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

Peripheral T-cell Lymphomas (PTCL) Clinical Trial

— FIL_PTCL13  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02223208
• Other study ID #: FIL_PTCL13
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: September 2014
• Est. completion date: October 2026

Study information

• Verified date: June 2024
• Source: Fondazione Italiana Linfomi - ETS
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter study that includes two phases:

1. 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.

2. 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 89
• Est. completion date: October 2026
• Est. primary completion date: October 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Age =18 e = 65 years

2. Peripheral T-cell lymphomas at diagnosis including: PTCL-NOS, AITL including other nodal TFH, ALK-ALCL

3. Stage II-IV

4. Written informed consent

5. No prior treatment for lymphoma

6. No Central Nervous System (CNS) disease (meningeal and/or brain involvement by lymphoma)

7. HIV negativity

8. Absence of active hepatitis C virus (HCV) infection

9. HBV negativity or patients with HBcAb +, HBsAg -, HBs Ab+/- with HBV-DNA negativity (in these patients Lamivudine prophylaxis is mandatory)

10. Levels of serum bilirubin, alkaline phosphatase and transaminases < 2 the upper normal limit, if not disease related

11. No psychiatric illness that precludes understanding concepts of the trial or signing informed consent

12. Ejection fraction > 50% and myocardial stroke in the last year nor QT prolongation (QTc interval < 480 msec using the Fridericia formula)

13. Clearance of creatinine > 60 ml/min if not disease related

14. Spirometry Diffusion Capacity (DLCO) > 50%

15. Absence of active, uncontrolled infection

16. 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

17. Availability of histological material for central review and pathobiological studies.

Exclusion Criteria:

1. Age <18 e > 65 years

2. Hystology other than: PTCL-NOS, AITL, ALK-ALCL

3. Stage I

4. Prior treatment for lymphoma

5. Positive serologic markers for human immunodeficiency virus (HIV)

6. Active hepatitis B virus (HBV) infection

7. Active hepatitis C virus (HCV) infection

8. Levels of serum bilirubin, alkaline phosphatase and transaminases > 2 the upper normal limit, if not disease related

9. Ejection fraction < 50% and no myocardial stroke in the last year or QT prolongation (QTc interval > 480 msec using the Fridericia formula)

10. Clearance of creatinine < 60 ml/min if not disease related

11. Spirometry Diffusion Capacity (DLCO) < 50%

12. Pregnancy or lactation

13. Patient not agreeing to take adequate contraceptive measures during the study

14. Psychiatric disease that precludes understanding concepts of the trial or signing informed consent

15. Any active, uncontrolled infection

16. 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).

Related Conditions & MeSH terms

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

Intervention

Drug:
• Ro-CHOEP-21 (PHASE I)
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)
• Ro-CHOEP-21 (PHASE II)
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)

Locations

Country	Name	City	State
Italy	Ospedale SS. Antonio e Biagio e Cesare Arrigo	Alessandria	AL
Italy	IRCCS Centro di Riferimento Oncologico (CRO)	Aviano	PN
Italy	Policlinico S. Orsola Malpighi	Bologna	BO
Italy	Spedali Civili	Brescia	BS
Italy	Ospedale Businco	Cagliari	CA
Italy	Azienda Ospedaliera S.Croce e Carle	Cuneo	CN
Italy	IRCCS AOU San Martino - Clinica Ematologica	Genova	GE
Italy	IRCCS AOU San Martino - UO Ematologia 1	Genova	GE
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) - Sede di Meldola	Meldola	FC
Italy	Azienda Ospedaliera Ospedale Niguarda Ca' Granda	Milano	MI
Italy	Fondazione IRCCS "Istituto Nazionale dei Tumori"	Milano	MI
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano	MI
Italy	Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale	Napoli
Italy	Ospedale Maggiore della Carità - SCDU Ematologia	Novara
Italy	AO Ospedali Riuniti Villa Sofia - Cervello (Presidio Cervello)	Palermo	PA
Italy	AOU di Parma	Parma	PR
Italy	Fondazione IRCCS - Policlinico San Matteo	Pavia	PV
Italy	A.O. di Perugia - Santa Maria della Misericordia	Perugia
Italy	Ospedale G. Da Saliceto - AUSL di Piacenza	Piacenza
Italy	UO Ematologia Ospedale S.Maria delle Croci	Ravenna
Italy	IRCCS Arcispedale "Santa Maria Nuova"	Reggio Emilia	RE
Italy	Ospedale degli Infermi	Rimini	RN
Italy	Istituto Clinico Humanitas	Rozzano	Milano
Italy	AO Città della Salute e della Scienza - Ematologia 1U	Torino	TO
Italy	AO Città della Salute e della Scienza - SC Ematologia	Torino	TO
Italy	AOU "Santa Maria della Misericordia"	Udine	UD
Italy	Ospedale Borgo Roma	Verona	VR

Sponsors (1)

Lead Sponsor	Collaborator
Fondazione Italiana Linfomi - ETS

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Evaluation of response biomarkers (eg TET2 mutations)	Evaluation of response biomarkers (eg TET2 mutations)	8 years
Primary	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
Primary	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	Proportion of patients reaching SCT (Phase I endpoint)	Proportion of patients reaching SCT	6 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Treatment-related mortality (TRM) (Phase II Endpoint)	Treatment-related mortality defined as any death that was not attributable to the lymphoma.	24 months
Secondary	Graft-versus-host disease (GVHD) (Phase II endpoint)	Incidence of acute and chronic GVHD in allografted patients	24 months