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Phase I/II Trial of IMC-A12 in Combination With Temsirolimus in Patients With Metastatic Breast Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

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Trial Information

Phase I/II Trial of IMC-A12 in Combination With Temsirolimus in Patients With Metastatic Breast Cancer


I. To establish the recommended dose level of cixutumumab and temsirolimus for the phase II
study in patients with metastatic breast cancer. (Phase I) II. To examine the safety profile
of this combination in patients with metastatic breast cancer. (Phase I) III. To assess the
anti-tumor activity (in terms of overall response rate) and toxicity profile of cixutumumab
in combination with temsirolimus in patients with metastatic breast cancer. (Phase II)


I. To estimate the progression-free survival (PFS) and overall survival distributions (as
well as the 6-month PFS rate).

II. To evaluate the in vivo mechanisms of action of temsirolimus in combination with
cixutumumab and to examine potential biomarker predictors of treatment response.

OUTLINE: This is a dose-escalation study of cixutumumab. Patients receive temsirolimus IV
over 30 minutes and cixutumumab IV over 60 minutes on days 1, 8, 15, and 22. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

Peripheral blood samples are collected periodically for circulating markers and mononuclear
cells. Samples are analyzed for pharmacodynamic assessments via western blot and proteomic
studies. If pre-existing tumor tissue is available, tissue is examined by
immunohistochemical staining for markers (e.g., pIRS-1, pIGF-IR, pMAPK, pAKT [S473], pS6,
PTEN, Stathmin). Fluorescence in situ hybridization is used to assess IGF-IR amplification.
Gene resequencing is performed to identify mutations of PIK3CA (exons 9 and 20), AKT1, and
other genes. Genes IGF-1, IGF-II, IGFBP-1, IGFBP-3, and others are analyzed by reverse
transcriptase-polymerase chain reaction.

After completion of study treatment, patients are followed up periodically for up to 2
(phase I) or 5 (phase II) years.

Inclusion Criteria:

- Histologically confirmed diagnosis of breast cancer

- Metastatic or locally recurrent disease (locally recurrent disease should be
stage IV [e.g, chest wall involvement])

- Measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded) as ≥ 20 mm by conventional
techniques or as ≥ 10 mm by spiral CT scan (phase II only)

- Must have received at least 1, but no more than 2, prior chemotherapy regimens in the
setting of metastatic or locally recurrent (stage IV chest wall involvement) disease
(phase II only)

- No uncontrolled brain metastases

- Brain metastases are not permitted on study unless the metastases have been
treated by surgery or radiotherapy, and the patient has been neurologically
stable and off of steroids for ≥ 12 weeks

- ECOG performance status (PS) 0-1 OR Karnofsky PS 80-100%

- Life expectancy > 12 weeks

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after
completion of study treatment

- Absolute neutrophil count ≥ 1,500/μL

- Hemoglobin ≥ 8.5 g/dL

- Platelets ≥ 100,000/μL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 3 times ULN (5 times ULN if LFT elevations due to liver metastases)

- Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

- Fasting serum cholesterol ≤ 350 mg/dL (9.0 mmol/L)

- Fasting triglycerides ≤ 400 mg/dL (4.56 mmol/L)

- Albumin ≥ 3.4 mg/dL

- Fasting serum glucose < 120 mg/dL

- No baseline diabetes requiring oral hypoglycemics or insulin (phase I only)

- No poorly controlled diabetes mellitus (phase II only)

- Patients with a history of diabetes mellitus on oral hypoglycemics or insulin
are allowed to participate, provided that their fasting blood glucose is < 120
mg/dL and that they are on a stable dietary or therapeutic regimen for this

- No prior invasive non-breast malignancy, except for adequately treated basal cell or
squamous cell carcinoma of the skin or other cancer from which the patient has been
disease free for ≥ 5 years

- No known hypersensitivity reactions to macrolide antibiotics (such as erythromycin,
clarithromycin, and azithromycin)

- No allergic reactions attributed to compounds of similar chemical or biologic
composition toanti-IGF-1R recombinant monoclonal antibody IMC-A12 or temsirolimus

- Known HIV-positive patients who have CD4 counts below the normal range are not

- No uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Uncontrolled symptomatic cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study

- No systemic anticancer therapy within the past 3 weeks

- No radiotherapy within the past 2 weeks

- No prior treatment with agents targeting the IGF-IR/IGFs or PI3K/Akt/mT OR pathway

- Any number of prior therapy regimens allowed (phase I only)

- No concurrent hormonal agents used for the treatment of breast cancer with the
exception that premenopausal women who have been on a gonadotrophin-releasing hormone
(GnRH)agonist and subsequently progressed may, at the discretion of the treating
physician, continue on the GnRH agonist

- No other concurrent investigational agents or herbal preparations

- No concurrent oral corticosteroids except for replacement for adrenal insufficiency

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent enzyme-inducing antiepileptic drugs (EIAEDs) (e.g., phenytoin,
carbamazepine, phenobarbital) or any other CYP3A4 inducer such as rifampin or
Hypericum perforatum (St. John's wort)

- No other concurrent chemotherapy or radiotherapy

Type of Study:


Study Design:

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

Outcome Measure:

Recommended dose level for phase II testing (RPTD) (Phase I)

Outcome Description:

The RPTD is defined as the highest dose level at which at most one of 6 patients develops a dose limiting toxicity (DLT) during the first course of treatment. A two-stage Simon Phase II clinical trial design will be used to assess the toxicity profile of the combination of Temsirolimus and IMC-A12 at the recommended phase II dose in patients with metastatic breast cancer.

Outcome Time Frame:

During first course

Safety Issue:


Principal Investigator

Cynthia Ma

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

October 2008

Completion Date:

Related Keywords:

  • Male Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male



Mayo Clinic Rochester, Minnesota  55905
Washington University School of Medicine Saint Louis, Missouri  63110
Bismarck Cancer Center Bismarck, North Dakota  58501
Mid Dakota Clinic Bismarck, North Dakota  58501
University of Chicago Comprehensive Cancer Center Chicago, Illinois  60637-1470
Saint Alexius Medical Center Bismarck, North Dakota  58501
Medcenter One Health Systems Bismarck, North Dakota  58501