Prephase Treatment With Prednisone +/- Vitamin D Supplementation Followed by Immunochemotherapy

Phase 3

Recruiting

• Conditions: Diffuse Large B-Cell Lymphoma; Elderly Patients
• Interventions: Drug: Vitamin D3 (Cholecalciferol); Drug: RCHOP o R-miniCHOP at standard doses

• Registration Number: NCT04442412
• Lead Sponsor: Fondazione Italiana Linfomi - ETS

Brief Summary

This is an open-label, multicenter, randomized phase III trial. The study plans to randomize patients with a 1 to 1 ratio to Arm A (Standard arm) or Arm B (Experimental arm).

All patients of both arms will receive a prephase with oral prednisone before 6 cycles Q21 of immunochemotherapy with R-CHOP or R-miniCHOP at standard doses; patients in the Experimental arm (Arm B) will receive also a prephase therapy with VitD and a supplementation of VitD during the intere period of immunochemotherapy according to a prefixed schedule. Choice of type of immunochemotherapy will not rely on Comprehensive Geriatric Assessment result, but treatment at reduced doses with R-miniCHOP is highly recommended option for UNFIT and FRAIL patients.

Detailed Description

After the patient signs the written informed consent the patient will enter the screening phase planning baseline assessments and will be randomly allocated with a 1 to 1 ratio to Arm A (Standard arm) or Arm B (Experimental arm).

Patients randomized to Arm A will receive a prephase with oral prednisone (50 mg for 7 days \[day -6 to day 0\]) followed by 6 courses of R-CHOP or R-miniCHOP every 21 days.

If patients randomized to arm A are already on VitD, they are allowed to continue receiving VitD supplementation at a dose that can be considered part of the standard of care and does not exceed the maximum standard VitD dose recommended for general adult and elderly population , up to 10,000 U/week VitD .

If clinically indicated at treating physician judgement, patients could receive 1 mg of vincristine on the first day of prephase ; in this case vincristine administration in cycle 1 of immunochemotherapy should be skipped, in patients receiving R-miniCHOP; reduced to 1 mg, in patients receiving R-CHOP.

Patients randomized to Arm B will receive a prephase with oral prednisone and a prephase therapy with VitD according to the below reported schedule followed by 6 courses of R-CHOP or R-miniCHOP every 21 days.

Schedule for VitD (Cholecalciferol) supplementation: 25,000 U/day starting on day -6:

daily loading dose for 7 days if 25 VitD baseline level 20-40 ng/ml daily loading dose for 14 days if 25 VitD baseline level \< 20 ng/ml followed by weekly maintenance supplementation of 25,000 U for the entire duration of immunochemotherapy (6 courses every 21 days - 18 weeks), regardless of the baseline level of 25 VitD.

If clinically indicated at treating physician judgement, patients could receive 1 mg of vincristine on the first day of prephase (DAY -6); in this case vincristine administration in cycle 1 of immunochemotherapy should be: skipped, in patients receiving R-miniCHOP; reduced to 1 mg, in patients receiving R-CHOP.

Patients with 25(OH)VitD levels \<30 ng/ml on d1 cycle 2 will receive and additional loading phase of Cholecalciferol 25,000 U/day for 7 days and then 25,000 U once weekly for the duration of immunochemotherapy.

Patients may continue with VitD supplementation after the end of the immunochemotherapy at a (reduced) standard dose of 25,000 U once a month for up to 2 years from end of immunochemotherapy.

Patients experimenting toxicity leading to a delay in treatment administration \> 4 weeks will discontinue study treatment and will be addressed to a salvage treatment: these patients will be followed-up for survival until the end of the study.

Consolidation radiotherapy:

Study Timeline

• Study First Submitted: 2020-05-26
• Study First Submitted QC: 2020-06-19
• Study First Posted: 2020-06-22
• Study Start: 2021-03-23
• Status Verified: 2022-08
• Last Update Submitted: 2022-08-23
• Last Update Posted: 2022-08-26
• Primary Completion: 2025-09-01
• Study Completion: 2030-09-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 430

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B (Experimental):	Vitamin D3 (Cholecalciferol)	Patients randomized to Arm B will receive a prephase with oral prednisone and a prephase therapy with VitD according to the below reported schedule followed by 6 courses of R-CHOP or R-miniCHOP every 21 days. Schedule for VitD supplementation: 25,000 U/day starting on day -6: daily loading dose for 7 days if 25 VitD baseline level 20-40 ng/ml daily loading dose for 14 days if 25 VitD baseline level \< 20 ng/ml followed by weekly maintenance supplementation of 25,000 U for the entire duration of immunochemotherapy (6 courses every 21 days - 18 weeks), regardless of the baseline level of 25 VitD.
Arm B (Experimental):	RCHOP o R-miniCHOP at standard doses	Patients randomized to Arm B will receive a prephase with oral prednisone and a prephase therapy with VitD according to the below reported schedule followed by 6 courses of R-CHOP or R-miniCHOP every 21 days. Schedule for VitD supplementation: 25,000 U/day starting on day -6: daily loading dose for 7 days if 25 VitD baseline level 20-40 ng/ml daily loading dose for 14 days if 25 VitD baseline level \< 20 ng/ml followed by weekly maintenance supplementation of 25,000 U for the entire duration of immunochemotherapy (6 courses every 21 days - 18 weeks), regardless of the baseline level of 25 VitD.
Arm A (Standard arm)	RCHOP o R-miniCHOP at standard doses	Patients randomized to Arm A will receive a prephase with oral prednisone followed by 6 courses of R-CHOP or R-miniCHOP every 21 days. If patients randomized to arm A are already on VitD, they are allowed to continue receiving VitD supplementation at a dose that can be considered part of the standard of care and does not exceed the maximum standard VitD dose recommended for general adult and elderly population , up to 10,000 U/week VitD

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival	at the end of treatment - 54 months	Progression-Free Survival

Secondary Outcome Measures

Name	Time	Method
Event Free Survival	at the end of treatment - 54 months	Event Free Survival (EFS)
Early death rate	at the end of treatment - 54 months	Early death rate
Rate of ECOG changes after prephase	at the end of treatment - 54 months	Rate of ECOG changes after prephase
Rate of patients who maintain 25(OH)VitD levels	At the beginning of Cycle 2 (each cycle is 21 days)	Rate of patients who maintain 25(OH)VitD levels
Rate of 25(OH)VitD correction (VitD supplementation arm)	At the beginning of Cycle 2 (each cycle is 21 days)	Rate of 25(OH)VitD correction (VitD supplementation arm)
time-to-deterioration physical functioning and fatigue	At the beginning of Cycle 2 (each cycle is 21 days)	time-to-deterioration physical functioning and fatigue
Overall Survival	at the end of treatment - 54 months	Overall Survival
Response rate	at the end of treatment - 54 months	Response rate

Trial Locations

Locations (49)

SC Ematologia Spedali Civili; 🇮🇹 Brescia, BS, Italy

UO Ematologia e CTMO di Piacenza; 🇮🇹 Piacenza, PC, Italy

Ospedale Oncologico regionale CROB; 🇮🇹 Rionero in Vulture, Piacenza, Italy

A.O. SS. Antonio e Biagio e Cesare Arrigo - S.C. Ematologia; 🇮🇹 Alessandria, Italy

A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona; 🇮🇹 Ancona, Italy

Ascoli Piceno - Ospedale C.e G. Mazzoni - U.O.C. di Ematologia; 🇮🇹 Ascoli Piceno, Italy

Aviano - Centro Riferimento Oncologico - S.O.C. Oncologia Medica A; 🇮🇹 Aviano, Italy

Barletta - Ospedale "Monsignor Raffaele Dimiccoli" - Ematologia; 🇮🇹 Barletta, Italy

Bergamo - Cliniche Humanitas Gavazzeni - Oncologia - Cliniche Humanitas Gavazzeni; 🇮🇹 Bergamo, Italy

Biella - Ospedale Degli Infermi - S.C. Oncologia; 🇮🇹 Biella, Italy

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