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Study of LN-145, Autologous Tumor Infiltrating Lymphocytes in the Treatment of Patients With Cervical Carcinoma

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ClinicalTrials.gov Identifier: NCT03108495
Recruitment Status : Recruiting
First Posted : April 11, 2017
Last Update Posted : June 9, 2021
Sponsor:
Information provided by (Responsible Party):
Iovance Biotherapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE March 27, 2017
First Posted Date  ICMJE April 11, 2017
Last Update Posted Date June 9, 2021
Actual Study Start Date  ICMJE June 22, 2017
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 7, 2021)
  • Cohort 1 and 2: Objective Response Rate [ Time Frame: Up to 6 months ]
    To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma based on the objective response rate (ORR) as assessed by the Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
  • Cohort 3: Adverse Events [ Time Frame: Up to 60 months ]
    To characterize the safety profile of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma as assessed by incidence of adverse events.
  • Cohort 4: Efficacy and Adverse Events [ Time Frame: Up to 60 months ]
    To explore the efficacy and safety profile of LN-145 in previously enrolled patients with recurrent, metastatic, or persistent cervical carcinoma
  • Cohort 5: Efficacy and Adverse Events [ Time Frame: Up to 60 months ]
    To explore the efficacy and safety profile of LN-145 in re-treated patients with recurrent, metastatic, or persistent cervical carcinoma
Original Primary Outcome Measures  ICMJE
 (submitted: April 5, 2017)
  • Adverse Events [ Time Frame: Up to 24 months ]
    Incidence of treatment-emergent AEs (TEAEs), including SAEs, therapy-related AEs, AEs leading to early discontinuation of treatment or withdrawal from the study or death
  • Objective Response Rate [ Time Frame: Up to 24 months ]
    To evaluate the efficacy of therapy based on objective response rate
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2021)
  • Cohort 1 and 2: Duration of Response [ Time Frame: Up to 60 months ]
    To evaluate the efficacy parameters of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing duration of response (DOR) as assessed by the IRC per RECIST v1.1
  • Cohort 1 and 2: Disease Control Rate [ Time Frame: Up to 60 months ]
    To evaluate the efficacy parameters of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing disease control rate (DCR) as assessed by the IRC per RECIST v1.1
  • Cohort 1 and 2: Progression-Free Survival [ Time Frame: Up to 60 months ]
    To evaluate the efficacy parameters of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing progression-free survival (PFS) as assessed by the IRC per RECIST v1.1
  • Cohort 1 and 2: Objective Response Rate [ Time Frame: Up to 60 months ]
    To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma based on the objective response rate (ORR) as assessed by the Investigator per RECIST v1.1
  • Cohort 1 and 2: Duration of Response [ Time Frame: Up to 60 months ]
    To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing duration of response (DOR) as assessed by the Investigator per RECIST v1.1
  • Cohort 1 and 2: Disease Control Rate [ Time Frame: Up to 60 months ]
    To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing disease control rate (DCR) as assessed by the Investigator per RECIST v1.1
  • Cohort 1 and 2: Progression-Free Survival [ Time Frame: Up to 60 months ]
    To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing progression-free survival (PFS) as assessed by the Investigator per RECIST v1.1
  • Cohort 1 and 2: Overall Survival [ Time Frame: Up to 60 months ]
    To evaluate overall survival (OS) in patients with recurrent, metastatic, or persistent cervical carcinoma
  • Cohort 1 and 2: Adverse Events [ Time Frame: Up to 60 months ]
    To characterize the safety profile of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma as assessed by incidence of adverse events
  • Cohort 3: Objective Response Rate [ Time Frame: Up to 60 months ]
    To evaluate the efficacy of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma based on the objective response rate (ORR) as assessed by the Investigator per RECIST v1.1
  • Cohort 3: Duration of Response [ Time Frame: Up to 60 months ]
    To evaluate the efficacy of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing duration of response (DOR) as assessed by the Investigator per RECIST v1.1.
  • Cohort 3: Disease Control Rate [ Time Frame: Up to 60 months ]
    To evaluate the efficacy of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing disease control rate (DCR) as assessed by the Investigator per RECIST v1.1.
  • Cohort 3: Progression-Free Survival [ Time Frame: Up to 60 months ]
    To evaluate the efficacy of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing progression-free survival (PFS) as assessed by the Investigator per RECIST v1.1.
  • Cohort 3: Overall Survival [ Time Frame: Up to 60 months ]
    To evaluate overall survival (OS) in patients with recurrent, metastatic, or persistent cervical carcinoma
Original Secondary Outcome Measures  ICMJE
 (submitted: April 5, 2017)
  • Complete Response Rate [ Time Frame: Up to 24 months ]
    To evaluate efficacy parameters such Complete Response (CR) rate
  • Duration of Response [ Time Frame: Up to 24 months ]
    To evaluate efficacy parameters such Duration of Response (DOR)
  • Progression-Free Survival [ Time Frame: Up to 24 months ]
    To evaluate efficacy parameters such Progression-Free Survival (PFS)
  • Overall Survival [ Time Frame: Up to 24 months ]
    To evaluate efficacy parameters such Overall Survival (OS)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of LN-145, Autologous Tumor Infiltrating Lymphocytes in the Treatment of Patients With Cervical Carcinoma
Official Title  ICMJE A Phase 2, Multicenter Study to Evaluate the Efficacy and Safety Using Autologous Tumor Infiltrating Lymphocytes (LN-145) in Patients With Recurrent, Metastatic or Persistent Cervical Carcinoma
Brief Summary Prospective, multicenter, single-arm, open label, interventional study evaluating adoptive cell therapy (ACT) with autologous tumor infiltrating lymphocytes (TIL) infusion (LN-145) followed by IL-2 after a non-myeloablative (NMA) lymphodepletion preparative regimen for the treatment of patients with recurrent, metastatic, or persistent cervical carcinoma
Detailed Description LN-145 is an adoptive cell transfer therapy that utilizes an autologous TIL manufacturing process, as originally developed by the NCI, for the treatment of patients with recurrent, metastatic, or persistent cervical carcinoma. The cell transfer therapy used in this study involves patients receiving a NMA lymphocyte depleting preparative regimen, followed by infusion of autologous TIL followed by the administration of a regimen of IL-2.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cervical Carcinoma
Intervention  ICMJE
  • Biological: LN-145
    A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes.
    Other Name: TIL, autologous tumor infiltrating lymphocytes
  • Biological: LN-145 + pembrolizumab
    A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. The first dose of anti-PD-1 immunotherapy will be administered following tumor resection.
    Other Name: TIL, autologous tumor infiltrating lymphocytes; pembrolizumab (anti-PD-1 immunotherapy)
Study Arms  ICMJE
  • Experimental: Cohort 1 LN-145 monotherapy
    Post-NMA lymphodepletion, patients are infused with their autologous TIL (LN-145) followed by IL-2 administration.
    Intervention: Biological: LN-145
  • Experimental: Cohort 2 LN-145 monotherapy
    Patients previously treated with an antiprogrammed cell death protein-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) checkpoint inhibitor: Post-NMA lymphodepletion, patients are infused with their autologous TIL (LN-145) followed by IL-2 administration.
    Intervention: Biological: LN-145
  • Experimental: Cohort 3 - Combination Arm (TIL + Pembrolizumab) - US Only
    Patients will be administered with pembrolizumab, followed by NMA lymphodepletion, then infused with their autologous TIL (LN-145) followed by pembrolizumab every 3 or 6 weeks post IL-2 administration up to 24 months.
    Intervention: Biological: LN-145 + pembrolizumab
  • Experimental: Cohort 4 - Non-enrolling Cohort
    Cohort includes patient population not meeting inclusion criteria in cohort 1 and 2. Post-NMA lymphodepletion, patients are infused with their autologous TIL (LN-145) followed by IL-2 administration.
    Intervention: Biological: LN-145
  • Experimental: Cohort 5 Retreatment Cohort
    Patients who have been previously treated with LN-145 may be given a second treatment with TIL.
    Intervention: Biological: LN-145
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 4, 2019)
138
Original Estimated Enrollment  ICMJE
 (submitted: April 5, 2017)
47
Estimated Study Completion Date  ICMJE December 2026
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

To be eligible for the study, patients must meet ALL of the following criteria prior to participation:

  1. Must be ≥ 18 years of age at the time of consent

    Enrollment of patients > 70 years of age may be allowed after consultation with the Medical Monitor.

  2. Must have recurrent, metastatic, or persistent squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix that is not amenable to curative treatment with surgery and/or radiation therapy
  3. At least one resectable lesion (or aggregate of lesions resected) of a minimum 1.5 cm in diameter post resection to generate TIL; surgical removal with minimal morbidity (defined as any procedure for which expected hospitalization is ≤ 3 days)
  4. At least one measurable target lesion, as defined by RECIST v1.1
  5. Cohort 1 and Cohort 2: Progression during or following at least one, but no more than three, prior systemic chemotherapeutic treatments (such as carboplatin/cisplatin, paclitaxel, and bevacizumab except where there are contraindications) for recurrent, metastatic or persistent cervical carcinoma

    • A line of systemic therapy is defined as any chemotherapy or multiple-agent chemotherapy regimen that was administered for recurrent, metastatic or persistent SCC, ASC, or AC of the cervix.
    • A bevacizumab and chemotherapy combination is encouraged as a prior line of treatment
    • Neither chemoradiation, nor chemotherapy in the neoadjuvant or adjuvant settings are considered as a prior line of systemic therapy.

    Cohort 2: Must also have previously received treatment with a checkpoint inhibitor (ie, PD-1, PD-L1])

    Cohort 3: Must have not received any therapies other than prior chemoradiation or surgery for loco-regional disease

  6. Any prior therapy directed at the malignant tumor must be discontinued at least 28 days prior to tumor resection. Radiation therapy may have been received up to 28 days prior to tumor resection for lesions not expected to be used for TIL generation or target lesions.
  7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  8. Patients must be seronegative for the human immunodeficiency virus (HIV). Patients with positive serology for hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), or hepatitis C virus antibody (HCV Ab) indicating acute or chronic infection may be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment.
  9. Patients of childbearing potential must be willing to take the appropriate precaution to avoid pregnancy for the duration of the study and practice an approved, highly effective method of birth control during treatment and for 12 months after receiving the last protocol-related therapy.
  10. Prior to study Enrollment (tumor resection), patient must have documentation of radiological disease progression after the most recent therapy.

Exclusion Criteria:

  1. Patients who have received an organ allograft or prior cell transfer therapy except for prior LN-145 therapy in the setting of re-treatment only.
  2. Patients who are on chronic systemic steroid therapy
  3. Patients who currently have prior therapy-related toxicities Grade > 1 according to National Cancer Institute (NCI-) Common Terminology Criteria for Adverse Events (CTCAE) v5.0; except for peripheral neuropathy, alopecia, or vitiligo prior to Enrollment (tumor resection)

    • Patients may not have any pre-planned procedures within 2 weeks prior to the start of NMA-LD preparative regimen

  4. Patients who have a history of hypersensitivity to any component or excipient of LN-145 or other study drugs:

    • NMA-LD preparative regimen (cyclophosphamide, mesna, and fludarabine)

  5. Patients who have active systemic infections, coagulation disorders or other active major medical illnesse(es) of the cardiovascular, respiratory, or immune system, including evidence in the medical history of urinary tract obstruction, a positive cardiac stress test, myocardial infarction, cardiac arrhythmia, obstructive or restrictive pulmonary disease, or other conditions that in the opinion of the Investigator would increase the risk of participation
  6. Patients with symptomatic and/or untreated brain metastases (of any size and any number)

    • Patients with definitively treated brain metastases may be considered for Enrollment, and must be stable for ≥ 14 days prior to beginning the NMA-LD preparative regimen

  7. Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency [SCID] or acquired immunodeficiency syndrome [AIDS])
  8. Patients who have a diagnosis of end-stage renal disorder requiring hemodialysis.
  9. Patients who have a left ventricular ejection fraction (LVEF) < 45% or who are New York Heart Association (NYHA) Class 2 or higher.
  10. Patients who have a documented forced expiratory volume in 1 second (FEV1) of ≤ 60%
  11. Patients who have had another primary malignancy within the previous 3 years (except for curatively treated localized malignancy that has not required treatment for > 1 year, and in the judgement of the Investigator, does not pose a significant risk of recurrence including, but not limited to, non-melanoma skin cancer or bladder cancer)
  12. Patients who have received a live or attenuated vaccine within 28 days prior to beginning NMA-LD preparative regimen.
  13. Patients whose cancer requires immediate attention or who would otherwise suffer a disadvantage by participating in this study
  14. Cohort 1 and Cohort 3: Patients who have received prior treatment with immunotherapy (eg, PD-1, PD-L1, or anti-cytotoxic T lymphocyte-associated antigen-4 [CTLA-4] antibodies)
  15. Patients who have Grade ≥ 2 hemorrhage within 14 days prior to Enrollment (tumor resection)
  16. Cohort 3: Patients may not have active or prior documented autoimmune or inflammatory disorders (including pneumonitis, inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]).
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Iovance Biotherapeutics Clinical Inquiries 650-260-7120 Clinical.Inquiries@iovance.com
Contact: Iovance Biotherapeutics Clinical Inquiries 866-565-4410 Clinical.Inquiries@iovance.com
Listed Location Countries  ICMJE France,   Germany,   Italy,   Netherlands,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03108495
Other Study ID Numbers  ICMJE C-145-04
2016-003447-11 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Iovance Biotherapeutics, Inc.
Study Sponsor  ICMJE Iovance Biotherapeutics, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Iovance Medical Monitor Iovance Biotherapeutics, Inc.
PRS Account Iovance Biotherapeutics, Inc.
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP