Clinical trial NCT04442412: Prephase Treatment With Prednisone +/- Vitamin D Supplementation Followed by Immunochemotherapy
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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Diffuse Large B-Cell Lymphoma
Elderly Patients
Keywords: Vitamin D
prednisone +/- Vitamin D supplementation
randomized, open label, phase III
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
Collaborators: name: GRADE Onlus
First posted: 2020-06-22
Enrollment: 430
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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:

Eligibility criteria: 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.

Primary outcomes:
measure: Progression-Free Survival
timeFrame: at the end of treatment - 54 months
Secondary outcomes:
measure: Overall Survival
timeFrame: at the end of treatment - 54 months
measure: Event Free Survival
timeFrame: at the end of treatment - 54 months
measure: Response rate
timeFrame: at the end of treatment - 54 months
measure: Early death rate
timeFrame: at the end of treatment - 54 months
measure: Rate of ECOG changes after prephase
timeFrame: at the end of treatment - 54 months
measure: Rate of patients who maintain 25(OH)VitD levels
timeFrame: At the beginning of Cycle 2 (each cycle is 21 days)
measure: Rate of 25(OH)VitD correction (VitD supplementation arm)
timeFrame: At the beginning of Cycle 2 (each cycle is 21 days)
measure: time-to-deterioration physical functioning and fatigue
timeFrame: At the beginning of Cycle 2 (each cycle is 21 days)
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: SC Ematologia Spedali Civili
state: BS
city: Piacenza
country: Italy
facility: UO Ematologia e CTMO di Piacenza
state: PC
city: Rionero in Vulture
country: Italy
facility: Ospedale Oncologico regionale CROB
state: Piacenza
city: Alessandria
country: Italy
facility: A.O. SS. Antonio e Biagio e Cesare Arrigo - S.C. Ematologia
city: Ancona
country: Italy
facility: A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona
city: Ascoli Piceno
country: Italy
facility: Ascoli Piceno - Ospedale C.e G. Mazzoni - U.O.C. di Ematologia
city: Aviano
country: Italy
facility: Aviano - Centro Riferimento Oncologico - S.O.C. Oncologia Medica A
city: Barletta
country: Italy
facility: Barletta - Ospedale "Monsignor Raffaele Dimiccoli" - Ematologia
city: Bergamo
country: Italy
facility: Bergamo - Cliniche Humanitas Gavazzeni - Oncologia - Cliniche Humanitas Gavazzeni
city: Biella
country: Italy
facility: Biella - Ospedale Degli Infermi - S.C. Oncologia
city: Campobasso
country: Italy
facility: Campobasso - Universitа Cattolica del Sacro Cuore - Ematologia
city: Castelfranco Veneto
country: Italy
facility: Castelfranco Veneto - Ospedale di Castelfranco Veneto - Ematologia
city: Firenze
country: Italy
facility: Unità Funzionale di Ematologia AOU Careggi
city: Frosinone
country: Italy
facility: Frosinone - Presidio Ospedaliero F. Spaziani - UOC Ematologia
city: Matera
country: Italy
facility: Matera - Ospedale Madonna delle Grazie - Ematologia
city: Meldola
country: Italy
facility: Meldola - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) - Ematologia
city: Mestre
country: Italy
facility: Mestre - Ospedale Dell Angelo - U.O. Ematologia
city: Milano
country: Italy
facility: SC Ematologia AO Niguarda Cà Granda
city: Monza
country: Italy
facility: Monza - ASST MONZA Ospedale S. Gerardo - Ematologia
city: Napoli
country: Italy
facility: Napoli - AOU Universitа degli Studi della Campania Luigi Vanvitelli - Oncologia Medica ed Ematologia
city: Novara
country: Italy
facility: Università del Piemonte Orientale - Novara
city: Padova
country: Italy
facility: Padova - I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1
city: Pagani
country: Italy
facility: Pagani - Presidio ospedaliero "A. TORTORA" - U.O. Onco-ematologia
city: Palermo
country: Italy
facility: Palermo - A.O. Ospedali Riuniti Villa Sofia-Cervello - Divisione di Ematologia
city: Palermo
country: Italy
facility: Palermo - AOU Policlinico Giaccone - Ematologia
city: Pavia
country: Italy
facility: UO Ematologia Università - Policlinico San Matteo
city: Pescara
country: Italy
facility: Pescara - P.O. Spirito Santo di Pescara - UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi
city: Potenza
country: Italy
facility: Potenza - AOR San Carlo
city: Ravenna
country: Italy
facility: UO Ematologia Ospedale Santa Maria delle Croci
city: Reggio Emilia
country: Italy
facility: Reggio Emilia - AO Santa Maria Nuova
city: Rimini
country: Italy
facility: UO Ematologia - Ospedale degli Infermi
city: Roma
country: Italy
facility: Roma - IRCCS Spallanzani - Servizio di Ematologia in malattie infettive
city: Roma
country: Italy
facility: Roma - Ospedale S. Camillo - Ematologia
city: Roma
country: Italy
facility: Roma - Policlinico Universitario Campus Bio-Medico - Ematologia - Trapianto cellule staminali - Medicina Trasfusionale e Terapia cellulare
city: Roma
country: Italy
facility: Università Cattolica S. Cuore, Ematologia
city: Roma
country: Italy
facility: Università La Sapienza Ematologia
city: Roma
country: Italy
facility: UOC Ematologia - A.O. Sant'Andrea
city: Salerno
country: Italy
facility: Salerno - Ematologia e Trapianti A.O. San Giovanni di Dio e Ruggi D Aragona - U.O. Ematologia
city: San Giovanni Rotondo
country: Italy
facility: San Giovanni Rotondo - Casa Sollievo della Sofferenza - U.O. Ematologia
city: Sassari
country: Italy
facility: Sassari - AOU di Sassari - Ematologia
city: Sassuolo
country: Italy
facility: UOC Medicina Interna MO DH Oncologico
city: Siena
country: Italy
facility: UOC Ematologia, AOU Senese
city: Terni
country: Italy
facility: Univ. Perugia Sede Terni - Oncoematologia
city: Torino
country: Italy
facility: AOU Citta della Salute e della Scienza di Torino - Ematologia Universitaria
city: Torino
country: Italy
facility: SC. Ematologia A.O. Città della Salute e della Scienza
city: Torino
country: Italy
facility: Torino - San Giovanni Bosco - ASL Cittа di Torino - SSD di Ematologia e Malattie Trombotiche
city: Trieste
country: Italy
facility: Trieste - Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) - SC Ematologia
city: Udine
country: Italy
facility: Udine - Azienda Sanitaria Universitaria Friuli Centrale (ASU FC) - SOC Clinica Ematologica
city: Vicenza
country: Italy
facility: ULSS 8 Berica - Ospedale S. Bortolo - Ematologia
Study officials:
affiliation: Reggio Emilia - Azienda Unitа Sanitaria Locale-IRCCS
name: Francesco Merli, Dott.
role: PRINCIPAL_INVESTIGATOR
References: