dexrazoxane

P3, N=110, Not yet recruiting, Children's Oncology Group | Initiation date: Dec 2024 --> Mar 2025

P1, N=25, Recruiting, University of Arkansas | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P2, N=83, Active, not recruiting, Memorial Sloan Kettering Cancer Center

P2, N=65, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

We established a rat model of DOX-induced cardiotoxicity by intraperitoneal injection with DOX (1.25 mg/kg twice weekly for 6 weeks), and found that both IMP (25 mg/kg and 12.5 mg/kg) and dexrazoxane 12.5 mg/kg relieved DOX-induced reductions in heart weight, change in cardiac histopathology, and elevated serum levels of LDH, AST and CK-MB. In conclusion, IMP had a protective effect against DOX-induced cardiotoxicity via repressing the activation of NLRP3 inflammasome. These findings suggest that IMP may be a promising alternative or adjunctive drug for the prevention of anthracycline cardiotoxicity.

This gap is highlighted by the scarcity of reliable therapeutic interventions, with dexrazoxane being the sole FDA-approved drug to mitigate AIC risks. Furthermore, we investigated the clinical relevance by comparing our results with those from a study based on hiPSC-CMs derived from patients with doxorubicin-induced cardiotoxicity, identifying overlapping TFs and their regulatory roles in critical cellular processes like the cell cycle and DNA repair. This approach not only advances the understanding of the molecular mechanisms behind AIC but also opens possible windows for new therapeutic approaches to mitigate the negative side-effects from patient AC treatment.

P3, N=110, Not yet recruiting, Children's Oncology Group

P2, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

Our results not only confirm the cardioprotective effects of DEXRA against DOX-induced cardiotoxicity but also add preservation of vascular endothelial cell function as an important mechanism. Moreover, the study demonstrates the potential of SERPINA3N as a biomarker for monitoring cardiovascular complications of DOX in high-risk patients.

The mice in the treatment group received dexrazoxane, MCC950, and Cyn every two days. We attribute it to the mediation of AMPK/SIRT3/Nrf2 pathway, which plays a central role in preventing DOX-induced cardiomyocyte injury. In conclusion, the present study confirms the therapeutic potential of Cyn in DIC by regulating the AMPK/SIRT3/Nrf2 pathway.

P3, N=324, Recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Not yet recruiting --> Recruiting

P3; Recruiting --> Active, not recruiting

P3, N=560, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Nov 2028 --> Nov 2034

P3, N=478, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P2, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Sep 2024

P3, N=236, Active, not recruiting, National Cancer Institute (NCI)

P=N/A, N=420, Recruiting, Children's Oncology Group | Trial completion date: Dec 2023 --> Dec 2025

P3, N=1400, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study's findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.

P1, N=25, Recruiting, University of Arkansas | Trial completion date: Jun 2025 --> Oct 2025 | Trial primary completion date: Jun 2024 --> Oct 2024

P2, N=60, Recruiting, Princess Maxima Center for Pediatric Oncology

P3, N=324, Not yet recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland

Dexrazoxane (DXZ), an iron chelator, is the only drug approved by the FDA for reducing DIC, but it has many side effects and cannot be used as a preventive drug in clinical practice. Notably, SeMet exerted antitumor effects on breast cancer models with DOX while providing cardiac protection for the same animal without detectable toxicities. These findings suggest that pharmacological activation of GPX4 is a valuable and promising strategy for preventing the cardiotoxicity of doxorubicin.

P3, N=478, Not yet recruiting, National Cancer Institute (NCI)

Dexrazoxane (DEX) has been adopted to prevent AIC. Using the cardiomyocyte cell lines AC16 and H9c2, we determined that autophagy was initiated during AIC. Our results suggest that inhibition of autophagy at its early phase with SAR405 combined with DEX represents an effective therapeutic strategy to prevent AIC.

P2, N=83, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

Dexrazoxane was permitted, but not mandated. In early follow-up, N-AVD and BV-AVD are well tolerated and associated with low rates of irAEs in pts ages 12-17 y. With 12.1 mos median follow-up the PFS benefit observed for N-AVD in pediatric pts mirrors that observed in the overall study. RT usage is lower, and cumulative doxorubicin dose is higher than historical pediatric cHL trials. The difference in rate of discontinuation between study arms and by age group needs further evaluation.

Building on the successes achieved by the recent trial from this consortium (NOPHO-DBH AML-2012, preliminary data as per June 2023, n=878: 5-years pEFS 63%, 5-years pOS 78%), CHIP-AML22 will incorporate innovative elements, mainly the FLT3-inhibitor quizartinib (Vanflyta®) that was recently approved by the FDA and PMDA in combination with chemotherapy for the treatment of newly diagnosed adult AML patients with FLT3-ITD mutations, and gemtuzumab ozogamicin (GO, Mylotarg®) that improved outcome in adult and pediatric AML when added to chemotherapy...Further, dexrazoxane is recommended to all patients before receiving daunorubicin or mitoxantrone, aiming to prevent late-onset cardiotoxicity...Study Ri and the linked quizartinib trial are expected to open in Q4 2023. At least 15 other countries with nearly 60 sites will participate in CHIP-AML22: Belgium, Denmark, Estonia, Finland, Hong Kong, Iceland, Israel, Latvia, Lithuania, Norway, Portugal, Spain, Sweden, Switzerland and Uruguay.

P2, N=65, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

Group I served as the control and received tween 80 (0.2%), group II received the vehicle and DOX, group III received the standard drug dexrazoxane and DOX, whereas groups IV, V, and VI were treated orally with citronellol (25, 50, and 100 mg/kg) and DOX, respectively. Citronellol also increased the expression of anti-inflammatory cytokines while reducing the expression of pro-inflammatory cytokines. Therefore, it can be concluded that citronellol may have potential cardioprotective effects in preventing DOX-induced cardiotoxicity.

P3, N=724, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

This study reveals that the combination of CPET, CMR acquisitions and CircAdapt model was sensitive enough to observe slight changes in the assessment of VAC and CWE parameters. Our study contributes to improving survivors' follow-up and detection of cardiac problems induced by doxorubicin-related cardiotoxicity.

According to the analysis of the CellMiner database (Tumor cell and drug related database tools), high CD109 levels showed significant drug sensitivity to Dexrazoxane, which has the potential to be a therapeutic agent for ACP. Our findings extend understandings of the molecular immune mechanisms of ACP and suggest possible biomarkers for the targeted and precise treatment of ACP.

P2, N=93, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2023 --> May 2027 | Trial primary completion date: May 2023 --> May 2027

Anthracyclines such as doxorubicin are widely used chemotherapy drugs...Dexrazoxane and heart failure medications (i.e., beta blockers and drugs targeting the renin-angiotensin system) are prescribed for the primary prevention of cancer therapy-related cardiotoxicity and for the management of cardiac dysfunction and symptoms if they arise during chemotherapy...In this review, we summarise findings from experimental models which provide insight into cellular mechanisms by which exercise may protect the heart from anthracycline-mediated damage, and identify knowledge gaps that require further investigation. Improved understanding of the mechanisms by which exercise protects the heart from anthracyclines may lead to the development of novel therapies to treat cancer therapy-related cardiotoxicity.

The efficacy of dexrazoxane has been demonstrated in clinical trials within the pediatric population with roughly 60%-80% reduction in risk of developing cardiotoxicity with a very tolerable and limited side effect profile. Further research is required to not only establish the efficacy of dexrazoxane within the pediatric population but also to explore other medications that may serve alongside the function of dexrazoxane.

As far as the authors know, this is the first meta-analysis assessing the impact of DRZ specifically in haematological patients. We demonstrate its efficacy as a cardioprotective measure, but also the increased risk of secondary neoplasms. Further studies may analyze the patient- and disease-related characteristics that make individuals more prone to develop secondary neoplasms, herein allowing the selection of patients in whom the beneficial cardioprotective effect is associated with a safer profile.

Among patients with preexisting HF who received an anthracycline, dexrazoxane or liposomal doxorubicin were used in 78 of 1119 patients (7.0%)...In this study, preexisting HF in patients with newly diagnosed DLBCL was common and was associated with lower use of anthracyclines and lower use of any chemotherapy. Trials are needed for this high-risk population.

P2, N=73, Completed, Washington University School of Medicine | Active, not recruiting --> Completed | Trial completion date: Apr 2027 --> Jul 2022 | Trial primary completion date: Apr 2027 --> Jul 2022

female, 5 years in remission from stage IIA HL nodular lymphocyte predominant subtype, treated with 3 cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide...She underwent radical nephrectomy and received 14 cycles of vincristine, doxorubicin, cyclophosphamide alternating every 2 weeks with ifosfamide etoposide (VDC/IE)...Dexrazoxane was provided as a cardioprotective agent...Through shared decision-making, we elected to treat with pazopanib in conjunction with 3-weeks cycle of palliative chemotherapy (vincristine, irinotecan, and temozolomide)... We present the first case of renal DSRCT following HL. This case was also unique as whole genome sequencing was performed without actionable/germline mutations; suggesting EWSR1-WT1 translocation fusion mutation alone is sufficient to cause DSRCT. Outcomes remain poor despite aggressive conventional therapies and new targeted therapies, such as pazopanib.

P2, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2023 --> Dec 2023

Candidate molecules such as Dexrazoxane/Mitoxantrone, with interleukin-2 and antitumor lymphocytes, may potentially replicate permanent tumor regression process of melanoma. To conclude, episodic permanent tumor regression is a unique biological reversal process of malignant progression, and signaling pathway understanding, with candidate biomolecules, may plausibly therapeutically replicate the regression process on tumors clinically. The online version contains supplementary material available at 10.1007/s13205-023-03515-0.