A Phase 1, Open-Label, Dose Escalation Study of ANG1005 in Patients With Malignant Glioma

Trial Information

This is a phase 1, multi-centre, sequential cohort, open-label, dose-escalation study of the
safety, tolerability, and PK of ANG1005 in patients with recurrent or progressive malignant
glioma. ANG1005 will be given by IV infusion once every 21 days (1 treatment cycle). Each
patient will participate in only 1 dose group and will receive up to 6 cycles. Patients may
receive additional cycles of ANG1005 if there is no evidence of tumor progression, there is
recovery to ≤Grade 1 or baseline nonhematologic, ANG1005-related toxicity (except alopecia),
the absolute neutrophil count is ≥1.5 x 109/L, and the platelet count is ≥100 x 109/L.

Initially, cohorts of 1 - 3 patients will be enrolled into each dose group. Dose escalation
by dose doubling will be done for the first 3 dose groups followed by a modified Fibonacci
dose escalation scheme with increases of 67%, 50%, 40% and 33% thereafter. If > 1 patient in
a cohort experience an emergent ≥ Grade 2 drug-related toxicity during the first treatment
cycle, then a minimum of 3 patients will be enrolled into that, and all subsequent cohort(s)
and dose doubling will be stopped if applicable.

If > 1 patient in a cohort experience a dose limiting toxicity (DLT) during the first
treatment cycle, defined as any of the following that are both treatment-emergent and at
least possibly related to ANG1005: i) Any Grade 3 or 4 nonhematologic toxicity, ii) Febrile
neutropenia, iii) Grade 4 neutropenia of ≥7 days duration, and/or iv) Any Grade 4
thrombocytopenia, then dose escalation will stop and prior doses will be explored as the
maximum tolerated dose (MTD), that dose-level at which ≤1 of 6 patients in a cohort develop
an emergent DLT).

Once the MTD is established, approximately 14 patients will be enrolled at that dose-level
in order to further assess the safety and tolerability of ANG1005, the PK profile of ANG1005
at the MTD, and the preliminary anti-tumor activity of ANG1005 in patients with malignant
glioma.

Approximately 8 additional patients who are scheduled for debulking surgery for recurrent
disease may be enrolled into a separate sub-study to obtain preliminary information about
whether or not ANG1005 crosses the blood-brain barrier into malignant glioma tumors. These
patients will receive ANG1005 prior to surgery at the dose level established to be safe and
tolerable at that time and may continue to receive additional cycles of ANG1005 following
surgery, if appropriate.

Inclusion Criteria:

1. Written informed consent

2. Histologically confirmed malignant glioma

3. Radiologically confirmed progression of malignant glioma

4. Patients must, in the opinion of the investigator, be ineligible for current standard
of care treatment

5. No evidence of acute intracranial/intratumoral hemorrhage

6. Male and female patients

7. Age ≥18 years

8. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

9. An expected survival of at least 3 months

10. Measurable disease according to Macdonald response criteria

11. Male and female subjects who are not surgically sterile or post-menopausal must agree
to use reliable methods of birth control for the duration of the study and for 90
days after the last dose of study drug administration; male partners of female
subjects should use condoms for the duration of the study, and for 90 days after the
last dose of study drug administration

Exclusion Criteria:

1. Chemotherapy, radiotherapy (except palliative radiation delivered to <20% of bone
marrow), or investigational agents within 4 weeks before the first dose of study
drug. Biologic therapy (such as 13-cis-retinoic acid, thalidomide, tamoxifen,
celebrex, erlotinib, imatinib, vorinostat, and lapatinib) and immunotherapy (such as
interferon a or b, cdx-110 (EGFR vIII vaccine), interleukin 2, thalidomide) within 1
week before the first dose of study drug. Bevacizumab within 6 weeks before the first
dose of study drug

2. Pregnant or lactating females

3. Any acute viral, bacterial, or fungal infection that requires parenteral therapy
within 14 days prior to study treatment

4. Known severe hypersensitivity to paclitaxel

5. Severe toxicity with previous taxane treatment

6. Patients being treated with P450 CYP 3A4 or CYP 2C8 enzyme-inducing anti-convulsant
drugs within 14 days prior to treatment with study drug

7. Patients with inadequate hematological, liver, and renal function

8. Known or suspected acute or chronic active Hepatitis B, or Hepatitis C or HIV/AIDS

9. Patients with unstable or uncompensated respiratory, cardiac, hepatic or renal
disease or any other organ system dysfunction, medical condition, or laboratory
abnormality which, in the opinion of the investigator, would either comprise the
patient's safety or interfere with the evaluation of the test material

10. Evidence of persistent Grade 2 or greater neurotoxicity

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To characterize the safety and tolerability of intravenously administered ANG1005 in patients with malignant glioma.

Outcome Time Frame:

On-going

Safety Issue:

Yes

Authority:

United States: Food and Drug Administration

Study ID:

ANG1005-CLN-01

NCT ID:

NCT00539344

Start Date:

October 2007

Completion Date:

March 2010

Related Keywords:

Recurrent or Progressive Malignant Glioma
Glioblastoma multiforme
Anaplastic astrocytoma
Anaplastic oligodendroglioma
Glioma

Name	Location
Henry Ford Health System	Detroit, Michigan 48202
Dana Farber Cancer Institute	Boston, Massachusetts 02115
University of Texas, MD Anderson Cancer Center	Houston, Texas 77030
University of Virginia Health System	Charlottesville, Virginia 22903
Irving Comprehensive Cancer Center, Columbia University Medical Center	New York, New York 10032
UT Health Science Center at the Cancer Therapy and Research Center (CTRC)	San Antonio, Texas 78229

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