) and class II (DRB1, DQB1). In case, no class I and class II completely identical urelated donor (10 out of 10 gene loci) can be identified, the degree of histocompatibility between patient and donor must fulfill with the minimal degree of matching established by the Italian Bone Marrow Donor Registry: HLA-A and HLA-B antigen histocompatibility and HLA-DRB1 allelic histocompatibility. when a suitable donor is not available: BEAM or FEAM or CEAM followed by Auto-SCT. Haploidentical transplantation is allowed in selected cases < PR: Treatment failures, proceed to salvage according to each institutional policy. PHASE II A1) Induction phase Ro-CHOEP-21 x 3 cycles Romidepsin dose according to phase I iv day +1 and +8 Doxorubicin 50 mg/ms iv day +1, Vincristin 1.4 mg/ms (maximum 2.0 mg total dose) iv day+1, Cyclophosphamide 750 mg/ms iv day +1, Etoposide 100mg/ms iv from day +1 to +3 Prednisone100 mg orally from days +1 to +5 According to the response achieved after the first 3 Ro-CHOEP-21 cycles: PR or CR: Ro-CHOEP-21 for 3 additional cycles followed by phase A2 SD or PD: Treatment failures, proceed to salvage according to each institutional policy. A2) Stem cell mobilization and transplantation phase Response evaluation and one DHAP course followed by peripheral stem cell harvesting. According to response achieved after 6 Ro-CHOEP-21 cycles: CR: BEAM or FEAM or CEAM followed by auto-SCT PR Allogeneic SCT with HLA-identical (A, B, C, DR, DQ loci) or one antigen mismatched (class I) sibling donors. Donor selection is based on molecular high-resolution typing (4 digits) of the HLA gene loci class I (HLA-A, B, and C) and class II (DRB1, DQB1). In case, no class I and class II completely identical urelated donor (10 out of 10 gene loci) can be identified, the degree of histocompatibility between patient and donor must fulfill with the minimal degree of matching established by the Italian Bone Marrow Donor Registry: HLA-A and HLA-B antigen histocompatibility and HLA-DRB1 allelic histocompatibility. when a suitable donor is not available: BEAM or FEAM or CEAM followed by Auto-SCT. Haploidentical transplantation is allowed in selected cases < PR: Treatment failures, proceed to salvage according to each institutional policy.

Official Title
-----------------
Romidepsin in Combination With CHOEP as First Line Treatment Before Hematopoietic Stem Cell Transplantation in Young Patients With Nodal Peripheral T-cell Lymphomas: a Phase I-II Study

Conditions
-----------------
Peripheral T-cell Lymphomas (PTCL), PTCL-NOS, Angioimmunoblastic T-cell Lymphoma (AITL), ALK- Anaplastic Large Cell Lymphoma (ALCL), Nodal Peripheral T-Cell Lymphoma of T Follicular Helper Cell Origin

Intervention / Treatment
-----------------
* Drug: Ro-CHOEP-21 (PHASE I)
* Drug: Ro-CHOEP-21 (PHASE II)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 e ≤ 65 years Peripheral T-cell lymphomas at diagnosis including: PTCL-NOS, AITL including other nodal TFH, ALK-ALCL Stage II-IV Written informed consent No prior treatment for lymphoma No Central Nervous System (CNS) disease (meningeal and/or brain involvement by lymphoma) HIV negativity Absence of active hepatitis C virus (HCV) infection HBV negativity or patients with HBcAb +, HBsAg -, HBs Ab+/- with HBV-DNA negativity (in these patients Lamivudine prophylaxis is mandatory) Levels of serum bilirubin, alkaline phosphatase and transaminases < 2 the upper normal limit, if not disease related No psychiatric illness that precludes understanding concepts of the trial or signing informed consent Ejection fraction > 50% and myocardial stroke in the last year nor QT prolongation (QTc interval < 480 msec using the Fridericia formula) Clearance of creatinine > 60 ml/min if not disease related Spirometry Diffusion Capacity (DLCO) > 50% Absence of active, uncontrolled infection For males and females of child-bearing potential, agreement upon the use of effective contraceptive methods prior to study entry, for the duration of study participation and in the following 90 days after discontinuation of study treatment Availability of histological material for central review and pathobiological studies. Exclusion Criteria: Age <18 e > 65 years Hystology other than: PTCL-NOS, AITL, ALK-ALCL Stage I Prior treatment for lymphoma Positive serologic markers for human immunodeficiency virus (HIV) Active hepatitis B virus (HBV) infection Active hepatitis C virus (HCV) infection Levels of serum bilirubin, alkaline phosphatase and transaminases > 2 the upper normal limit, if not disease related Ejection fraction < 50% and no myocardial stroke in the last year or QT prolongation (QTc interval > 480 msec using the Fridericia formula) Clearance of creatinine < 60 ml/min if not disease related Spirometry Diffusion Capacity (DLCO) < 50% Pregnancy or lactation Patient not agreeing to take adequate contraceptive measures during the study Psychiatric disease that precludes understanding concepts of the trial or signing informed consent Any active, uncontrolled infection Prior history of malignancies other than PTCLs in the last five years (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 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: Ro-CHOEP-21<br>During the Phase I It will administered Romidepsin (dose escalation) and the combination of CHOEP-21. During the Phase II It will administered Romidepsin (dose according to phase I) and the combination of CHOEP-21. | Drug: Ro-CHOEP-21 (PHASE I)<br>* Romidepsin (dose escalation) Starting dose: 12mg/ms iv day +1 and +8 Dose modification according to toxicity: 14mg/ms day +1 and +8 10mg/ms day +1 and +8 8mg/ms day +1 and +8 CHOEP-21 Doxorubicin 50 mg/ms iv day +1 or +2, Vincristin 1.4 mg/ms (maximum 2.0 mg total dose) iv day+1 or +2 Cyclophosphamide 750 mg/ms iv day +1 or +2 Etoposide 100mg/ms iv from day +1 to +3 or from day +2 to +4 Prednisone100 mg orally from days +1 to +5 or from days +2 to +6 PR or CR:Ro-CHOEP-21 for 3 additional cycles followed by stem cell mobilization and transplantation phase (CR --> AUTO-SCT, PR --> ALLO-SCT)<br>* Other names: Prednisone;Drug: Ro-CHOEP-21 (PHASE II)<br>* Ro-CHOEP-21 x 3 cycles Romidepsin dose according to phase I iv day +1 and +8 Doxorubicin 50 mg/ms iv day +1 or +2, Vincristin 1.4 mg/ms (maximum 2.0 mg total dose) iv day+1 or +2, Cyclophosphamide 750 mg/ms iv day +1 or +2 Etoposide 100mg/ms iv from day +1 to +3 or from day +2 to +4 Prednisone100 mg orally from days +1 to +5 or from days +2 to +6 PR or CR: Ro-CHOEP-21 for 3 additional cycles followed by stem cell mobilization and transplantation phase (CR --> AUTO-SCT, PR --> ALLO-SCT)<br>* Other names: Prednisone;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) of Ro-CHOEP-21 (Phase I endpoint) | Incidence of dose-limiting toxicity (DLT) of Ro-CHOEP-21, considering as maximum dose the one causing induction of any grade ≥ 3 non hematologic toxicity or a delay >15 days of planned cycle date observed during the first two cycles according to the definitions of NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (2009) | 3 months | 
| Progression Free Survival (PFS) of Ro-CHOEP-21 (Phase II endpoint) | PFS on intention to treatment (ITT) evaluated at 18 months. PFS will be defined as the time between the date of enrolment and the date of disease progression, relapse or death from any cause. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients reaching SCT (Phase I endpoint) | Proportion of patients reaching SCT | 6 months | 
| ORR = Overall response rate (Phase I endpoint) | Overall response rate (ORR, defined according to the Cheson 2007 response criteria) of the combination of Ro-CHOEP-21. | 6 months | 
| Overall Response Rate (ORR) and Complete Response (CR)(Phase II endpoint) | ORR and CR (defined according to the Cheson 2007 response criteria), after induction treatment and after SCT. | 6 months | 
| Event free survival (EFS) (Phase II endpoint) | Event free survival (EFS) defined as the time between the date of enrollment and the date of discontinuation of treatment for any reason | 18 months | 
| Overall survival (OS) (Phase II endpoint) | Overall survival (OS) defined as the time between the date of enrolment and the date of death from any cause in the ITT population enrolled in the study | 24 months | 
| Progression Free Survival (PFS) and Overall Survival (OS) (Phase II endpoint) | PFS and OS in patients not responding to the first 3 courses of Ro-CHOEP-21 | 3 months | 
| Toxicities (Phase II endpoint) | Evaluation during the interim analyses of any grade III or higher toxicities, recorded and classified according to the definitions of NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (2009) | 18 months | 
| Higher toxicities (Phase II endpoint) | Evaluation during all the pretransplant phase of any grade III or higher toxicities, recorded and classified according to the definitions of NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (2009) | 18 months | 
| Treatment-related mortality (TRM) (Phase II Endpoint) | Treatment-related mortality defined as any death that was not attributable to the lymphoma. | 24 months | 
| Graft-versus-host disease (GVHD) (Phase II endpoint) | Incidence of acute and chronic GVHD in allografted patients | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PTCL, PTCL-NOS, AITL, ALCL