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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00781911

Enrollment

Registered

2008-10-29

Start date

2009-02-28

Completion date

2016-05-31

Last updated

2019-09-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Carcinoma, Neuroendocrine Tumors

Keywords

Islet Cell, CARCINOMA, ISLET CELL, Octreotide, depot octreotide acetate, Insulin-Like Growth Factor (IGF) 1, Metastatic, Carcinoid or Islet Cell, Neuroendocrine Tumors

Brief summary

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.

Interventions

BIOLOGICALCixutumumab

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.

DRUGdepot octreotide

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.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Progression-Free Survival (PFS) Rate at Six Months	From Start of Study Treatment to Progressive Disease or Death Due to Any Cause (Up to 6 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.

Secondary

Measure	Time frame	Description
Percentage of Participants With a Biochemical Response Rate	From Start of Treatment Up to 18 Months	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.
Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)	18 months	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.
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	—
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)	From Start of Treatment Baseline to Disease Progression (Up to 18 Months)	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.
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	—
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	—

Countries

United States

Participant flow

Pre-assignment details

Participants who completed the study include those who died and had progressive disease.

Participants by arm

Arm	Count
Carcinoid Tumor Participants with carcinoid tumor received cixutumumab 10 mg/kg IV over 1 hour every 2 weeks. Treatment continued 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 continued to receive the same dose and schedule of their last regimen.	31
Islet Cell Carcinoma Participants received cixutumumab 10 mg/kg IV over 1 hour every 2 weeks. Treatment continued 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 continued to receive the same dose and schedule of their last regimen.	12
Total	43

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	4	4
Overall Study	Physician Decision	0	2
Overall Study	Sponsor Decision	1	0
Overall Study	Withdrawal by Subject	1	2

Baseline characteristics

Characteristic	Total	Carcinoid Tumor	Islet Cell Carcinoma
Age, Continuous	60.6 years STANDARD_DEVIATION 9.6	60.3 years STANDARD_DEVIATION 9.65	61.3 years STANDARD_DEVIATION 9.85
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants	2 Participants	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	38 Participants	29 Participants	9 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	42 Participants	30 Participants	12 Participants
Region of Enrollment United States	43 Participants	31 Participants	12 Participants
Sex: Female, Male Female	21 Participants	17 Participants	4 Participants
Sex: Female, Male Male	22 Participants	14 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	31 / 31	12 / 12
serious Total, serious adverse events	12 / 31	6 / 12

Outcome results

Primary

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.

Time frame: From Start of Study Treatment to Progressive Disease or Death Due to Any Cause (Up to 6 Months)

Population: All participants who received at least one dose of study drug. Participants censored in the carcinoid tumor arm were 8 and in the islet cell carcinoma arm were 4.

Arm	Measure	Group	Value (NUMBER)
Carcinoid Tumor	Percentage of Participants With Progression-Free Survival (PFS) Rate at Six Months	Binomial Distribution; Primary Analysis	45.2 percentage of participants
Carcinoid Tumor	Percentage of Participants With Progression-Free Survival (PFS) Rate at Six Months	Kaplan-Meier Method; Secondary Analysis	54.1 percentage of participants
Islet Cell Carcinoma	Percentage of Participants With Progression-Free Survival (PFS) Rate at Six Months	Binomial Distribution; Primary Analysis	41.7 percentage of participants
Islet Cell Carcinoma	Percentage of Participants With Progression-Free Survival (PFS) Rate at Six Months	Kaplan-Meier Method; Secondary Analysis	61.4 percentage of participants

Secondary

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.

Time frame: 18 months

Population: All participants who had received at least one dose of study drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Carcinoid Tumor	Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)	31 Participants
Islet Cell Carcinoma	Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)	12 Participants

Secondary

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.

Time frame: From Start of Treatment Baseline to Disease Progression (Up to 18 Months)

Population: All participants who received at least one dose of study drug.

Arm	Measure	Value (NUMBER)
Carcinoid Tumor	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)	3.2 percentage of participants
Islet Cell Carcinoma	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)	0 percentage of participants

Secondary

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.

Time frame: From Start of Treatment Up to 18 Months

Population: All participants who received at least one dose of study drug and had evaluable baseline and post-baseline Chromogranin A and Gastrin data.

Arm	Measure	Group	Value (NUMBER)
Carcinoid Tumor	Percentage of Participants With a Biochemical Response Rate	Chromogranin A	0.0 percentage of participants
Carcinoid Tumor	Percentage of Participants With a Biochemical Response Rate	Gastrin	0.0 percentage of participants
Islet Cell Carcinoma	Percentage of Participants With a Biochemical Response Rate	Chromogranin A	22.2 percentage of participants
Islet Cell Carcinoma	Percentage of Participants With a Biochemical Response Rate	Gastrin	0.0 percentage of participants

Secondary

Pharmacodynamics Markers; Concentration of Insulin-like Growth Factor I, II (IGF-I, IGF-II), IGF Body Fat (IGFBF)-1 and IGFBF-2

Time frame: 18 months

Population: Zero participants were analyzed due to no data collection due to low number of clinical responses observed.

Secondary