A Trial of AMG 386 and Temsirolimus in Advanced Solid Tumors

• Levels of certain biomarkers at different timepoints after AMG386 and Temsirolimus are administered. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Tie2 Expressing Monocytes (TEMs), and circulating angiogenic factors (CAFs) and cytokines, including PlGF, SDF-1alpha, sVCAM-1, angiogenin, endostatin, FGF, PDGF, thrombospondin, VEGF, sVEGFR-1,2, and 3, and sESM1.
• Preliminary anti-tumor activity of both drugs when administered at the recommended phase 2 dose to patients with advanced endometrial cancer, renal cell carcinoma, or carcinoid tumor. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Response Evaluation Criteria in Solid Tumors(RECIST) guideline (version 1.1)

• Pharmacodynamic (PD) effects of both drugs when administered in combination, including potential predictive and PD markers that need further exploration and validation in future trials. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Tie2 Expressing Monocytes (TEMs), and circulating angiogenic factors (CAFs) and cytokines, including PlGF, SDF-1alpha, sVCAM-1, angiogenin, endostatin, FGF, PDGF, thrombospondin, VEGF, sVEGFR-1,2, and 3, and sESM1.
• Preliminary anti-tumor activity of both drugs when administered at the recommended phase 2 dose to patients with advanced endometrial cancer, renal cell carcinoma, or carcinoid tumor. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Response Evaluation Criteria in Solid Tumors(RECIST) guideline (version 1.1)

This is a phase 1 study to find out if investigational drug AMG 386, when given by vein at different doses, in combination with temsirolimus, is safe for patients with advanced cancers.This study will also look for the best possible dose for the combination.

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.

• Drug: AMG 386
  AMG 386, IV over 60 minutes before Temsirolimus, on Days 1, 8, 15, 22 of every 28 day cycles.
• Drug: Temsirolimus
  Temsirolimus, IV over 30-60 minutes after AMG 386, on Days 1, 8, 15, 22 of every 28 day cycles.
  Other Name: Torisel

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 inhibitors
• 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 mAbs)
• 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