Preventing Nephrotoxicity and Ototoxicity From Osteosarcoma Therapy

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Children's Hospital of Philadelphia
Sponsor:
Collaborator:
Gateway for Cancer Research
Information provided by (Responsible Party):
Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:
NCT01848457
First received: April 29, 2013
Last updated: May 28, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Osteosarcoma
Nephrotoxicity
Ototoxicity
Drug: Pantoprazole
Drug: High-dose methotrexate infusion duration
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Supportive Care
Official Title: Pilot Study to Prevent Nephrotoxicity of High-Dose Methotrexate by Prolonging the Infusion Duration and Prevent Nephrotoxicity and Ototoxicity of Cisplatin With Pantoprazole in Children, Adolescents and Young Adults With Osteosarcoma

Resource links provided by NLM:


Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • Change of urinary biomarker concentration from pre treatment and 24 hours after cisplatin or High-dose Methotrexate [ Time Frame: pretreatment and 24 hours after cisplatin or high-dose methotrexate ] [ Designated as safety issue: No ]
    Biomarkers of acute kidney injury (urinary KIM-1, NAG, NGAL), glomerular function (serum creatinine, cystatin C), renal tubular function (fractional excretion of Mg)

  • Change of urinary biomarker concentration from pre treatment and 7 days after cisplatin or High-dose Methotrexate [ Time Frame: pretreatment and 7 days after cisplatin or high-dose methotrexate ] [ Designated as safety issue: No ]
    Biomarkers of acute kidney injury (urinary KIM-1, NAG, NGAL), glomerular function (serum creatinine, cystatin C), renal tubular function (fractional excretion of Mg)


Secondary Outcome Measures:
  • Toxicity [ Time Frame: After each treatment cycle (Cycles 1-4 are 29 days and cycles 5-6 are 22 days) ] [ Designated as safety issue: Yes ]
    The incidence and severity (CTCAE grade) of common toxicities from cisplatin/doxorubicin administered with and without pantoprazole as well as from HDMTX administered as a 4 and 12 h infusion will be compared.

  • Response to neoadjuvant therapy [ Time Frame: After each treatment cycle (Cycles 1-4 are 29 days and cycles 5-6 are 22 days) ] [ Designated as safety issue: Yes ]
    Radiographic response (log ratio of pretreatment and pre-operative tumor volumes) and histological response (percent tumor necrosis) to two cycles (10 weeks) of neoadjuvant chemotherapy for the two infusion durations of HDMTX and for cisplatin with and without pantoprazole will be compared.

  • Validating urinary biomarkers [ Time Frame: After each course of cisplatin (day 2 of cycles 1-4) and HDMTX during cycles 1-4 (day 29 of cycles 1-4) ] [ Designated as safety issue: No ]
    Urinary biomarkers of acute kidney injury (AKI) and glomerular filtration rate (GFR) estimated from serum cystatin C will be compared to standard measures of renal function (serum creatinine, urinalysis, estimated creatinine clearance, fractional excretion of Mg).

  • Tissue microarray [ Time Frame: Preteatment (biopsy) at baseline and postoperative (in between cycle 2 and cycle 3) ] [ Designated as safety issue: No ]
    Tissue microarray will be constructed from biopsy specimens, primary resection and resected metastatic tumors to evaluate the expression of proteins that are responsible for resistance to the drugs in the MAP regimen and to assess expression of proteins that are targeted by new anticancer drugs under development for childhood cancers.

  • Bone specific alkaline phosphatase (BSAP) [ Time Frame: Pretreatment (baseline), pre-operative (after cycle 2 and before surgery), post-operative (after surgery), end of therapy (after cycle 6) ] [ Designated as safety issue: No ]
    Serum BSAP will be longitudinally evaluated as a potential biomarker for osteosarcoma

  • Nutritional status [ Time Frame: Prior to each cycle (Day 1 of cycles 1-6) and end of therapy (at the end of cycle 6) ] [ Designated as safety issue: No ]
    Nutritional status (weight, arm circumference, skin fold thickness, pre-albumin) will be throughout the course of treatment

  • Patient reported measure of symptoms [ Time Frame: Baseline, Day 1 of cycle 2, before surgery, Day 1 of cycle 3, Day 1 of cycle 4, Day 1 of cycle 5, Day 1 of cycle 6 and at the end of cycle 6 ] [ Designated as safety issue: No ]
    Pilot an osteosarcoma-specific patient reported outcomes survey to assess the incidence and severity of tumor-related and treatment-related symptoms.

  • Ototoxicity [ Time Frame: Baseline, on Day 1 of cycles 2, 3, 4 and end of therapy (after cycle 6) ] [ Designated as safety issue: No ]
    Average hearing level (HL) threshold in decibels (dB) over the frequency range of 4,000-8,000 hertz (Hz) will be derived separately for each ear from audiograms performed before each dose of cisplatin.


Estimated Enrollment: 24
Study Start Date: April 2013
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
Cycles 1 and 2: HDMTX administered as a 4-hour infusion and pantoprazole is administered with cisplatin Cycles 3 and 4: HDMTX administered as a 12-hour infusion and cisplatin is administered alone
Drug: Pantoprazole
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)
Other Name: Protonix IV
Drug: High-dose methotrexate infusion duration
High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours
Experimental: Arm 2
Cycles 1 and 2: HDMTX administered as a 4-hour infusion and cisplatin is administered alone Cycles 3 and 4: HDMTX administered as a 12-hour infusion and pantoprazole is administered with cisplatin
Drug: Pantoprazole
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)
Other Name: Protonix IV
Drug: High-dose methotrexate infusion duration
High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours
Experimental: Arm 3
Cycles 1 and 2: HDMTX administered as a 12-hour infusion and pantoprazole is administered with cisplatin Cycles 3 and 4: HDMTX administered as a 4-hour infusion and cisplatin is administered alone
Drug: Pantoprazole
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)
Other Name: Protonix IV
Drug: High-dose methotrexate infusion duration
High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours
Experimental: Arm 4
Cycles 1 and 2: HDMTX administered as a 12-hour infusion and cisplatin is administered alone Cycles 3 and 4: HDMTX administered as a 4-hour infusion and pantoprazole is administered with cisplatin
Drug: Pantoprazole
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)
Other Name: Protonix IV
Drug: High-dose methotrexate infusion duration
High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours

Detailed Description:

Current osteosarcoma treatment regimens include cisplatin and high-dose methotrexate (HDMTX), which are nephrotoxic and ototoxic, and the damage to kidneys and cochlear hair cells may be irreversible. Preventing these toxicities will improve the outcome in long-term survivors and may also prevent short-term treatment delays and dose reductions that can compromise the efficacy of the treatment regimen and allow for administration of higher cumulative doses of cisplatin. This pilot study evaluates pharmacologically-based approaches to prevent the nephrotoxic effect of HDMTX by prolonging the infusion duration and thereby lowering the risk of drug precipitation in renal tubules; and to selectively block the uptake of cisplatin into renal tubular cells and cochlear hair cells by inhibiting the organic cation transporter 2 (OCT2) with the proton pump inhibitor (PPI), pantoprazole. Participants with previously untreated biopsy-proven, localized or metastatic osteosarcoma will receive six cycles of the standard MAP chemotherapy regimen, which includes high-dose methotrexate, doxorubicin and cisplatin. The first 2 cycles are administered neoadjuvantly followed by surgery to remove the primary tumor, when feasible.

A novel randomized, crossover, 2 x 2 factorial clinical trial design allows all patients to receive the new interventions to prevent toxicity and to serve as their own controls. New, sensitive urinary biomarkers of acute kidney injury serve as primary endpoints for evaluating treatment-related renal damage. Ototoxicity will be monitored using audiograms. The effect of these interventions on tumor response (radiographic and histologic) and toxicity (including a patient reported outcome survey and nutritional status) will be closely monitored. Other secondary objectives include evaluating bone-specific alkaline phosphatase as a biomarker of tumor burden and constructing a tissue microarray to evaluate expression of proteins that are responsible for resistance to the current drugs used to treat osteosarcoma and assess expression of proteins that are targeted by new anticancer drugs under development for childhood cancers.

  Eligibility

Ages Eligible for Study:   1 Year to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  • Inability to tolerate a PPI
  • Pregnant or breastfeeding
  • Unable to cooperate with research procedures
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01848457

Contacts
Contact: Frank M Balis, MD BalisF@email.chop.edu

Locations
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Sub-Investigator: Rochelle Bagatell, M.D.         
Sub-Investigator: Naomi Balamuth, M.D.         
Sub-Investigator: John P Dormans, M.D.         
Sub-Investigator: Elizabeth Fox, M.D.         
Sub-Investigator: Bruce Pawel, M.D.         
Sub-Investigator: Lisa States, M.D.         
Sub-Investigator: Richard Womer, M.D.         
Sponsors and Collaborators
Children's Hospital of Philadelphia
Gateway for Cancer Research
Investigators
Principal Investigator: Frank M Balis, MD Children's Hospital of Philadelphia
  More Information

No publications provided

Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT01848457     History of Changes
Other Study ID Numbers: 13-009967, CHP12ST051 OS Pilot
Study First Received: April 29, 2013
Last Updated: May 28, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Children's Hospital of Philadelphia:
Osteosarcoma
Cancer
Nephrotoxicity
Ototoxicity
Cisplatin
High-dose methotrexate
Biomarkers
Patient reported outcomes

Additional relevant MeSH terms:
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sarcoma
Cisplatin
Methotrexate
Pantoprazole
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Anti-Ulcer Agents
Gastrointestinal Agents

ClinicalTrials.gov processed this record on September 15, 2014