Cixutumumab, Everolimus, and Octreotide Acetate in Treating Patients With Advanced Low to Intermediate Grade Neuroendocrine Carcinoma

This is an interventional treatment trial for Gastrin-Producing Neuroendocrine Tumor Read More

Inclusion Criteria:

• All patients must sign an informed consent indicating that they are aware of the investigational nature of this study
• Patients must have histologically or cytologically confirmed low or intermediate grade neuroendocrine carcinoma, for which standard curative measures do not exist; patients with neuroendocrine tumors associated with multiple endocrine neoplasia type 1 (MEN1) syndrome will be eligible
• Patients must have disease that is amenable to computed tomography (CT) or ultrasound (U/S) guided biopsies; patients must agree to undergo 2 biopsies; the disease identified for biopsy cannot be the only site of measurable disease
• Patients must be registered in the M.D. Anderson Cancer Center (MDACC) institutional database prior to treatment with study drug
• Zubrod performance status of 0 or 1
• Leukocytes > 3,000/mcL
• Absolute neutrophil count > 1,500/mcL
• Hemoglobin > 9 g/dL; eligibility level for hemoglobin may be reached by transfusion
• Platelets > 100,000/mcL
• Total bilirubin =< 1.5 X upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 1.5 X institutional ULN (5 x ULN if liver function tests [LFT] elevations due to liver metastases)
• Creatinine =< 1.5 X institutional ULN OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• The patient must have fasting serum glucose =< 1.2 X upper limit of normal
• Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN; NOTE: in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
• Women of child-bearing potential and men must agree to use adequate contraception from the time of study enrollment continuing for the duration of study therapy and for 3 months after the last dose of IMC-A12 and/or everolimus; oral, implantable, or injectable contraceptives are not considered effective for this study; if barrier contraceptives are being used, these must be continued for the specified time by both sexes; women are considered to be of child-bearing potential if they have not undergone surgical sterilization (laparoscopic tubal ligation, hysterectomy, bilateral salping-oophorectomy) or have not reached menopause, defined as amenorrhea persisting for at least twelve consecutive months; men of any age are considered to be fertile unless they have undergone bilateral vasectomy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; if the subject becomes pregnant while on study, she must discontinue study treatment
• Negative pregnancy test (serum beta-human chorionic gonadotropin [HCG]) within 7 days of starting study treatment is required in women of childbearing potential; neuroendocrine tumor (NET) patients with positive beta-HCG are eligible if pregnancy can be excluded by lack of expected doubling of beta-HCG; the usual beta-HCG doubling time is every 2 days during the first 4 weeks of pregnancy and lengthens to every 3 ½ days by weeks 6 to 7; patients can also be eligible if pregnancy can be excluded by vaginal ultrasound in consultation with Obstetrics/Gynecology
• Patients must have at least one measurable site of disease according to RECIST that has not been previously irradiated; if the patient has had previous radiation to the target lesion(s), there must be evidence of progression in the lesion(s) since the radiation
• Prior radiation therapy is permitted; a recovery period of at least 4 weeks after completion of radiotherapy is required prior to enrollment
• Patients may have received prior systemic anti-neoplastic therapy (except prior mammalian target of rapamycin [mTOR] inhibitors or agents targeting insulin-like growth factor 1 receptor [IGF1R]); there are no limitations on the number of prior regimens; at least 28 days must have elapsed since last treatment

• Patients not on anticoagulation must have international normalized ratio (INR) =< 1.5; patients on full-dose anticoagulation (warfarin or low molecular weight heparin) are eligible provided that both of the following criteria are met:

  • The patient has an in-range INR (between 2 and 3) on a stable (no change in the 2 weeks prior to registration) dose of oral anticoagulant or on a stable (no change in the prior 2 weeks) dose of low molecular weight heparin
  • The patient has no active bleeding or known pathological condition that carries a high risk of bleeding such as varices

Exclusion Criteria:

• Patients may not be receiving any other investigational agents

• Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection requiring parenteral therapy at the time of study registration
  • Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C); note: a detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients
  • Symptomatic congestive heart failure resulting in a resting oxygen saturation of < 92% on room air
  • Unstable angina or pectoris myocardial infarction within 6 months of start of study drug
  • Serious uncontrolled cardiac arrhythmia
  • Known severely impaired lung function as defined as spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or oxygen saturation that is 88% or less at rest on room air; pulmonary function test (PFT) is not required at study entry
• A known history of human immunodeficiency virus (HIV) seropositivity
• Chronic treatment with systemic steroids or another immunosuppressive agent
• Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods; pregnant women are excluded from the study; breastfeeding women should be excluded
• Patients with a known history of allergic reactions and/or hypersensitivity attributed compounds of similar chemical or biologic composition to IMC-A12, everolimus or other rapamycins (sirolimus, temsirolimus)
• Known history of brain or leptomeningeal metastases
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
• Patients who have had hormonal therapy (other than replacement) within 4 weeks prior to entering the study
• Not recovered from adverse events related to previous treatment (excluding alopecia) to active Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1
• With the exception of tumor common to a single genetic cancer syndrome (i.e. MEN1, multiple endocrine neoplasia type 2 [MEN2], von Hippel-Lindau [vHL], tuberous sclerosis complex [TSC] etc), patients with evidence of more than one active malignancy are excluded; active malignancy is defined as the presence of primary, regional nodal, or distant metastatic neoplasm that has not undergone definitive therapy
• The patient has poorly controlled diabetes mellitus; patients with a history of diabetes mellitus are allowed to participate, providing that their blood glucose is within 1.2 X institutional upper limit of normal and that they are on a stable dietary or therapeutic regimen for this condition
• Patients who have received prior treatment with IMC-A12, everolimus, other agents targeting the insulin-like growth factor receptor (IGFR) or an mTOR inhibitor (sirolimus, temsirolimus, everolimus)