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A Phase I Trial of AMG 386 and Temsirolimus in Advanced Solid Tumors With an Expansion Cohort in Uterine Cancer, Renal Cell Carcinoma and Carcinoid Tumors

Phase 1
18 Years
Open (Enrolling)
Malignant Solid Tumour

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Trial Information

A Phase I Trial of AMG 386 and Temsirolimus in Advanced Solid Tumors With an Expansion Cohort in Uterine Cancer, Renal Cell Carcinoma and Carcinoid Tumors

AMG 386 is an intravenous (given by vein) drug that blocks a protein called angiopoietin. As
cancers grow they need to develop their own new blood supply to survive and this development
of new blood supply vessels is known as angiogenesis. AMG 386 works by slowing or stopping
the growth of these new blood vessels which is expected to interfere with the tumor's
ability to grow and spread to other parts of the body.

Temsirolimus is an intravenous (given by vein) drug that is commercially available and
approved for treatment of some types of kidney cancer. Temsirolimus interferes with a
protein in the cell that is part of one pathway that transmits signals to stimulate cell
growth and survival. By inhibiting this protein, called mTOR, cancer cells may stop growing
or die.

This study has two parts. The first part, called the dose escalation phase, will include
patients with any type of solid tumor (a cancer with a tissue mass) to find out the highest
dose of AMG386 and temsirolimus that can be given to patients without causing side effects
that are too severe. After this dose is found, another group of patients that take part in
the study will receive this dose in the second phase called the dose expansion phase. The
dose expansion phase of the study will only include patients that have recurrent (the cancer
has come back) or metastatic uterine, renal cell, and carcinoid tumors.

Inclusion Criteria:

- Histologically or cytologically confirmed metastatic or unresectable malignancy

- Measurable disease (RECIST version 1.1.)

- Prior therapies

- ALL: No prior PI3K-Akt-mTOR inhibitors

- Dose escalation cohorts: No limits

- Dose expansion (up to n=12 each ):

- Uterine: At least 1 prior chemo required. Hormones allowed

- Renal: At least one anti-VEGF/R treatment (Rx) required.

- Carcinoid: Long-acting somatostatin analogue allowed. Prior regional Rx for
liver mets allowed. Prior anti-VEGF/R Rx allowed

- Age ≥ 18

- ECOG 0-1

- Life expectancy ≥ 12 weeks

- Well controlled blood pressure (BP): ≤140/90 mmHg (anti-hypertension meds allowed)

- Normal organ function

- leukocytes ≥3.0 x 109/L

- absolute neutrophil count ≥1.5 x 109/L

- platelets ≥100 x 109/L

- hemoglobin > 90 g/L (or > 9 g/dL)

- total bilirubin ≤ institutional ULN

- AST(SGOT)/ALT(SGPT)≤2.5 X institutional upper limit of normal if no known liver
metastasis or ≤5 X institutional upper limit of normal if known liver metastasis

- PTT or aPTT ≤1.5 X ULN per institutional laboratory range and INR ≤1.5

- creatinine ≤ institutional ULN OR >40 mL/min per 24 h urine collection or
calculated according to the Cockcroft-Gault formula

- urinary protein ≤30 mg/dL in urinalysis or ≤1+ on dipstick, unless quantitative
protein is <1000 mg in a 24 h urine sample

Exclusion Criteria:

- History of CNS metastases

- History of arterial or venous thromboembolism ≤ 12 months

- Therapeutic anticoagulation (neither with LMWH nor warfarin)

- Clinically significant bleeding ≤ 6 months

- Clinically significant cardiovascular disease

- Major surgery ≤ 28 days

- Current of previous treatment with AMG 386 or other angiopoietins or TIE2 receptor

- Minor surgery ≤ 3 days (7 days if prior VEGF inhibitor)

- Prior (≤ 4 weeks) chemo- or radiotherapy

- Prior treatment (≤ 30 days) with immunomodulators

- Patients who have not yet completed prior Rx at least 21 days (30 days prior for

- Non-healing wound, ulcer, fracture

- Uncontrolled intercurrent illness

- Pregnant women/subjects not consenting for double-barrier contraception

- Not recovery from prior Grade ≥2 toxicities (NCI CTC v4.0)

- Strong inducers or inhibitors of CYP3A4

- Pre-existing clinically significant pulmonary infiltrates

- Patients with an indwelling peritoneal or pleural catheter that is used to manage
malignant effusions.

- Known intra-abdominal inflammatory process or serious gastrointestinal ulceration.

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 6 months

- No gastric or esophageal varices

- Patients with primary bowel tumors in situ or recurrent disease at bowel anastomosis

Type of Study:


Study Design:

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

Outcome Measure:

Recommended phase II dose (RP2D) and safety profile of AMG 386 in combination with temsirolimus in patients with advanced solid tumors.

Outcome Description:

The recommended phase II dose is defined as <1 out of 6 at highest dose level below the maximally administered dose. The safety profile will include the number of participants who experience an adverse event, description of adverse events, grade of events, relationship to the drugs, and frequency of events.

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Philippe Bedard, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Princess Margaret Cancer Centre


Canada: Ethics Review Committee

Study ID:

PJC-008 (NCI 9041)



Start Date:

March 2012

Completion Date:

June 2014

Related Keywords:

  • Malignant Solid Tumour
  • Metastatic
  • Unresectable
  • Solid
  • Malignancies
  • Tumor
  • Cancer
  • Uterine
  • Renal cell
  • Carcinoid
  • AMG 386
  • Temsirolimus
  • Neoplasms