A Study of IMC-A12 in Advanced Solid Tumors

Study Overview
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Brief Summary
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In this study, participants will initially receive intravenous (IV) cixutumumab (IMC-A12) every 2 weeks or every 3 weeks for 6 weeks (one cycle). After the first cycle, participants experiencing a best overall response of complete response, partial response, or stable disease will continue to receive cixutumumab at their cohort dose and schedule until there is evidence of progressive disease (PD), or until other withdrawal criteria are met. Participants will be enrolled at one study center, located in the National Cancer Center Hospital - East, Kashiwa, Japan. Approximately 20-30 participants are anticipated.

Detailed Description
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Participants in this single-center, open-label, dose-escalation, Phase 1 study will initially receive intravenous (IV) cixutumumab every 2 weeks or every 3 weeks for 6 weeks (one cycle). After the first cycle, participants experiencing a best overall response of complete response (CR), partial response (PR), or stable disease (SD) will continue to receive cixutumumab at their cohort dose and schedule until there is evidence of progressive disease (PD), or until other withdrawal criteria are met. A minimum of three participants will be enrolled in each cohort. The starting dose in Cohort 1 will be 6 mg/kg, administered every 2 weeks. Dose escalation from Cohort 1 to Cohort 2 (10 mg/kg administered every 2 weeks) will occur once at least three participants in Cohort 1 have completed one cycle of therapy (ie, completed the initial 6 week treatment period or discontinued therapy due to an cixutumumab - related adverse event [AE]). Enrollment into Cohort 3 (starting dose: 15 mg/kg administered every 3 weeks) will not proceed until all participants have completed one cycle of therapy (as defined above) in Cohort 2. Similarly, participants will be enrolled in Cohort 4 once at least three participants have completed one cycle of therapy in Cohort 3;participants in Cohort 4 will receive 20 mg/kg administered every 3 weeks. Toxicity data for each cohort will be reviewed prior to any dose escalation. No intrapatient dose escalation is permitted. Participants in any cohort who do not complete the first 6 weeks of treatment for reasons other than an cixutumumab-related toxicity will be replaced. A dose-limiting toxicity (DLT) is defined as one of the following events, if considered by the investigator to be definitely, probably, or possibly related to cixutumumab: Grade 4 neutropenia lasting > 7 days; Grade 4 anemia; Grade ≥ 3 thrombocytopenia; Grade ≥ 3 neutropenia associated with fever; Grade 3 or 4 nonhematologic toxicity, excluding electrolyte abnormality and Grade 3 hyperglycemia; Grade 4 hyperglycemia; and/or Grade 4 or uncontrollable hypertension. If three participants complete the first 6-week cycle (according to the definition outlined above) with no DLTs, dose escalation to Cohort 2 may proceed. If one DLT is observed in the initial three participants of Cohort 1 (or any cohort) during Cycle 1, three additional participants will be enrolled into that cohort. If no additional DLTs are observed, dose escalation may continue as described above. If two or more participants in Cohort 1 experience a DLT, six participants will be enrolled into Cohort 1A (receiving 4 mg/kg every 2 weeks). If two or more participants experience a DLT in dose Cohort 3, six participants will be enrolled into dose Cohort 3A (10 mg/kg every 3 weeks). If two or more participants experience a DLT in dose Cohorts 2 or 4, six additional participants will be enrolled into the previous cohort (Cohort 1 or Cohort 3, respectively), and the previous cohort will be considered the maximum tolerated dose for that dosing schedule. If two or more participants in any cohort experience a DLT on Week 7 or beyond (after Cycle 1), the data will be reviewed and enrollment may be suspended. The Sponsor and Principal Investigator, with reference to the review of the Independent Data Safety Evaluation Committee (established in a separate document), will determine whether enrollment should resume.

Official Title
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A Phase 1 Study Evaluating the Safety and Pharmacokinetic Profiles of IMC-A12 Administered Every 2 Weeks or Every 3 Weeks to Japanese Patients With Advanced Solid Tumors

Conditions
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Tumors

Intervention / Treatment
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* Biological: Cixutumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Solid tumor participant who has been histopathologically or cytologically documented Advanced primary or recurrent solid tumor participant who has not responded to standard therapy or for whom no standard therapy is available The participant has measurable or nonmeasurable lesions according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0) guidelines The participant has an Eastern Cooperative Oncology Group performance status (ECOG PS)score of 0-1 at study entry The participant is able to provide informed consent The participant is age 20 years or older The participant has a life expectancy of > 3 months The participant has adequate hematologic function, as defined by: An absolute neutrophil count (ANC) ≥ 1500/m3 or /μL A hemoglobin ≥ 10 g/dL; and A platelet count ≥ 100,000/mm3 or /μL The participant has adequate hepatic function, as defined by: Total bilirubin ≤ 1.8 mg/dL Aspartate transaminase (AST) ≤ 2.5 times the upper limit of site-specific normal ranges (five times in case of liver metastasis) Alanine transaminase (ALT) ≤ 2.5 times the upper limit of site-specific normal ranges (five times in case of liver metastasis) The participant has adequate renal function, as defined by: Serum creatinine ≤ 1.5 mg/dL Calculated serum creatinine clearance (Cockcroft-Gault) ≥ 60 mL/min The participant has fasting blood sugar < 120 mg/dL or below the institutional upper limit of normal (ULN) before study entry (one retest of an elevated level is permitted at the discretion of the investigator) The participant has adequate coagulation function, as defined by an international normalized ratio (INR) ¬ 1.5 The participant agrees to use adequate contraception for the duration of study participation and for 12 weeks after the last dose of study therapy. The participant has adequate recovery from recent surgery, chemotherapy, and radiation therapy (including palliative radiation therapy). At least 28 days (6 weeks for nitrosoureas or mitomycin C) must have elapsed from major surgery, prior chemotherapy, prior treatment with an investigational agent or device, or prior radiation therapy. For treatment with unapproved monoclonal antibodies, a minimum of 8 weeks must have elapsed The participant is willing to comply with study procedures until the end of therapy Exclusion Criteria: The participant has received chemotherapy or therapeutic radiotherapy within 28 days (6 weeks for nitrosoureas or mitomycin C) prior to entering the study, or the participant has ongoing side effects ≥ Grade 2 due to agents administered more than 28 days earlier The participant has undergone major surgery (eg,laparotomy, thoracotomy,removal of organ(s)) within 28 days prior to study entry, or subcutaneous venous access device placement within 7 days prior to study entry The participant has elective or planned surgery to be conducted during the trial The participant has documented and/or symptomatic brain or leptomeningeal metastases (participants who are clinically stable (no symptoms during the 4 weeks prior to enrollment) with an assessment that no further treatment (radiation, surgical excision, or administration of steroids) is required are permitted to enter the study) The participant has an uncontrolled intercurrent illness including, but not limited to: Thrombotic or hemorrhagic disorders Gross hemoptysis (approximately one-half a teaspoon) Ongoing or active infection requiring systemic antibiotic treatment Congestive heart failure (Class III or IV per the New York Heart Association classification for heart disease) Angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months Uncontrolled hypertension (systolic blood pressure > 150 mm Hg, diastolic blood pressure > 95 mm Hg) Cardiac arrhythmia requiring treatment (NCICTCAE Version 3.0 Grade 3), or asymptomatic sustained ventricular tachycardia Peripheral neuropathy of any etiology ≥ Grade 2 (NCI-CTCAE Version 3.0); or Any other serious uncontrolled medical disorder(s) in the opinion of the investigator The participant has a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to study entry The participant has experienced any Grade 3/4 gastrointestinal bleeding within 3 months prior to study entry The participant has participated in clinical studies of unapproved experimental agents or procedures within 4 weeks prior to study entry for small molecules, or 8 weeks prior to study entry for unapproved monoclonal antibodies The participant has received any previous treatment with agents targeting the insulin-like growth factor hormone (IGF-IR), approved or unapproved The participant has a known allergy to any of the treatment components (monoclonal antibodies or other therapeutic proteins such as fresh frozen plasma, human serum albumin, cytokines, or interleukins). In the event that there is suspicion the participant may have allergies, the participant should be excluded The participant, if female, is pregnant (confirmed by urine or serum pregnancy test) or lactating The participant has a known alcohol or drug dependency The participant is Hepatitis B Virus (HBV) antigen-, Hepatitis C Virus (HCV) antibody-, or HIV antibody-positive (asymptomatic healthy carriers with detectable HBV-DNA, HCV-RNA may be enrolled into the trial) The participant is assessed as inadequate for the study by the investigator

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cixutumumab<br>Participants receive IV cixutumumab every 2 or 3 weeks. A cycle equals 6 weeks, with radiological evaluation of tumor response after each cycle. After 1st cycle, pts with a complete response (CR), PR, or SD continue to receive cixutumumab cohort dose and schedule disease progression. 3 pts enroll in each cohort. Starting dose in Cohort 1 is 6 mg/kg every 2 weeks. Dose escalation from Cohort 1 to Cohort 2 (10 mg/kg every 2 weeks) occurs at least 3 pts in Cohort 1 completes 1 cycle of therapy. Enrollment into Cohort 3 (starting dose: 15 mg/kg administered every 3 weeks) will not proceed until at least 3 pts have completed one cycle of therapy in Cohort 2. Pts enroll in Cohort 4 once at least 3 pts have completed once cycle of therapy in Cohort 3; pts in Cohort 4 receive 20 mg/kg every 3 weeks. | Biological: Cixutumumab<br>* Cixutumumab intravenously<br>* Other names: LY3012217;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary Listing of Percentage of Participants Reporting Treatment-Emergent Adverse Events | A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section. | Up To 63 Months | 
| Number of Participants With a Dose Limiting Toxicity (DLT) | DLTs were defined as any cixutumumab-related Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE 3.0) Grade 3 or 4 adverse events (reported in the subsequent Primary Outcome Measure). | First Dose Up to 6 Weeks | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) |  | Prior to Infusion and Immediately Following End of Infusion (Cohorts 1 and 2) at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 hours and (Cohorts 3 and 4) at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264, 336, 408 and 504 Hours Following End of Infusion | 
| PK: Area Under the Curve From Zero to Infinity AUC(0-∞) |  | Prior to Infusion and Immediately Following End of Infusion (Cohorts 1 and 2) at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 hours and (Cohorts 3 and 4) at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264, 336, 408 and 504 Hours Following End of Infusion | 
| PK: Area Under Concentration Versus Time Curve During One Dosing Interval (AUCtau) |  | Prior to Infusion and Immediately Following End of Infusion (Cohorts 1 and 2) at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 hours and (Cohorts 3 and 4) at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264, 336, 408 and 504 Hours Following End of Infusion | 
| Half-life (t1/2) |  | Prior to Infusion and Immediately Following End of Infusion (Cohorts 1 and 2) at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264, and 336 hours and (Cohorts 3 and 4) at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264, 336, 408 and 504 hours) Following End of Infusion | 
| Drug Clearance (CL) |  | Prior to Infusion and Immediately Following End of Infusion (Cohorts 1 and 2) at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264, and 336 hours and (Cohorts 3 and 4) at 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264, 336, 408 and 504 hours) Following End of Infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serum Anti-Cixutumumab Antibody Assessment Immunogenicity | No participants were analyzed for the development of circulating positive anti-cixutumumab antibodies due to no assay available. | 6 months | 
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | Response defined per Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria: Complete Response (CR)=disappearance of all target lesions; Partial Response (PR)=30% decrease in sum of longest diameter of target lesions; Progressive Disease=20% increase in sum of longest diameter of target lesions. | From the First Dose up to 32 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-IGF-IR, monoclonal, solid tumor, insulin-like growth factor