Clinical Trials /

Glucarpidase After High-Dose Methotrexate in Patients With Osteosarcoma

NCT03960177

Description:

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.

Related Conditions:
  • Osteosarcoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Glucarpidase After High-Dose Methotrexate in Patients With Osteosarcoma
  • Official Title: An Open-Label, Multi-Institutional Pilot Study to Assess the Use of Glucarpidase in Adult Patients With Osteosarcoma Receiving High-Dose Methotrexate

Clinical Trial IDs

  • ORG STUDY ID: STUDY00019380
  • SECONDARY ID: NCI-2019-02257
  • SECONDARY ID: STUDY00019380
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT03960177

Conditions

  • Osteosarcoma

Interventions

DrugSynonymsArms
GlucarpidaseAcetylaspartylglutamate Dipeptidase, Carboxypeptidase G2, carboxypeptidase-G2, CPDG2, CPG2, Poly(gamma-glutamic Acid) Endohydrolase, Pteroylpolygammaglutamyl Hydrolase, Voraxaze, 9074-87-7Supportive care (glucarpidase)

Purpose

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) on day 1 of weeks 4, 5, 9, and 10
      as part of a standard osteosarcoma chemotherapy regimen. 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 32 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Supportive care (glucarpidase)ExperimentalPatients receive standard of care HDMTX intravenously (IV) on day 1 of weeks 4, 5, 9, and 10 as part of a standard osteosarcoma chemotherapy regimen. 24 hours after the start of each HDMTX infusion, patients also receive glucarpidase IV over 5 minutes.
  • Glucarpidase

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:25 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description:Will be estimated with an exact 95% confidence interval (CI).

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure:Percent treatment effect at resection
Time Frame:From start of surgery until end of surgery
Safety Issue:
Description: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.
Measure:Incidence of glucarpidase hypersensitivity
Time Frame:From first dose of glucarpidase until 30 days after last dose of glucarpidase
Safety Issue:
Description: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.
Measure:Incidence of glucarpidase neutralizing antibodies
Time Frame:From first dose of glucarpidase to 30 days after last dose of glucarpidase
Safety Issue:
Description: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.
Measure:Incidence and severity of MTX-related toxicities
Time Frame:From start of first planned MTX infusion to 30 days after last dose of glucarpidase
Safety Issue:
Description: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.
Measure:Incidence and severity of glucarpidase toxicities
Time Frame:From first dose of glucarpidase to 30 days after last dose of glucarpidase
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description:
Measure: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:From first dose of glucarpidase to end of study treatment (week 10)
Safety Issue:
Description:Will be presented along with 95% confidence intervals.
Measure:Proportion of glucarpidase doses (flat dose of 1000 units) that result in 48 hour serum MTX level < 1 uM
Time Frame:From first dose of glucarpidase to end of study treatment (week 10)
Safety Issue:
Description:Will be presented along with 95% confidence intervals.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

Last Updated

May 11, 2020