Sodium Thiosulfate Otoprotection During Salvage Cisplatin Therapy

Early Phase 1

Recruiting

• Conditions: Ototoxicity, Drug-Induced
• Interventions: Drug: Sodium Thiosulfate

• Registration Number: NCT05756660
• Lead Sponsor: Children's Hospital Medical Center, Cincinnati

Brief Summary

This study will attempt to demonstrate the efficacy of Sodium Thiosulfate (STS) in preventing hearing loss in patients re-treated with cisplatin-based therapy according to regimens Cisplatin and STS (regimen CS) and Cisplatin, STS and Vorinostat/SAHA (regimen CSS).

Detailed Description

This trial will assess the effect of STS in preventing subsequent hearing loss when patients are re-challenged with cisplatin therapy at relapse/progression, as well as the efficacy of cisplatin/STS or cisplatin/STS/SAHA for patients with relapsed hepatoblastoma, Wilms, Germ Cell Tumor (GCT) and Neuroblastoma stratified by initial cisplatin sensitivity. Important pharmacokinetic measurements focused on cisplatin and STS in children, with varying degrees of renal function, will be assessed. Such pharmacokinetic data will fill a current gap in our clinical knowledge base and enable safer use of such agents for all children with such cancers, regardless of kidney function, in the future.

Study Timeline

• Study First Submitted: 2023-02-09
• Study Start: 2023-03-01
• Study First Submitted QC: 2023-03-02
• Study First Posted: 2023-03-06
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-16
• Last Update Posted: 2024-01-18
• Primary Completion: 2025-01
• Study Completion: 2027-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 33

Inclusion Criteria

• Patients must be > 1 month and ≤ 39 years old at study enrollment

• Histologically proven, at time of diagnosis or relapse:

  1. Stratum 1: Arm CS (Cisplatin/STS): Previously chemosensitive to cisplatin defined as an AFP drop of 1 log (90%) and/or an objective tumor response of 30% or greater on imaging while receiving cisplatin.
  2. Stratum 2A: Cisplatin/STS/SAHA (CSS): Previously chemosensitive but with noted subsequent progression on cisplatin or initially chemoresistant to cisplatin (all other hepatoblastoma patients). Resistance to cisplatin is defined as rising alpha-fetoprotein (AFP) x 2 consecutive measurements or imaging progression including growth of known lesions or new lesions while patient is receiving a cycle of chemotherapy containing cisplatin or relapse noted within 3 months of last cisplatin administration.
  3. Stratum 2B: CSS: Relapsed/refractory Wilms tumor, Germ Cell Tumor, or Neuroblastoma

• Patients must have a life expectancy of ≥ 8 weeks.

• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study:

  1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study. Previous SAHA administration is permitted. Tacrolimus and Sirolimus with levels <= 10 ng/ml are not considered myelosuppressive.
  2. Immunotherapy: Must not have received within 2 weeks of entry onto this study.
  3. Radiation therapy (RT): greater than or equal to 2 weeks for local palliative RT (small port); greater than or equal to 6 months must have elapsed if prior craniospinal RT or if greater than or equal to 50% radiation of pelvis

• Patients may not be enrolled on another clinical trial or receiving any other investigational therapies (within 2 weeks prior to study enrollment).

• Organ Function Requirements

  1. Adequate Bone Marrow Function Defined as:

     1. Peripheral absolute neutrophil count (ANC) greater than or equal to 750/uL
     2. Platelet count greater than or equal to 75,000/uL (transfusion independent defined as no platelet transfusions within 7 days)
     3. Hemoglobin greater than or equal to 8.0 g/dL (may receive red blood cell transfusions)

  2. Adequate Liver Function Defined As:

     1. Total OR direct bilirubin less than or equal to 1.5 x upper limit of normal (ULN) for age, and
     2. Aspartate aminotransferase (AST) or Alanine transaminase (ALT) < 10x ULN

  3. Adequate Renal Function Defined As:

     1. Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 30 mL/min/1.73 m2

• Baseline Audiology Requirements:

  1. Subjects must have a successful audiology examination prior to enrollment. Patients may have Boston grade III or IV hearing loss and still be eligible to enroll as long as they did not receive 3 or more cycles of cisplatin during upfront therapy WITH sodium thiosulfate. There is no specific baseline hearing level/grade requirement beyond that to be eligible, but the baseline level of hearing must be clearly established and recorded

Exclusion Criteria

• Patients with any uncontrolled, intercurrent illness including, but not limited to, uncontrolled infection

• Patients with symptomatic congestive heart failure (defined as Grade 2 or higher heart failure per CTCAE version 5.0)

• Patients with Renal Tubular Acidosis (RTA) as evidenced by serum bicarbonate < 16 mmol/L and serum phosphate ≤ 2 mg/dL (or < 0.8 mmol/L) without supplementation. Patients requiring electrolyte supplementation for RTA will be permitted if bicarbonate ≥16 mmol/L and phosphate > 2mg/dL after at least 7 days of stable supplementation regimen

• Pregnancy and Breastfeeding:

  1. Female patients who are pregnant or breast-feeding will not be entered in the study. A negative pregnancy test within 72 hours of starting therapy is required for female patients of childbearing potential
  2. Lactating females who plan to breastfeed their infants.
  3. Sexually active patients of reproductive potential must agree to use an effective contraceptive method for the duration of their study participation

• Patients on tacrolimus and/or sirolimus with levels of either targeted > 10 ng/mL

• Known allergy to any component of CS or CSS therapy, as indicated

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Stratum 2B- Regimen CSS	Sodium Thiosulfate	Wilms tumor, GCT, Neuroblastoma
Stratum 1- Regimen CS	Sodium Thiosulfate	Cisplatin sensitive/no progression on cisplatin (when given at first diagnosis)
Stratum 2A- Regimen CSS	Sodium Thiosulfate	Cisplatin resistant or progressed on cisplatin after initial response (when given at first diagnosis)

Primary Outcome Measures

Name	Time	Method
Prevention of hearing loss	Through study completion up to 5 years	To demonstrate the efficacy of Sodium Thiosulfate (STS) in preventing hearing loss in patients re-treated with cisplatin-based therapy according to regimens Cisplatin/STS (CS) and Cisplatin/STS/SAHA (CSS)

Secondary Outcome Measures

Name	Time	Method
Prevention of hearing loss and tumor reduction	Through study completion up to 5 years	Number of patients with minimal hearing loss as measure by audiogram evaluations. Number of patients with positive tumor response as measured by Response Evaluation Criteria in Solid Tumors (RECIST).
Number of Participants with Treatment-Related Adverse Events	Through study completion up to 5 years	Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Stratum 1 efficacy	Through study completion up to 5 years	Arm A/CS: To describe the clinical efficacy of CS, as defined by objective response, in patients with relapsed/refractory Hepatoblastoma that was initially sensitive to cisplatin and without progression on cisplatin
Stratum 2 efficacy	Through study completion up to 5 years	To define the clinical efficacy of CSS, as defined by objective response, in patients with initial cisplatin refractory Hepatoblastoma or in patients who progress on cisplatin
Maximum Plasma Concentration [Cmax]	Through study completion up to 5 years	To investigate the concentration of cisplatin in patients with varying degrees of renal dysfunction

Trial Locations

Locations (1)

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States