A Phase 2 Study of Autologous Tumor Infiltrating Lymphocytes (LN-145) in Patients With Pretreated Metastatic Triple Negative Breast Cancer
- Study HIC#:2000025837
- Last Updated:07/15/2021
This study will investigate the safety and efficacy of TIL therapy in patients with metastatic TNBC who have progressed on at least one and no more than three prior systemic anticancer therapies.
- Start Date05/28/2020
- End Date01/01/2022
Trial Purpose and Description
The primary aims of the study are:
- To evaluate the efficacy of autologous LN-145 as a single therapy in Metastatic Triple Negative Breast Cancer (TNBC) patients by determining the objective response rate (ORR), using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by the Investigator.
- To characterize the safety profile of tumor infiltrating lymphocytes (TIL) as a single therapy in Metastatic Triple Negative Breast Cancer patients as measured by the incidence of Grade ≥ 3 treatment-emergent adverse events (TEAEs).
The secondary aims of the study are:
• To further evaluate the efficacy of autologous LN-145 as a single therapy in Metastatic Triple Negative Breast Cancer patients using complete response duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS), using RECIST 1.1, as assessed by the Investigator, overall survival (OS) and (CR) rate.
- Ability to understand the requirements of the study. Specifically, the patient has to provide written informed consent (as evidenced by signature on an ICF approved by the Yale Human Investigation Committee (HIC).
- All patients must have a triple negative metastatic breast cancer (Estrogen Receptor negative, Progesterone Receptor negative, HER2 negative) as defined by the 2018 ASCO CAP guidelines.
- Patients must have a confirmed diagnosis of metastatic triple negative breast cancer (Stage IV) histologically confirmed as per American Joint Committee on Cancer [AJCC] staging system).
- Patients must have had at least one and no more than three prior lines of systemic anticancer therapies for metastatic disease.
- Patients must have at least one resectable lesion of a minimum 1.5 cm in diameter (or aggregate of 1.5 cm if multiple lesions are sampled) post-resection for TIL investigational product production. It is encouraged that tumor tissue be obtained from multiple and diverse metastatic lesions, as long as the surgical resection does not pose additional risks to the patient.
- If the lesion considered for resection for TIL generation is within a previously irradiated field, the lesion must have demonstrated radiographic progression post-radiotherapy (XRT) and prior to resection.
- Patients must have an adequate histopathology specimen for protocol-required testing.
- Patients must have remaining measurable disease as defined by RECIST 1.1 following tumor resection for TIL manufacturing:
- Lesions in previously irradiated areas should not be selected as target lesions unless there has been demonstrated progression in those lesions.
- Lesions partially resected for TIL production may be chosen as non-target lesions but cannot be used as target lesions for RECIST assessment.
- Patients must be ≥ 18 years of age at the time of consent.
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and an estimated life expectancy of ≥ 3 months in the opinion of the Investigator.
- Female patients of childbearing potential or female partners of childbearing potential of male participants, must be willing to practice an approved method of birth control during treatment and for 12 months after receiving all protocol-related therapy.
- Patients must have the following hematologic parameters:
- Absolute neutrophil count (ANC) ≥ 1000/mm3;
- Hemoglobin ≥ 9.0 g/dL;
- Platelet count ≥ 100,000/mm3
- Patients must have adequate organ function:
- Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal (ULN), patients with liver metastasis ≤ 5 times ULN;
- An estimated creatinine clearance ≥ 40 mL/min using the Cockcroft Gault formula;
- Total bilirubin ≤ 2 mg/dL:
- Patients with Gilbert's Syndrome must have a total bilirubin ≤ 3 mg/dL
- Patients must be seronegative for the human immunodeficiency virus (HIV1 and HIV2). Patients with positive serology for hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), or hepatitis C virus (anti-HCV) indicating acute or chronic infection may be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment.
- Patients must have a washout period of 5 half-lives from last anticancer therapy prior to the first study treatment (ie, start of NMA-LD).
- Palliative radiation therapy: prior external beam radiation is allowed provided all radiation-related toxicities are resolved to Grade 1 or baseline;
- The tumor lesion(s) being assessed as target for response via RECIST 1.1 must be outside of the radiation portal (however, if within the portal, they must have demonstrated progression);
- Surgery/pre-planned procedure: previous surgical procedure(s) is permitted provided that wound healing has occurred, all complications have resolved, and at least 14 days have elapsed (for major operative procedures) prior to the tumor resection.
- Patients must have recovered from all prior anticancer treatment-related adverse events (TRAEs) to Grade ≤ 1 (per Common Terminology Criteria for Adverse Events [CTCAE], version 5.0). Exceptions may be made, at the Investigator's discretion, for persistent adverse events (AEs) that are corrected or do not pose a clinical risk, such as hypothyroidism, adrenal insufficiency, alopecia, and vitiligo:
- Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis;
- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment may be included at the Investigator's discretion;
- Patients with Grade ≥ 2 toxicity from prior anticancer therapy may be considered on a case-by-case basis after consultation with the Investigator.
- Patients must have provided written authorization for use and disclosure of protected health information.
- Must be able and willing to comply with the study visit schedule and protocol requirements including long-term follow-up (LTFU).
- Patients who have received an organ allograft or prior cell transfer therapy within the past 20 years that included a nonmyeloablative or myeloablative chemotherapy regimen.
- Patients with symptomatic and/or untreated brain metastases:
• Patients with definitively-treated brain metastases will be considered for enrollment if, prior to tumor resection for TIL, the patient is clinically stable for ≥ 2 weeks, there are no new brain lesions via magnetic resonance imaging (MRI) post-treatment, and the patient does not require ongoing corticosteroid treatment.
- Patients who are on systemic steroid therapy except for those requiring steroid for management of adrenal insufficiency. Patients receiving steroids for management of adrenal insufficiency may receive no more than 10 mg prednisone or its equivalent daily.
- Patients who are pregnant or breastfeeding.
- Patients who have active medical illness(es) that would pose increased risk for study participation, including: active systemic infections requiring systemic antibiotics (ABX), coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory, or immune systems.
- Patients who have received a live or attenuated vaccination within 28 days prior to the start of NMA-LD.
- Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency disease [SCID] and acquired immune deficiency syndrome [AIDS]).
- Patients with a history of hypersensitivity to any component of the study drugs. LN-145 should not be administered to patients with a known hypersensitivity to any component of TIL product formulation and TIL treatment regimen including, but not limited to:
- NMA-LD (cyclophosphamide, mesna, and fludarabine);
- Proleukin®, aldesleukin, IL-2;
- ABX of the aminoglycoside group (ie, streptomycin, gentamicin);
- Any component of the TIL product formulation including dimethyl sulfoxide [DMSO], human serum albumin [HSA], IL-2, and dextran-40.
- Patients who have a left ventricular ejection fraction (LVEF) < 45% or who are New York Heart Association (NYHA) Class II or higher. A cardiac stress test demonstrating any irreversible wall movement abnormality in any patients ≥ 60 years of age or in patients who have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias.
- Patients who have obstructive or restrictive pulmonary disease and have a documented FEV1 (forced expiratory volume in 1 second) ≤ 60% of predicted normal:
• If a patient is not able to perform reliable spirometry due to abnormal upper airway anatomy (ie, tracheostomy), a 6-minute walk test may be used to assess pulmonary function. Patients who are unable to walk a distance of at least 80% predicted for age and sex or demonstrates evidence of hypoxia at any point during the test (SpO2 < 90%) are excluded.
- Patients who have had another primary malignancy within the previous 3 years (except for curatively treated localized malignancy that has not required treatment for greater than 1 year, and in the judgment of the Investigator, does not pose a significant risk of recurrence including, but not limited to, non-melanoma skin cancer or bladder cancer or cancers that do not require treatment in the judgement of the Investigator).
- Participation in another clinical study with an investigational product within 21 days of the initiation of NMA-LD treatment.