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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00699491
Recruitment Status : Active, not recruiting
First Posted : June 18, 2008
Results First Posted : May 21, 2015
Last Update Posted : February 15, 2017
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Male Breast Cancer Recurrent Breast Cancer Stage IV Breast Cancer Biological: cixutumumab Drug: temsirolimus Other: laboratory biomarker analysis Phase 1 Phase 2

Detailed Description:


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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial of IMC-A12 in Combination With Temsirolimus in Patients With Metastatic Breast Cancer
Study Start Date : October 2008
Actual Primary Completion Date : September 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
U.S. FDA Resources

Arm Intervention/treatment
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
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

Primary Outcome Measures :
  1. Recommended Dose Level for Phase II Testing (RPTD) (Phase I) [ Time Frame: During first course ]

    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)

  2. 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 ]

    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.

Secondary Outcome Measures :
  1. Adverse Events Graded Using the NCI CTCAE Version. 3 (Phase II) [ Time Frame: Up to 5 years ]
    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.

  2. Duration of Response (Phase II) [ Time Frame: Up to 5 years ]
    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.

  3. Progression Free Survival (PFS) (Phase II) [ Time Frame: Time from registration to documentation of disease progression, up to 5 years ]
    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.

  4. Progression Free Survival Rate [ Time Frame: At 6 months ]
    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.

  5. Survival Time (Phase II) [ Time Frame: Time from registration to death due to any cause ]
    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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00699491

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Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Cynthia Ma Mayo Clinic

Responsible Party: National Cancer Institute (NCI) Identifier: NCT00699491     History of Changes
Other Study ID Numbers: NCI-2009-00284
NCI-2009-00284 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC0736 ( Other Identifier: Mayo Clinic )
8129 ( Other Identifier: CTEP )
P30CA015083 ( U.S. NIH Grant/Contract )
N01CM00099 ( U.S. NIH Grant/Contract )
First Posted: June 18, 2008    Key Record Dates
Results First Posted: May 21, 2015
Last Update Posted: February 15, 2017
Last Verified: December 2016

Additional relevant MeSH terms:
Breast Neoplasms
Breast Neoplasms, Male
Neoplasms by Site
Breast Diseases
Skin Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Immunosuppressive Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents