A Phase 2 interventional study of Pantoprazole and High-dose methotrexate infusion duration in Osteosarcoma, Nephrotoxicity and Ototoxicity, sponsored by Children's Hospital of Philadelphia. Completed at 1 site in United States. Open to participants aged Up to 30 Years. Per ClinicalTrials.gov, last updated 2020-03-16.
Sponsored by Children's Hospital of Philadelphia · Phase 2, Interventional, and Supportive care
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.
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.
488 studies on the registry are indexed under Osteosarcoma; 124 are open to participants now.
This study's enrollment of 13 is below the median of 40 across 354 interventional studies indexed under Osteosarcoma.
Browse Osteosarcoma studies →Children's Hospital of Philadelphia is the lead sponsor of 489 studies on the registry; 90 are open to participants now.
Of its 28 completed or terminated interventional studies of FDA-regulated products, 22 (79%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Metastases
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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 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 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 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
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
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
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).
Time frame: Pretreatment/Baseline, Day 2 of Cycles 1 & 2, Day 8 of Cycles 1 & 2
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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: Pretreatment/Baseline, Cycle 3
Nutritional Status
Nutritional status (weight, arm circumference, skin fold thickness, pre-albumin) will be throughout the course of treatment
Time frame: 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.
Time frame: 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.
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)
| Milestone | Cycles 1 & 2: HDMTX 4h, PTZ+C; Then Cycles 3 & 4: HDTMX 12h, C | Cycles 1 & 2: HDMTX 4h, C; Then Cycles 3 & 4: HDTMX 12h, C+PTZ | Cycles 1 & 2: HDMTX 12h, PTZ+C; Then Cycles 3 & 4: HDTMX 4h, C | Cycles 1 & 2: HDMTX 12h, C; Then Cycles 3 & 4: HDTMX 4h, C+PTZ |
|---|---|---|---|---|
| Started | 4 | 3 | 3 | 3 |
| Baseline | 4 | 3 | 3 | 3 |
| Cycle 1 | 4 | 3 | 3 | 3 |
| Cycle 2 | 3 | 3 | 3 | 3 |
| Cycle 3 | 3 | 3 | 3 | 3 |
| Cycle 4 | 3 | 3 | 3 | 3 |
| Completed | 3 | 3 | 3 | 3 |
| Not completed | 1 | 0 | 0 | 0 |
| Withdrew: Death | 1 | 0 | 0 | 0 |
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).
| μg/g | Treatments Arms 1 & 3 (Groups With PTZ in Cycles 1 & 2) | Treatments Arms 2 & 4 (Groups Without PTZ in Cycles 1 & 2) |
|---|---|---|
| Day 1 Kim-1 (Pretreatment) | 1.7 (0.5 to 5.9) | 1.7 (0.3 to 15) |
| Day 2 Kim-1 (post 2 doses Cisplatin) | 2.1 (0.2 to 182) | 3.3 (0.2 to 8.1) |
| Day 8 Kim-1 (post HDTMX infusion) | 4.1 (0.5 to 11) | 4.6 (0.4 to 11) |
| Day 1 NGAL (Pretreatment) | 18 (2 to 900) | 10 (2.9 to 165) |
| Day 2 NGAL (post 2 doses Cisplatin) | 27 (2.6 to 542) | 18 (1.1 to 209) |
| Day 8 NGAL (post HDTMX infusion) | 12 (2.2 to 1193) | 12 (1.6 to 841) |
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.
| Participants | Localized Disease at Baseline | Metastatic Disease at Baseline |
|---|---|---|
| Complete Response to Chemotherapy | 9 | 0 |
| Progressive Disease after Chemotherapy | 0 | 4 |
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.
| mL/min per 1.73m2 | Treatment Arms 1, 3 (w/ Pantoprazole) | Treatment Arms 2, 4 (w/o Pantoprazole) |
|---|---|---|
| Day 1 GFRcr (pretreatment) | 131 (96 to 252) | 132 (95 to 252) |
| Day 8 GFRcr | 120 (81 to 252) | 124 (81 to 252) |
| Day 22 GFRcr | 134 (96 to 252) | 141 (64 to 252) |
| Day 1 GFRcysC (pretreatment) | 126 (89 to 169) | 120 (87 to 180) |
| Day 8 GFRcysC | 105 (78 to 193) | 109 (72 to 186) |
| Day 22 GFRcysC | 122 (94 to 160) | 125 (77 to 176) |
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.
No measurements were reported for this outcome.
Serum BSAP will be longitudinally evaluated as a potential biomarker for osteosarcoma
| U/L | Arm 1 | Arm 2 | Arm 3 | Arm 4 |
|---|---|---|---|---|
| Pretreatment (baseline) | 197.1 (40.2 to 354) | 265 (106 to 557) | 169.67 (111 to 265) | 179.63 (66.7 to 398) |
| Cycle 3 | 73.05 (46.1 to 100) | 106.87 (18.6 to 193) | 71.2 (26.1 to 137) | 76.1 (44.6 to 125) |
Nutritional status (weight, arm circumference, skin fold thickness, pre-albumin) will be throughout the course of treatment
No measurements were reported for this outcome.
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.
| score on a scale | All Study Participants (Arms 1-4) |
|---|---|
| Baseline | 23 (16 to 43) |
| Cycle 2 | 30 (17 to 46) |
| Surgery | 22 (10 to 30) |
| Cycle 3 | 24 (4 to 34) |
| Cycle 4 | 24 (7 to 42) |
| Cycle 5 | 19 (9 to 32) |
| Cycle 6 | 20 (5 to 32) |
| End of Therapy | 17 (12 to 23) |
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.
| decibels | Treatment Arms 1, 3 (w/ Pantoprazole) | Treatment Arms 2, 4 (w/o Pantoprazole) |
|---|---|---|
| Baseline Right Ear | 3.6 (0.0 to 8.3) | 3.8 (1.7 to 6.7) |
| Baseline Left Ear | 3.3 (0.0 to 5.0) | 5.4 (1.7 to 10) |
| End of Therapy Right Ear | 34.6 (11.7 to 58.3) | 26.7 (10 to 41.7) |
| End of Therapy Left Ear | 35.0 (23.3 to 58.3) | 26.7 (10 to 41.7) |
Collected over Adverse events are tracked from the time of the first subject's enrollment, until completion of study therapy of the last enrolled subject, spanning 3.5 years. Each treatment cycle is 4-5 weeks, and there are 6 treatment cycles per subject (24-30 weeks of treatment cycles). In addition, surgery recovery after Cycle 2 is 1-2 weeks. Each fully evaluable subject participated in the study 25-32 weeks (6-8 months).. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Arm 1 | 1/4 (25%) | 0/4 (0%) | 0/4 (0%) |
| Arm 2 | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) |
| Arm 3 | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) |
| Arm 4 | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) |
| Age, Categorical(Participants) | Arm 1 | Arm 2 | Arm 3 | Arm 4 | Total |
|---|---|---|---|---|---|
| <=18 years | 4 | 3 | 2 | 3 | 12 |
| Between 18 and 65 years | 0 | 0 | 1 | 0 | 1 |
| >=65 years | 0 | 0 | 0 | 0 | 0 |
| Age, Continuous(years) | Arm 1 | Arm 2 | Arm 3 | Arm 4 | Total |
|---|---|---|---|---|---|
| Mean | 14.3 (9 to 17) | 10.3 (5 to 17) | 8.3 (6 to 19) | 10.7 (7 to 14) | 11.4 (5 to 19) |
| Sex: Female, Male(Participants) | Arm 1 | Arm 2 | Arm 3 | Arm 4 | Total |
|---|---|---|---|---|---|
| Female | 2 | 3 | 2 | 1 | 8 |
| Male | 2 | 0 | 1 | 2 | 5 |
| Ethnicity (NIH/OMB)(Participants) | Arm 1 | Arm 2 | Arm 3 | Arm 4 | Total |
|---|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 | 0 | 0 |
| Not Hispanic or Latino | 4 | 3 | 3 | 3 | 13 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 |
| Region of Enrollment(participants) | Arm 1 | Arm 2 | Arm 3 | Arm 4 | Total |
|---|---|---|---|---|---|
| United States | 4 | 3 | 3 | 3 | 13 |
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Studies of the drug tested here: Pantoprazole
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