Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors

PRIMARY OBJECTIVE:

I. Evaluate the incidence of clinically meaningful ototoxicity in adults with metastatic germ cell tumor (GCT) receiving sodium thiosulfate anhydrous (Pedmark) plus cisplatin-based chemotherapy compared to those receiving cisplatin-based chemotherapy alone.

SECONDARY OBJECTIVES:

I. Assess the incidence of high-frequency ototoxicity (affecting frequencies within 8000-12,500 Hz) between adults in both arms.

II. Assess the severity and progression of ototoxicity between adults in both arms.

III. Determine the safety and tolerability of Pedmark plus cisplatin-based chemotherapy compared to cisplatin-based chemotherapy alone.

IV. Examine the efficacy of Pedmark plus cisplatin-based chemotherapy compared to cisplatin-based chemotherapy alone.

EXPLORATORY OBJECTIVES:

I. Evaluate the incidence of tinnitus between adults in both arms. II. Disease assessment 6 months post-primary treatment in both arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive cisplatin intravenously (IV) over 60 minutes on days 1-5 or 2-5 of each standard of care (SOC) cisplatin-based chemotherapy regimen cycle. Cycles repeat every 21 days for 3-4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the trial.

ARM II: Patients receive cisplatin IV over 60 minutes on days 1-5 or 2-5 of each SOC cisplatin-based chemotherapy regimen cycle. Patients also receive Pedmark IV over 30 minutes, 6 hours after each SOC cisplatin infusion, on days 1-5 or 2-5 of each cycle. Cycles repeat every 21 days for 3-4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year and then per SOC for year 2.

Inclusion criteria

• Documented informed consent of the participant and/or legally authorized representative

• Assent, when appropriate, will be obtained per institutional guidelines
• Willing and able to sign informed consent form
• Willing and able to participate in baseline and serial audiometry exams
• Age: ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) of 0 or 1 or Karnofsky score ≥ 70
• Histologically confirmed germ cell tumor (seminoma or non-seminoma)
• Presence of metastatic disease (stage II or III)
• Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
• Receiving first or second line cisplatin-based chemotherapy
• Planned cumulative cisplatin dose of ≥ 300mg/m^2 (including previous treatment)
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Absolute neutrophil count (ANC) ≥ 1,500/mm^3
• Platelets ≥ 100,000/mm^3

• NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
• Hemoglobin ≥ 9g/dL

• NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment unless cytopenia is secondary to disease involvement
• Total bilirubin ≤ 1.5 X upper limit of normal (ULN)

• Patients with known Gilbert disease who have serum bilirubin level < 3 x ULN may be enrolled
• Aspartate aminotransferase (AST) ≤ 3.0 x ULN
• Alanine aminotransferase (ALT) ≤ 3.0 x ULN
• Creatinine clearance of ≥ 60 mL/min per the Cockcroft-Gault formula or serum creatinine ≤ 1.5 x ULN
• * If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN

• If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
• * If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN

• If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months after the last dose of cisplatin for injection

Exclusion criteria

• Any cisplatin-based therapies within 4 weeks prior to initiation of study treatment
• If cisplatin infusion during study is planned to be longer than 6 hours, as Pedmark safety and efficacy has not been established when administered following longer cisplatin infusions
• Chronic steroid use, defined as greater than prednisone 5 mg daily for longer than 21 days (steroids used as antiemetic during treatment is permitted)
• Concurrent use of other ototoxic drugs other than cisplatin (loop diuretics, aminoglycosides, etc)
• Patient must adhere to low sodium diet given other comorbidities
• History of severe hypersensitivity to sodium thiosulfate or any components such as sulfites or thiols
• Known symptomatic brain metastases, leptomeningeal carcinomatosis, or prior cranial irradiation
• Deemed cisplatin ineligible due to poor performance status, cardiac dysfunction, renal insufficiency, or significant peripheral neuropathy
• Greater than or equal to moderate hearing loss (HL) at baseline per World Health Organization (WHO) classification
• Unstable cardiac disease as defined by one of the following:

• Cardiac events such as myocardial infarction (MI) within the past 6 months
• NYHA (New York Heart Association) heart failure class III-IV
• Uncontrolled atrial fibrillation or hypertension
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)