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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00699491
First received: June 17, 2008
Last updated: June 9, 2014
Last verified: June 2014
  Purpose

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 Intervention Phase
Male Breast Cancer
Recurrent Breast Cancer
Stage IV Breast Cancer
Biological: cixutumumab
Drug: temsirolimus
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of IMC-A12 in Combination With Temsirolimus in Patients With Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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. 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.

  • 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 two-stage Simon Phase II clinical trial design will be used to assess the anti-tumor activity of the combination of Temsirolimus and IMC-A12 at the recommended phase II dose in patients with metastatic breast cancer. A ninety percent confidence interval for the true tumor response rate will be calculated using the Duffy-Santer approach.


Secondary Outcome Measures:
  • Adverse events graded using the NCI CTCAE version. 3 (phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    The maximum grade for each adverse event considered to be 'at least possibly related to treatment' will be recorded. Frequency tables will be constructed.

  • 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.

  • PFS (phase II) [ Time Frame: Time from registration to documentation of disease progression ] [ Designated as safety issue: No ]
    The distribution of PFS times will be estimated using the Kaplan-Meier method.

  • PFS rate [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
    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 ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier.


Enrollment: 48
Study Start Date: October 2008
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 minues 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

Detailed Description:

PRIMARY OBJECTIVES:

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)

SECONDARY OBJECTIVES:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 toanti-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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00699491

  Show 191 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Cynthia Ma Mayo Clinic
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00699491     History of Changes
Other Study ID Numbers: NCI-2009-00284, NCI-2009-00284, CDR0000598057, MC0736, 8129, P30CA015083, N01CM00099
Study First Received: June 17, 2008
Last Updated: June 9, 2014
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on October 22, 2014