Cixutumumab and Temsirolimus in Treating Patients With Locally Recurrent or Metastatic Breast Cancer

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: June 17, 2008
Last updated: May 5, 2015
Last verified: January 2015

June 17, 2008
May 5, 2015
October 2008
September 2013   (final data collection date for primary outcome measure)
  • Recommended Dose Level for Phase II Testing (RPTD) (Phase I) [ Time Frame: During first course ] [ Designated as safety issue: Yes ]

    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 and the next highest dose level has 2 or more DLTs. The number of patients in each cohort reporting a DLT is reported.

    Dose-limiting toxicities (DLTs) are defined as any of the following adverse events (AEs) that are related to study agent with an attribution of possible, probably, or definite and fulfilling one of the following criteria:

    • Any grade 4 hematologic toxicity
    • Hyperglycemia that cannot be stably controlled with diabetic medication
    • Any grade 3 or 4 non-hematologic toxicity (except asymptomatic medically manageable laboratory abnormalities such as hyperlipidemia, hypophosphatemia, and hypokalemia)
  • Tumor Response Rate (TRR) (Complete Response [CR] or Partial Response [PR]) by the Response Evaluation Criteria in Solid Tumors (RECIST) (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

    A response is defined as a disease burden that meets the RECIST criteria for Complete Response (CR) or Partial Response (PR) on 2 consecutive evaluations at least 6-8 weeks apart.

    Complete Response (CR): All of the following must be true:

    1. Disappearance of all target and non-target lesions.
    2. Each target lymph node must have reduction in short axis to <1.0 cm.

    Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline measures.

    The rate is calculated by dividing the number of patients with a CR or PR by the number of evaluable patients. A ninety percent confidence interval for the true tumor response rate will be calculated using the Duffy-Santer approach.

  • Recommended dose level (phase I) [ Designated as safety issue: Yes ]
  • Safety profile (phase I) [ Designated as safety issue: Yes ]
  • Antitumor activity (phase II) [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00699491 on Archive Site
  • Adverse Events Graded Using the NCI CTCAE Version. 3 (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Adverse events will be graded using the NCI-CTCAE v3.0 coding scheme. The maximum grade for each adverse event considered to be 'at least possibly related to treatment' will be recorded. Frequency tables will be constructed and the number of patients reporting an adverse event of grade 3 or higher at least possibly related to treatment will be reported.
  • Duration of Response (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Duration of response is defined for all evaluable patients with changes in disease burden that met the RECIST criteria for CR or PR on 2 consecutive evaluations at least 6-8 weeks apart as the date at which the CR or PR to the date progression is documented. The distribution of response durations will be estimated using the Kaplan-Meier method.
  • Progression Free Survival (PFS) (Phase II) [ Time Frame: Time from registration to documentation of disease progression, up to 5 years ] [ Designated as safety issue: No ]
    Progression free survival is defined as the time from registration to documentation of disease progression. If a patient dies without a documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. In the case of a patient starting treatment and then never returning for any evaluations, the patient will be censored for progression on the last day of therapy was administered. The distribution of progression-free survival times will be estimated using the Kaplan-Meier method.The distribution of PFS times will be estimated using the Kaplan-Meier method.
  • Progression Free Survival Rate [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
    Progression free survival (PFS) is defined as the time from registration to documentation of disease progression. A point and interval estimate of the 6 month PFS rate will be obtained using the Kaplan-Meier method.
  • Survival Time (Phase II) [ Time Frame: Time from registration to death due to any cause ] [ Designated as safety issue: No ]
    Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.
  • Adverse events (phase II) [ Designated as safety issue: Yes ]
  • Duration of response (phase II) [ Designated as safety issue: No ]
  • Progression-free survival (phase II) [ Designated as safety issue: No ]
  • Survival Time (Phase II) [ Designated as safety issue: No ]
  • Serum estradiol and progesterone levels prior to treatment (phase II) [ Designated as safety issue: No ]
  • Levels of IGF-1, IGF-2, IGFBP1-3, insulin, glucose, C-peptide (Phase II) [ Designated as safety issue: No ]
Not Provided
Not Provided
Cixutumumab and Temsirolimus in Treating Patients With Locally Recurrent or Metastatic Breast Cancer
Phase I/II Trial of IMC-A12 in Combination With Temsirolimus in Patients With Metastatic Breast Cancer
This phase I/II trial is studying the side effects and best dose of IMC-A12 when given together with temsirolimus and to see how well they work in treating patients with locally recurrent or metastatic breast cancer. Monoclonal antibodies, such as cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving IMC-A12 together with temsirolimus may kill more tumor cells.


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.

Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Male Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Biological: cixutumumab
    Given IV
    Other Names:
    • anti-IGF-1R recombinant monoclonal antibody IMC-A12
    • IMC-A12
  • Drug: temsirolimus
    Given IV
    Other Names:
    • CCI-779
    • cell cycle inhibitor 779
    • Torisel
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (monoclonal antibody and enzyme inhibitor therapy)

Phase I patients were accrued in 3 patient cohorts to assess toxicity. In sequence, each cohort received the following treatment:

  • temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 (25 mg in cohort I, 20 mg in cohort 2, 15 mg in cohort 3, 4, and 5).
  • cixutumumab IV over 60 minutes on days 1, 8, 15, and 22 (3 mg/ks in cohort 1, 2, and 3; 4 mg/kg in cohort 4, and 5 mg/kg in cohort 5).

Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Phase II patients receive the recommended phase II dose determined in the phase I portion.

  • 15 mg temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.
  • 4 mg/kg 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.

  • Biological: cixutumumab
  • Drug: temsirolimus
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Active, not recruiting
January 2016
September 2013   (final data collection date for primary outcome measure)

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 condition
  • 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 to anti-IGF-1R recombinant monoclonal antibody IMC-A12 or temsirolimus
  • Known HIV-positive patients who have CD4 counts below the normal range are not eligible
  • 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 requirements
  • 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
18 Years and older
Contact information is only displayed when the study is recruiting subjects
United States
NCI-2009-00284, NCI-2009-00284, CDR0000598057, MC0736, 8129, P30CA015083, N01CM00099
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Cynthia Ma Mayo Clinic
National Cancer Institute (NCI)
January 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP