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A PHASE 1 STUDY OF AMG 386 (IND# 114215), AN ANGIOPOIETIN NEUTRALIZING PEPTIBODY, IN CHILDREN WITH RELAPSED OR REFRACTORY SOLID TUMORS, INCLUDING CNS TUMORS


Phase 1
2 Years
21 Years
Open (Enrolling)
Both
Recurrent Childhood Anaplastic Astrocytoma, Recurrent Childhood Anaplastic Oligoastrocytoma, Recurrent Childhood Anaplastic Oligodendroglioma, Recurrent Childhood Cerebellar Astrocytoma, Recurrent Childhood Cerebral Astrocytoma, Recurrent Childhood Diffuse Astrocytoma, Recurrent Childhood Fibrillary Astrocytoma, Recurrent Childhood Gemistocytic Astrocytoma, Recurrent Childhood Giant Cell Glioblastoma, Recurrent Childhood Glioblastoma, Recurrent Childhood Gliomatosis Cerebri, Recurrent Childhood Gliosarcoma, Recurrent Childhood Oligoastrocytoma, Recurrent Childhood Oligodendroglioma, Recurrent Childhood Pilocytic Astrocytoma, Recurrent Childhood Pineoblastoma, Recurrent Childhood Pleomorphic Xanthoastrocytoma, Recurrent Childhood Protoplasmic Astrocytoma, Recurrent Childhood Subependymal Giant Cell Astrocytoma, Recurrent Childhood Visual Pathway and Hypothalamic Glioma, Recurrent Childhood Visual Pathway Glioma, Unspecified Childhood Solid Tumor, Protocol Specific

Thank you

Trial Information

A PHASE 1 STUDY OF AMG 386 (IND# 114215), AN ANGIOPOIETIN NEUTRALIZING PEPTIBODY, IN CHILDREN WITH RELAPSED OR REFRACTORY SOLID TUMORS, INCLUDING CNS TUMORS


PRIMARY OBJECTIVES:

I. To estimate the maximum-tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of
trebananib (AMG 386) administered as a weekly intravenous infusion to children with
recurrent or refractory solid tumors.

II. To determine the tolerability of the solid tumor MTD and/or RP2D of AMG 386 in children
with central nervous system (CNS) tumors.

III. To define and describe the toxicities of AMG 386 administered on this schedule.

IV. To characterize the pharmacokinetics and immunogenicity of AMG 386 in children with
refractory cancer.

V. To measure changes in vascular permeability relative to baseline, evaluated by magnetic
resonance imaging (MRI) perfusion, following AMG 386 administration in pediatric patients
with CNS tumors.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of AMG 386 within the confines of a Phase
1 study.

II. To measure biologic markers of angiogenesis with potential for correlation with disease
response.

OUTLINE: This is a multicenter, dose-escalation study (part 1) followed by a safety and
imaging study (part 2).

Patients receive trebananib intravenously (IV) over 30-60 minutes on days 1, 8, 15, and 22.
Treatment repeats every 28 days in the absence of disease progression or unacceptable
toxicity.

Patients undergo blood sample collection at baseline and periodically during study for
pharmacokinetic and immunogenicity studies. Blood may also be collected for correlative
studies. Some patients also undergo dynamic contrast-enhanced (DCE)-MRI at baseline and
periodically during study.

After completion of study treatment, patients are followed up every 3 to 6 months for up to
1 year.


Inclusion Criteria:



- Part 1: Patients must have had histologic verification of non-central nervous system
(CNS) solid tumor malignancy at original diagnosis or relapse

- Part 2: Patients must have had histologic verification of CNS malignancy at original
diagnosis or relapse except in patients with intrinsic brain stem tumors, optic
pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid
(CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic
gonadotropin (HCG)

- Patients must have either measurable or evaluable disease

- 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

- Karnofsky >= 50% for patients > 16 years of age and Lansky>= 50% for patients =< 16
years of age Note: neurologic deficits in patients with CNS tumors (Part 2 of the
study) must have been relatively stable for at least 7 days prior to study
enrollment; patients who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the
performance score

- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer chemotherapy

- Myelosuppressive chemotherapy: At least 21 days after the last dose of
myelosuppressive chemotherapy (42 days if prior nitrosourea)

- Hematopoietic growth factors: At least 14 days after the last dose of a
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth
factor. For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which
adverse events are known to occur; the duration of this interval must be
discussed with the study chair

- Biologic (anti-neoplastic agent): at least 7 days after the last dose of a
biologic agent; for agents that have known adverse events occurring beyond 7
days after administration, this period must be extended beyond the time during
which adverse events are known to occur; the duration of this interval must be
discussed with the study chair

- Immunotherapy: At least 42 days after the completion of any type of
immunotherapy, e.g. tumor vaccines

- Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose
of a monoclonal antibody

- Radiation therapy (XRT): At least 14 days after local palliative XRT (small
port); at least 150 days must have elapsed if prior total-body irradiation
(TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must
have elapsed if other substantial bone marrow (BM) radiation

- Stem Cell Infusion without TBI: No evidence of active graft vs host disease and
at least 56 days must have elapsed after transplant or stem cell infusion

- Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

- Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment

- Patients with known bone marrow metastatic disease will be eligible for study
provided they meet the required blood counts (may receive transfusions provided they
are not known to be refractory to red cell or platelet transfusions)

- Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73m^2 or a serum creatinine
based on age/gender as follows:

- 0.6 mg/dL (1 to < 2 years of age)

- 0.8 mg/dL (2 to < 6 years of age)

- 1.0 mg/dL (6 to < 10 years of age)

- 1.2 mg/dL (10 to < 13 years of age)

- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

- 1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age)

- Urine protein: =< 30 mg/dL in urinalysis or =< 1+ on dipstick, unless quantitative
protein is < 1,000 mg in a 24-hour urine sample

- Bilirubin (sum of conjugated + unconjugated) =< 1.5 times upper limit of normal (ULN)
for age

- Serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

- Serum albumin >= 2 g/dL

- Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 50% by
gated radionuclide study

- No known cardiac disease

- No history of myocardial infarction, severe or unstable angina, peripheral
vascular disease or familial QTc prolongation

- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled

- Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] v.
4) resulting from prior therapy must be =< grade 2

- No evidence of new central nervous system (CNS) hemorrhage defined as more than
punctate size and/or more than three foci of unctate hemorrhage on baseline magnetic
resonance imaging (MRI) obtained within 14 days prior to study enrollment

- No evidence of active bleeding

- Prothrombin time(PT) and partial thromboplastin time(PTT) =< 1.2 times ULN and an INR
=< 1.2

- A blood pressure (BP) =< the 95th percentile for age, height, and gender, and not
receiving medication for treatment of hypertension

- All patients and/or their parents or legally authorized representatives must sign a
written informed consent; assent, when appropriate, will be obtained according to
institutional guidelines

Exclusion Criteria:

- Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies; pregnancy tests
must be obtained in girls who are post-menarchal; males or females of reproductive
potential may not participate unless they have agreed to use an effective
contraceptive method for the duration of study participation, and for 6 months after
completion of AMG 386 administration

- Patients receiving corticosteroids who have not been on a stable or decreasing dose
of corticosteroid for at least 7 days prior to enrollment are not eligible

- Patients who are currently receiving another investigational drug are not eligible

- Patients who are currently receiving other anticancer agents are not eligible

- Patients who are receiving cyclosporine, tacrolimus, or other agents to prevent
graft-versus-host disease post bone marrow transplant are not eligible for this trial

- Patients who are currently receiving therapeutic anticoagulation with heparin,
low-molecular weight heparin, or coumadin are not eligible for this trial

- Patients who are currently receiving aspirin, ibuprofen, or other non-steroidal
anti-inflammatory drugs or anti-platelet agents are not eligible

- Patients who are receiving anti-hypertensive medications for control of blood
pressure at the time of enrollment are not eligible for this trial

- Patients who have an uncontrolled infection are not eligible

- Patients who have received a prior solid organ transplantation are not eligible

- Patients who have had or are planning to have the following invasive procedures are
not eligible:

- Major surgical procedure, laparoscopic procedure, open biopsy, or significant
traumatic injury within 28 days prior to enrollment

- Central line placement or subcutaneous port placement is not considered major
surgery but must be placed at least 3 days prior to enrollment for external
lines (e.g., Hickman or Broviac) and at least 7 days prior to enrollment for
subcutaneous port

- Core biopsy within 7 days prior to enrollment

- Fine-needle aspirate within 7 days prior to enrollment

- Patients with evidence of active bleeding: intratumoral hemorrhage by current
imaging, or bleeding diathesis are not eligible

- Patients with a history (within 365 days prior to study enrollment) of
arterial/venous thromboembolic events including transient ischemic attack (TIA) or
cerebrovascular accident (CVA) are not eligible

- Patients with a history of hemoptysis within 42 days prior to study enrollment are
not eligible

- For Part 2: Patients with CNS tumors and evidence of new CNS hemorrhage of more than
punctate size and/or more than three foci of punctate hemorrhage on baseline MRI
obtained within 14 days prior to study enrollment are not eligible; Note: ECHO
Gradient MRI sequences per institutional guidelines are required for patients with
CNS tumors

- Patients who have a history of serious or non-healing wound, abdominal fistula,
gastrointestinal ulcer or perforation, bone fracture, or intra-abdominal abscess
within 28 days of study enrollment are not eligible

- Patients with known cardiac or peripheral vascular disease are not eligible

- Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study are not eligible

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity of AMG 386 as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Sarah Leary

Investigator Role:

Principal Investigator

Investigator Affiliation:

COG Phase I Consortium

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-00252

NCT ID:

NCT01538095

Start Date:

February 2012

Completion Date:

Related Keywords:

  • Recurrent Childhood Anaplastic Astrocytoma
  • Recurrent Childhood Anaplastic Oligoastrocytoma
  • Recurrent Childhood Anaplastic Oligodendroglioma
  • Recurrent Childhood Cerebellar Astrocytoma
  • Recurrent Childhood Cerebral Astrocytoma
  • Recurrent Childhood Diffuse Astrocytoma
  • Recurrent Childhood Fibrillary Astrocytoma
  • Recurrent Childhood Gemistocytic Astrocytoma
  • Recurrent Childhood Giant Cell Glioblastoma
  • Recurrent Childhood Glioblastoma
  • Recurrent Childhood Gliomatosis Cerebri
  • Recurrent Childhood Gliosarcoma
  • Recurrent Childhood Oligoastrocytoma
  • Recurrent Childhood Oligodendroglioma
  • Recurrent Childhood Pilocytic Astrocytoma
  • Recurrent Childhood Pineoblastoma
  • Recurrent Childhood Pleomorphic Xanthoastrocytoma
  • Recurrent Childhood Protoplasmic Astrocytoma
  • Recurrent Childhood Subependymal Giant Cell Astrocytoma
  • Recurrent Childhood Visual Pathway and Hypothalamic Glioma
  • Recurrent Childhood Visual Pathway Glioma
  • Unspecified Childhood Solid Tumor, Protocol Specific
  • Astrocytoma
  • Glioblastoma
  • Glioma
  • Nervous System Neoplasms
  • Oligodendroglioma
  • Central Nervous System Neoplasms
  • Pinealoma
  • Gliosarcoma
  • Optic Nerve Glioma
  • Neoplasms
  • Neoplasms, Neuroepithelial

Name

Location

Baylor College of MedicineHouston, Texas  77030
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Washington University School of MedicineSaint Louis, Missouri  63110
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Children's National Medical CenterWashington, District of Columbia  20010-2970
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Children's Hospital of AlabamaBirmingham, Alabama  35233
Oregon Health and Science UniversityPortland, Oregon  97201
Seattle Children's HospitalSeattle, Washington  98105
Childrens Memorial HospitalChicago, Illinois  60614
Columbia University Medical CenterNew York, New York  10032
University of Minnesota Medical Center-FairviewMinneapolis, Minnesota  55455
Children's Oncology GroupArcadia, California  91006-3776
C S Mott Children's HospitalAnn Arbor, Michigan  48109
Riley Hospital for ChildrenIndianapolis, Indiana  46202
Childrens Hospital of Orange CountyOrange, California  92868-3874
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143