Preventing Nephrotoxicity and Ototoxicity From Osteosarcoma Therapy

NCT ID: NCT01848457

Last Updated: 2020-03-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-04-30
• Study Completion Date: 2016-10-01

Brief 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.

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 Methotrexate, Adriamycin (doxorubicin),cisplatin (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.

Conditions

Osteosarcoma; Nephrotoxicity; Ototoxicity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: NONE

Study Groups

Cycles 1 & 2: HDMTX 4 h, PTZ+C; Cycles 3 & 4: HDMTX 12 h, C

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

Group Type: EXPERIMENTAL

Pantoprazole

Intervention Type: DRUG

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 infusion duration

Intervention Type: DRUG

High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours

Cycles 1 & 2: HDMTX 4 h, C; Cycles 3 & 4: HDMTX 12 h, PTZ + C

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

Group Type: EXPERIMENTAL

Pantoprazole

Intervention Type: DRUG

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 infusion duration

Intervention Type: DRUG

High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours

Cycles 1 & 2: HDMTX 12 h, PTZ+C; Cycles 3 & 4: HDMTX 4 h, C

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

Group Type: EXPERIMENTAL

Pantoprazole

Intervention Type: DRUG

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 infusion duration

Intervention Type: DRUG

High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours

Cycles 1 & 2: HDMTX 12 h, C; Cycles 3 & 4: HDMTX 4 h, C + PTZ

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

Group Type: EXPERIMENTAL

Pantoprazole

Intervention Type: DRUG

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 infusion duration

Intervention Type: DRUG

High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours

Interventions

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)

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Protonix IV; Otrexup (PF), Xatmep, Trexall

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

• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gateway for Cancer Research

OTHER

Sponsor Role: collaborator

Children's Hospital of Philadelphia

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Frank M Balis, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia

Locations

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Countries

United States

References

Fox E, Busch C, DeBernardo A, Segers B, Gottschalk J, Womer R, Balamuth N, Bagatell R, Balis F. A pharmacologically-based approach to high dose methotrexate administration to investigate nephrotoxicity and acute kidney injury biomarkers in children and adolescents with newly diagnosed osteosarcoma. Cancer Chemother Pharmacol. 2021 Jun;87(6):807-815. doi: 10.1007/s00280-021-04248-8. Epub 2021 Mar 7.

Reference Type: DERIVED

PMID: 33677616 (View on PubMed)

Fox E, Levin K, Zhu Y, Segers B, Balamuth N, Womer R, Bagatell R, Balis F. Pantoprazole, an Inhibitor of the Organic Cation Transporter 2, Does Not Ameliorate Cisplatin-Related Ototoxicity or Nephrotoxicity in Children and Adolescents with Newly Diagnosed Osteosarcoma Treated with Methotrexate, Doxorubicin, and Cisplatin. Oncologist. 2018 Jul;23(7):762-e79. doi: 10.1634/theoncologist.2018-0037. Epub 2018 Feb 14.

Reference Type: DERIVED

PMID: 29445029 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

CHP12ST051 OS Pilot

Identifier Type: OTHER

Identifier Source: secondary_id

13-009967

Identifier Type: -

Identifier Source: org_study_id