Safety and Preliminary Efficacy of Meldonium in Patients with Metastatic Renal Cell Carcinoma and Treatment-associated Fatigue

A Phase 1/2 Study of the Safety and Preliminary Efficacy of Meldonium in Patients with Metastatic Renal Cell Carcinoma and Treatment-associated Fatigue.

Fatigue is a prevalent adverse event associated with systemic therapy using tyrosine kinase inhibitors (TKIs). Meldonium, a fatty acid oxidation inhibitor, modifies the carnitine pathway, a nutrient critical for fat metabolism. The World Anti-Doping Agency (WADA) classified meldonium as a banned substance due to its documented use by athletes aiming to enhance physical performance. In this study, the safety and preliminary efficacy of meldonium in treatment-related fatigue will be assessed.

Study Overview

• Status: Completed
• Conditions: Kidney Cancer; Renal Cell Cancer Metastatic; Fatigue Related to Cancer Treatment
• Intervention / Treatment: Drug: meldonium

Detailed Description

Fatigue is a frequent symptom of cancer and the most common adverse event of treatment with tyrosine kinase inhibitors. For example, in phase 2 randomized study 59% of patients with metastatic renal cell carcinoma experienced any grade fatigue during treatment with the combination of lenvatinib and everolimus. Fourteen percent of patients had grade 3 fatigue or asthenia. Fatigue was also most frequently reported treatment-related adverse event in patients with unresectable hepatocellular carcinoma (30%), and advanced thyroid cancer (60%) treated with lenvatinib. Additionally, fatigue is one of the most common adverse events associated with the administration of checkpoint inhibitors. Frequency of fatigue was 55% in patients with endometrial cancer treated with combination of pembrolizumab and lenvatinib.

Meldonium is a fatty acid oxidation inhibitor, and it is now principally used for heart conditions, such as angina, heart attack, heart failure, and others. The compound works by altering pathways for carnitine, a nutrient involved in fat metabolism. Meldonium received the greatest fame in sport. The World Anti-Doping Agency (WADA) added meldonium to their list of banned substances in 2016 because of evidence of its use by athletes with the intention of enhancing performance. Center for Preventive Doping Research and European Monitoring Center for Emerging Doping Agents showed that mildronate demonstrates an increase in endurance performance of athletes, improved rehabilitation after exercise, protection against stress, and enhanced activations of the central nervous system functions. Based on these data, meldonium can be a possible option in cancer patients with fatigue treated with targeted or imminotargeted therapy. Moreover, the compound could decrease the number of vascular adverse events of TKIs.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Albania
  • Tirana, Albania
    • Megis medical clinic
• Azerbaijan
  • Baku, Azerbaijan
    • National Center of Oncology
• Russian Federation
  • Moscow, Russian Federation
    • STOONCO clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• metastatic renal cell carcinoma
• measurable disease based on RECIST 1.1 criteria
• systemic therapy with targeted or immunotargeted therapy
• any grade of fatigue associated with targeted or immunotargeted therapy
• ECOG PS <2
• signed informed consent

Exclusion Criteria:

• Any treatment for fatigue
• Uncompensated hypothyroidism
• Anemia
• Pregnant or nursing
• Local and/or systemic infections requiring antibiotics or COVID-19 within 28 days prior to study entry
• Other malignancy
• Brain metastases

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: First-line TKI therapy, Meldonium 500 mg; meldonium 500 mg orally daily for six weeks.	Drug: meldonium; 500 mg (Arm A) or 1,000 mg (Arms B and C) orally daily, weeks 1-6
Experimental: Arm B: Second-line TKI therapy, Meldonium 1,000 mg; meldonium 1,000 mg orally daily for six weeks.	Drug: meldonium; 500 mg (Arm A) or 1,000 mg (Arms B and C) orally daily, weeks 1-6
Experimental: Arm C: First-line IO-TKI therapy, Meldonium 1,000 mg; meldonium 1,000 mg orally daily for six weeks.	Drug: meldonium; 500 mg (Arm A) or 1,000 mg (Arms B and C) orally daily, weeks 1-6

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	Incidence of meldonium-related adverse events	From enrollment to the end of treatment at 6 weeks
Changes in fatigue levels based on FACIT Fatigue Scale	Changes in fatigue levels, measured at six weeks using the FACIT Fatigue Scale (Version 4).	From enrollment to the end of treatment at 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity of anti-cancer systemic therapy	Rate of adverse events	From enrollment to the end of treatment at 8 weeks
Rate of discontinuation of anti-cancer therapy and/or dose reduction of the drug	Rate of discontinuation of anti-cancer therapy and/or dose reduction of the drug	From enrollment to the end of treatment at 12 weeks
Rate of arterial hypertension	Rate of arterial hypertension as an adverse event of targeted therapy	From enrollment to the end of treatment at 12 weeks

Collaborators and Investigators

• Sponsor: Kidney Cancer Research Bureau

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Actual): September 1, 2024
• Study Completion (Actual): September 1, 2024

Study Registration Dates

• First Submitted: September 22, 2024
• First Submitted That Met QC Criteria: October 17, 2024
• First Posted (Actual): October 18, 2024

Study Record Updates

• Last Update Posted (Actual): October 18, 2024
• Last Update Submitted That Met QC Criteria: October 17, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Neoplasms; Carcinoma, Renal Cell; Fatigue; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; 3-(2,2,2-trimethylhydrazine)propionate
• Other Study ID Numbers: KCRB-0102-MEL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No