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Glucarpidase After High-Dose Methotrexate in Patients With Osteosarcoma

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ClinicalTrials.gov Identifier: NCT03960177
Recruitment Status : Recruiting
First Posted : May 22, 2019
Last Update Posted : June 29, 2021
Sponsor:
Collaborators:
BTG International Inc.
Oregon Health and Science University
Information provided by (Responsible Party):
Lara Davis, OHSU Knight Cancer Institute

Tracking Information
First Submitted Date  ICMJE May 13, 2019
First Posted Date  ICMJE May 22, 2019
Last Update Posted Date June 29, 2021
Actual Study Start Date  ICMJE March 27, 2019
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 21, 2019)
Proportion of subjects completing 4 planned doses of high dose methotrexate (HDMTX) [ Time Frame: Time from first dose of HDMTX to time of last dose of HDMTX (week 10) ]
Will be estimated with an exact 95% confidence interval (CI).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 25, 2021)
  • Length of hospital stay (LOS) for methotrexate (MTX) clearance [ Time Frame: Time of start of MTX administration to time of MTX =< 0.1uM sample collection for each planned MTX infusion (up to 15 days) ]
  • LOS for all causes (excluding MTX-related AEs) [ Time Frame: Date of admission for each planned MTX infusion to date of discharge for each planned MTX infusion (up to 15 days) ]
  • Length of hospital stay (LOS) for methotrexate (MTX)-related adverse events (AEs) [ Time Frame: Date of admission for each planned MTX infusion to date of discharge for each planned MTX infusion (up to 15 days) ]
  • Percent treatment effect at resection [ Time Frame: From start of surgery until end of surgery ]
    Defined as an admixture of degenerating wispy osteoid matrix with empty lacunae, necrotic ghost cells, and edematous stroma with loose fibrous tissue. Dense fibrosis or hyalinization or sheets of sclerotic acellular osteoid may also be present. These features are quantified by estimating the percentage of each parameter in each tumor slide and calculating the mean based on the total number of tumor slides examined. The percentage of tumor necrosis or treatment effect will be recorded from each participant's surgical pathology report.
  • Incidence of glucarpidase hypersensitivity [ Time Frame: From first dose of glucarpidase until 30 days after last dose of glucarpidase ]
    Will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Will be determined for participants that received at least 1 dose of glucarpidase following an HDMTX infusion. The 95% CI will be reported with the point estimate of toxicity rate.
  • Incidence of glucarpidase neutralizing antibodies [ Time Frame: From first dose of glucarpidase to 30 days after last dose of glucarpidase ]
    Will be determined for participants that received at least 1 dose of glucarpidase following an HDMTX infusion. The 95% CI will be reported with the point estimate of toxicity rate.
  • Incidence and severity of MTX-related toxicities [ Time Frame: From start of first planned MTX infusion to 30 days after last dose of MTX ]
    Will be assessed according to CTCAE v 5.0. Will be determined for participants that received at least 1 dose of glucarpidase following an HDMTX infusion. The 95% CI will be reported with the point estimate of toxicity rate.
  • Incidence and severity of glucarpidase toxicities [ Time Frame: From first dose of glucarpidase to 30 days after last dose of glucarpidase ]
    Will be assessed according to CTCAE v 5.0. Will be determined for participants that received at least 1 dose of glucarpidase following an HDMTX infusion. The 95% CI will be reported with the point estimate of toxicity rate.
  • MTX and DAMPA serum concentration (umol/L) at 4, 24, 24.5, 36, 48 and every 24 hours after the start of MTX infusion [ Time Frame: From start of each planned MTX infusion to time when MTX =< 0.1 uM (for each planned MTX infusion) (up to 15 days) ]
  • Proportion of glucarpidase doses (flat dose) that result in MTX serum concentration reduction of >= 97% from hour 24 to hour 24.5 [ Time Frame: From first dose of glucarpidase to end of study treatment (week 10) ]
    Will be presented along with 95% confidence intervals. Summary statistics will be reported on the efficacy analysis set with sub-analyses stratified by glucarpidase dose.
  • Proportion of glucarpidase doses (flat dose) that result in 48 hour serum MTX level < 1 uM [ Time Frame: From first dose of glucarpidase to end of study treatment (week 10) ]
    Will be presented along with 95% confidence intervals. Summary statistics will be reported on the efficacy analysis set with sub-analyses stratified by glucarpidase dose.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 21, 2019)
  • Length of hospital stay (LOS) for methotrexate (MTX)-related adverse events (AEs) [ Time Frame: Date of admission for each planned MTX infusion to date of discharge for each planned MTX infusion (up to 15 days) ]
  • LOS for all causes (excluding MTX-related AEs) [ Time Frame: Date of admission for each planned MTX infusion to date of discharge for each planned MTX infusion (up to 15 days) ]
  • MTX and 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) serum concentration (umol/L) at 4, 24, 24.5, 36, 48, 72 hours after start of MTX infusion [ Time Frame: Start of each planned MTX infusion until the time when MTX =< 0.1 uM following each planned MTX infusion (up to 72 hours) ]
  • Average percent tumor necrosis at resection [ Time Frame: Start of surgery to end of surgery ]
    Tumor necrosis is defined as areas occupied by ghost cells, cellular debris, and empty lacunar spaces, and excluded areas of hemorrhage, fibrosis, and extracellular matrix. These features are quantified by estimating the percentage of each parameter in each tumor slide and calculating the mean based on the total number of tumor slides examined. The percentage of tumor necrosis will be recorded from each participant's surgical pathology report.
  • Incidence of MTX-related dose limiting toxicities (DLTs) [ Time Frame: Start of first planned MTX infusion until 30 days after last dose of glucarpidase ]
    DLTs are defined as time to serum MTX level =< 0.1 uM exceeding 7 days, serum creatinine > 3 x upper limit of normal or estimated glomerular filtration rate < 30 mL/min, grade 3 or higher mucositis, or any grade 4 toxicity. The 95% CI will be reported with the point estimate of toxicity rate.
  • Incidence of glucarpidase hypersensitivity [ Time Frame: First dose of glucarpidase until 30 days after last dose of glucarpidase ]
    Assessed by Common Terminology Criteria for Adverse Events version 5.0. The 95% CI will be reported with the point estimate of toxicity rate.
  • Incidence of glucarpidase neutralizing antibodies [ Time Frame: First dose of glucarpidase until end of study treatment (week 10) ]
    Will be summarized using descriptive statistics such as mean (standard deviation), median (IQR), and proportion (95% exact binomial CI).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Glucarpidase After High-Dose Methotrexate in Patients With Osteosarcoma
Official Title  ICMJE An Open-Label, Multi-Institutional Pilot Study to Assess the Use of Glucarpidase in Adult Patients With Osteosarcoma Receiving High-Dose Methotrexate
Brief Summary This early phase I trial studies how well glucarpidase works in reducing toxicity in patients with osteosarcoma receiving high dose methotrexate treatment. Glucarpidase may reduce the levels of methotrexate in patients' blood and lead to shorter hospitalizations and a reduction in toxicities.
Detailed Description

PRIMARY OBJECTIVE:

I. To determine the rate of completion of 4 planned high dose methotrexate (HDMTX) doses when glucarpidase is administered after each dose.

SECONDARY OBJECTIVES:

I. To assess the length of hospital stay (LOS) associated with methotrexate (MTX) clearance following administration of glucarpidase 24 hours after HDMTX.

II. To assess the LOS associated with all causes following administration of glucarpidase 24 hours after HDMTX.

III. To assess the impact of glucarpidase administration on HDMTX efficacy. IV. To assess the safety and tolerability of 4 doses of HDMTX administered with glucarpidase in an adult osteosarcoma population.

V. To assess the efficacy of glucarpidase flat dose of 1,000 units.

OUTLINE:

Patients receive standard of care HDMTX intravenously (IV) over 4 hours on day 1 of weeks 4, 5, 9, and 10. After 24 and 48 hours after the start of each HDMTX infusion, patients also receive glucarpidase IV over 5 minutes in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 32 weeks.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Osteosarcoma
Intervention  ICMJE
  • Drug: Glucarpidase
    Given IV
    Other Names:
    • Acetylaspartylglutamate Dipeptidase
    • Carboxypeptidase G2
    • carboxypeptidase-G2
    • CPDG2
    • CPG2
    • Poly(gamma-glutamic Acid) Endohydrolase
    • Pteroylpolygammaglutamyl Hydrolase
    • Voraxaze
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
Study Arms  ICMJE Experimental: Treatment (glucarpidase)
Patients receive standard of care HDMTX IV over 4 hours on day 1 of weeks 4, 5, 9, and 10. After 24 hours after the start of each HDMTX infusion, patients also receive glucarpidase IV over 5 minutes in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: Glucarpidase
  • Other: Quality-of-Life Assessment
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 21, 2019)
12
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 1, 2023
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • All races and ethnic groups will be eligible

    • A minimum of 6 individuals aged >= 40 years will be enrolled. These participants are considered high-risk.
  • Eastern Cooperative Oncology Group (ECOG) performance score 0-2.
  • Participants must have pathologically confirmed diagnosis of osteosarcoma. Participants must be newly diagnosed and previously untreated, although initiation of doxorubicin/cisplatin prior to enrollment is permitted.
  • Participants must have a recommended treatment plan for their osteosarcoma that includes planned MTX treatment at 8-12 g/m^2.
  • Absolute neutrophil count (ANC) >= 1,000/mm^3 (or >= 1.0 x 10^9/L).
  • Platelet count 75,000/mm^3 (or >= 75 x 10^9/L).
  • Hemoglobin >= 8 g/dL.
  • Serum creatinine =< 1.5 x the upper limit of normal (ULN), or glomerular filtration rate (GFR) >= 60 ml/min/1.73 m^2 as calculated by the Modification of Diet in Renal Disease (MDRD) formula.
  • Total serum bilirubin =< 2 x ULN.
  • Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =< 2.5 x ULN.
  • Participants must be willing to use appropriate contraception for the duration of study treatment and four months after completing HDMTX therapy.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Malignant disease, other than those being treated in this study. Exceptions to this exclusion include the following:

    • Malignancies that were treated curatively and have not recurred within 2 years after completion of treatment;
    • Completely resected basal cell and squamous cell skin cancers;
    • Any malignancy considered to be indolent and that has never required therapy;
    • Completely resected carcinoma in situ of any type.
  • Participants with rapidly progressive disease or organ dysfunction that would prevent them from receiving planned HDMTX treatment regimen.
  • Previous MTX treatment at doses >= 3 g/m^2.
  • Previous treatment with glucarpidase.
  • Known clinically significant liver disease defined as ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, portal hypertension, or history of autoimmune hepatitis. Patients who have completed curative therapy for HCV are eligible. Patients with known history of human immunodeficiency virus (HIV) infection are eligible.
  • Participants with a history of hypersensitivity reactions to study agent or its excipients.
  • Participants with a history of hypersensitivity to Escherichia (E.)coli-derived proteins.
  • Participants with large pleural or ascitic fluid collection.
  • Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
  • Uncontrolled intercurrent illness, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
  • Unable or unwilling to discontinue use of agents that interact significantly with methotrexate metabolism or excretion.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 25 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03960177
Other Study ID Numbers  ICMJE STUDY00019380
NCI-2019-02257 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STUDY00019380 ( Other Identifier: OHSU Knight Cancer Institute )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Lara Davis, OHSU Knight Cancer Institute
Study Sponsor  ICMJE OHSU Knight Cancer Institute
Collaborators  ICMJE
  • BTG International Inc.
  • Oregon Health and Science University
Investigators  ICMJE
Principal Investigator: Lara E Davis OHSU Knight Cancer Institute
PRS Account OHSU Knight Cancer Institute
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP