Glembatumumab Vedotin in Treating Patients With Recurrent or Refractory Osteosarcoma

Phase 2

Completed

Conditions: Recurrent Osteosarcoma

Interventions: Drug: Glembatumumab Vedotin
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study

Registration Number: NCT02487979

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial studies how well glembatumumab vedotin works in treating patients with osteosarcoma that has come back (recurrent) or does not respond to treatment (refractory). Monoclonal antibodies, such as glembatumumab vedotin, may find tumor cells and help kill them.

Detailed Description: PRIMARY OBJECTIVES:

I. To estimate whether CDX-011 (glembatumumab vedotin) therapy either increases the disease control rate at 4 months in patients with recurrent measurable osteosarcoma as compared to an historical Children's Oncology Group (COG) experience or produces an objective response rate in patients without previous eribulin (eribulin mesylate) treatment.

SECONDARY OBJECTIVES:

I. To assess the feasibility and toxicity profile of CDX-011 in patients with recurrent osteosarcoma.

II. To describe the pharmacokinetics of CDX-011 in adolescents and young adults with recurrent osteosarcoma enrolled at COG sites and COG phase I consortium sites only.

III. To determine if there is a relationship between tumor GPNMB expression by immunohistochemistry (IHC) and response to CDX-011 therapy.

IV. To estimate, in the cohort of patients previously treated with eribulin, the proportion who will experience disease progression during the first 4 months of CDX-011 therapy and the proportion of patients who experience a Response Evaluation Criteria in Solid Tumors (RECIST)-defined complete or partial response.

OUTLINE:

Patients receive glembatumumab vedotin intravenously (IV) over 90 minutes on day 1. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Patients must have had histologic verification of osteosarcoma at original diagnosis or relapse
Patients must have measurable disease according to RECIST 1.1, and have relapsed or become refractory to conventional therapy
Patient must have archival tumor specimen available for submission
Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
- Myelosuppressive chemotherapy: must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea)
- Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy with a biologic agent
- Radiation therapy (RT): >= 2 weeks for local palliative RT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation
- Monoclonal antibodies: must not have received any monoclonal based therapies within 4 weeks, and all other immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) within 2 weeks, prior to study enrollment
Peripheral absolute neutrophil count (ANC) >= 1000/uL
Platelet count >= 75,000/uL (transfusion independent)
Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
- Age 1 to < 2 years (male and female: 0.6 mg/dL)
- Age 2 to < 6 years (male and female: 0.8 mg/dL)
- Age 6 to < 10 years (male and female: 1 mg/dL)
- Age 10 to < 13 years (male and female: 1.2 mg/dL)
- Age 13 to < 16 years (male: 1.5 mg/dL and female: 1.4 mg/dL)
- Age >= 16 (male: 1.7 mg/dL and female: 1.4 mg/dL)
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 110 U/L; for the purposes of this study the ULN for SGPT is defined as 45 U/L
Serum albumin > 2 g/dL
Shortening fraction of >= 27% by echocardiogram, or
Ejection fraction of >= 50% by radionuclide angiogram
All patients and/or their parents or legal guardians must sign a written informed consent
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

Patients with > grade 2 neuropathy according to the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies will be excluded except in cases in which neuropathy is secondary to prior surgery
Patients who have previously received CDX-011 (CR011-vc monomethyl auristatin E [MMAE]; CDX-011) or other MMAE-containing agents
Patients who have received other investigational drugs within 2 weeks or 5 half-lives (whichever is longer) prior to study enrollment
Patients with a history of allergic reactions attributed to compounds of similar composition to dolastatin or auristatin; compounds of similar composition include auristatin PHE as an anti-fungal agent, auristatin PE (TZT-1027, Soblidotin, NSC-654663) as an anti-tumor agent and symplostatin 1 as an anti-tumor agent
Patients with known central nervous system metastasis are not eligible
Patients who have had major surgery within 2 weeks prior to enrollment are not eligible; procedures such as placement of a central vascular catheter, or limited tumor biopsy, are not considered major surgery
Female patients who are pregnant are ineligible
Lactating females are not eligible unless they have agreed not to breastfeed their infants
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 2 months after the end of study treatment

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (glembatumumab vedotin)	Glembatumumab Vedotin	Patients receive glembatumumab vedotin IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.
Treatment (glembatumumab vedotin)	Laboratory Biomarker Analysis	Patients receive glembatumumab vedotin IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.
Treatment (glembatumumab vedotin)	Pharmacological Study	Patients receive glembatumumab vedotin IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Disease Control Success	First six cycles (21-day cycle) of protocol therapy	The number of patients who do not experience disease progression or death in the six cycles following enrollment on AOST1521

Secondary Outcome Measures

Name	Time	Method
Toxicity Associated With Chemotherapy	Duration of protocol therapy - Up to two years	The number of cycles aggregated across all patients where CTC Version 4 grade 3 or higher.
Pharmacokinetics of Glembatumumab Vedotin: Total Antibody and Antibody-drug Conjugate Half-life	Baseline to 24 hours post infusion on course 1	Total antibody and antibody-drug conjugate half-life are estimated from the sampling time points: Before first dose (Baseline), end of infusion, at 1, 2, 4, and 24 hours post infusion
Pharmacokinetics of Glembatumumab Vedotin: Total Antibody and Antibody-drug Conjugate Clearance	Baseline to 24 hours post infusion on course 1	Total antibody and antibody-drug conjugate clearance are estimated from the sampling time points: Before first dose (Baseline), end of infusion, at 1, 2, 4, and 24 hours post infusion
Pharmacokinetics of Glembatumumab Vedotin: Total Antibody and Antibody-drug Conjugate Areas Under the Curve	Baseline to 24 hours post infusion on course 1	Total antibody and antibody-drug conjugate areas under the curve are estimated from the sampling time points: Before first dose (Baseline), end of infusion, at 1, 2, 4, and 24 hours post infusion
Number of Participants With Glycoprotein NMB (GPNMB) Expression Stratified by Immunohistochemistry (IHC) Staining Strength	Prior to the time of enrollment	GPNMB expression by IHC of 0+ to 3+ staining strength as assessed on archived tumor specimens. 0 being no GPNMB expression and 3 indicating strong GPNMB expression.
RECIST Response	First six cycles (21-day cycle) of protocol therapy	The number of patients who experience a complete or partial response according the RECIST criteria for target lesions complete response (CR) disappearance of all lesions; partial response (PR ) \>= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR+PR.

Trial Locations

Locations (155): Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
🇺🇸
Tucson, Arizona, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
Kaiser Permanente-Anaheim
🇺🇸
Anaheim, California, United States
PCR Oncology
🇺🇸
Arroyo Grande, California, United States
Kaiser Permanente-Bellflower
🇺🇸
Bellflower, California, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
Kaiser Permanente-Fontana
🇺🇸
Fontana, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
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Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States