Study of IMC-11F8 in Participants With Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This study is to establish the safety and pharmacokinetic (PK) profile of IMC-11F8, administered either: (1) in a 3-week cycle; or (2) in a 2-week cycle to Japanese participants with advanced solid tumors who have not responded to standard therapy or for whom no standard therapy is available.

Detailed Description
-----------------
This single center, open-label, single-arm, Phase 1 study will enroll 18 participants at a maximum. The actual size will vary depending on the dose-limiting toxicities (DLTs) observed and the resultant sizes of the cohorts. Participants will receive IMC-11F8 administered intravenously, once every 2 weeks or on Days 1 and 8 every 3 weeks for 6 weeks (1 cycle). All infusions can be administered within ± 1 day of the scheduled administration date. After 1 cycle of treatment, participants who have an objective response or stable disease may continue to receive IMC-11F8 at the same dose and schedule until disease progression or other withdrawal criteria are met. A minimum of 3 participants will be enrolled in each cohort. Dose escalation in successive cohorts will occur once all participants complete 1 cycle of therapy. Participants will be enrolled sequentially into each cohort. A completed participant will be either a participant who completes the initial 6-week treatment period (Cycle 1) or a participant who discontinues therapy for an IMC-11F8-related toxicity during Cycle 1. Participants who do not complete the first 6 weeks of treatment for reasons other than an IMC-11F8-related toxicity will be replaced. Toxicity data for each cohort will be reviewed prior to dose escalation. Upon completion of all required safety evaluations during the initial 6 weeks, the next cohort of new participants will be treated at the next higher dose level using a dose escalation scheme.

Official Title
-----------------
A Phase 1 Study of IMC-11F8 in Patients With Advanced Solid Tumors

Conditions
-----------------
Neoplasms

Intervention / Treatment
-----------------
* Biological: IMC-11F8
* Biological: IMC-11F8
* Biological: IMC-11F8


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Solid tumor participant who has been histopathologically or cytologically documented Advanced primary or recurrent solid tumors 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 or 1 at study entry The participant is able to provide written 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 The participant has adequate renal function The participant agrees to use adequate contraception for the duration of study participation and for at least 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 nonapproved monoclonal antibodies, a minimum of 8 weeks must have elapsed The participant is willing to comply with study procedures until the End-of-Therapy visit 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 (except alopecia) 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: Ongoing or active infection requiring systemic antibiotic treatment Congestive heart failure (Class III or IV per the New York Heart Association heart disease classification guidelines) The participant has participated in clinical studies of nonapproved experimental agents or procedures within 4 weeks prior to first dose of study therapy, or within 8 weeks prior to first dose of study therapy for nonapproved monoclonal antibodies The participant has received any previous treatment with monoclonal antibodies targeting the epidermal growth factor receptor (EGFR). Previous treatment with EGFR tyrosine kinase inhibitors (TKI), approved or nonapproved, is allowed. There must be a time interval of at least 4 weeks between the last EGFR TKI dose and the first dose of IMC-11F8 The participant has acute or subacute intestinal occlusion/obstruction The participant has a history of inflammatory bowel disease (for example, Crohn's disease, ulcerative colitis) requiring medical intervention in the 3 years prior to study entry The participant has acute pulmonary disorder, interstitial pneumonia, pulmonary fibrosis, or history thereof The participant has a known allergy to any of the treatment components, or to monoclonal antibodies or other therapeutic proteins such as fresh frozen plasma, human serum albumin, cytokines, or interleukins. In the event that there is suspicion that 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 known alcohol or drug dependency The participant is hepatitis B virus (HBV) antigen, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody positive The participant is assessed as inadequate for the study by the investigator

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br> | Biological: IMC-11F8<br>* 600 milligrams (mg) intravenously, Days 1 and 8 every 3 weeks<br>* Other names: LY3012211;|
| Experimental: Cohort 2<br> | Biological: IMC-11F8<br>* 800 mg intravenously, every 2 weeks<br>* Other names: LY3012211;|
| Experimental: Cohort 3<br> | Biological: IMC-11F8<br>* 800 mg intravenously, Days 1 and 8 every 3 weeks<br>* Other names: LY3012211;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) | Data presented are the number of participants who experienced 1 or more TEAEs or SAEs regardless of causality. An adverse event was considered as TEAE if it occurred any time after the administration of the first dose of study drug or up to 30 days after the last dose of study treatment or if it occurred prior to the first dose and worsened while on treatment. A summary of SAEs and other non-SAEs regardless of causality is located in the Reported Adverse Events module. | Baseline up to 24 weeks plus 30 days post last dose of study drug | 
| Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Necitumumab After a Single Dose |  | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 hours (h) after end of infusion. Cohort 2: predose, immediately after infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 
| PK: Cmax of Necitumumab After Multiple Doses | Cmax at steady state (after the last dose of the initial 6-week treatment cycle). | Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 
| PK: Minimum Concentration (Cmin) of Necitumumab After a Single Dose | Cmin is defined as the minimum concentration the drug achieved after administration of first infusion and prior to the administration of second infusion. | Cycle 1; Cohorts 1, 2 and 3: prior to second infusion | 
| PK: Cmin of Necitumumab After Multiple Doses | Cmin was calculated prior to the last dose of the initial 6-week treatment cycle. | Cycle 1; Cohorts 1and 3: prior to fourth infusion. Cohort 2: prior to third infusion | 
| PK: Area Under the Concentration-Time Curve From Time 0 to Last Time Point [AUC (0-tlast)] of Necitumumab After a Single Dose |  | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 
| PK: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of Necitumumab After a Single Dose | AUC(0-∞) was calculated only for participants in Cohort 2 as the percentage of AUC extrapolated beyond tlast was greater than 30% for all the remaining participants. | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 
| PK: Area Under the Concentration-Time Curve From Time 0 to 336 h Postdose [AUC(0-336)] of Necitumumab After Multiple Doses | Steady state AUC(0-336) values are reported. | Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 
| PK: Half-Life (t½) of Necitumumab After a Single Dose | The t½ is defined as the time taken for study drug in blood to decrease to half of its concentration. | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 
| PK: t½ of Necitumumab After Multiple Doses | The t½ is defined as the time taken for study drug in blood to decrease to half of its concentration. | Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 
| PK: Clearance (CL) of Necitumumab After a Single Dose | CL is defined as the volume of plasma that is cleared of study drug per unit time. CL was not analyzed for participants in Cohorts 1 and 3 as CL is derived from AUC(0-∞). AUC(0-∞) was calculated only for participants in Cohort 2 as the percentage of AUC extrapolated beyond tlast was greater than 30% for the remaining participants. | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 
| PK: CL of Necitumumab After Multiple Doses | CL is defined as the volume of plasma that is cleared of study drug per unit time. Data did not allow calculation of CL for participants in Cohorts 1 and 3. | Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 
| PK: Steady-State Volume of Distribution (Vss) of Necitumumab After Single Dose | Vss is that amount of plasma in which the study drug needs to be dissolved to attain a steady state drug concentration. Vss was not analyzed for participants in Cohorts 1 and 3 as Vss is derived from AUC (0-∞). AUC(0-∞) was calculated only for participants in Cohort 2 as the percentage of AUC extrapolated beyond tlast was greater than 30% for the remaining participants. | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 
| PK: Vss of Necitumumab After Multiple Doses | Vss is that amount of plasma in which the study drug needs to be dissolved to attain a steady state drug concentration. Data did not allow calculation of Vss for participants in Cohorts 1 and 3. | Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity (IK): Number of Participants With Treatment-Emergent Anti-IMC-11F8 Antibodies | Treatment-emergent samples were defined as samples which showed at least 4-fold difference (2 dilution increase) at post-baseline in IK titer over the baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20). | For Cohorts 1, 2 and 3: Prior to first infusions of Cycles 1, 2, and 4 and at the 30-day follow-up visit (+7 days) after the last dose of study drug | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Human Immunoglobulin Gamma-1 (IgG1), Monoclonal Antibody (MAb), Epidermal Growth Factor Receptor (EGFR), Advanced Solid Tumors