Adoptive Cell Therapy With (LN-145) in Combination With Pembrolizumab in Treating Patients With Unresectable or Metastatic Transitional Cell Cancer Who Have Failed Cisplatin-Based Chemotherapy

Phase 2 Study of Autologous Tumor Infiltrating Lymphocytes (LN-145) With Pembrolizumab, in Subjects Who Have Failed Cisplatin-Based Chemotherapy With Locally Advanced (Unresectable) or Metastatic Transitional Cell Cancer (TCC) of the Urothelium

This phase II trial studies how well autologous tumor infiltrating lymphocytes (LN-145) and pembrolizumab work in treating patients with transitional cell cancer that cannot be removed by surgery or has spread to other places in the body and have failed cisplatin-based chemotherapy. LN-145 is made up of specialized immune cells called lymphocytes or T cells that are taken from a patient's tumor, grown in a manufacturing facility and infused back into the preconditioned patient to attack the tumor. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving LN-145 may help control transitional cell bladder cancer when given together with pembrolizumab

Study Overview

• Status: Withdrawn
• Conditions: Metastatic Bladder Urothelial Carcinoma; Metastatic Renal Pelvis Urothelial Carcinoma; Metastatic Ureter Urothelial Carcinoma; Metastatic Urethral Urothelial Carcinoma; Unresectable Renal Pelvis Urothelial Carcinoma; Unresectable Ureter Urothelial Carcinoma
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Aldesleukin; Drug: Fludarabine Phosphate; Biological: Autologous Tumor Infiltrating Lymphocytes LN-145

Detailed Description

PRIMARY OBJECTIVES:

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).

SECONDARY OBJECTIVES:

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).

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The subject must understand the requirements of the study and voluntarily sign the informed consent form (ICF)
• All subjects must have a histologically confirmed unresectable TCC (including renal pelvis, ureters, urinary bladder, and urethra)
• Failed one and only one line of cisplatin-based chemotherapy per FDA guidelines.
• 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.Have at least one resectable lesion to generate TILs
• At least one measurable target lesion as defined by RECIST version 1.1
• An Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
• Estimated life expectancy of >= 6 months
• Adequate bone marrow function
• Adequate organ function
• Subjects must be seronegative for the human immunodeficiency virus (HIV)
• Recovered from all prior anticancer therapy-related AEs to grade 1 or less
• 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
• Must be able and willing to comply with the study visit schedule and protocol requirements including long-term follow-up

Exclusion Criteria:

• 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
• Active or prior documented autoimmune or inflammatory disorders
• Subjects who have any form of human immondeficiency virus (HIV)infection
• Have severe infections within 4 weeks before initiation of study treatment
• 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

  • 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
• Serious illnesses or medical conditions, which would pose increased risk for study participation and/or compliance with the protocol
• Known clinically significant liver disease
• Have obstructive or restrictive pulmonary disease and have a documented FEV1 (forced expiratory volume in 1 second) of =< 60%
• Subjects with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases
• Subjects who are pregnant or breastfeeding
• Active infection including tuberculosis (TB), hepatitis B, hepatitis C, or human immunodeficiency virus
• Treatment with any other investigational agent within 4 weeks before initiation of study treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (cyclophosphamide, fludarabine, pembrolizumab); Patients receive cyclophosphamide 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.

Biological: Pembrolizumab; Given IV; Other Names: Immunoglobulin G4; Anti-(Human Programmed Cell Death 1); 1374853-91-4; Drug: Cyclophosphamide; Given IV; Other Names: Cyclostine; Revimmune; Syklofosfamid; WR- 138719; 1-bis(2-chloroethyl)-amino-1-oxo-2-aza-5-oxaphosphoridin monohydrate; 2-[bi(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate; Drug: Fludarabine; Given IV; Other Names: Fluradosa; 9-Beta-D-arabinofuranosyl-2-fluoro-9H-purin-6-amine; 9-Beta-D-arabinofuranosyl-2-fluoroadenine; 118218; 2-Fluoro-9-beta-arabinofuranosyladenine; 2-Fluorovidarabine, 21679-14-1; Biological: Aldesleukin; Given IV; Other Names: 125-L-Serine-2-133-interleukin 2; Recombinant Human Interleukin-2; 110942-02-4; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; SH T 586; 75607-67-9; 312887; 328002; 9H-Purin-6-amine; Fludarabine-5'-Monophosphate; 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl; Biological: Autologous Tumor Infiltrating Lymphocytes LN-145; Given IV; Other Names: Autologous TILs LN-145; LN-145; LN145

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	The proportion of subjects who achieve either a confirmed partial response (PR) or complete response (CR) as best response as assessed per Response Evaluation Criteria in Solid Tumors 1.1. Will be evaluated per each disease assessment and calculated with the corresponding 95% two-sided confidence interval	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events (AEs)	Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5 by grade of severity and relationship to the study treatment.	From the first dose of cyclophosphamide up to 30 days from the last dose of IL-
Duration of response	Will be assessed by Kaplan-Meier methods	Up to 3 years
Disease Control Rate	Derived as the sum of the number of subjects who achieved confirmed PR/CR or sustained stable disease (at least 6 weeks) divided by the number of subjects in the all-treated population x 100%. Will be assessed by Kaplan-Meier methods	Up to 3 years
Progression-free survival	Will be assessed by Kaplan-Meier methods	Up to 3 years
Overall Survival	From time of lymphodepletion to death due to any cause	Up to 3 years

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Collaborators: Iovance Biotherapeutics, Inc.
• Investigators: Principal Investigator: Gurkamal Chatta, MD, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2019
• Primary Completion (Anticipated): May 1, 2022
• Study Completion (Anticipated): May 1, 2023

Study Registration Dates

• First Submitted: April 30, 2019
• First Submitted That Met QC Criteria: April 30, 2019
• First Posted (Actual): May 2, 2019

Study Record Updates

• Last Update Posted (Actual): January 2, 2020
• Last Update Submitted That Met QC Criteria: December 27, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Aldesleukin; Cyclophosphamide; Immunoglobulins; Pembrolizumab; Fludarabine; Fludarabine phosphate; Immunoglobulin G; Interleukin-2; Vidarabine
• Other Study ID Numbers: I 77218; P30CA16056OD (Other Grant/Funding Number: NCI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No