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A Phase I Open-label Dose Escalation Study of AT13387 in Patients With Metastatic Solid Tumors

Phase 1
18 Years
Open (Enrolling)
Metastatic Solid Tumors

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Trial Information

A Phase I Open-label Dose Escalation Study of AT13387 in Patients With Metastatic Solid Tumors

Increasing doses of AT13387 will be administered to groups of 3 to 6 patients at each dose
level. The pharmacokinetic profile of AT13387 following a one hour intravenous infusion will
be determined and the effect of AT13387 on predefined biomarkers in blood plasma and
circulating white blood cells will be established. Patients will be closely monitored for
the development of side effects which would preclude further dose escalation.

Inclusion Criteria:

- Provision of signed informed consent.

- Age 18 years or older.

- Histological or cytological evidence of a metastatic solid tumor including lymphoma,
which is refractory to standard therapy. The following tumor types are of particular
interest as they may be more likely to respond to HSP90 inhibition and all efforts
should be made to recruit patients into the study with these diagnoses. Only
patients with these diagnoses and others thought to be responsive to HSP90 inhibitors
are to be enrolled following the identification of MTD.

- Metastatic breast cancer which is HER2 positive either by FISH or 3+
immunohistochemistry staining,

- Adenocarcinoma of the prostate which is refractory to treatment with androgen

- Metastatic melanoma,

- Stage IIIb or IV NSCLC,


- High grade gliomas (patients must have been on a stable dose of corticosteroids
for at least one week prior to treatment with AT13387 and have not experienced
neurological deterioration during this period),


- ECOG performance status ≤ 2.

- Adequate marrow function as defined by:

- Hemoglobin > 9 g/dL,

- Neutrophils > 1.4 x 10^9/L,

- Platelets ≥ 100 x 10^9/L.

- Negative serum or urine pregnancy test or evidence of surgical sterility or evidence
of post-menopausal status. Post-menopausal status is defined as any of the following:
natural menopause with menses >1 year ago; radiation induced oophorectomy with last
menses >1 year ago; chemotherapy-induced menopause with 1 year interval since last

Exclusion Criteria:

- Be pregnant or lactating (women of childbearing potential must have a negative
pregnancy test within 7 days prior to enrolment). Male and female patients of
childbearing potential must use appropriate birth control (barrier methods, oral
contraceptives and/or intrauterine devices) during the entire duration of the study,
or the patient must be surgically sterile (with documentation in the patient's
medical records).

- Ongoing central nervous system metastases in patients with an extracranial primary
tumor (unless the patient's neurological signs or symptoms have been stable during
the preceding three months and the patient has not received corticosteroid treatment
for four weeks prior to study entry).

- Inadequate liver function as demonstrated by serum bilirubin > 2.5 times the upper
limits of reference range (ULRR) or alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) or alkaline phosphatase (ALP) ≥ 2.5 times the ULRR (unless due
to the presence of liver metastases when ALT and/or AST may be up to five times the
upper limits of reference range). Patients with an isolated increase in ALP ≤ 5 times
ULRR in the absence of liver metastases but with known bone metastases are eligible
for the study.

- Left ventricular ejection fraction <50% on echocardiography or MUGA scan.

- Moderate or severe renal impairment defined as serum creatinine > 1.5 ULRR or > +
proteinuria on two occasions no less than 24 hours apart.

- Previous treatment with a HSP90 inhibitor.

- Anticancer therapies that have not been completed at least 28 days prior to treatment
with AT13387 (other than surgery or treatment with a protein kinase inhibitor which
must have been completed no less than one week prior to treatment with AT13387).

- Incomplete recovery from previous radiotherapy or surgery other than residual
cutaneous effects or stable < Grade 2 gastrointestinal toxicity.

- History of an ischemic cardiac event, myocardial infarction or unstable cardiac
disease within 3 months of study entry.

- QTc > 460 ms according to the Fridericia's correction.

- Previous malignancy, except for non-basal-cell carcinoma of skin or carcinoma-in-situ
of the uterine cervix, unless the tumor was treated with curative intent more than 2
years prior to study entry.

- Any evidence of severe or uncontrolled systemic conditions (e.g., systemic infection)
or current unstable or uncompensated respiratory or cardiac conditions which makes it
undesirable for the patient to participate in the study or which could jeopardize
compliance with the protocol.

- Prior history of infection with human immunodeficiency virus (HIV), known active
hepatitis B or C viruses - screening for viral infections is not required for entry
to this study.

- Chronic treatment with known CYP450 inducers e.g. phenytoin, within four weeks of
receiving treatment with AT13387 (see Appendix D for list) other than Dexamethasone
in patients with glioma.

Type of Study:


Study Design:

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

Outcome Measure:

The identification of the maximum tolerated dose for twice or once weekly dosing, on three weeks out of four

Outcome Time Frame:

12 months

Safety Issue:


Principal Investigator

Geoffrey Shapiro, MD PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

May 2008

Completion Date:

June 2013

Related Keywords:

  • Metastatic Solid Tumors
  • HSP90
  • Metastatic solid tumor including lymphoma which are
  • refractory to standard therapy
  • Neoplasms



Beth Israel Deaconess Medical Center Boston, Massachusetts  02215
Massachusetts General Hospital Boston, Massachusetts  02114-2617
Dana Farber Cancer Institute Boston, Massachusetts  02115
The University of Arizona Cancer Center Tuscon, Arizona  85724-5024