Preventing Nephrotoxicity and Ototoxicity From Osteosarcoma Therapy
Condition: Osteosarcoma; Nephrotoxicity; Ototoxicity
MeSH terms: Osteosarcoma; Ototoxicity
Intervention: Pantoprazole; High-dose methotrexate infusion duration
Intervention description: 0.3 mg/kg IV over 15 min immediately prior to cisplatin as a loading dose on days 1 & 2 followed by 1.3 mg/kg IV infused over 4 h concurrent with the 4 h cisplatin infusion on days 1 & 2 of treatment Cycles 1 & 2 (Treatment Arms 1, 3) OR Cycles 3 & 4 (Treatment Arms 2, 4); High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours
Intervention MeSH terms: Methotrexate; Pantoprazole
Phase: Phase 2
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Maximum age: 30 Years
Healthy volunteers: No
Keywords: Osteosarcoma; Cancer; Nephrotoxicity; Ototoxicity; Cisplatin; High-dose methotrexate; Biomarkers; Patient reported outcomes

Summary:

      Osteosarcoma is the most common type of bone cancer in children, adolescents and young
      adults. Treatment with surgery and a combination of three conventional chemotherapy drugs can
      cure nearly two-thirds patients with osteosarcoma, but the treatment can also cause
      irreversible damage to the kidneys and cause permanent hearing loss. The purpose of this
      study is to evaluate new approaches to prevent these side effects without interfering with
      the beneficial effects of the chemotherapy drugs on the cancer by using our knowledge of how
      the drugs damage the kidney and cochlear hair cells in the ear to selectively block these
      side effects. Preventing these side effects without interfering with the anti-cancer effect
      of the drugs will improve the outcome in survivors and may also improve the effectiveness of
      the chemotherapy regimen by preventing treatment delays and dose reductions that are often
      caused by the side effects. Patients will be carefully monitored to ensure that the new
      interventions do not adversely affect response to the treatment and do not increase the other
      side effects of the chemotherapy. Specifically, we will monitor the nutritional status of the
      patients closely and ask patients to complete a survey describing the side effects after each
      treatment cycle. We will also collect a small sample of cancer tissue at the time of biopsy
      and surgery from each patient on this study for testing to determine new classes of
      anti-cancer drugs currently under development may have a role in treating osteosarcoma. If
      effective, these new approaches to prevent kidney damage and hearing loss will be applicable
      in other types of cancers treated with the same chemotherapy drugs.
    

Eligibility criteria:

        Inclusion Criteria:

          -  <30 years of age

          -  histological diagnosis of high-grade osteosarcoma

          -  Extremity or central axis (including craniofacial) primary tumor; localized or
             metastatic

          -  No prior chemotherapy or radiation therapy for osteosarcoma. Subjects who develop
             osteosarcoma as a second cancer are eligible if they have not previously received
             cisplatin, doxorubicin or other anthracyclines, or MTX

          -  Serum creatinine at or below the upper limit of normal (ULN) for age and gender

          -  Shortening fraction on echocardiogram >28%

          -  Hearing level threshold ≤25 dB at all frequencies in both ears to be evaluable for
             evaluation of pantoprazole's effect on cisplatin ototoxicity. Patients with hearing
             loss can be enrolled but will not be evaluable for ototoxicity objective.

          -  Absolute neutrophil count >1,000/microliter(mcL) and platelet count >100,000/mcL

        Exclusion Criteria:

          -  Receiving H2 antagonists (cimetidine, ranitidine, famotidine, nizatidine) or proton
             pump inhibitors (lansoprazole, omeprazole, pantoprazole, esomeprazole, rabeprazole,
             dexlansoprazole) AND unable to hold the drug for 24 h prior to and 24 h after each
             cisplatin course on cycles 1-4.

          -  Pregnant or breastfeeding

          -  Unable to cooperate with research procedures