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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

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ClinicalTrials.gov Identifier: NCT03935347
Recruitment Status : Recruiting
First Posted : May 2, 2019
Last Update Posted : October 9, 2019
Sponsor:
Collaborator:
Iovance Biotherapeutics, Inc.
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
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

Condition or disease Intervention/treatment Phase
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 Drug: Cyclophosphamide Drug: Fludarabine Drug: Fludarabine Phosphate Biological: Pembrolizumab Biological: Autologous Tumor Infiltrating Lymphocytes LN-145 Biological: Aldesleukin Phase 2

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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 20, 2019
Estimated Primary Completion Date : May 1, 2022
Estimated Study Completion Date : May 1, 2023

Resource links provided by the National Library of Medicine


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.
Drug: Cyclophosphamide
Given IV
Other Names:
  • 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
  • Cyclostine
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Fludarabine
Given IV
Other Names:
  • 118218
  • 2-Fluoro-9-beta-arabinofuranosyladenine
  • 2-Fluorovidarabine, 21679-14-1
  • 9-Beta-D-arabinofuranosyl-2-fluoro-9H-purin-6-amine
  • 9-Beta-D-arabinofuranosyl-2-fluoroadenine
  • Fluradosa

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 312887
  • 328002
  • 75607-67-9
  • 9H-Purin-6-amine
  • 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl
  • Fludarabine-5'-Monophosphate
  • SH T 586

Biological: Pembrolizumab
Given IV
Other Names:
  • 1374853-91-4
  • Immunoglobulin G4
  • Anti-(Human Programmed Cell Death 1)

Biological: Autologous Tumor Infiltrating Lymphocytes LN-145
Given IV
Other Names:
  • Autologous TILs LN-145
  • LN-145
  • LN145

Biological: Aldesleukin
Given IV
Other Names:
  • 110942-02-4
  • 125-L-Serine-2-133-interleukin 2
  • Recombinant Human Interleukin-2




Primary Outcome Measures :
  1. Objective response rate [ Time Frame: Up to 3 years ]
    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


Secondary Outcome Measures :
  1. Incidence of adverse events (AEs) [ Time Frame: From the first dose of cyclophosphamide up to 30 days from the last dose of IL- ]
    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.

  2. Duration of response [ Time Frame: Up to 3 years ]
    Will be assessed by Kaplan-Meier methods

  3. Disease Control Rate [ Time Frame: Up to 3 years ]
    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

  4. Progression-free survival [ Time Frame: Up to 3 years ]
    Will be assessed by Kaplan-Meier methods

  5. Overall Survival [ Time Frame: Up to 3 years ]
    From time of lymphodepletion to death due to any cause



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03935347


Contacts
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Contact: ASK RPCI 1-800-767-9355 Askroswell@roswellpark.org

Locations
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United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263-0001
Contact: ASK RPCI    877-275-7724    ASKRPCI@RoswellPark.org   
Sponsors and Collaborators
Roswell Park Cancer Institute
Iovance Biotherapeutics, Inc.
Investigators
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Principal Investigator: Gurkamal Chatta, MD Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT03935347     History of Changes
Other Study ID Numbers: I 77218
P30CA16056OD ( Other Grant/Funding Number: NCI )
First Posted: May 2, 2019    Key Record Dates
Last Update Posted: October 9, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Vidarabine
Aldesleukin
Cisplatin
Cyclophosphamide
Pembrolizumab
Fludarabine
Fludarabine phosphate
Interleukin-2
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Antineoplastic Agents, Immunological
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents