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Modified Immune Cells (LN-145) for the Treatment of Pretreated Metastatic Triple Negative Breast Cancer

Trial Status: Active

This phase II trial studies how well modified immune cells (LN-145) work in treating patients with triple negative breast cancer that has spread to other places in the body (metastatic). LN-145 is made up of specialized white blood cells called lymphocytes or “T cells” that are derived from a patient's tumor after a small piece is obtained by surgical removal. This piece of the patient's tumor is sent to a centralized manufacturing facility where T cells that have infiltrated the tumor are isolated and grown to create LN-145, which is infused back into the body. Tumor infiltrating lymphocyte therapy with LN-145 involves expanding and activating tumor-derived T cells in vitro (in tissue culture) and then infusing the cells back into the patient where they may then attack the tumor.

Inclusion Criteria

  • Ability to understand the requirements of the study. Specifically, the patient has to provide written informed consent (as evidenced by signature on an informed consent form [ICF] approved by the 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 2018 American Society of Clinical Oncology (ASCO) College of American Pathologists (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 it 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 a 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 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. Approved methods of birth control are as follows: * Combined (estrogen and progestogen containing) hormonal birth control associated with inhibition of ovulation: oral; intravaginal; transdermal * Progestogen-only hormonal birth control associated with inhibition of ovulation: oral; injectable; implantable * Intrauterine device (IUD) * Intrauterine hormone-releasing system (IUS) * Bilateral tubal occlusion * Vasectomized partner (female participant)/vasectomized male participant * True sexual abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar ovulation, symptothermal, post-ovulation methods) is not acceptable
  • Absolute neutrophil count (ANC) >= 1000/mm^3
  • Hemoglobin >= 9.0 g/dL
  • Platelet count >= 100,000/mm^3
  • 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 at screening
  • 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 (i.e., start of non-myeloablative lymphodepletion [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)

Exclusion Criteria

  • 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 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 including, but not limited to: * NMA-LD (cyclophosphamide, mesna, and fludarabine) * Proleukin, aldesleukin, IL-2 * ABX of the aminoglycoside group (i.e., 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 (i.e., 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 (oxygen saturation [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

Connecticut

New Haven
Yale University
Status: ACTIVE
Contact: Michael E. Hurwitz
Phone: 203-737-4556

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of autologous tumor infiltrating lymphocyte (TIL) LN-145 as a single therapy in metastatic triple negative breast cancer patients by determining the objective response rate (ORR), by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by the investigator.

II. To characterize the safety profile of TIL LN-145 as a single-therapy in metastatic triple negative breast cancer patients as measured by the incidence of grade >= 3 treatment-emergent adverse events (TEAEs).

SECONDARY OBJECTIVE:

I. To further evaluate the efficacy of autologous TIL LN-145 as a single therapy in metastatic triple negative breast cancer patients using duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), using RECIST 1.1, as assessed by the investigator, overall survival (OS) and complete response (CR) rate.

EXPLORATORY OBJECTIVES:

I. To explore the persistence of TIL LN-145 cells as a single therapy and its resultant immune correlates which may affect response, outcome, and toxicity variables.

II. To explore efficacy parameters (excluding OS) using the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), as assessed by the investigator.

III. To explore the feasibility of generating TIL (LN-145) from patient derived triple negative breast cancer (TNBC) core biopsy tumor specimens using Iovance manufacturing process.

OUTLINE:

LYMPHODEPLETION: Patients receive cyclophosphamide intravenously (IV) over 2 hours on days -7 and -6 and fludarabine IV over 30 minutes on days -5 to -1 in the absence of disease progression or unacceptable toxicity.

LN-145 INFUSION: At least 24 hours after completion of lymphodepletion, patients receive LN-145 IV on day 0. Beginning 3-24 hours after infusion of LN-145, patients receive aldesleukin IV every 8-12 hours on days 1-3 for up to 6 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at days 14, 28, 42, 84, and 126, at 6 months, and then every 3 months for up to 60 months (5 years).

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Yale University

Principal Investigator
Michael E. Hurwitz

  • Primary ID 2000025837
  • Secondary IDs NCI-2020-02510
  • Clinicaltrials.gov ID NCT04111510