Preventing Nephrotoxicity and Ototoxicity From Osteosarcoma Therapy

NCT01848457 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 13-009967CHP12ST051 OS Pilot
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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.

Conditions

Osteosarcoma; Nephrotoxicity; Ototoxicity

Keywords

Osteosarcoma; Cancer; Nephrotoxicity; Ototoxicity; Cisplatin; High-dose methotrexate; Biomarkers; Patient reported outcomes

Outcome Measures

Primary Outcomes (1)

• Change in Urinary Biomarkers of Acute Kidney Injury (AKI) Between Pre-Treatment (Baseline), After CISplatin (C) Treatments, and After HDTMX Treatments

  This measure describes the urinary biomarkers of AKI after each course of C throughout Cycles 1-2, compared to baseline (pre-infusion) values. Biomarkers of AKI, include: Kidney Injury Molecule-1 (KIM-1), and Neutrophil Gelatinase-Associated Lipocalin (NGAL).

  Pretreatment/Baseline, Day 2 of Cycles 1 & 2, Day 8 of Cycles 1 & 2

Secondary Outcomes (7)

• Change in Tumor Volume

  Baseline (Week 1), Pre-operative (Month 2)

• Validating Urinary Biomarkers

  Day 1 (Pretreatment/Baseline), Day 8, and Day 22 of Cycles 1 & 2

• Tissue Microarray

  Pretreatment (biopsy) at baseline and postoperative (in between cycle 2 and cycle 3)

• Bone Specific Alkaline Phosphatase (BSAP)

  Pretreatment/Baseline, Cycle 3

• Nutritional Status

  Prior to each cycle (Day 1 of cycles 1-6) and end of therapy (at the end of cycle 6)

Study Arms (4)

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

EXPERIMENTAL

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; Drug: High-dose methotrexate infusion duration

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

EXPERIMENTAL

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; Drug: High-dose methotrexate infusion duration

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

EXPERIMENTAL

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; Drug: High-dose methotrexate infusion duration

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

EXPERIMENTAL

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; Drug: High-dose methotrexate infusion duration

Interventions

Pantoprazole 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)

Also known as: Protonix IV

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

High-dose methotrexate infusion duration DRUG

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

Also known as: Otrexup (PF), Xatmep, Trexall

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

Eligibility Criteria

• Age: Up to 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• \<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

You may not qualify if:

• 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

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead
• Gateway for Cancer Research: collaborator

Study Sites (1)

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (2)

• 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.

  PMID: 33677616 DERIVED

• 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.

  PMID: 29445029 DERIVED

MeSH Terms

Conditions

Osteosarcoma; Ototoxicity; Neoplasms

Interventions

Pantoprazole; Methotrexate

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Sarcoma; Ear Diseases; Otorhinolaryngologic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries

Intervention Hierarchy (Ancestors)

2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Aminopterin; Pterins; Pteridines

Results Point of Contact

• Title: Frank Balis, MD
• Organization: The Children's Hospital of Philadelphia

balisf@email.chop.edu

2674265414

Study Officials

• Frank M Balis, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2013
• First Posted: May 7, 2013
• Study Start: April 1, 2013
• Primary Completion: January 4, 2016
• Study Completion: October 1, 2016
• Last Updated: March 16, 2020
• Results First Posted: March 16, 2020

Record last verified: 2020-03

Locations

US (1)