Phase I Study of Cixutumumab and mTOR Inhibitor, Everolimus, in Advanced Low to Intermediate Grade Neuroendocrine Carcinoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01204476
First received: September 16, 2010
Last updated: March 20, 2014
Last verified: September 2013
  Purpose

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. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Octreotide acetate may interfere with the growth of tumor cells and slow the growth of neuroendocrine cancer. This phase I trial is studying the side effects and best dose of cixutumumab when given together with everolimus and octreotide acetate in treating patients with advanced low- or intermediate-grade neuroendocrine cancer.


Condition Intervention Phase
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
Biological: cixutumumab
Drug: octreotide acetate
Drug: everolimus
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Anti-IGF-1R Monoclonal Antibody, IMC-A12, and mTOR Inhibitor, Everolimus, in Advanced Low to Intermediate Grade Neuroendocrine Carcinoma

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Dose-limiting toxicities (DLT) for the combination of IMC-A12 and everolimus [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
  • Safety profile of IMC-A12 and everolimus with or without octreotide among patients with advanced neuroendocrine tumors [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
  • Pharmacodynamic markers in blood and tumor tissue [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Descriptive statistics for the changes from baseline in blood and tissue biomarkers will be presented by response category in an attempt to characterize these changes with respect to efficacy.


Secondary Outcome Measures:
  • Anti-tumor activity as determined by RECIST [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Enrollment: 19
Study Start Date: October 2010
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (cixutumumab, octreotide acetate, everolimus)
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 toxicity.
Biological: cixutumumab
Given IV
Other Names:
  • anti-IGF-1R recombinant monoclonal antibody IMC-A12
  • IMC-A12
Drug: octreotide acetate
Given intramuscularly
Other Names:
  • Longastatin
  • Longastatina
  • Samilstin
  • SMS 201-995
Drug: everolimus
Given orally
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

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 everolimus.

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

SECONDARY OBJECTIVES:

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).

TERTIARY OBJECTIVES:

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 toxicity.

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

  Eligibility

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

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 radiation
  • 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 registration
    • 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 excluded
  • Patients with a known hypersensitivity to IMC-A12 or 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
  • 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)
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01204476

Locations
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Investigators
Principal Investigator: James Yao M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01204476     History of Changes
Other Study ID Numbers: NCI-2010-02196, NCI-2010-02196, CDR0000685267, 2009-0734, 8354, U01CA062461, P30CA016672
Study First Received: September 16, 2010
Last Updated: March 20, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
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
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Endocrine System Diseases
Neoplasms, Ductal, Lobular, and Medullary
Head and Neck Neoplasms
Thyroid Diseases
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases

ClinicalTrials.gov processed this record on April 17, 2014