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Phase I Study of Anti-IGF-1R Monoclonal Antibody, IMC-A12, and mTOR Inhibitor, Everolimus, in Advanced Low to Intermediate Grade Neuroendocrine Carcinoma

Phase 1
18 Years
Open (Enrolling)
Endocrine Cancer, Metastatic Gastrointestinal Carcinoid Tumor, Recurrent Gastrointestinal Carcinoid Tumor, Recurrent Islet Cell Carcinoma, Recurrent Neuroendocrine Carcinoma of the Skin, Stage IV Neuroendocrine Carcinoma of the Skin, Thyroid Gland Medullary Carcinoma

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Trial Information

Phase I Study of Anti-IGF-1R Monoclonal Antibody, IMC-A12, and mTOR Inhibitor, Everolimus, in Advanced Low to Intermediate Grade Neuroendocrine Carcinoma


I. To recommend a phase 2 dose for the combination of IMC-A12 (cixutumumab) and everolimus.

II. To describe the pharmacokinetics of IMC-A12 given once every 21 days in combination with

III. To evaluate pharmacodynamic markers in blood, and tumor tissue.


I. To evaluate the safety profile of IMC-A12 and everolimus with or without octreotide among
patients with advanced neuroendocrine tumors.

II. To explore the anti-tumor activity of the combination of IMC-A12 and everolimus as
defined by Response Evaluation Criteria in Solid Tumors (RECIST) response rate and
progression-free survival (PFS).


I. To explore baseline molecular marker and drug-induced molecular marker changes that may
predict clinical outcome.

OUTLINE: This is a dose-escalation study of cixutumumab.

Patients receive cixutumumab IV over 60-90 minutes and depot octreotide acetate
intramuscularly on day 1 and oral everolimus once daily on days 1-21. Treatment repeats
every 21 days for up to 18 courses in the absence of disease progression or unacceptable

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

Inclusion Criteria:

- All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study

- For dose escalation cohorts:

- Patients must have histologically confirmed neuroendocrine carcinoma, malignant
endocrine cancer, or other carcinoma of gastrointestinal origin that is
metastatic or unresectable for which standard curative or palliative measures do
not exist or are no longer effective

- For dose expansion cohorts:

- Patients must have histologically or cytologically confirmed low or intermediate
grade neuroendocrine carcinoma; patients with neuroendocrine tumors associated
with MEN1 syndrome will be eligible

- For dose expansion cohorts:

- Patients must have disease that is amenable to computed tomography (CT) or
ultrasound (US)-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)

- AST(SGOT) and ALT(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 < 120 mg/dL

- 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

- The effects of IMC-A12 and everolimus on the developing human fetus are unknown; for
this reason, women of child-bearing potential and men must agree to use contraception
(hormonal or barrier method of birth control; abstinence) 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; 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; beta-HCG
may be secreted by a small percentage of NETs and be a tumor marker; thus, NET
patients with positive beta-HCG are eligible if pregnancy can be excluded by vaginal
ultrasound or lack of expected doubling of beta-HCG

- 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

- Patients who are on a somatostatin analogue must be on a stable dose (no change in mg
dose of long acting octreotide), changes in dosing interval of +/- 1 week is allowed)
for 2 months prior to start of treatment

- 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 agents
targeting 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

- 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

- Severely impaired lung function as defined as spirometry and diffusion capacity
of 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

- A known history of human immunodeficiency virus (HIV) seropositivity

- Chronic treatment with systemic steroids or another immunosuppressive agent

- Pregnant women are excluded from the study because IMC-A12 is a monoclonal antibody
to IGF-IR with the potential for teratogenic or abortifacient effects; IgG antibody
may also potentially be secreted in milk and therefore breastfeeding women should be

- Patients with a known hypersensitivity to IMC-A12 or compounds of similar chemical or
biologic composition to IMC-A12, everolimus or other rapamycins (sirolimus,

- 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

- Not recovered from adverse events related to previous treatment (excluding alopecia)
to Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1

- Patients with evidence of more than one active malignancy are excluded

- The patient has poorly controlled diabetes mellitus are excluded; patients with a
history of diabetes mellitus are allowed to participate, providing that their blood
glucose level is within normal range (fasting < 120 mg/dL or below 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 an mTOR inhibitor (sirolimus,
temsirolimus, everolimus)

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose-limiting toxicities (DLT) for the combination of IMC-A12 and everolimus

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

James Yao

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

October 2010

Completion Date:

Related Keywords:

  • Endocrine Cancer
  • Metastatic Gastrointestinal Carcinoid Tumor
  • Recurrent Gastrointestinal Carcinoid Tumor
  • Recurrent Islet Cell Carcinoma
  • Recurrent Neuroendocrine Carcinoma of the Skin
  • Stage IV Neuroendocrine Carcinoma of the Skin
  • Thyroid Gland Medullary Carcinoma
  • Carcinoid Tumor
  • Carcinoma
  • Carcinoma, Merkel Cell
  • Endocrine Gland Neoplasms
  • Carcinoma, Medullary
  • Thyroid Neoplasms
  • Carcinoma, Neuroendocrine
  • Malignant Carcinoid Syndrome
  • Gastrointestinal Neoplasms
  • Skin Neoplasms
  • Carcinoma, Basal Cell
  • Carcinoma, Basosquamous
  • Carcinoma, Squamous Cell
  • Carcinoma, Islet Cell



M D Anderson Cancer CenterHouston, Texas  77030