- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01848457
Preventing Nephrotoxicity and Ototoxicity From Osteosarcoma Therapy
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
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Pennsylvania
-
Philadelphia, Pennsylvania, United States, 19104
- Children's Hospital of Philadelphia
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Supportive Care
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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
|
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 Names:
High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours
Other Names:
|
Experimental: 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
|
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 Names:
High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours
Other Names:
|
Experimental: 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
|
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 Names:
High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours
Other Names:
|
Experimental: 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
|
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 Names:
High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Urinary Biomarkers of Acute Kidney Injury (AKI) Between Pre-Treatment (Baseline), After CISplatin (C) Treatments, and After HDTMX Treatments
Time Frame: Pretreatment/Baseline, Day 2 of Cycles 1 & 2, Day 8 of Cycles 1 & 2
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Tumor Volume
Time Frame: Baseline (Week 1), Pre-operative (Month 2)
|
Response of the primary tumor to the first two treatment cycles (Cycles 1 and 2) will be assessed by quantifying the change in tumor volume on MRI, after treatment (pre-operative) relative to the pre-treatment tumor volume.
By using the log ratio of the tumor volume post-treatment, to the tumor volume pre-treatment.
The larger the change, the more effective the treatment.
|
Baseline (Week 1), Pre-operative (Month 2)
|
Validating Urinary Biomarkers
Time Frame: Day 1 (Pretreatment/Baseline), Day 8, and Day 22 of Cycles 1 & 2
|
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).
Single reported values are averaged and reported with full ranges.
|
Day 1 (Pretreatment/Baseline), Day 8, and Day 22 of Cycles 1 & 2
|
Tissue Microarray
Time Frame: Pretreatment (biopsy) at baseline and postoperative (in between cycle 2 and cycle 3)
|
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.
|
Pretreatment (biopsy) at baseline and postoperative (in between cycle 2 and cycle 3)
|
Bone Specific Alkaline Phosphatase (BSAP)
Time Frame: Pretreatment/Baseline, Cycle 3
|
Serum BSAP will be longitudinally evaluated as a potential biomarker for osteosarcoma
|
Pretreatment/Baseline, Cycle 3
|
Nutritional Status
Time Frame: Prior to each cycle (Day 1 of cycles 1-6) and end of therapy (at the end of cycle 6)
|
Nutritional status (weight, arm circumference, skin fold thickness, pre-albumin) will be throughout the course of treatment
|
Prior to each cycle (Day 1 of cycles 1-6) and end of therapy (at the end of cycle 6)
|
Patient Reported Outcome Survey (PROS)
Time Frame: Baseline, Cycle 2, Surgery, Cycle 3, Cycle 4, Cycle 5, Cycle 6, and End of Therapy
|
PROS survey measures quality of life for pediatric oncology patients, in 17 scaled questions.
Each question scaled 0-4 (0 = Never, 1 = Rarely, 2 = Sometimes, 3 = Often, 4 = Almost Always).
The higher the final sum of the questions, the lower the quality of life/more severe the side effects of oncology treatment.
Total scores can range between 0 = highest quality of life, and 100 = experiencing most severe side effects of oncology treatment/worst quality of life experience.
|
Baseline, Cycle 2, Surgery, Cycle 3, Cycle 4, Cycle 5, Cycle 6, and End of Therapy
|
Ototoxicity
Time Frame: Baseline (Week 1), Day 1 of Cycle 1 (Week 1), Day 1 of Cycle 2(Week 6), Day 1 of Cycle 3(Week 11), Day 1 of Cycle 4 (Week 16), and end of therapy/after the end of cycle 6 (Day 28 of cycle 6, Week 28)
|
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.
|
Baseline (Week 1), Day 1 of Cycle 1 (Week 1), Day 1 of Cycle 2(Week 6), Day 1 of Cycle 3(Week 11), Day 1 of Cycle 4 (Week 16), and end of therapy/after the end of cycle 6 (Day 28 of cycle 6, Week 28)
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Frank M Balis, MD, Children's Hospital of Philadelphia
Publications and helpful links
General Publications
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Chemically-Induced Disorders
- Pathologic Processes
- Neoplasms, Connective and Soft Tissue
- Neoplasms by Histologic Type
- Neoplasms
- Wounds and Injuries
- Otorhinolaryngologic Diseases
- Ear Diseases
- Neoplasms, Bone Tissue
- Neoplasms, Connective Tissue
- Sarcoma
- Drug-Related Side Effects and Adverse Reactions
- Radiation Injuries
- Osteosarcoma
- Ototoxicity
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Antirheumatic Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Gastrointestinal Agents
- Dermatologic Agents
- Reproductive Control Agents
- Anti-Ulcer Agents
- Proton Pump Inhibitors
- Abortifacient Agents, Nonsteroidal
- Abortifacient Agents
- Folic Acid Antagonists
- Methotrexate
- Pantoprazole
Other Study ID Numbers
- 13-009967
- CHP12ST051 OS Pilot (Other Identifier: The Children's Hospital of Philadelphia)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Osteosarcoma
-
Klinikum StuttgartKlinikum Kassel GmbH (COSS-Biobank)Not yet recruitingOsteosarcoma | High Grade Sarcoma | Recurrent Osteosarcoma | Bone Sarcoma | Undifferentiated Pleomorphic Sarcoma | Bone Tumor | Extraskeletal Osteosarcoma | Osseous Sarcoma | Parosteal Osteosarcoma | Osteoblastic Osteosarcoma | Chondroblastic Osteosarcoma | Fibroblastic Osteosarcoma | Conventional Osteosarcoma | Conventional... and other conditions
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Osteosarcoma | Refractory Osteosarcoma | Stage IV Osteosarcoma AJCC v7 | Stage IVA Osteosarcoma AJCC v7 | Stage IVB Osteosarcoma AJCC v7 | Metastatic OsteosarcomaUnited States, Canada, Puerto Rico
-
M.D. Anderson Cancer CenterRecruitingRecurrent Osteosarcoma | Refractory Osteosarcoma | Metastatic Osteosarcoma | Unresectable Osteosarcoma | Locally Advanced OsteosarcomaUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)Not yet recruitingMetastatic Osteosarcoma | Localized Osteosarcoma | Unresectable Osteosarcoma | Resectable Osteosarcoma
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Osteosarcoma | Metastatic Osteosarcoma | Localized Osteosarcoma | Osteoblastic OsteosarcomaUnited States
-
National Cancer Institute (NCI)SuspendedMetastatic Osteosarcoma | Localized Osteosarcoma | High Grade Osteosarcoma | Secondary OsteosarcomaUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Osteosarcoma | Metastatic Osteosarcoma | Localized OsteosarcomaUnited States
-
National Cancer Institute (NCI)Active, not recruitingRecurrent Ewing Sarcoma | Recurrent Osteosarcoma | Stage III Osteosarcoma AJCC v7 | Stage IV Osteosarcoma AJCC v7 | Stage IVA Osteosarcoma AJCC v7 | Stage IVB Osteosarcoma AJCC v7 | Metastatic Osteosarcoma | Metastatic Ewing Sarcoma | Unresectable Ewing Sarcoma | Unresectable OsteosarcomaFrance
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Osteosarcoma | Metastatic Osteosarcoma | Localized OsteosarcomaUnited States
-
Sarcoma Alliance for Research through CollaborationActive, not recruitingOsteosarcoma | Osteosarcoma Recurrent | Osteosarcoma Metastatic | Osteosarcoma in ChildrenUnited States
Clinical Trials on Pantoprazole
-
AbbottCompleted
-
Kwong Wah HospitalCompleted
-
Alexandria UniversityCompletedPortal Hypertension | Variceal Hemorrhage | Ulcer HemorrhageEgypt
-
PfizerRecruitingEsophagitisBelgium, United States, United Kingdom, Serbia, Georgia, Hungary, Bosnia and Herzegovina, Puerto Rico, Turkey, Slovakia, India
-
National Taiwan University HospitalUnknownBleeding | Peptic Ulcer | Endoscopy | Proton Pump InhibitorsTaiwan
-
TakedaWithdrawnGastric pH ControlMexico
-
University of Auckland, New ZealandCompletedBreast Cancer | Chemotherapy-induced Nausea and Vomiting | OncologyNew Zealand
-
Wyeth is now a wholly owned subsidiary of PfizerCompletedGastroesophageal Reflux
-
PfizerTerminatedGastroesophageal Reflux DiseaseUnited States, Bosnia and Herzegovina, Slovakia, Italy, Germany, Argentina, Georgia, Serbia, Ukraine
-
Emory UniversityWyeth is now a wholly owned subsidiary of PfizerCompleted