Prevention of Anthracycline-Induced Cardiac Dysfunction With Dexrazoxane in Patients With Diffuse Large-B Cell Lymphoma
ANTICIPATE: Prevention of ANThracycline-Induced Cardiac Dysfunction by Dexrazoxane In PATients With diffusE Large B-cell Lymphoma: a Phase III National Multicenter Prospective Randomized Open-label Trial
Stichting Hemato-Oncologie voor Volwassenen Nederland
324 participants
Aug 15, 2024
INTERVENTIONAL
Conditions
Summary
Patients treated for DLBCL are at high risk of developing AICD. This adverse event is characterized by irreversible damage to the heart muscle with a loss of cardiomyocytes and subsequent decline in cardiac pumping capacity. Thereby patients treated for this malignancy are at double the risk of developing symptomatic heart failure / cardiomyopathy when compared to the general population. This corresponds to a cumulative incidence of 5-10% within 5-years after receiving R-CHOP. In the elderly, an incidence of 26% has been reported after 8-years of follow-up. Among patients who die in complete remission, heart failure has been described to be one of the most important causes of death. ANTICIPATE aims to evaluate if dexrazoxane can prevent AICD in DLBCL patients and identify those at highest risk of AICD. Of all patients treated with anthracyclines in a first-line setting, DLBCL patients were chosen for this trial for two primary reasons. Firstly, these patients have a favourable oncological prognosis with a 5-year relative survival in the Netherlands of 64-78% in those aged 18-74 years increasing the importance of preventing long-term toxicity. Secondly, the cumulative anthracycline dose used for the treatment of DLBCL is higher than the dose used in breast cancer. The cumulative anthracycline dose is the most important risk factor for AICD known.
Eligibility
Inclusion Criteria22
- Untreated patients with a confirmed histologic diagnosis of CD20+ DLBCL according to WHO classification 2022:
- DLBCL, not otherwise specified (NOS)
- High-grade B-cell lymphoma NOS
- High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocation when DA-EPOCH-R is not an option. R2- CHOP is allowed.
- Follicular lymphoma
- T-cell/histiocyte-rich B cell lymphoma (THRBCL)
- Note: Transformed, previously untreated lymphoma is allowed.
- Note: 5-day treatment of dexamethasone 15 mg/day or prednisone 100 mg/day or local radiotherapy in order to control life-threatening/invalidating tumor related symptoms is allowed.
- Note: It is allowed to start with a first cycle of R-CHOP21 pending the FISH results.
- Planned treatment with 6 R-CHOP21. The following regimens are also allowed:
- Treatment with reversed R-CHOP21
- Treatment with R2-CHOP21 (6 R-CHOP21 + lenalidomide 15 mg day 1-14) in case of double hit lymphoma
- Two additional administrations of rituximab after 6 cycles of R-CHOP21
- High dosis MTX and/or MTX-it for CNS prophylaxis
- Ann Abor stages II-IV and stage I if the treatment plan is 6 R-CHOP21 in case of bulky disease (defined as a ≥10 cm mass);
- Age ≥ 18 years;
- WHO performance status ≤ 2, WHO 3 performance status is allowed when considered directly related to the DLBCL;
- Negative pregnancy test at study entry for women of childbearing potential;
- Female patient is either post-menopausal for at least 1 year before the screening visit or surgically sterile or if of childbearing potential, agrees to practice two effective methods of contraception, at the same time, from the time of signing the informed consent through at least 12 months after the last dose of protocol treatment, or agrees to completely abstain from heterosexual intercourse;
- Male patient, even if surgically sterilized, (i.e., status post vasectomy) agrees to practice effective barrier contraception during the entire study period and through 12 months after the last dose of protocol treatment, or agrees to completely abstain from heterosexual intercourse;
- Patient is able to adhere to the study visit schedule and other protocol requirements;
- Written informed consent.
Exclusion Criteria27
- Any of the following B-cell lymphomas according to WHO classification 2022:
- o Central Nervous System involvement by DLBCL;
- Note: high CNS-IPI is allowed
- Testicular DLBCL;
- Primary mediastinal B-cell lymphoma;
- Epstein-Barr virus (EBV) post-transplant lymphoproliferative disorder;
- Any prior malignancy or present malignancy other than DLBCL that required or requires systemic therapy. Prior surgery or local radiotherapy is allowed in case the heart has not been exposed.
- Patients requiring treatment with mini-R-CHOP
- Pre-existing cardiac disease including:
- LVEF \<50% measured with echocardiography (2D or 3D)
- Symptomatic heart failure (NYHA ≥II) or hospitalization for heart failure in the last year;
- Refractory anginal symptoms
- Cardiac arrhythmias not controlled with optimal medical treatment, in case of atrial fibrillation the ventricular response needs to be \<110/min;
- Significant valvular dysfunction on echocardiography;
- Non-ischemic cardiomyopathy
- Non-diagnostic/poor transthoracic echocardiography imaging quality at baseline;
- Severe pulmonary dysfunction defined as breathlessness at rest (COPD GOLD III or IV), unless clearly related to DLBCL;
- Severe neurological or psychiatric disease;
- Inadequate hematological function (absolute Neutrophil Count (ANC) \<1.0x109/L or platelets \<75x109/L), unless clearly related to DLBCL;
- Significant hepatic dysfunction (serum bilirubin or transaminases ≥ 3 times the upper limit of normal) unless related to lymphoma infiltration of the liver;
- Active hepatitis B or C infection (serology testing is required at screening). Patients positive for hepatitis B surface antigen (HBsAg) regardless of antibody status or HBsAg negative but anti-HBc positive are only eligible if HBV-PCR is negative and patients are protected with lamuvidine or entecavir. Patients with positive hepatitis C serology are only eligible if HCV-(RNA) is confirmed negative;
- Significant renal dysfunction (creatinine clearance \< 30 ml/min after rehydration) or requiring dialysis;
- Active uncontrolled fungal, bacterial and/or viral infection;
- Patient known to be HIV-positive;
- Breast-feeding female patients;
- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
- Participation in another clinical trial with anti-cancer therapy or a cardiovascular drug.
Interventions
Day 1 Cycle 1-6: Dexrazoxane 500 mg/m2 (iv) will be given 30 minutes before doxorubicin infusion and should be infused during 15 minutes.
Day 1 Cycle 1-6: 375 mg/m2 (iv)
Day 1 Cycle 1-6: 750 mg/m2 (iv)
Day 1 Cycle 1-6: 50 mg/m2 (iv)
Day 1 Cycle 1-6: 1.4 mg/m2 (max 2 mg) (iv)
Day 1-5 Cycle 1-6: 100 mg (oral)
Day 1-14 Cycle 1-6: 15 mg day (oral) Only in case of a double hit lymphoma.
6 mg (1 dose per cycle) in case of neutropenia. Pegfilgastim is mandatory in patients that receive R2-CHOP21.
Locations(25)
View Full Details on ClinicalTrials.gov
For the most up-to-date information, visit the official listing.
NCT06220032