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

Study Overview
=================
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:

Official Title
-----------------
Prephase Treatment With Prednisone +/- Vitamin D Supplementation Followed by Immunochemotherapy in Elderly Patients With Diffuse Large B-Cell Lymphoma (DLBCL) A Randomized, Open Label, Phase III Study by Fondazione Italiana Linfomi.

Conditions
-----------------
Diffuse Large B-Cell Lymphoma, Elderly Patients

Intervention / Treatment
-----------------
* Drug: Vitamin D3 (Cholecalciferol)
* Drug: RCHOP o R-miniCHOP at standard doses


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria Histologically documented diagnosis of Diffuse Large B-cell Lymphoma or Follicular grade IIIb lymphoma, as defined in the 2017 edition of the World Health Organization (WHO) classification. Age ≥ 65 years Comprehensive Geriatric Assessment performed at baseline, before start of any treatment. Eastern Cooperative Oncology Group performance status (PS) ≤3 Eligibility for anthracycline containing regimen (R-CHOP or R-miniCHOP) No previous treatment for DLBCL or Follicular grade IIIb lymphoma Ann Arbor stage I-IV At least one site of measurable nodal disease at baseline ≥ 1.5 cm in the longest transverse diameter as determined by CT scan ; or one metabolic active site of disease at baseline FDG-PET scan Serum basic levels of Vitamin D [25 (OH) VitD] ≤ 40 ng / ml; Adequate hematological counts defined as follows: Absolute Neutrophil count > 1.5 x 109/L unless due to bone marrow involvement by lymphoma Platelet count ≥ 80.000/mm3 unless due to bone marrow involvement by lymphoma Adequate renal function defined as follows: - Creatinine ≤ 2 mg/dL, unless secondary to lymphoma Adequate hepatic function defined as follows: - Bilirubin ≤ 2 mg/dL unless secondary to lymphoma LVEF > 50% at bidimensionally echocardiogram Life expectancy ≥ 6 months Subject understands and voluntarily signs an informed consent form approved by an Independent Ethics Committee , prior to the initiation of any screening or study-specific procedures Subject must be able to adhere to the study visit schedule and other protocol requirements Men must agree to use one of the below reported acceptable method of contraception for the duration of the study and for 3 months after receiving the last dose of immunochemotherapy, and to not donate sperm while on study. Exclusion criteria Histological diagnosis different from Diffuse large B-Cell Lymphoma or Follicular grade IIIb lymphoma, including diagnosis of HGBL, with rearrangement of MYC, BCL2 and/or BCL6 (double-hit) Use of VitD supplementation as standard of care at dose higher than 10,000 U/week Suspect or clinical evidence of CNS involvement by lymphoma Contraindication to the use of rituximab Contraindication to the use of VitD supplementation (Hypercalcemia/Hyperphosphatemia) Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy, including targeted small molecule agents within 14 days prior to the first dose of study drug Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent Any history of other active malignancies within 2 years prior to study entry, with the exception of adequately treated in situ carcinoma of the cervix uterine, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin or limited stage surgically removed breast cancer or adequately treated with radiation therapy or limited stage prostate carcinoma surgically removed or adequately treated with radiation therapy or previous malignancy confined and surgically resected with curative intent Evidence of other clinically significant uncontrolled condition including, but not limited to: Uncontrolled and/or active systemic infection (viral, bacterial or fungal) Chronic hepatitis B virus or hepatitis C requiring treatment.

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm B (Experimental):<br>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. | Drug: Vitamin D3 (Cholecalciferol)<br>* 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 (CGA) result, but treatment at reduced doses with R-miniCHOP is highly recommended option for UNFIT and FRAIL patients.<br>Drug: RCHOP o R-miniCHOP at standard doses<br>* Patients on both arms receive pre-treatment with prednisone oral before 6 cycles of 21 days each of immunochemotherapy with RCHOP o R-miniCHOP at standard doses<br>|
| Other: Arm A (Standard arm)<br>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 | Drug: RCHOP o R-miniCHOP at standard doses<br>* Patients on both arms receive pre-treatment with prednisone oral before 6 cycles of 21 days each of immunochemotherapy with RCHOP o R-miniCHOP at standard doses<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | Progression-Free Survival | at the end of treatment - 54 months | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vitamin D, prednisone +/- Vitamin D supplementation, randomized, open label, phase III