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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Italiana Linfomi Ets

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

23 Mar 2021 → ongoing

Decision date (initial)

2024-11-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

FONDAZIONE GRADE ONLUS

External identifiers

EU CT number

2024-511637-35-00

EudraCT number

2019-004474-26

ClinicalTrials.gov

NCT04442412

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To demonstrate the superiority in terms of Progression-free survival (PFS) of a prephase therapy with oral prednisone and Vitamin D supplementation versus a prephase therapy with oral prednisone alone, followed by 6 cycles of conventional immunochemotherapy, on an elderly patients population diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular lymphoma grade IIIb (FL3B).

Secondary objectives 7

1. To assess the safety of VitD supplementation in terms of hematological and extra-hematological AEs rates;
2. To evaluate the effect of VitD supplementation in terms of early death rate, response rate, OS, EFS.
3. To confirm the efficacy of a prephase with VitD supplementation to correct baseline 25(OH)VitD levels.
4. To correlate baseline clinical, laboratory and biological features with 25(OH)VitD correction.
5. To correlate 25(OH)VitD baseline levels with known and novel prognostic biomarkers (IPI, Cell of Origin, etc.) and with activity of immunochemotherapy.
6. To identify high risk category of individuals showing insufficient response to Vitamin D supplementation.
7. To describe the health-related quality of life (HRQoL) by the use of Patient-Reported Outcomes (PROs): EORTC-QLQ-C30 and FACT-Lym-LymS questionnaires.

Conditions and MedDRA coding

Elderly patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

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. Simplified Geriatric Assessment (sGA) performed at baseline, before start of any treatment.
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤3
5. Eligibility for 6 cycle treatment of 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 (MRI is allowed only if CT scan cannot be performed); or one metabolic active site of disease at baseline FDG-PET scan
9. Baseline Vitamin D [25(OH)VitD] serum level ≤ 40 ng/ml
10. Adequate hematological counts defined as follows: - Absolute Neutrophil count (ANC) > 1.5 x 10^9/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 > 40% at bidimensionally echocardiogram
14. Life expectancy ≥ 6 months
15. Subject understands and voluntarily signs an informed consent form approved by an Independent Ethics Committee (IEC), 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 themselves or female partners if WOCBP) 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. Acceptable methods for birth control, to be adopted even if male is surgically sterilized (i.e., status post vasectomy) are: - practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of immunochemotherapy, or - agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner] and withdrawal are not acceptable methods of contraception)

Exclusion criteria 10

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 (or higher than 2,000 U/day).
3. Suspect or clinical evidence of CNS involvement by lymphoma.
4. Contraindication to the use of rituximab.
5. Localized stage patients candidates for 3-4 cycles of R-CHOP/R-miniCHOP +RT.
6. Contraindication to the use of VitD supplementation (Hypercalcemia/Hyperphosphatemia).
7. 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.
8. 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.
9. 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.
10. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: - Uncontrolled and/or active systemic infection (viral, bacterial or fungal) - Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-Free Survival (PFS).

Secondary endpoints 9

1. Overall Survival (OS).
2. Event Free Survival (EFS).
3. Response rate (ORR, CRR; Cheson 2014).
4. Early death rate (EDR): all deaths recorded within 90 days from the date of diagnosis.
5. AEs rate (CTCAE current version).
6. Rate of ECOG changes after prephase.
7. Rate of 25(OH)VitD correction (VitD supplementation arm): number of patients with 25(OH)VitD levels above or equal 20ng/ml at day 1 of cycle 2.
8. Rate of patients who maintain 25(OH)VitD levels in the normal range at EOI.
9. PROs endpoints include: time-to-deterioration in EORTC QLQ-C30 physical functioning and fatigue and FACT-Lym-LymS; proportion of patients in each arm achieving meaningful improvement in EORTC-QLQ-C30 physical functioning and fatigue, and FACT-Lym-LymS; and a comparison of EORTC-QLQ-C30 treatment-related symptoms between the two treatment arms.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Italiana Linfomi Ets

Sponsor organisation

Fondazione Italiana Linfomi Ets

Address

Piazza Filippo Turati 5

City

Alexandria

Postcode

15121

Country

Italy

Scientific contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Francesco Merli, MD

Public contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Marco Ladetto, MD

Locations

1 EU/EEA country · 45 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications