HGS-ETR2 to Treat Children With Solid Tumors

NCT00428272 | Terminated Phase 1

• 2 other identifiers: 07004007-C-0040
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Background

• HGS-ETR2 is a monoclonal antibody, produced in the laboratory from human genes.
• HGS-ETR2 targets a protein called the TRAIL receptor that is located on the surface of some tumor cells. When the TRAIL receptor is activated, it can cause the tumor cell to self-destruct. Objectives:
• To determine the highest dose of HGS-ETR2 that can be given safely in children and young adults with cancer.
• To study the pharmacology (how the body handles the drug) of HGS-ETR2 by measuring the amount of drug in the bloodstream over time before and after a dose is given to the patient.
• To determine if HGS-ETR2 can stop or slow tumor growth.
• To determine whether proteins in tumor tissue before treatment can predict whether the tumor will respond to HGS-ETR2 therapy. Eligibility:
• Patients 1 to 21 years of age with solid cancers that do not respond to standard therapy. Design:
• HGS-ETR2 is given through a vein (intravenously, IV) once every 14 days. Each treatment cycle is 28 days long and consists of two doses of HGS-ETR2.
• The dose of HGS-ETR2 is increased in successive small groups of patients until the maximum tolerated dose (highest dose with acceptable side effects) is determined.
• During the treatment period, patients have a physical examination at least once a week, and routine blood tests at least twice a week. These tests are done less frequently in later treatment cycles.
• Additional blood samples are drawn for immunology and pharmacology studies.
• Tests to monitor the size of the tumor (X-rays, CT scans, MRI, PET scans) are done periodically throughout the treatment period.
• Patients may continue to receive HGS-ETR2 until unacceptable side effects develop or the tumor grows.

Conditions

Ewing's Sarcoma; Osteosarcoma; Neuroblastoma; Rhabdomyosarcoma

Keywords

Monoclonal Antibody Lexatumumab; Interferon Gamma; Solid Tumor; Phase I; Malignant Tumor; Metastatic Tumor; Pediatric Solid Tumor; Ewing Sarcoma; Osteosarcoma; Neuroblastoma; Rhabdomyosarcoma

Outcome Measures

Primary Outcomes (3)

• Asult MTD and DLTs of lexatumumab

  6 months

• MTD of lexatumumab w/interferon gamma 1b

  6 months

• Pharmacokinetics

  2 years

Secondary Outcomes (3)

• Tumor response rate

  2 years

• Correlation of immunohistochemical expression of pro-apoptotic proteins with response to therapy

  2 years

• Determine if anti-HGS-ETR2 antibodies are produced

  2 years

Study Arms (3)

1

EXPERIMENTAL

Lexatumumab alone dose escalation

Drug: Lexatumumab alone

2

EXPERIMENTAL

Lexatumumab with interferon - dose escalation

Drug: Lexatumumab in combination; Drug: Interferon gamma 1b in combination

3

OTHER

Lexatumumab 10mg/kg with interferon expansion at

Drug: Lexatumumab in combination; Drug: Gamma 1b potential expansion

Interventions

Lexatumumab alone DRUG

Dose escalation : 3mg/kg, 5mg/kg, 8mg/kg, 10mg/kg

1

Lexatumumab in combination DRUG

Dose escalation : 1mg/kg, 3mg/kg, 5mg/kg, 8mg/kg, 10mg/kg

2; 3

Interferon gamma 1b in combination DRUG

Dosing at the following for each lexatumumab dose level: .75mcg/m2/dose and 25mcg/m2/dose

2

Gamma 1b potential expansion DRUG

Potential expansion (at 10mg/kg lexatumumab): 1.5mcg/m2/dose and 50mcg/m2/dose

3

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• AGE: Patients must be greater than or equal to 1 years and less than or equal to 30 years of age in order to encompass a broad range of ages in children as well as to capture the young adult population which is highly represented in many of these types of sarcomas being studied.
• DIAGNOSIS: Histologically confirmed solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing s sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilm s tumor, Hodgkin's or non-Hodgkin's lymphoma. Patients with primary or untreated metastatic CNS tumors or primary or metastatic hepatic tumors will not be treated on this study.
• MEASURABLE/EVALUABLE DISEASE: Patients must have measurable or evaluable tumors.
• PRIOR THERAPY:
• The patient s cancer must have relapsed following or failed to respond to standard therapy, and the patient s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
• Patients must have completed their last dose of irradiation, chemotherapy, monoclonal antibody, or investigational therapy at least 4 weeks prior to enrollment or their last dose of nitrosurea (CCNU, BCNU) 6 weeks prior to enrollment. For patients who have undergone autologous stem cell transplantation, at least 3 months must have elapsed since transplant.
• Patients must have recovered from the toxic effects of all prior therapy prior to enrollment.
• Patients must have been off colony stimulating factors (e.g. G-CSF, GM-CSF, Epo) for at least 72 hours prior to enrollment.
• Patients must have completed any biological therapy (including investigational therapies) at least 7 days prior to study entry.
• PERFORMANCE STATUS: Patients greater than 10 years old must have a Karnofsky Score of greater than or equal to 50 and children less than or equal to 10 years old must have a Lansky score of greater than 50. Patients who are unable to walk because of paralysis or weakness, but who are up in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.
• HEMATOLOGIC FUNCTION: Patients must have adequate bone marrow function, defined as a peripheral absolute granulocyte count of greater than or equal to 1000/microliter, hemoglobin greater than or equal to 8 gm/dl, and a transfusion independent platelet count greater than or equal to 75,000/microliter.
• Cardiac Function: Patients must have an ejection fraction of greater than 40% via MUGA or Echo or a shortening fraction greater than 27% by Echo and must not have had a history of congestive heart failure.
• HEPATIC FUNCTION: Aspartate transaminase (AST) and alanine transaminase (ALT), less than or equal to 2.5-fold the upper limit of normal (ULN). Direct bilirubin within normal limits.
• RENAL FUNCTION: Patients must have normal age-adjusted serum creatinine (see Table below) OR a creatinine clearance greater than or equal to 60 mL/min/1.73 m(2).
• Age Less than or equal to 5 with a max serum creatinine (mg/dl) of 0.8

You may not qualify if:

• Clinically significant unrelated systemic illness, such as serious infections or organ dysfunction, which in the judgment of the Principal or Associate Investigators would compromise the patient s ability to tolerate the agents in this trial or are likely to interfere with the study procedures or results.
• Patients with a history of allogeneic bone marrow transplantation. Patients who have received autologous stem cell transplantation are eligible greater than 3 months after completion of therapy if they meet other eligibility requirements.
• Patients with hepatic tumors or metastases are excluded due to the potential for hepatotoxicity with agents that target the TRAIL-R pathway. Patients with primary CNS tumors will be excluded due to unknown penetration into the CNS.
• Untreated CNS metastases will render the patient ineligible however patients with a previous history of CNS metastases are eligible if: the metastases have been treated with surgery and/or radiotherapy, are clinically stable as evidenced by no requirements for corticosteroids, the patient has no evolving neurologic deficits and no change in residual brain abnormalities without specific therapy over 6 weeks.
• Pregnant or breastfeeding females are excluded because the risks of lexatumumab to the developing fetus or nursing child are unknown.
• Patients currently receiving other investigational agents.
• History of any infection requiring hospitalization or parenteral antibiotics within 2 weeks of study entry.
• Co-existing medical illness that would place the subject at undue risk.
• On immunosupressant therapy (with the exception of prednisone up to 10 mg/day, or dexamethasone up to 4 mg/day), or with known human immunodeficiency virus (HIV) infection or hepatitis B or C. Subjects with immune deficiency are excluded due to their increased risk of life threatening toxicity when treated with anticancer agents.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995 Dec;3(6):673-82. doi: 10.1016/1074-7613(95)90057-8.

  PMID: 8777713 BACKGROUND

• Georgakis GV, Li Y, Humphreys R, Andreeff M, O'Brien S, Younes M, Carbone A, Albert V, Younes A. Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death. Br J Haematol. 2005 Aug;130(4):501-10. doi: 10.1111/j.1365-2141.2005.05656.x.

  PMID: 16098063 BACKGROUND

• Younes M, Georgakis GV, Rahmani M, Beer D, Younes A. Functional expression of TRAIL receptors TRAIL-R1 and TRAIL-R2 in esophageal adenocarcinoma. Eur J Cancer. 2006 Mar;42(4):542-7. doi: 10.1016/j.ejca.2005.11.013. Epub 2006 Jan 19.

  PMID: 16426839 BACKGROUND

• Merchant MS, Geller JI, Baird K, Chou AJ, Galli S, Charles A, Amaoko M, Rhee EH, Price A, Wexler LH, Meyers PA, Widemann BC, Tsokos M, Mackall CL. Phase I trial and pharmacokinetic study of lexatumumab in pediatric patients with solid tumors. J Clin Oncol. 2012 Nov 20;30(33):4141-7. doi: 10.1200/JCO.2012.44.1055. Epub 2012 Oct 15.

  PMID: 23071222 DERIVED

MeSH Terms

Conditions

Sarcoma, Ewing; Osteosarcoma; Neuroblastoma; Rhabdomyosarcoma; Neoplasms; Neoplasm Metastasis

Interventions

lexatumumab; Interferon-gamma

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Sarcoma; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Myosarcoma; Neoplasms, Muscle Tissue; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Macrophage-Activating Factors; Lymphokines; Proteins; Biological Factors

Study Officials

• Crystal L Mackall, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH

Study Record Dates

• First Submitted: January 25, 2007
• First Posted: January 29, 2007
• Study Start: December 4, 2006
• Primary Completion: April 28, 2011
• Study Completion: October 9, 2015
• Last Updated: December 17, 2019

Record last verified: 2015-10-09

Locations

US (1)