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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 : August 6, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Lara Davis, OHSU Knight Cancer Institute

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.

Condition or disease Intervention/treatment Phase
Osteosarcoma Drug: Glucarpidase Early Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

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)-related adverse events (AEs) 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 glucarpidase administered with HDMTX in an adult population.

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

OUTLINE:

Patients receive standard of care HDMTX intravenously (IV) over 4 hours as scheduled by their treating physician. 24 hours after the start of each HDMTX infusion, patients also receive glucarpidase IV over 5 minutes.

After completion of study treatment, patients are followed up for 30 days.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Multi-Institutional Pilot Study to Assess the Use of Glucarpidase in Patients With Osteosarcoma Receiving High-Dose Methotrexate
Actual Study Start Date : March 27, 2019
Estimated Primary Completion Date : October 1, 2020
Estimated Study Completion Date : October 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Supportive care (glucarpidase)
Patients receive standard of care HDMTX IV over 4 hours. 24 hours after the start of each HDMTX infusion, patients also receive glucarpidase IV over 5 minutes.
Drug: Glucarpidase
Given IV
Other Names:
  • Carboxypeptidase G2
  • carboxypeptidase-G2
  • CPDG2
  • CPG2
  • Voraxaze




Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. Length of hospital stay (LOS) for methotrexate (MTX) clearance [ Time Frame: Date of admission for each planned MTX infusion to date of MTX < 0.1μM for each planned MTX infusion (up to 15 days) ]
  2. LOS for all causes [ Time Frame: Date of admission for each planned MTX infusion to date of discharge for each planned MTX infusion (up to 15 days) ]
  3. 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) ]
  4. 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.

  5. 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.

  6. Incidence of glucarpidase neutralizing antibodies [ Time Frame: First dose of glucarpidase until 30 days after last dose of glucarpidase ]
    Will be summarized using descriptive statistics such as mean (standard deviation), median (IQR), and proportion (95% exact binomial CI).

  7. Incidence and severity of MTX-related toxicities [ Time Frame: First dose of planned MTX infusion to 30 days after last dose of MTX ]
    Assessed by Common Terminology Criteria for Adverse Events version 5.0. The 95% CI will be reported with the point estimate of toxicity rate

  8. Incidence and severity of glucarpidase toxicities [ 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

  9. MTX and DAMPA serum concentration (µmol/L) at 4, 24, 24.5, 36, 48 and every 24 hours after the start of MTX infusion. [ Time Frame: Date of each planned MTX infusion to date of MTX < 0.1μM for each planned MTX infusion (up to 15 days) ]
  10. Proportion of glucarpidase doses [flat dose of 1000 Units] that result in MTX serum concentration reduction of ≥97% from hour 24 to hour 24.5 [ Time Frame: First dose of glucarpidase until end of study treatment (week 10) ]
  11. Proportion of glucarpidase doses [flat dose of 1000 Units] that result in 48 hour serum MTX level <1 µM. [ Time Frame: First dose of glucarpidase until end of study treatment (week 10) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   25 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants aged >= 25 years. Both men and women and members of all races and ethnic groups will be eligible

    • A minimum of 6 individuals aged >= 40 years will be enrolled.
  • Eastern Cooperative Oncology Group (ECOG) performance score 0-2.
  • Participants must have pathologically confirmed diagnosis of osteosarcoma.
  • 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) and platelet count 75,000/mm^3 (or >= 75 x 10^9/L), and hemoglobin >=8g/dL
  • Serum creatinine =< 1.5 x the upper limit of normal (ULN), or glomerular filtration rate (GFR) >= 60ml/min/1.73 m^2 as calculated by the Modification of Diet in Renal Disease (MDRD) formula.
  • Serum potassium, magnesium, and calcium (corrected for albumin) within institutional normal limits or can be corrected with supplementation.
  • 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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03960177


Locations
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United States, Florida
Mayo Clinic Not yet recruiting
Jacksonville, Florida, United States, 32224
Contact: Steven Attia, D.O.    904-953-7290    Attia.Steven@mayo.edu   
Principal Investigator: Steven Attia         
United States, Minnesota
Mayo Clinic Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: Brittany Siontis, M.D.    507-284-2511    Siontis.Brittany@mayo.edu   
Principal Investigator: Brittany Siontis         
United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: Knight Cancer Clinical Trials Information    503-494-1080    trials@ohsu.edu   
Principal Investigator: Lara E. Davis         
Sponsors and Collaborators
OHSU Knight Cancer Institute
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Lara E Davis OHSU Knight Cancer Institute

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Responsible Party: Lara Davis, Principal Investigator, OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT03960177     History of Changes
Other Study ID Numbers: STUDY00019380
NCI-2019-02257 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STUDY00019380 ( Other Identifier: OHSU Knight Cancer Institute )
P30CA069533 ( U.S. NIH Grant/Contract )
First Posted: May 22, 2019    Key Record Dates
Last Update Posted: August 6, 2019
Last Verified: August 2019

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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
Additional relevant MeSH terms:
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Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sarcoma
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors