Sodium Thiosulfate Otoprotection During Salvage Cisplatin Therapy

Cisplatin and Sodium Thiosulfate Otoprotection With or Without SAHA/Vorinostat Histone Deacetylase Inhibition for Relapsed/Refractory Hepatoblastoma and Other Embryonal Tumors

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).

Study Overview

• Status: Recruiting
• Conditions: Ototoxicity, Drug-Induced
• Intervention / Treatment: Drug: Sodium Thiosulfate

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 Type: Interventional
• Enrollment (Estimated): 33
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Site Contact Cincinnati Children's Hospital Medical Center; Phone Number: 513-636-2799; Email: cancer@cchmc.org

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Principal Investigator: James Geller, MD
      • Contact: Site Public Contact; Phone Number: 513-636-2799; Email: cancer@cchmc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 39 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stratum 1- Regimen CS; Cisplatin sensitive/no progression on cisplatin (when given at first diagnosis)	Drug: Sodium Thiosulfate; This goal of this study is to evaluate the efficacy of the proposed regimens in patients with relapsed/refractory platinum pre-treated patients with Hepatoblastoma, Wilms tumor, Germ Cell Tumor (GCT), and Neuroblastoma. The patients' initial cisplatin response (hepatoblastoma) and diagnosis will determine their treatment regimen on this study.; Other Names: Cisplatin; Vorinostat/ SAHA
Experimental: Stratum 2A- Regimen CSS; Cisplatin resistant or progressed on cisplatin after initial response (when given at first diagnosis)	Drug: Sodium Thiosulfate; This goal of this study is to evaluate the efficacy of the proposed regimens in patients with relapsed/refractory platinum pre-treated patients with Hepatoblastoma, Wilms tumor, Germ Cell Tumor (GCT), and Neuroblastoma. The patients' initial cisplatin response (hepatoblastoma) and diagnosis will determine their treatment regimen on this study.; Other Names: Cisplatin; Vorinostat/ SAHA
Experimental: Stratum 2B- Regimen CSS; Wilms tumor, GCT, Neuroblastoma	Drug: Sodium Thiosulfate; This goal of this study is to evaluate the efficacy of the proposed regimens in patients with relapsed/refractory platinum pre-treated patients with Hepatoblastoma, Wilms tumor, Germ Cell Tumor (GCT), and Neuroblastoma. The patients' initial cisplatin response (hepatoblastoma) and diagnosis will determine their treatment regimen on this study.; Other Names: Cisplatin; Vorinostat/ SAHA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevention of hearing loss	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)	Through study completion up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevention of hearing loss and tumor reduction	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).	Through study completion up to 5 years
Number of Participants with Treatment-Related Adverse Events	Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0	Through study completion up to 5 years
Maximum Plasma Concentration [Cmax]	To investigate the concentration of cisplatin in patients with varying degrees of renal dysfunction	Through study completion up to 5 years
Stratum 1 efficacy	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	Through study completion up to 5 years
Stratum 2 efficacy	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	Through study completion up to 5 years

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: James Geller, MD, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

Helpful Links

• Cincinnati Children's Hospital Medical Center home page

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2023
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: February 9, 2023
• First Submitted That Met QC Criteria: March 2, 2023
• First Posted (Actual): March 6, 2023

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 16, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Cisplatin; Sodium Thiosulfate; Embryonal Tumor; Relapsed/Refractory Hepatoblastoma; PedMark
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Wounds and Injuries; Otorhinolaryngologic Diseases; Ear Diseases; Neoplasms, Complex and Mixed; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Ototoxicity; Hepatoblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Anti-Bacterial Agents; Antioxidants; Antidotes; Antitubercular Agents; Chelating Agents; Sequestering Agents; Histone Deacetylase Inhibitors; Cisplatin; Vorinostat; Sodium thiosulfate
• Other Study ID Numbers: CSS-JG-2201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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