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

Diffuse Large B-Cell Lymphoma Clinical Trial

— FIL_PREVID  

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04442412
• Other study ID #: FIL_PREVID
• Status: Recruiting
• Phase: Phase 3
• Start date: March 23, 2021
• Est. completion date: September 1, 2030

Study information

• Verified date: August 2022
• Source: Fondazione Italiana Linfomi ONLUS
• Contact: Lorenza Randi, Dott.ssa
• Phone: 0000000000
• Email: lrandi[@]filinf.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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:

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 430
• Est. completion date: September 1, 2030
• Est. primary completion date: September 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

Inclusion criteria

1. 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.

2. Age = 65 years

3. Comprehensive Geriatric Assessment performed at baseline, before start of any treatment.

4. Eastern Cooperative Oncology Group performance status (PS) =3

5. Eligibility for anthracycline containing regimen (R-CHOP or R-miniCHOP)

6. No previous treatment for DLBCL or Follicular grade IIIb lymphoma

7. Ann Arbor stage I-IV

8. 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

9. Serum basic levels of Vitamin D [25 (OH) VitD] = 40 ng / ml;

10. 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

11. Adequate renal function defined as follows:

• Creatinine = 2 mg/dL, unless secondary to lymphoma

12. Adequate hepatic function defined as follows:

• Bilirubin = 2 mg/dL unless secondary to lymphoma

13. LVEF > 50% at bidimensionally echocardiogram

14. Life expectancy = 6 months

15. 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

16. Subject must be able to adhere to the study visit schedule and other protocol requirements

17. 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

1. 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)

2. Use of VitD supplementation as standard of care at dose higher than 10,000 U/week

3. Suspect or clinical evidence of CNS involvement by lymphoma

4. Contraindication to the use of rituximab

5. Contraindication to the use of VitD supplementation (Hypercalcemia/Hyperphosphatemia)

6. 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

7. 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

8. 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

9. 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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• Vitamin D3 (Cholecalciferol)
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.
• RCHOP o R-miniCHOP at standard doses
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

Locations

Country	Name	City	State
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	SC Ematologia Spedali Civili	Brescia	BS
Italy	Campobasso - Universit? Cattolica del Sacro Cuore - Ematologia	Campobasso
Italy	Castelfranco Veneto - Ospedale di Castelfranco Veneto - Ematologia	Castelfranco Veneto
Italy	Unità Funzionale di Ematologia AOU Careggi	Firenze
Italy	Frosinone - Presidio Ospedaliero F. Spaziani - UOC Ematologia	Frosinone
Italy	Matera - Ospedale Madonna delle Grazie - Ematologia	Matera
Italy	Meldola - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) - Ematologia	Meldola
Italy	Mestre - Ospedale Dell Angelo - U.O. Ematologia	Mestre
Italy	SC Ematologia AO Niguarda Cà Granda	Milano
Italy	Monza - ASST MONZA Ospedale S. Gerardo - Ematologia	Monza
Italy	Napoli - AOU Universit? degli Studi della Campania Luigi Vanvitelli - Oncologia Medica ed Ematologia	Napoli
Italy	Università del Piemonte Orientale - Novara	Novara
Italy	Padova - I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1	Padova
Italy	Pagani - Presidio ospedaliero "A. TORTORA" - U.O. Onco-ematologia	Pagani
Italy	Palermo - A.O. Ospedali Riuniti Villa Sofia-Cervello - Divisione di Ematologia	Palermo
Italy	Palermo - AOU Policlinico Giaccone - Ematologia	Palermo
Italy	UO Ematologia Università - Policlinico San Matteo	Pavia
Italy	Pescara - P.O. Spirito Santo di Pescara - UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi	Pescara
Italy	UO Ematologia e CTMO di Piacenza	Piacenza	PC
Italy	Potenza - AOR San Carlo	Potenza
Italy	UO Ematologia Ospedale Santa Maria delle Croci	Ravenna
Italy	Reggio Emilia - AO Santa Maria Nuova	Reggio Emilia
Italy	UO Ematologia - Ospedale degli Infermi	Rimini
Italy	Ospedale Oncologico regionale CROB	Rionero in Vulture	Piacenza
Italy	Roma - IRCCS Spallanzani - Servizio di Ematologia in malattie infettive	Roma
Italy	Roma - Ospedale S. Camillo - Ematologia	Roma
Italy	Roma - Policlinico Universitario Campus Bio-Medico - Ematologia - Trapianto cellule staminali - Medicina Trasfusionale e Terapia cellulare	Roma
Italy	Università Cattolica S. Cuore, Ematologia	Roma
Italy	Università La Sapienza Ematologia	Roma
Italy	UOC Ematologia - A.O. Sant'Andrea	Roma
Italy	Salerno - Ematologia e Trapianti A.O. San Giovanni di Dio e Ruggi D Aragona - U.O. Ematologia	Salerno
Italy	San Giovanni Rotondo - Casa Sollievo della Sofferenza - U.O. Ematologia	San Giovanni Rotondo
Italy	Sassari - AOU di Sassari - Ematologia	Sassari
Italy	UOC Medicina Interna MO DH Oncologico	Sassuolo
Italy	UOC Ematologia, AOU Senese	Siena
Italy	Univ. Perugia Sede Terni - Oncoematologia	Terni
Italy	AOU Citta della Salute e della Scienza di Torino - Ematologia Universitaria	Torino
Italy	SC. Ematologia A.O. Città della Salute e della Scienza	Torino
Italy	Torino - San Giovanni Bosco - ASL Citt? di Torino - SSD di Ematologia e Malattie Trombotiche	Torino
Italy	Trieste - Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) - SC Ematologia	Trieste
Italy	Udine - Azienda Sanitaria Universitaria Friuli Centrale (ASU FC) - SOC Clinica Ematologica	Udine
Italy	ULSS 8 Berica - Ospedale S. Bortolo - Ematologia	Vicenza

Sponsors (2)

Lead Sponsor	Collaborator
Fondazione Italiana Linfomi ONLUS	GRADE Onlus

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival	Progression-Free Survival	at the end of treatment - 54 months
Secondary	Overall Survival	Overall Survival	at the end of treatment - 54 months
Secondary	Event Free Survival	Event Free Survival (EFS)	at the end of treatment - 54 months
Secondary	Response rate	Response rate	at the end of treatment - 54 months
Secondary	Early death rate	Early death rate	at the end of treatment - 54 months
Secondary	Rate of ECOG changes after prephase	Rate of ECOG changes after prephase	at the end of treatment - 54 months
Secondary	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)
Secondary	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)
Secondary	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)