Cixutumumab and Temsirolimus in Treating Patients With Locally Advanced or Metastatic Cancer

Phase I Study of IMC-A12 (NSC# 742460) in Combination With Temsirolimus CCI-779 (NSC# 683864) in Patients With Advanced Cancers

This phase I trial studies the side effects and best dose of cixutumumab and temsirolimus in treating patients with locally advanced or metastatic cancer. Monoclonal antibodies, such as cixutumumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Temsirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving cixutumumab together with temsirolimus may kill more cancer cells.

Study Overview

• Status: Completed
• Conditions: Malignant Neoplasm
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Temsirolimus; Drug: Cixutumumab

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability; and to determine maximum tolerated dose (MTD) of the combination of IMC-A12 (cixutumumab) with temsirolimus in patients with or without biopsiable advanced cancers.

II. To evaluate the biologic effect of each individual drug and this drug combination on expression/phosphorylation of potential markers of response in patients with biopsiable disease.

III. To assess tumor metabolism by positron emission tomography (PET).

SECONDARY OBJECTIVES:

I. To report the clinical tumor response of this combination in a descriptive fashion.

OUTLINE:

DOSE ESCALATION PHASE: Patients receive temsirolimus intravenously (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. After the MTD is determined, subsequent patients are enrolled into the MTD expansion cohort.

MTD EXPANSION COHORT: Patients are assigned to 1 of 3 treatment groups.

GROUP A: Patients receive temsirolimus IV over 30 minutes on days 15 and 22 for course 1 and on days 1, 8, 15, and 22 for all subsequent courses. Patients also receive 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.

GROUP B: Patients receive cixutumumab IV over 60 minutes on days 15 and 22 for course 1 and on days 1, 8, 15, and 22 for all subsequent courses. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP C: 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.

After completion of study treatment, patients are followed up within 30 days.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with advanced or metastatic cancer
• Patients enrolled in the expansion cohorts may be on antidiabetic treatment, but baseline glucose should be =< 120
• All patients must sign an informed consent indicating that they are aware of the investigational nature of this study; patients must also have signed an authorization for the release of their protected health information
• Patients are allowed to have unlimited prior treatments
• Patients must be registered in the MD Anderson Cancer Center (MDACC) institutional database (CORE) prior to treatment with study drug
• Estimated life expectancy of greater than 3 months
• Patients must be ≥ 4 weeks beyond treatment of any chemotherapy, other investigational therapy, biological, targeted agents or radiotherapy, and must have recovered to =< grade 1 toxicity or previous baseline for each toxicity; exceptions: patients must be >= 6 weeks beyond treatment with monoclonal antibodies; patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy provided pelvis, sternum, scapulae, vertebrae, or skull were not included in the radiotherapy field
• Patients must be >= 2 weeks beyond treatment of hormonal therapy
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Absolute neutrophil count >= 1500/mL
• Platelets >= 100,000/mL
• Creatinine =< 2 X upper limit of normal (ULN)
• Total (T.) bilirubin =< 1.5 X ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X ULN
• Women of childbearing potential MUST have a negative serum or urine human chorionic gonadotropin (HCG) test unless prior hysterectomy or menopause (defined as 12 consecutive months without menstrual activity); patients should not become pregnant or breastfeed while on this study; sexually active patients must agree to use contraception prior to study entry, for the duration of study participation, and for 3 months after the last dose
• Patients must be >= 16 years of age; patients with Ewing's Sarcoma must be >= 14 years of age

Exclusion Criteria:

• Patients may not be receiving any other investigational agents
• Patients who are pregnant or breastfeeding
• Patients with history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days
• Patients with uncontrolled intercurrent illness including, but not limited to, active infection requiring hospitalization
• Patients with history of hypersensitivity to monoclonal antibody treatment or immunosuppressant agents
• Patients with history of cerebrovascular accident (CVA), myocardial infarction or unstable angina within the previous six months before starting therapy
• Patients with New York Heart Association class III or greater congestive heart failure or uncontrolled hyperlipidemia (cholesterol > 300 mg/dl; triglyceride 2.5 X ULN despite lipid lowering agent)
• Patients with fasting blood sugar > 120; patients who are on oral hypoglycemic agents and insulin will be excluded; exception: patients in the expansion cohorts may be on antidiabetic treatment (including hypoglycemic agents and/or insulin) if controlled
• Patients on drugs that are strong P450 cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors or inducers; these drugs should be stopped 5 half-lives prior to starting investigational agents with temsirolimus; the strong inducing or inhibiting agents should not restart until 1 week after the end of study treatment; the principal investigator (PI) or his designee will go over/check the list of medication for individual patients; NOTE: Physiologic replacement of steroids (with either prednisone or hydrocortisone) in patients with adrenalectomy will be allowed
• Patients with history of brain metastasis are eligible, however the brain metastases should have been treated (treatment defined as surgery or radiation therapy [RT]) and the patient should have been free from symptoms/signs and off steroids for at least 3 months before study entry
• Patients with highly aggressive lymphoma (i.e. Burkitt's)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (temsirolimus on days 15 and 22 course 1); Patients receive temsirolimus IV over 30 minutes on days 15 and 22 for course 1 and on days 1, 8, 15, and 22 for all subsequent courses. Patients also receive cixutumumab IV over 60 minutes on days 1, 8, 15, and 22.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Temsirolimus; Given IV; Other Names: Torisel; CCI-779; CCI-779 Rapamycin Analog; Cell Cycle Inhibitor 779; Rapamycin Analog; Rapamycin Analog CCI-779; Drug: Cixutumumab; Given IV; Other Names: IMC-A12; Anti-IGF-1R Recombinant Monoclonal Antibody IMC-A12
Experimental: Group B (cixutumumab on days 15 and 22 of course 1); Patients receive cixutumumab IV over 60 minutes on days 15 and 22 for course 1 and on days 1, 8, 15, and 22 for all subsequent courses. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Temsirolimus; Given IV; Other Names: Torisel; CCI-779; CCI-779 Rapamycin Analog; Cell Cycle Inhibitor 779; Rapamycin Analog; Rapamycin Analog CCI-779; Drug: Cixutumumab; Given IV; Other Names: IMC-A12; Anti-IGF-1R Recombinant Monoclonal Antibody IMC-A12
Experimental: Group C (temsirolimus on days 1, 8, 15, and 22); Patients receive temsirolimus IV over 30 minutes and cixutumumab IV over 60 minutes on days 1, 8, 15, and 22.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Temsirolimus; Given IV; Other Names: Torisel; CCI-779; CCI-779 Rapamycin Analog; Cell Cycle Inhibitor 779; Rapamycin Analog; Rapamycin Analog CCI-779; Drug: Cixutumumab; Given IV; Other Names: IMC-A12; Anti-IGF-1R Recombinant Monoclonal Antibody IMC-A12

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in phosphorylation levels of other biomarkers before and after treatment	Other markers include: insulin-like growth factor 1 receptor (IGF-1R), phosphorylated (p)IGF-1R, insulin receptor substrate-1 (IRS-1), phosphatase and tensin homolog gene (PTEN), vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and cluster of differentiation (CD)31. Generalized Estimating Equations model will be used to model the correlated IHC score between treatment arms.	Baseline to up to day 11
Change in phosphorylation levels of v-akt murine thymoma viral oncogene homolog 1 in terms of difference in IHC score	Generalized Estimating Equations model will be used to model the correlated IHC score between treatment arms.	Baseline to up to day 11
MTD of combination of cixutumumab and temsirolimus defined as the highest dose level at which no more than 1 of 6 evaluable patients has had a dose-limiting toxicity		28 days
Tumor metabolism as assessed by PET scan before and after treatment	The PET standardized uptake value (SUV) of all patients will be pooled together to plot the overall trend of PET SUV over time, the percent change in PET SUV will be estimated and 95% confidence intervals will be provided.	Baseline to up to day 28 of course 2

Secondary Outcome Measures

Outcome Measure	Time Frame
Tumor response rate defined as CR + PR assessed by Response Evaluation Criteria in Solid Tumors and CHESON criteria	Up to 30 days after completion of study treatment

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Aung Naing, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• Liu X, Lorusso P, Mita M, Piha-Paul S, Hong DS, Fu S, McQuinn L, Asatiani E, Doyle LA, Chen HX, Hess KR, Kurzrock R, Naing A. Incidence of mucositis in patients treated with temsirolimus-based regimens and correlation to treatment response. Oncologist. 2014 Apr;19(4):426-8. doi: 10.1634/theoncologist.2013-0231. Epub 2014 Mar 25.

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: May 14, 2008
• First Submitted That Met QC Criteria: May 14, 2008
• First Posted (Estimate): May 16, 2008

Study Record Updates

• Last Update Posted (Estimate): November 4, 2015
• Last Update Submitted That Met QC Criteria: November 3, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antibodies, Monoclonal; Sirolimus
• Other Study ID Numbers: NCI-2009-00282 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA016672 (U.S. NIH Grant/Contract); U01CA062461 (U.S. NIH Grant/Contract); U01CA062487 (U.S. NIH Grant/Contract); CDR0000595388; 2007-0595 (Other Identifier: M D Anderson Cancer Center); 8109 (Other Identifier: CTEP)