Study to Assess the Tolerability of a Bispecific Targeted Biologic IMCgp100 in Malignant Melanoma

Study Overview
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Brief Summary
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IMCgp100 is a new biological therapy designed for the treatment of melanoma skin cancer. The drug is designed to target melanoma cells and stimulate immune cells to kill them. This trial is designed to establish the level of drug that can be given to a patient that is tolerable. It also designed to establish the best dosing schedule for the drug and to look for signals that the drug is working as intended.

Detailed Description
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IMCgp100 is a bispecific biologic incorporating an engineered T cell receptor (TCR) specific for a peptide antigen derived from the protein gp100 presented in the context of HLA A2 on the surface of melanoma cells. The TCR is fused to an anti-CD3 antibody single-chain variable fragment (scFv) that recruits and activates non-melanoma specific T cells (killer T cells) in physical contact with the cancer T cell. This is a Phase I study designed to assess the safety profile and establish a tolerable dose of IMCgp100 in HLA A2 positive malignant melanoma patients. The study has two treatment arms with different treatment schedules, weekly or daily dosing. Each treatment arm in the study has two parts. In the first part, dose escalation, the safety and tolerability of the drug are examined and the optimal dose of drug is established. In the second part of the trial, participants will receive an extended course of treatment with a view to assessing the effect of the drug on disease.

Official Title
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A Phase 1, Open Label, Dose Finding Study to Assess the Safety and Tolerability of IMCgp100, a Monoclonal T Cell Receptor Anti-CD3 scFv Fusion Protein in Patients With Advanced Malignant Melanoma

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: IMCgp100


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically documented Stage IV malignant melanoma or unresectable Stage III melanoma for which no standard effective therapy exists or for which an appropriate window exists between alternative therapeutic options. Participants for whom early treatment with vemurafenib is indicated, e.g. rapidly progressing or symptomatic disease, are excluded from this trial. Previous surgery (other than resection of skin metastases), radiotherapy, chemotherapy, immunotherapy or experimental therapy completed > 4 weeks before and all adverse events resolved to ≤ grade 1. In cases where localized radiotherapy has been applied, treatment with IMCgp100 can be commenced after a two week period. Human leukocyte antigen (HLA) A2 positive. ≥ 18 years old. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Participants participating in the dose escalation part of Arm 2 only require assessable disease. Life expectancy > 3 months. Blood tests within the following parameters: Platelet count ≥ 100 x10⁹/L Hemoglobin ≥ 9g/dL (blood transfusion to achieve this level is permitted) Calculated creatinine clearance ≥ 50 mL/min using the modified Cockroft-Gault equation Neutrophil count ≥1x10⁹/L Lymphocyte count ≥ 0.5x10⁹/L Female participants of childbearing potential must use maximally effective birth control during the period of therapy, must be willing to use contraception for 6 months following the last study drug infusion and must have a negative urine or serum pregnancy test upon entry into this study. Otherwise, female participants must be postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile. Male participants must be surgically sterile or willing to use a double barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last study drug infusion. Participants with a history of adrenal insufficiency, maintained on stable replacement dose corticosteroid (< 10 mg/d prednisone or the equivalent) are eligible for treatment with IMCgp100, unless there is a past history of adrenal crisis. Eligible participants with a history of adrenal insufficiency receiving replacement dose corticosteroid must receive prophylactic stress dose corticosteroid prior to dosing during the first four doses of IMCgp100 treatment, regardless of weekly or daily dosing regimen. Able to give informed consent. Exclusion Criteria: Participants meeting any of the following criteria will be excluded from the study: Symptomatic brain metastases that are unstable, require steroids, or that have required radiation within the last 28 days. Other active malignancy in the past 5 years except carcinoma in situ, completely excised nonmelanomatous skin cancer or any other malignancy that in the opinion of the investigator is considered to be cured. Comorbid medical condition that would increase the risk of toxicity in the opinion of the investigator or sponsor. Symptomatic on-going infection must be resolved before the patient can be treated in the study. Uveitis. Had myocardial infarction within 1 year before enrolment, symptomatic congestive heart failure (New York Heart Association > Class II), unstable angina or unstable cardiac arrhythmia requiring medication. Has an ejection fraction < 50%. Clinically significant electrocardiogram (ECG) changes that obscure the ability to assess the RR, PR and QT intervals. Participants with corrected QT interval (QTc) calculated by Bazetts or locally preferred formula which is greater than 500 ms. Has hepatic function as follows: Aspartate aminotransferase > 2.5 x upper limit of normal (ULN) Alanine aminotransferase > 2.5 x ULN Bilirubin > 2.0 x ULN Prothrombin time or partial thromboplastin time > 1.5 x ULN Bleeding diathesis Immunosuppressive condition or treatment including previous transplantation, splenectomy or known human immunodeficiency virus (HIV) infection. Has a history of adult seizures. Participants with evidence of a raised intracranial pressure in Arm 2 of the study who will have a cerebrospinal fluid sample taken. Participants receiving chronic corticosteroid treatment (longer than 8 weeks duration) for management of pre-existing adverse events at any dose, or participants with a history of chronic corticosteroid treatment longer than 8 weeks duration for adverse events within 6 months.

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: IMCgp100 weekly dosing regimen<br>Weekly intravenous (IV) infusions of IMCgp100 over treatment cycles of 8 weeks each. | Drug: IMCgp100<br>* For each arm, the study will be divided into two parts: In part 1, dose escalation, the MTD or RP2D for each dosing regimen will be established. In part 2, dose expansion, a cohort of participants will be treated at the RP2D or MTD.<br>* Other names: ImmTACgp100;|
| Experimental: IMCgp100 daily dosing regimen<br>Daily IV infusions of IMCgp100 administered on days 1 to 4 and days 22 to 25 of a six-week treatment cycle. | Drug: IMCgp100<br>* For each arm, the study will be divided into two parts: In part 1, dose escalation, the MTD or RP2D for each dosing regimen will be established. In part 2, dose expansion, a cohort of participants will be treated at the RP2D or MTD.<br>* Other names: ImmTACgp100;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of IMCgp100 Administered Weekly (Dose Escalation Part) | The maximum tolerated dose (MTD) for IMCgp100 administered by weekly dosing was determined based on the frequency of dose-limiting toxicity (DLT) occurring during Days 1 to 8. Participants presented at MTD in the dose escalation phase. Abbreviations: ng/kg=nanograms/kilogram | Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8 | 
| MTD of IMCgp100 Administered Daily (Dose Escalation Part) | The MTD for IMCgp100 administered by daily dosing was determined based on the frequency of DLT occurring during Days 1 to 8. The 50 mcg dose was the RP2D for daily dosing, as the MTD was not achieved. Abbreviations: mcg=micrograms | Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8 | 
| Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) | Treatment-emergent adverse events (TEAEs) were defined as adverse events (AEs) with an onset date after the date of first dose and within 30 days after the last administration of study medication in either treatment arm. AEs with missing date of onset were considered treatment emergent. | Day 1 (first dose), 30 days after the last dose | 
| Number of Participants Experiencing Clinically Significant Laboratory Parameters (Hematology) | Laboratory parameters included clinical chemistry, hematology, and urinalysis. For hematology, this included red cell count, hemoglobin, hematocrit, mean cell volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, white blood cell count, leukocyte differential count (percentage or absolute), prothrombin time, and activated partial tissue thromboplastin time. Clinically significant findings were defined as such in the opinion of the investigator occurring at any time on treatment from normal pre-dose. | 28 months | 
| Number of Participants Experiencing ≥Grade 3 Severity in Laboratory Parameters (Hematology) | Laboratory parameters included clinical chemistry, hematology, and urinalysis. For hematology, this included red cell count, hemoglobin, hematocrit, mean cell volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, white blood cell count, leukocyte differential count (percentage or absolute), prothrombin time, and activated partial tissue thromboplastin time. Laboratory parameter abnormalities were graded by the investigator using Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 at any time on treatment from normal pre-dose. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5: death. | 28 months | 
| Number of Participants Experiencing Clinically Significant Laboratory Parameters (Clinical Chemistry) | Laboratory parameters included clinical chemistry, hematology, and urinalysis. Clinical chemistry parameters included calcium, phosphorus, magnesium, albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase, sodium, potassium, bicarbonate, creatinine, chloride, glucose, urea, uric acid, and C-reactive protein. Clinically significant findings were defined as such in the opinion of the investigator occurring at any time on treatment from normal pre-dose. | 28 months | 
| Number of Participants Experiencing ≥Grade 3 Severity in Laboratory Parameters (Clinical Chemistry) | Laboratory parameters included clinical chemistry, hematology, and urinalysis. Clinical chemistry parameters included calcium, phosphorus, magnesium, albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase, sodium, potassium, bicarbonate, creatinine, chloride, glucose, urea, uric acid, and C-reactive protein. Laboratory parameter abnormalities were graded by the investigator using CTCAE v 4.0 at any time on treatment from normal pre-dose. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5: death. | 28 months | 
| Number of Participants Experiencing Clinically Significant Electrocardiograms (ECGs) | Twelve lead ECGs were obtained after the participant has rested in a supine position for at least 5 minutes. Clinically significant findings were defined as such in the opinion of the investigator or designated physician occurring at any time on treatment from normal pre-dose. | 28 months | 
| Number of Participants Experiencing Clinically Significant Vital Signs | Vital signs included temperature, blood pressure, respiration rate, and heart rate. Measurements were made after the participant had been resting supine for a minimum of 5 minutes. Blood pressure and heart rate were measured using a recording device with an appropriate cuff size. Temperature and respiration rate were measured as per clinical practice. Clinically significant findings were defined as such in the opinion of the investigator occurring at any time on treatment from normal pre-dose. | 28 months | 
| Number of Participants Experiencing Clinically Significant Physical Examination Results (Weight Decrease) | Physical examination included weight, a record of skin pigmentation, and photographic record of any vitiligo if present. Clinically significant findings were defined as such in the opinion of the investigator occurring at any time on treatment from normal pre-dose. | 28 months | 
| Number of Participants Experiencing ≥Grade 3 Severity in Physical Examination Results (Skin Pigmentation) | Physical examination included weight, a record of skin pigmentation, and photographic record of any vitiligo if present. Abnormalities were graded by the investigator using CTCAE v 4.0 at any time on treatment from normal pre-dose. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5: death. | 28 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Best Overall Response Per Response Evaluation Criteria In Solid Tumors (RECIST) (Weekly Dosing-Dose Expansion Part) | The best overall response was assigned as complete response (CR), partial response (PR), minor response, stable disease, progressive disease (PD) or not evaluable (NE) per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. | 28 months | 
| Number of Participants With Anti-IMCgp100 Antibody Formation (Dose Escalation and Dose Expansion Parts) | To provide a comprehensive anti-drug antibody (ADA) summary for the study, individual participant data were combined and assessed as distinct groups based on characteristics of their ADA response. Evaluable participants were those with post-drug administration samples. ADA prevalence (pre- existing antibody response) was measured as the number of baseline-positive participant out of all participants who provided baseline samples. Overall ADA incidence was calculated based on the combined number of treatment-boosted and treatment-induced ADA-positive participants. The treatment-induced incidence was determined as the number of ADA- positive participants of those that were ADA-negative at baseline; while treatment-boosted incidence was determined as the number of participants with an ADA titer increase equal to or greater than the minimum significant dilution (3-fold) of the assay. | 28 months | 
| Estimated Maximum Plasma Concentration (Cmax) of IMCgp100 By-weight Doses (Dose Escalation) | The maximum plasma concentration (Cmax) is the highest concentration that a drug achieves in the blood after administration in a dosing interval. Abbreviations: ng/kg = nanograms/kilogram | Day 1, Cycle 1 | 
| Estimated Cmax of IMCgp100 of 900 ng/kg By-weight Dose (Dose Escalation and Dose Expansion Parts) | The Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval. | Day 1, Cycle 1 | 
| Estimated Cmax of IMCgp100 Flat Dose (Dose Escalation and Dose Expansion Parts) | The Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval. Abbreviations: mcg = micrograms | Day 1, Cycle 1 | 
| Estimated Cmax of IMCgp100 of 600 ng/kg By-weight Dose (Dose Escalation) | The Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval. | Cycle 1: Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, Day 43, Day 50 | 
| Estimated Cmax of IMCgp100 of 20/30/50 mcg Flat Dose (Dose Escalation) | The Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval. On Day 1, IMCgp100 20 mcg was given, IMCgp100 30 mcg was administered on Day 8, and IMCgp100 50 mcg was dosed on Days 15 and after. | Cycle 1: Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, Day 43, Day 50 | 
| Estimated Cmax of IMCgp100 of 40/40/50 mcg Flat Dose (Dose Escalation) | The Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval. This dosing regimen was implemented following the Urgent Safety Measure to adapt the dosing in the Phase 1 study that dropped Dose 1 to 40 mcg from the identified 50 mcg RP2D. | Cycle 1: Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, Day 43, Day 50 | 
| Estimated Cmax of IMCgp100 of 50 mcg Flat Dose (Dose Escalation) | The Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval. The RP2D identified in this study following review of all safety and pharmacokinetic data in the dose escalation of the Phase 1 study was the 50 mcg flat dose. | Cycle 1: Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, Day 43, Day 50 | 
| Estimated Cmax of IMCgp100 of a Single Infusion Flat Dose (Dose Escalation) | The Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval. | Cycle 1: Day 1 | 
| Area Under the Concentration-Time Curve (AUC) of IMCgp100 By-weight Dose (Dose Escalation) | The area under the concentration-time curve (AUC), measured in hours by picograms per milliliter ( h*pg/ml) is a method of measurement of the total exposure of a drug in blood. | Day 1, Cycle 1 | 
| AUC of IMCgp100 of 900 ng/kg By-weight Dose (Dose Escalation and Dose Expansion Parts) | The AUC, measured in h*pg/ml, is a method of measurement of the total exposure of a drug in blood. | Day 1, Cycle 1 | 
| AUC of IMCgp100 Flat Dose (Dose Escalation and Dose Expansion Parts) | The AUC (measured in h*pg/ml) is a method of measurement of the total exposure of a drug in blood. Participants in the 20 mcg and 40 mcg dose groups received intra-participant dose-escalation up to 50 mcg on Day 15. | Day 1, Cycle 1 | 
| AUC of IMCgp100 of 50 mcg Flat Dose (Dose Escalation and Dose Expansion Parts) | The AUC (measured in h*pg/ml) is a method of measurement of the total exposure of a drug in blood. | Day 1, Cycle 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Phase I, Biologic