A Study of Cixutumumab (IMC-A12) in Islet Cell Cancer

Study Overview
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Brief Summary
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Determine the 6-month progression free survival (PFS) rate associated with cixutumumab in combination with depot octreotide acetate (octreotide) in participants with metastatic neuroendocrine tumors.

Official Title
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A Phase 2, Multicenter, Two Tier Study of IMC-A12 in Combination With Depot Octreotide in Patients With Metastatic, Well or Moderately Differentiated Carcinoid or Islet Cell Carcinoma

Conditions
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Carcinoma, Neuroendocrine Tumors

Intervention / Treatment
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* Biological: Cixutumumab
* Drug: depot octreotide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has well-differentiated or moderately-differentiated, histologically confirmed neuroendocrine carcinoma, including carcinoid of any location and islet cell tumors The participant has metastatic disease at the time of study entry The participant must have a tumor measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, measurable by elevated tumor markers (eg, 24-hour urine 5-HIAA, chromogranin A, adrenocorticotropin hormone (ACTH), gastrin, or other tumor specific biochemical markers), or both The participant is age ≥ 18 years The participant's tumor has Ki-67 expression ≤ 20% The participant is receiving depot octreotide therapy at the time of enrolling into the study The participant has received 0 - 2 systemic anticancer regimens in addition to depot octreotide, which may have included chemotherapy, interferon, antiangiogenic therapy, other targeted treatments, or a combination of such treatments The participant is no longer a candidate for surgery, embolization, or radiofrequency ablation therapy The participant has experienced radiographic, biochemical, and/or scintigraphic disease progression while on a regimen that includes octreotide The participant has completed prior chemotherapy and/or radiotherapy with curative intent at least 3 weeks prior to the administration of the first dose of study therapy. Participants that have received palliative radiation therapy to bony metastases prior to the first dose of study medication are eligible The participant has a life expectancy of > 3 months The participant has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 The participant has adequate hematologic function as defined by absolute neutrophil count ≥ 1500/microliters (μL), hemoglobin ≥ 9 gram/deciliter (g/dL), and platelet count ≥100,000/μL The participant has adequate hepatic function as defined by a total bilirubin ≤ 1.5 x the upper limit of normal (ULN), and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x the ULN (or ≤ 5 x the ULN in the presence of known liver metastases) The participant either has adequate coagulation function as defined by international normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) no more than 5 seconds above the ULN, or is on a stable dose of anticoagulant The participant has adequate renal function as defined by serum creatinine ≤ 1.5 x the institutional ULN or creatinine clearance ≥ 60 milliliter/minute (mL/min) for participants with creatinine levels above the ULN The participant has fasting serum glucose < 160 milligram/deciliter (mg/dL) and hemoglobin A1c (HgbA1c)≤ 7. If baseline nonfasting glucose is < 160 mg/dL, fasting glucose measurement is not required Because the teratogenicity of cixutumumab is not known, women of childbearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation The participant has the ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: The participant has uncontrolled brain or leptomeningeal metastases The participant has not recovered to Grade ≤ 1 from adverse events due to agents administered more than 4 weeks prior to study entry (except for alopecia) The participant is receiving any other investigational agent(s) The participant has received therapeutic radiolabeled somatostatin analogues The participant has received more than 2 prior regimens of systemic therapy in the metastatic setting The participant has a history of treatment with other agents targeting the IGF receptor The participant has a history of allergic reactions attributed to compounds of chemical or biologic composition similar to that of cixutumumab or to octreotide The participant has poorly controlled diabetes mellitus. Participants with a history of diabetes mellitus are allowed to participate, provided that their fasting glucose < 160 mg/dL or below the ULN and that they are on a stable dietary or therapeutic regimen for this condition The participant has an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements The participant is pregnant or lactating The participant is known to be positive for infection with the human immunodeficiency virus The participant has a history of another primary cancer, with the exception of: a) curatively resected nonmelanomatous skin cancer; b) curatively treated cervical carcinoma in-situ; or c) other primary solid tumor curatively resected or treated with no known active disease present and no treatment administered for the last 3 years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carcinoid tumor<br>Participants with carcinoid tumor will receive cixutumumab 10 mg/kg over 1 hour every 2 weeks. Treatment will continue until there is evidence of disease progression, intolerable toxicity, or other withdrawal criteria are met. Participants must be receiving depot octreotide at the time of enrolling into the study. Participants on stable doses of depot octreotide will continue to receive the same dose and schedule of their last regimen. | Biological: Cixutumumab<br>* Participants will receive cixutumumab IV 10 mg/kg over 1 hour every 2 weeks. Treatment will continue until there is evidence of disease progression, intolerable toxicity, or other withdrawal criteria are met.<br>* Other names: LY3012217;Drug: depot octreotide<br>* Participants must be receiving depot octreotide at the time of enrolling into the study. Participants on stable doses of depot octreotide will continue to receive the same dose and schedule of their last regimen.<br>* Other names: SMS 201-995;|
| Experimental: Islet cell carcinoma<br>Participants with islet cell carcinoma will receive cixutumumab 10 mg/kg over 1 hour every 2 weeks. Treatment will continue until there is evidence of disease progression, intolerable toxicity, or other withdrawal criteria are met. Participants must be receiving depot octreotide at the time of enrolling into the study. Participants on stable doses of depot octreotide will continue to receive the same dose and schedule of their last regimen. | Biological: Cixutumumab<br>* Participants will receive cixutumumab IV 10 mg/kg over 1 hour every 2 weeks. Treatment will continue until there is evidence of disease progression, intolerable toxicity, or other withdrawal criteria are met.<br>* Other names: LY3012217;Drug: depot octreotide<br>* Participants must be receiving depot octreotide at the time of enrolling into the study. Participants on stable doses of depot octreotide will continue to receive the same dose and schedule of their last regimen.<br>* Other names: SMS 201-995;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Progression-Free Survival (PFS) Rate at Six Months | Percentage of participants who are alive and progression-free at 6 month from start of the study treatment over all participants. PFS is defined as the time from the start of study treatment until the date of objectively determined progressive disease (PD) or death due to any cause. Disease progression was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. Participants without documentation of progression or death will be censored at the date of last tumor assessment. The PFS was estimated by the binomial distribution and Kaplan-Meier method. | From Start of Study Treatment to Progressive Disease or Death Due to Any Cause (Up to 6 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieve Modified Objective Response Rate (ORR) of Complete Response (CR), Partial Response (PR) and Minor Response (MR) Modified Objective Response Rate (mORR) | Modified ORR is defined as CR+ PR + MR. According to RECIST v1.0, CR was defined as the disappearance of all target and non-target lesions; PR defined as a >30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD and MR defined as 20% - 29% reduction. Disease progression defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. | From Start of Treatment Baseline to Disease Progression (Up to 18 Months) | 
| Percentage of Participants With a Biochemical Response Rate | Determine the biochemical response rate (≥ 50% reduction in tumor-specific markers; may include, not limited to 24 hour urine 5-hydroxyindoleacetic acid, chromogranin A, adrenocorticotropin hormone (ACTH), or gastrin) in the subset of participants with biochemically measurable disease. | From Start of Treatment Up to 18 Months | 
| Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Number of participants that had at least one TEAE is presented. A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section. | 18 months | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) Cycle 1 |  | Prior to the final infusion, immediately after the infusion, and 1, 2, 4, 8, 48, 96, 168, and 336 hours after the completion of the final infusion | 
| PK: Half-life (t 1/2) Cycle 1 |  | Prior to the final infusion, immediately after the infusion, and 1, 2, 4, 8, 48, 96, 168, and 336 hours after the completion of the final infusion | 
| PK: Area Under Concentration (AUCinf) Cycle 1 |  | Prior to the final infusion, immediately after the infusion, and 1, 2, 4, 8, 48, 96, 168, and 336 hours after the completion of the final infusion | 
| PK: Clearance (CL) Cycle 1 |  | Prior to the final infusion, immediately after the infusion, and 1, 2, 4, 8, 48, 96, 168, and 336 hours after the completion of the final infusion | 
| PK: Volume at Steady State (Vss) Cycle 1 |  | Prior to the final infusion, immediately after the infusion, and 1, 2, 4, 8, 48, 96, 168, and 336 hours after the completion of the final infusion | 
| Serum Anti-Cixutumumab Antibody Assessment |  | 18 months | 
| Pharmacodynamics Markers; Concentration of Insulin-like Growth Factor I, II (IGF-I, IGF-II), IGF Body Fat (IGFBF)-1 and IGFBF-2 |  | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Islet Cell, CARCINOMA, ISLET CELL, Octreotide, depot octreotide acetate, Insulin-Like Growth Factor (IGF) 1, Metastatic, Carcinoid or Islet Cell, Neuroendocrine Tumors