Safety and Efficacy of MAGE-A3/A6 T Cell Receptor Engineered T Cells (KITE-718) in HLA-DPB1*04:01 Positive Adults With Advanced Cancers

Study Overview
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Brief Summary
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The primary objectives of Phase 1A are to evaluate the safety of KITE-718, determine a recommended Phase 1B dose, and to evaluate the efficacy of KITE-718 in Phase 1B.

Detailed Description
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Participants found to be human leukocyte antigen (HLA)-DPB1*04:01 positive and whose tumors are MAGE-A3 and/or MAGE-A6 positive can participate if all eligibility criteria are met. Other tests required to determine eligibility include a physical exam, electrocardiogram (ECG) and echocardiogram (ECHO) of the heart, CT or MRI scans, and blood draws. Eligible participants have white blood cells collected by leukapheresis. These cells are genetically modified to make the experimental treatment KITE-718. The desired outcome is that the genetically modified T cells will target tumor cells that express MAGE-A3 and/or MAGE-A6, which are proteins that can be expressed by cancer cells. Participants receive chemotherapy prior to the KITE-718 infusion. After the KITE-718 infusion, participants will be followed for side effects and have scans performed to see any potential impact on their cancers. Study procedures may be performed while hospitalized and/or in the outpatient setting. Subjects who received an infusion of KITE-718 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968

Official Title
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A Phase 1 Study Evaluating the Safety and Efficacy of MAGE-A3/A6 T Cell Receptor Engineered T Cells (KITE-718) in HLA-DPB1*04:01 Positive Subjects With Advanced Cancers

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: KITE-718
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Device: MAGE - A3/A6 Screening Test


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 years Advanced cancer defined as relapsed or refractory disease after a systemic standard of care treatment regimen and, if available, at least one standard of care salvage regimen unless the subject refuses such therapy. Multiple myeloma (MM) subjects must have had both a protease inhibitor (PI) and immunomodulatory drugs (IMiD) as part of the last regimen, or at least 3 prior lines of therapy, including a PI and an IMiD. Additionally, subjects must not have disease amenable to definitive locoregional therapy. MAGE-A3/A6 positive tumor as confirmed by the central laboratory HLA-DPB1*04:01 positive At least 1 measurable lesion on CT or MRI No evidence of central nervous system (CNS) disease by MRI or CT of the brain. Note: Prior brain metastasis which have been treated with definitive therapy are eligible provided that the definitive therapy was completed more than six months prior to screening. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Toxicities due to prior therapy must be recovered to baseline or ≤ grade 1, except for clinically non-significant toxicities such as alopecia Adequate bone marrow function as evidenced by: Absolute neutrophil count (ANC) ≥ 1000/mm^3 Platelet ≥ 100/mm^3 Hemoglobin > 8 g/dL Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by: Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 cc/min (24-hour urine creatinine clearance is also acceptable) Alanine transaminase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 x upper limit normal (ULN) or ≤ 5 x ULN if documented liver metastases Total bilirubin ≤ 1.5 mg/dL Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an ECHO, and no clinically significant ECG findings (For ejection fraction only, MUGA scan is also acceptable) No clinically significant pleural effusion Baseline oxygen saturation > 92% on room air Key Exclusion Criteria: Malignancy other than non-melanoma skin cancer, carcinoma in situ, or low grade prostate cancer for which watch-and-wait approach is standard of care, unless disease free for at least 3 years Clinically significant cardiac disease within last 12 months Stroke or transient ischemic attack (TIA) within 12 last months Symptomatic deep vein thrombosis or pulmonary embolism within last 6 months, catheter associated thrombosis is not included as exclusion criteria. Prior T-cell therapy, including KITE-718 or MAGE-A3/A6-targeting therapy. Live vaccine ≤ 4 weeks prior to enrollment Systemic corticosteroid therapy within 7 days before enrollment. History of severe, immediate hypersensitivity reaction attributed to aminoglycosides Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials for management. Presence of any indwelling line or drain. Note: Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter as well as feeding tubes such as a G-tube, are permitted. Primary immunodeficiency Autoimmune disease resulting in end-organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years prior to enrollment. Known history of infection with HIV, hepatitis B (HBsAg positive), or hepatitis C (anti-HCV positive). A history of treated hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing. Females who are pregnant as confirmed by a positive serum or urine pregnancy test or are breastfeeding. Individuals of both genders of child-bearing potential who are not willing to practice birth control from the time of consent through 6 months after the completion of KITE-718 Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KITE-718<br>Phase 1A: Participants will receive cyclophosphamide and fludarabine conditioning chemotherapy followed by the investigational treatment, KITE-718. Phase 1 B: Participants will receive cyclophosphamide and fludarabine conditioning chemotherapy followed by the investigational treatment, KITE-718, at a dose selected based on Phase 1A. | Drug: KITE-718<br>* A single infusion of autologous genetically modified MAGE-A3/A6 T-cell receptor (TCR) transduced autologous T cells (KITE-718).<br>Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>Device: MAGE - A3/A6 Screening Test<br>* A screening test for MAGE-A3/A6+ tumors<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1A - Percentage of Participants Experiencing Adverse Events Defined as Dose-Limiting Toxicities | Dose-limiting toxicity is defined as protocol-defined KITE-718 related events with onset within the first 21 days following KITE-718 infusion. | Up to 21 days | 
| Phase 1B - Efficacy: Objective Response Rate (ORR) | ORR is defined as complete response + partial response for participants evaluated by RECIST v1.1 and very good partial response (VGPR) or better for multiple myeloma participants evaluated by International Myeloma Working Group (IMWG) Consensus Panel 1 Criteria. | Up to year 2 for solid tumor participants and up to Year 5 for multiple myeloma participants | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | For participants who experience an objective response, DOR is defined as the time from the date of their first objective response to the date of disease progression per modified RECIST v1.1 or consensus panel 1 criteria or death regardless of cause. | Up to year 2 for solid tumor participants and up to year 5 for multiple myeloma participants | 
| Progression-Free Survival (PFS) | PFS is defined as the time from the KITE-718 infusion date to the date of disease progression per modified RECIST v1.1 or consensus panel 1 criteria or death from any cause. | Up to year 2 for solid tumor participants and up to year 5 for multiple myeloma participants | 
| Overall Survival | Overall survival is defined as the time from KITE-718 infusion to the date of death. | Up to 15 years | 
| Percentage of Participants Experiencing Adverse Events |  | Up to 15 years | 
| Percentage of Participants with Anti-KITE-718 Antibodies |  | Up to 2 years | 
| Percentage of Participants Experiencing Replication-competent Retrovirus (RCR) |  | Up to 2 years | 
| Levels of MAGE-A3/A6 TCR-transduced T Cells in Blood |  | Up to 2 years |