Lexatumumab With or Without Recombinant Interferon Gamma in Treating Young Patients With Solid Tumors or Lymphoma That Have Relapsed or Not Responded to Treatment

Condition(s) targeted: Kidney Cancer; Lymphoma; Neuroblastoma; Sarcoma; Unspecified Childhood Solid Tumor, Protocol Specific

Intervention: lexatumumab (Biological); recombinant interferon gamma (Biological); protein expression analysis (Genetic); flow cytometry (Other); immunoenzyme technique (Other); immunohistochemistry staining method (Other); laboratory biomarker analysis (Other); pharmacological study (Other)

Phase: Phase 1

Status: Recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Crystal Mackall, MD, Principal Investigator, Affiliation: NCI - Pediatric Oncology Branch

RATIONALE: Monoclonal antibodies, such as lexatumumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Biological therapies, such as recombinant interferon-gamma, may stimulate the immune system in different ways and stop cancer cells from growing. Giving recombinant interferon-gamma together with lexatumumab may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of lexatumumab alone and together with recombinant interferon gamma in treating young patients with solid tumors or lymphoma that have relapsed or not responded to treatment.

Official title: A Phase I Trial of Monoclonal Antibody HGS-ETR2 (Lexatumumab) With or Without Interferon Gamma in Patients With Refractory Pediatric Solid Tumors

Study design: Treatment, Open Label

Primary outcome:

Tolerability

Maximum tolerated dose of lexatumumab alone

Maximum tolerated dose of lexatumumab in combination with recombinant interferon gamma

Pharmacokinetics

Secondary outcome:

Tumor response

Immunohistochemical expression of pro-apoptotic proteins in pre-therapy tumor tissue

Anti-lexatumumab antibody response

Detailed description: OBJECTIVES:

Primary

- Determine the tolerability of the adult maximum tolerated dose (MTD) and dose-limiting

toxicities of lexatumumab in pediatric patients with relapsed or refractory solid tumors or lymphoma.

- Determine the MTD of lexatumumab in combination with recombinant interferon gamma in

these patients.

- Assess the pharmacokinetics of this regimen in these patients.

Secondary

- Quantify tumor response to this regimen in these patients.

- Correlate immunohistochemical expression of pro-apoptotic proteins in pre-therapy tumor

tissue with response in patients treated with this regimen.

- Determine whether anti-lexatumumab antibodies are produced in response to this regimen

in these patients.

OUTLINE: This is a multicenter, open-label, dose-escalation study of lexatumumab.

- Group I (lexatumumab alone): Patients receive lexatumumab IV over 1 hour on days 1 and

15. Treatment repeats every 28 days until the maximum tolerated dose (MTD) is determined.

- Group II (lexatumumab and recombinant interferon gamma): Patients receive lexatumumab

as in group I at the MTD. Patients also receive recombinant interferon gamma

subcutaneously 3 times a week beginning on day - 14 for 2 weeks and then once every 14

days until the MTD is determined. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection periodically for pharmacokinetic studies. Blood serum is analyzed for concentration of lexatumumab via immunoenzyme techniques; anti-lexatumumab antibodies, TNF-related apoptosis-inducing ligand expression and caspase 8 expression, recombinant interferon gamma activity, lymphocyte storage, and 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.

PROJECTED ACCRUAL: A total of 68 patients will be accrued for this study.

Minimum age: 1 Year. Maximum age: 30 Years. Gender(s): Both.

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:

- Karnofsky performance status (PS) 50-100% (patients > 10 years of age) OR Lansky PS

50-100% (patients ≤ 10 years of age)

- Absolute granulocyte count ≥ 1,000/mm^3

- Platelet count ≥ 75,000/mm^3 (transfusion independent)

- Hemoglobin ≥ 8 g/dL

- AST and ALT ≤ 2. 5 times upper limit of normal

- Bilirubin (direct) normal

- Creatinine clearance ≥ 60 mL/min OR creatinine normal

- Ejection fraction > 40% by MUGA scan or ECHO OR shortening fraction > 27% by ECHO

- 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 history of congestive heart failure

- 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:

- See Disease Characteristics

- Recovered from prior therapy

- At least 4 weeks since prior radiotherapy, chemotherapy, or monoclonal antibody

therapy (6 weeks for nitrosoureas [e. g., lomustine or carmustine])

- At least 7 days since prior biological therapy or investigational 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 or chemotherapy

- No concurrent immunosuppressant therapy (prednisone ≤ 10 mg/day or dexamethasone ≤ 4

mg/day allowed)

- No other concurrent investigational therapy

Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office, Bethesda, Maryland 20892-1182, United States; Recruiting
Clinical Trials Office - Warren Grant Magnusen Clinical Center, Phone: 888-NCI-1937

Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States; Recruiting
Alexander J. Chou, MD, Phone: 212-639-8895

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, United States; Recruiting
Clinical Trials Office - Cincinnati Children's Hospital Medica, Phone: 513-636-2799

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: July 2006
Last updated: August 14, 2009