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Bone and Soft Tissue Tumors

NCI-07-C-0040: A Phase I Trial of the Monoclonal Antibody HGS-ETR2 (Lexatumumab) in Patients with Refractory Pediatric Solid Tumors

Date Last Modified: 05-29-2007

TypeStatusAge Range (yrs.)SponsorProtocol ID
TreatmentActive1-21NIH/NCINCI-07-C-0040

Outline

This is a multicenter, open-label, dose-escalation study.

Patients receive lexatumumab IV over 1 hour on days 1 and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of lexatumumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 12 patients may be treated at the MTD, including at least 6 patients who are ≤ 12 years of age.

Patients undergo blood collection periodically for pharmacokinetic studies. Blood serum is analyzed for concentration of lexatumumab via immunoenzyme techniques, for anti-lexatumumab antibodies, and for immunogenicity via flow cytometry. Previously collected tissue samples are examined by immunohistochemistry for TR1, TR2, caspase 8, survivin, and bcl-2 expression.

After completion of study therapy, patients are followed periodically.

Objectives

Primary

  1. Determine the tolerability of the adult maximum tolerated dose and dose-limiting toxicities of lexatumumab in pediatric patients with relapsed or refractory solid tumors or lymphoma.
  2. Assess the pharmacokinetics of this drug in these patients.

Secondary

  1. Quantify tumor response to this drug in these patients
  2. Correlate immunohistochemical expression of pro-apoptotic proteins in pre-therapy tumor tissue with response in patients treated with this drug
  3. Determine whether anti-lexatumumab antibodies are produced in response to this drug in these patients

Projected Accrual

Up to 36 patients will be accrued for this study.

Mechanism of Action of Lexatumumab

HGS-ETR2 (Human Genome Sciences; human monoclonal antibody) is a fully human monoclonal antibody that agonistically binds TRAIL receptor 2 and, like TRAIL itself, induces apoptosis in a variety of malignant cell types with little effect on normal cells. Members of the TNF ligand superfamily induce death in tumor cells through direct ligation of death receptors and apoptosis induction. TRAIL (TNF-related apoptosis inducing ligand) has specific anti-tumor activity against a wide range of tumor cells without inducing death in normal cells. TRAIL-induced apoptosis has been demonstrated in a wide variety of pediatric solid tumors, including Ewing's sarcoma, osteosarcoma, neuroblastoma, and rhabdomyosarcoma.

Entry Criteria

Disease Characteristics:

  • Histologically confirmed malignancy, including, but not limited to, any of the following:
    • Rhabdomyosarcoma and other soft tissue sarcoma
    • Ewing's sarcoma family of tumors
    • Osteosarcoma
    • Neuroblastoma
    • Wilms tumor
    • Hodgkin's lymphoma
    • Non-Hodgkin's lymphoma
  • Measurable or evaluable disease
  • Must have relapsed after or failed to respond to prior standard therapy
  • No known curative therapy or therapy proven to prolong survival with an acceptable quality of life exists
  • No primary or metastatic hepatic tumors
  • No primary or untreated metastatic CNS tumors
    • Patients with prior CNS metastases must meet the following criteria:
      • Metastases have been treated with surgery and/or radiotherapy
      • Clinically stable as evidenced by no requirement for corticosteroids
      • No evolving neurologic deficits and no change in residual brain abnormalities without specific therapy within the past 6 weeks

Patient Characteristics:

Age

  • 1 to 21 years

Performance status*

  • Lansky 50-100% (for patients ≤ 10 years of age)
  • Karnofsky 50-100% (for patients > 10 years of age)

Life expectancy

  • Not specified

Hematopoietic

  • Absolute granulocyte count ≥ 1,000/mm3
  • Platelet count ≥ 75,000/mm3 (transfusion independent
  • Hemoglobin ≥ 8.0 g/dL

Hepatic

  • AST and ALT ≤ 2.5 times ULN
  • Bilirubin normal

Renal

  • Creatinine clearance ≥ 60 mL/min OR creatinine normal

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 60 days (females) or 30 days (males) after completion of study therapy
  • No clinically significant unrelated systemic illness (e.g., serious infection or organ dysfunction) that would preclude study treatment
  • No history of any infection requiring hospitalization or parenteral antibiotics within the past 2 weeks
  • No co-existing medical illness that would place the patient at undue risk
  • No known HIV infection
  • No immune deficiency
  • No hepatitis B or C

Prior Concurrent Therapy:

Biologic therapy

  • Recovered from prior therapy
  • At least 4 weeks since prior monoclonal antibody therapy
  • At least 72 hours since prior and no concurrent colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa)
  • At least 3 months since prior autologous stem cell transplantation
  • No prior allogeneic bone marrow transplantation
  • No other concurrent immunotherapy

Chemotherapy

  • Recovered from prior therapy
  • At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas [e.g., lomustine or carmustine])
  • No other concurrent chemotherapy

Endocrine therapy

  • No concurrent immunosuppressant therapy (prednisone ≤ 10 mg/day or dexamethasone ≤ 4 mg/day allowed)

Radiotherapy

  • At least 4 weeks since prior radiotherapy

Surgery

  • Not specified

Other

  • At least 4 weeks since prior investigational therapy
  • No other concurrent investigational therapy

Who should I contact for more information?

Rebecca Turner, MS, CCRP
Cincinnati Children's Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave.
Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org