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A Phase 1, Open-Label, Dose Finding Study Evaluating the Safety and Pharmacokinetics of AMG 479 in Subjects With Advanced Solid Tumors

Phase 1
18 Years
Not Enrolling
Lymphoma, Prostate Cancer, Sarcoma, Small Intestine Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase 1, Open-Label, Dose Finding Study Evaluating the Safety and Pharmacokinetics of AMG 479 in Subjects With Advanced Solid Tumors



- To assess the safety and pharmacokinetics of anti-IGF-1R fully human monoclonal
antibody AMG-479 (AMG-479) after multiple intravenous administrations in adult patients
with histologically documented advanced solid tumors that are refractory to standard
therapy or for which no curative therapy is available.


- To assess the tolerability and to determine the maximum tolerated dose of AMG-479.

- To assess tumor glucose metabolism using PET/CT scanning with the tracer
fludeoxyglucose F 18.

- To measure insulin-like growth factor receptor (IGF-1R) levels on peripheral blood

- To establish whether human anti-human antibodies to AMG-479 develop in patients with
advanced solid tumors.

- To measure the tumor response by modified Response Evaluation Criteria in Solid Tumors.


- To investigate bone turnover markers.

- To investigate potential biomarker development by biochemical analysis in blood cells
and tumor cells.

OUTLINE: This is a multicenter study.

- Part 1 (dose-escalation): Patients receive escalating doses of anti-IGF-1R fully human
monoclonal antibody AMG-479 (AMG-479) IV over 1 hour on days 1, 15, and 29. Patients
are evaluated in week 8, and those who demonstrate an objective tumor response or
stable disease continue treatment beginning on day 57. Treatment with AMG-479 repeats
every 2 weeks in the absence of disease progression or unacceptable toxicity.

- Part 2 (randomized dose-expansion): Patients are randomized to one of two dose

- Arm I: Patients receive AMG-479 IV over 1 hour at a lower dose on day 1.

- Arm II: Patients receive AMG-479 IV over 1 hour at a higher dose on day 1.
Treatment repeats every 14 days in the absence of disease progression or
unacceptable toxicity. Tumor tissue is obtained at baseline and after 4 weeks of
study therapy for biomarker analysis.

Blood is drawn periodically for biomarker analysis (insulin-like growth factor [IGF]-1,
IGF-binding protein 3 [IGF-BP3], IGF-1 receptor [IGF-1R], cross-linked c-telopeptides of
type 1 collagen [CTx], bone-specific alkaline phosphatase [BSAP], and tartrate-resistant
acid phosphatase [TRAP5b]) and pharmacokinetic studies.

After completion of study therapy, patients are followed for at least 4 weeks.

Inclusion Criteria


Inclusion criteria:

- Histologically or cytologically confirmed advanced solid tumors or non-Hodgkin
lymphoma that is refractory to standard treatment or for which no curative therapy is

- Tumor tissue that is accessible for biopsy by using minimally invasive procedures and
must consent to undergo biopsies of the tumor (part 2)

- Exception for patients with Ewing family tumors or desmoplastic small round cell
tumors whose anatomic location would pose an increase in the risk of injury due
to biopsy (i.e., bleeding or pneumothorax)

- Willing to provide existing and/or future paraffin-embedded tumor samples

Exclusion criteria:

- Primary CNS tumors or hematological malignancies, other than non-Hodgkin lymphoma

- Primary hepatic tumors or at increased risk for hepatic tumors, including any of the

- Hepatitis of any etiology

- Alcohol abuse or dependency

- Hepatic adenoma

- Follicular nodular hyperplasia

- Autoimmune conditions associated with biliary tract cancer

- Alpha 1 antitrypsin deficiency

- Hemochromatosis

- History of vinyl chloride or thorotrast/thorium dioxide exposure

- History of histiocytic (Kupffer cell) neoplasia

- Presence of untreated or symptomatic CNS metastases or symptoms of brain metastases

- Presence of ascites or pleural effusion requiring medical intervention


Inclusion criteria:

- ECOG performance status ≤ 2

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Able to provide fasting blood samples for triglyceride and glucose laboratory tests

- Able to fast for 4-6 hours for fludeoxyglucose F18-PET/CT scan

- Controlled type 1 or 2 diabetes (defined as hemoglobin A1c < 8.0% and fasting blood
glucose level < 160 mg/dL) allowed for part 2 only

Exclusion criteria:

- History of clinically significant hypoglycemia or hyperglycemia (in the opinion of
the investigator)

- Myocardial infarction within the past year

- Unstable or uncontrolled disease/condition related to or impacting cardiac function,
including any of the following:

- Unstable angina

- Congestive heart failure

- NYHA class III or IV heart disease

- Uncontrolled hypertension (diastolic BP > 90 mm Hg and systolic BP > 150 mm Hg)

- Clinically significant cardiac arrhythmia

- CTCAE version 3.0 ≥ grade 2

- Clinically significant electrocardiogram abnormalities

- History of arterial or venous (deep vein) thrombosis within the past year

- History of bleeding diathesis

- History of chronic hepatitis

- History of HIV infection

- Unable to tolerate intravenous administration

- Known sensitivity to mammalian-derived products

- ANC < 1,500/mm^3 (without filgrastim [G-CSF] support within the past 2 weeks)

- Platelet count < 100,000/mm^3 (without transfusion within the past 2 weeks)

- Hemoglobin < 9 g/dL (without transfusion within the past 4 weeks)

- PT/PTT > 1.5 x upper limit of normal (ULN)

- Serum creatinine > 1.5 x ULN

- AST and ALT > 2.5 x ULN

- Total bilirubin > 1.5 x ULN

- Urinary protein excretion > 1,000 mg/day (≥ 2+ using dipstick analysis)

- Any kind of disorder that compromises the ability of the patient to give written
informed consent and/or comply with study procedures

- Any comorbid medical condition, that in the sponsor's or investigator's opinion, may
put the patients at significant risk

- Known sensitivity to any of the products to be administered during dosing

- Unresolved toxicities > grade 1 from prior anticancer therapy, excluding alopecia


- No prior antitumor treatment within the past 28 days

- Palliative external-beam radiotherapy to a lesion not used for RECIST
measurement is acceptable during study for symptom management if patient is
stable or improving and not progressing

- At least 30 days since prior and no concurrent enrollment in another clinical trial
involving medication

- No antibody therapy for the treatment of underlying malignancy within the past 8

- No concurrent or prior anticoagulation therapy, except low-dose warfarin (< 2 mg/day)
for prophylaxis against central venous catheter thrombosis

- No concurrent insulin (except diabetic patients enrolled in dose expansion [part 2]
of the study)

- No other concurrent investigational procedures

- No concurrent blood or blood-product transfusions

- No concurrent herbal medications

- No other concurrent anticancer therapy including chemotherapy or hormonal therapy

- Gonadotropic releasing-hormone agonists or antagonists allowed for advanced
prostate cancer

- No major surgery within the past month and none planned for 28 days after completion
of study treatment

Type of Study:


Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Safety Issue:


Principal Investigator

Mace L. Rothenberg, MD, FACP

Investigator Role:

Study Chair

Investigator Affiliation:

Vanderbilt-Ingram Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

October 2005

Completion Date:

Related Keywords:

  • Lymphoma
  • Prostate Cancer
  • Sarcoma
  • Small Intestine Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • cutaneous B-cell non-Hodgkin lymphoma
  • angioimmunoblastic T-cell lymphoma
  • stage IV cutaneous T-cell non-Hodgkin lymphoma
  • adult nasal type extranodal NK/T-cell lymphoma
  • anaplastic large cell lymphoma
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • nodal marginal zone B-cell lymphoma
  • recurrent adult Burkitt lymphoma
  • recurrent adult diffuse large cell lymphoma
  • recurrent adult diffuse mixed cell lymphoma
  • recurrent adult diffuse small cleaved cell lymphoma
  • recurrent adult grade III lymphomatoid granulomatosis
  • recurrent adult immunoblastic large cell lymphoma
  • recurrent adult lymphoblastic lymphoma
  • recurrent cutaneous T-cell non-Hodgkin lymphoma
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • recurrent mantle cell lymphoma
  • recurrent marginal zone lymphoma
  • recurrent small lymphocytic lymphoma
  • small intestine lymphoma
  • splenic marginal zone lymphoma
  • unspecified adult solid tumor, protocol specific
  • recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor
  • adult desmoplastic small round cell tumor
  • recurrent adult soft tissue sarcoma
  • recurrent prostate cancer
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Prostatic Neoplasms
  • Duodenal Neoplasms
  • Ileal Neoplasms
  • Jejunal Neoplasms
  • Neoplasms
  • Intestinal Neoplasms
  • Sarcoma



Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838