Preventing Nephrotoxicity and Ototoxicity From Osteosarcoma Therapy

Study Overview
=================
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.

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

Conditions
-----------------
Osteosarcoma, Nephrotoxicity, Ototoxicity

Intervention / Treatment
-----------------
* Drug: Pantoprazole
* Drug: High-dose methotrexate infusion duration


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Maximum Age: 30 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention 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<br>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<br>* 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)<br>* Other names: Protonix IV;Drug: High-dose methotrexate infusion duration<br>* High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours<br>* Other names: Otrexup (PF), Xatmep, Trexall;|
| Experimental: Cycles 1 & 2: HDMTX 4 h, C; Cycles 3 & 4: HDMTX 12 h, PTZ + C<br>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<br>* 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)<br>* Other names: Protonix IV;Drug: High-dose methotrexate infusion duration<br>* High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours<br>* Other names: Otrexup (PF), Xatmep, Trexall;|
| Experimental: Cycles 1 & 2: HDMTX 12 h, PTZ+C; Cycles 3 & 4: HDMTX 4 h, C<br>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<br>* 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)<br>* Other names: Protonix IV;Drug: High-dose methotrexate infusion duration<br>* High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours<br>* Other names: Otrexup (PF), Xatmep, Trexall;|
| Experimental: Cycles 1 & 2: HDMTX 12 h, C; Cycles 3 & 4: HDMTX 4 h, C + PTZ<br>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<br>* 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)<br>* Other names: Protonix IV;Drug: High-dose methotrexate infusion duration<br>* High-dose methotrexate (12 g/sq m, maximum dose 20 g) will be infused over 4 hours or 12 hours<br>* Other names: Otrexup (PF), Xatmep, Trexall;|

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 | 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 | 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 | 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 | 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) | Serum BSAP will be longitudinally evaluated as a potential biomarker for osteosarcoma | Pretreatment/Baseline, Cycle 3 | 
| Nutritional Status | 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) | 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 | 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Osteosarcoma, Cancer, Nephrotoxicity, Ototoxicity, Cisplatin, High-dose methotrexate, Biomarkers, Patient reported outcomes