Modified Immune Cells (LN-145) and Pembrolizumab in Treating Patients with Unresectable or Metastatic Transitional Cell Cancer Who Have Failed Cisplatin-Based Chemotherapy
- Prior to any study-related assessments/procedures being conducted, the subject (or a legally authorized representative) must understand the requirements of the study and voluntarily sign the informed consent form (ICF) as approved by an Institutional Review Board/Independent Ethics Committee (IRB/IEC)
- All subjects must have a histologically confirmed unresectable TCC (including renal pelvis, ureters, urinary bladder, and urethra). Note: mixed histology tumors allowed if predominant histology is urothelial carcinoma. Small cell or neuroendocrine carcinoma is not allowed if predominant
- Failed one and only one line of cisplatin-based chemotherapy per Food and Drug Administration (FDA) guidelines * NOTE: Cisplatin-ineligible subjects will only be treated with 1st line pembrolizumab, if their tumors overexpress PDL-1. Subjects who are PDL-1 low, will be first offered Carboplatin-based chemotherapy
- Subjects must have an area of tumor amenable to excisional biopsy for the generation of TIL separate from, and in addition to, a target lesion to be used for response assessment. Ideally, the resected tumor is approximately 1.5 cm in diameter post-resection (primary disease or metastatic site). An aggregate of >= 1.5 cm in diameter from multiple lesions is permitted. If there is only one lesion, then it may be used for both TIL generation and as a target lesion, provided the appropriate criteria are met
- At least one measurable target lesion as defined by RECIST version 1.1. Lesions must not have been previously irradiated if they are the sole site of measurable disease, unless radiation was >= 3 months prior and the lesion has demonstrated disease progression since irradiation. The site resected for LN-145 generation should not be a measurable site; except if there is only 1 lesion, then it may be used for both TIL generation and as a target lesion, provided the appropriate criteria are met
- An Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
- Estimated life expectancy of >= 6 months
- Absolute neutrophil count (ANC) >= 1 x 10^9/L or 1000/mm^3
- Platelet count >= 100,000/mm^3
- Hemoglobin >= 9 g/dL (transfusion allowed)
- Alanine aminotransferase (ALT)/(serum glutamate pyruvate transaminase [SGPT]) and aspartate aminotransferase (AST)/(serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x the upper limit of normal (ULN) unless liver metastases are present, in which case liver function tests (LFT) =< 5 x ULN
- Calculated creatinine clearance >= 30 mL/min and < 60 mL/min using the Cockcroft-Gault formula
- Total bilirubin =< 2 x ULN (this will now apply to subjects with confirmed Gilbert’s syndrome [persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology], who will be allowed only in consultation with their physician)
- Subjects must be seronegative for the human immunodeficiency virus (HIV). Subjects 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
- A washout period from prior anticancer therapy(ies) of a minimum duration as detailed below is required prior to the first study treatment * Chemotherapy: adjuvant, neoadjuvant or definitive chemoradiation is allowed provided the washout is a minimum of 21 days prior to the start of non-myeloablative lymphodepletion (NMA-LD) * Radiation therapy: prior external beam radiation is allowed provided all toxicities have resolved to CTCAE grade =< 1, and there is measurable disease outside the radiation portal. If a lesion selected for response assessment had been previously irradiated, such lesion must have presented with disease progression prior to enrollment * Surgery: previous surgical procedure(s) is permitted provided that wound healing has occurred and at least 28 days have elapsed (for major operative procedures) prior to first study treatment
- Recovered from all prior anticancer therapy-related AEs to grade 1 or less (per CTCAE v5.0) prior to enrollment. Exceptions may be made, at the investigator’s discretion, for persistent AEs that are corrected or do not pose a clinical risk, such as hypothyroidism, adrenal insufficiency, alopecia, and vitiligo * Subjects with grade >= 2 neuropathy will be evaluated on a case-by-case basis * Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment may be included at the investigator’s discretion
- Negative serum pregnancy test (female subjects of childbearing potential)
- Subjects of childbearing potential must be willing to practice an approved method of birth control starting at the time of informed consent and for 12 months after the completion of the study treatment regimen. Approved methods of birth control are as follows: * Combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (e.g., oral, intravaginal, transdermal) * Progesterone-only hormonal contraception associated with inhibition of ovulation (e.g., oral, injectable, implantable) * Intrauterine device (IUD) * Intrauterine hormone-releasing system (IUS) * Bilateral tubal occlusion * Vasectomized partner * Note: Females of reproductive potential are to use effective contraception during treatment and for 12 months after their last dose of IL-2, or 4 months after their last dose of pembrolizumab, whichever occurs later
- Must be able and willing to comply with the study visit schedule and protocol requirements including long-term follow-up
- Have had another primary malignancy within the previous 3 years (with the exception of carcinoma in situ of the breast, cervix, or localized prostate cancer and non-melanoma skin cancer that has been adequately treated)
- Have received prior cell transfer therapy that included a nonmyeloablative or myeloablative chemotherapy regimen
- Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody, or pathway-targeting agents
- Chemotherapy or radiotherapy with projected completion within 4 weeks of initiating study treatment
- Bisphosphonate therapy for symptomatic hypercalcemia
- Have had treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks before initiation of study treatment. Subjects who are on a systemic steroid therapy at a dose of > 10 mg of prednisone or equivalent per day. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection) * Systemic corticosteroids at doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication) * Treatment of brain tumors up to 14 days before treatment (NMA-LD) * Temporary steroids for chronic obstructive pulmonary disease (COPD) exacerbation within 14 days before treatment (NMA-LD)
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome). The following are exceptions to this criterion: * Subjects with vitiligo or alopecia * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Subjects with celiac disease controlled by diet alone * Or other diseases that are deemed clinically insignificant by the investigator
- Subjects who have any form of human immunodeficiency virus (HIV) infection (such as severe combined immunodeficiency disease [SCID] and acquired immune deficiency syndrome [AIDS])
- Have severe infections within 4 weeks before initiation of study treatment, including, but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
- Have received a live or attenuated vaccine within 28 days of the non-myeloablative lymphodepletion (NMA-LD regimen)
- Subjects with a history of hypersensitivity reaction(s) to any component of the LN-145 therapy and/or the other study drugs: * NMA-LD (cyclophosphamide, mesna, fludarabine) * Proleukin, aldesleukin, IL-2 * Antibiotics of the aminoglycoside group (i.e., streptomycin, gentamicin) * Any component of the LN-145 product formulation including dimethyl sulfoxide (DMSO), human serum albumin (HSA), and dextran-40 * Pembrolizumab
- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 450 msec for males (and >= 470 msec for females) calculated from 3 electrocardiograms (ECGs) (within a 30-minute timeframe) or history of familiar long-QT syndrome
- Subjects who have a left ventricular ejection fraction (LVEF) < 45% or who are New York Heart Association functional classification class II or higher. A cardiac stress test demonstrating any irreversible wall movement abnormality in any subjects >= 60 years of age or in subjects who have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias * Subjects with an abnormal cardiac stress test may be enrolled if they have adequate ejection fraction and cardiology clearance at investigator’s discretion
- Serious illnesses or medical conditions, which would pose increased risk for study participation and/or compliance with the protocol, including but not limited to the following: uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, active peptic ulcer disease or gastritis, coagulation disorders, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent, or any other conditions that in the opinion of the investigator would pose increased risk
- Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver/non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH); and inherited liver disease
- Have obstructive or restrictive pulmonary disease and have a documented FEV1 (forced expiratory volume in 1 second) of =< 60% * If a subject 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. Subjects 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 (peripheral capillary oxygen saturation [SpO2] < 90%) are excluded
- Subjects with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases * Subjects with definitively-treated brain metastases will be considered for enrollment; if, prior to the start of NMA-LD the subject is clinically stable for >= 2 weeks, there are no new brain lesions via magnetic resonance imaging (MRI) post-treatment, and the subject does not require corticosteroid treatment > 10 mg prednisone or equivalent per day
- Subjects who are pregnant or breastfeeding
- Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV-1/2 antibodies). Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Treatment with any other investigational agent within 4 weeks before initiation of study treatment
- Subjects protected by the following constraints: * Hospitalized persons without consent, or persons deprived of liberty because of a judiciary or administrative decision * Adult persons with a legal protection measure, or persons who cannot express their consent; or * Subjects in emergency situations who cannot consent to participate in the trial
I. To evaluate the efficacy of autologous tumor infiltrating lymphocytes LN-145 (LN-145) in combination with pembrolizumab in subjects with advanced transitional cell bladder cancer (TCC) using the objective response rate (ORR) and the duration of response (DoR), using the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST version [v] 1.1).
I. To evaluate the efficacy of LN-145 in combination with pembrolizumab in subjects with TCC based on the progression-free survival (PFS) and overall survival (OS).
II. To evaluate the safety of LN-145 in combination with pembrolizumab in subjects with TCC based on the adverse event (AE) profile per Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0).
I. To determine the persistence of tumor-infiltrating lymphocytes (TILs) and potential immune correlates of response (outcome, and toxicity) of the treatment.
II. To determine efficacy based on immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).
III. To explore the neo-antigen repertoire.
Patients receive cyclophosphamide intravenously (IV) over 2 hours on days -8 and -7, fludarabine IV over 30 minutes on days -6 to -2, and pembrolizumab IV over 30 minutes on day -1. At least 24 hours later, patients receive autologous tumor infiltrating lymphocytes LN-145 IV on day 0, and receive aldesleukin IV over 30 minutes for up to 6 doses on days 1-4. Patients then continue receiving pembrolizumab IV over 30 minutes beginning on day 21. Cycles of pembrolizumab repeat every 21 days for 12 months in the absence of disease progression or unacceptable toxicity.
Patients are followed up every 3 months for 3 years from the end of LN-145 infusion (day 0).
Trial Phase Phase II
Trial Type Treatment
Roswell Park Cancer Institute
Gurkamal S. Chatta
- Primary ID I 77218
- Secondary IDs NCI-2019-01763
- Clinicaltrials.gov ID NCT03935347