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

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

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

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.

Detailed Summary:

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
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • 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)
  • 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

      Original Primary Outcome:

      • Recommended dose level (phase I)
      • Safety profile (phase I)
      • Antitumor activity (phase II)


      Current Secondary Outcome:

      • 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.
      • 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.
      • 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.
      • 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.
      • 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.


      Original Secondary Outcome:

      • Adverse events (phase II)
      • Duration of response (phase II)
      • Progression-free survival (phase II)
      • Survival Time (Phase II)
      • Serum estradiol and progesterone levels prior to treatment (phase II)
      • Levels of IGF-1, IGF-2, IGFBP1-3, insulin, glucose, C-peptide (Phase II)


      Information By: National Cancer Institute (NCI)

      Dates:
      Date Received: June 17, 2008
      Date Started: October 2008
      Date Completion:
      Last Updated: December 28, 2016
      Last Verified: December 2016