Multicenter Phase 2 Study to Evaluate the Efficacy and Safety of Autologous Tumor-Infiltrating Lymphocytes (LN-145) in Patients with Recurrent, Metastatic, or Persistent Cervical Carcinoma

France, Germany, Italy, Netherlands, Spain, Switzerland, United Kingdom, United States (ICTRP)

ID di studio ICTRP
EUCTR2016-003447-11 (ICTRP)

Titolo ufficiale (approvato dal comitato etico)
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 (BASEC)

Titolo accademico
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 - Study of LN-145 in the treatment of Patients with cervical cancer (ICTRP)

Titolo pubblico
A study to find out if an investigational product, called LN-145 (also called tumor infiltrating lymphocytes) is an effective and safe treatment in patients with recurrent, metastatic or persistent cervical carcinoma (ICTRP)

Malattie studiate
Recurrent, metastatic, or persistent Cervical Carcinoma
MedDRA version: 21.1Level: LLTClassification code 10008229Term: Cervical cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Cancer [C04] (ICTRP)

Intervento studiato

Product Name: Fludarabine
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: FLUDARABINE PHOSPHATE
CAS Number: 75607-67-9
Current Sponsor code: FLUDARABINE PHOSPHATE
Other descriptive name: FLUDARABINE PHOSPHATE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Trade Name: Cyclophosphamide
Product Name: Cyclophosphamide Injection
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 6055-19-2
Current Sponsor code: CYCLOPHOSPHAMIDE
Other descriptive name: CYCLOPHOSPHAMIDE MONOHYDRATE
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 1-

Trade Name: Proleukin
Product Name: Aldesleukin
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: Proleukin
CAS Number: 110942-02-4
Other descriptive name: ALDESLEUKIN
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 22000000-

Product Name: LN-145
Product Code: LN-145
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: LN-145
CAS Number: Not avail.
Current Sponsor code: LN-145
Other descriptive name: LN-145
Concentration unit: Other
Concentration type: range
Concentration number: 1000000000-150000000000

Product Name: Fludarabine
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: FLUDARABINE PHOSPHATE
CAS Number: 75607-67-9
Current Sponsor code: FLUDARABINE PHOSPHATE
Other descriptive name: FLUDARABINE PHOSPHATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Trade Name: Proleukin
Product Name: Aldesleukin
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: Proleukin
C (ICTRP)

Tipo di studio
Interventional clinical trial of medicinal product (ICTRP)

Disegno dello studio
Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1 (ICTRP)

Criteri di inclusione/esclusione
Gender:
Female: yes
Male: no

Inclusion criteria:
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. Patients (or legally authorized representative) must have the ability to understand the requirements of the study, have provided written informed consent as evidenced by signature on an ICF approved by an Institutional Review Board/Independent Ethics Committee, and agree to abide by the study restrictions and return to the site for the required assessments, including the OS Follow-up Period
3. Must be able and willing to comply to the study visit schedule and protocol requirements.
4. Must have recurrent, metastatic, or persistent SCC, ASC, or AC of the cervix that is not amenable to curative treatment with surgery and/or radiation therapy and, in Germany and Switzerland only, for which no other therapies are expected to have significant benefit, in the opinion of the Investigator.
5. At least one resectable lesion (or aggregate of leasions 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).
6. At least one measurable target lesion, as defined by RECIST v1.1: lesions in previously irradiated areas (or other local therapy) should not be selected as target lesions, unless treatment was = 3 months prior to enrollment, and there has been demonstrated disease progression in that particular lesion. If a lesion is partially resected to generate TIL, and remains visible on the Baseline scan after surgery, then the partially resected lesion can be used for RECIST v1.1 response assessment, but only as a non-target lesion.
7.Cohort 1 and 2: Progression during or following at least one, but no more than three, prior systemic chemotherapeutic treatments 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, or 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]) in the setting of recurrent, metastatic, or persistent disease either as monotherapy or in combination (eg, in combination with chemotherapy or another immune agent). Cohort 3 (United States only): Must have not received any therapies other than prior chemoradiation or surgery for loco-regional disease
8. Any prior therapy directed at the malignant tumor, including chemotherapy, biologic/targeted agents, and immunologic agents must be discontinued at least 28 days prior to tumor resection. Radiation therapy is permitted as long as the lesions irradiated are not expected to be used for TIL generation or as target lesions and any toxicities have resolved to Grade = 1 at least 2 weeks prior to NMA-LD.
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
10. Must meet the following laboratory criteria: Absolute neutrophil count (ANC) = 1000/mm3; Hemoglobin (Hb) = 8 g/dL or = 4.96 mmol/L; Platelet count = 100,000/mm3 Serum Alanine Transaminase (ALT)/ Serum Glutamic-Pyruvic Transaminase (SGPT) and aspartate Transaminase (AST (ICTRP)

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 require systemic steroid therapy (> 10 mg/day of prednisone or other steroid equivalent dose). Patients receiving steroids as replacement therapy for any reason adrenocortical insufficiency at = 10 mg/day of prednisone or other steroid equivalent may be eligible.
3. Patients who currently have prior therapy-related toxicities Grade > 1 according to NCI-Common Terminology Criteria for Adverse Events v5.0 (eg. uveitis); except for peripheral neuropathy, alopecia or vitiligo prior to enrollment. Patients with a history of uveitis must have an eye examination performed by a trained eye specialist at Screening to rule out active uveitis that requires treatment. Patients who have active uveitis that requires active treatment will be excluded. If toxicities have resolved to Grade = 1, a minimum of 2 weeks must elapse 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.
Cohort 2: Patients with documented Grade = 2 diarrhea or colitis as a result of previous treatment with a PD-1/PD-L1 checkpoint inhibitor(s) must have been asymptomatic for at least 6 months or had a normal colonoscopy post-checkpoint inhibitor treatment, by visual assessment, prior to tumor resection.
Cohort 2: Patients with immunotherapy-related endocrinopathies stable for at least 6 weeks (eg, hypothyroidism, stable on hormonal substitution) and controlled with hormonal replacement, are allowed.
4. No longer applicable
5. 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); antibiotics (ABX) of the aminoglycoside group (i.e. streptomycin, gentamicin); except those who are skin-test negative for gentamycin hypersensitivity; any component of the LN-145 infusion product formulation including DMSO, HSA, IL-2, and dextran-40
6. Patients who have active systemic infections, coagulation disorders or other active major medical illness(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.
Patients with corrected (ie, percutaneous nephrostomy tubes) urinary tract obstruction must have negative surveillance cultures from externalized tubes within 7 days prior to the start of NMA-LD preparative regimen. Asymptomatic patients with chronic colonization of indwelling urinary diversion tubes may be eligible after active urinary infection is ruled out and discussion with the Medical Monitor. Patients with evidence of any uncontrolled or active systemic infection requiring ongoing treatment cannot proceed to NMA-LD. Prophylactic
anti-infection therapy is acceptable.
7. Patients with symptomatic and/or untreated brain metastases. 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.
8. Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency or acquired immunodef

Endpoint primari e secondari
Main Objective: Cohort 1 and 2 ? To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma based on the objective response rate as assessed by the Independent Review Committee per Response Evaluation Criteria in Solid Tumors v1.1
Cohort 3 (US only) ? To characterize the safety profile of LN-145 in combination with pembrolizumab in patients with recurrent, metastatic, or persistent cervical carcinoma
Cohort 4 ? To explore the efficacy and safety profile for previously enrolled patients with recurrent, metastatic, or persistent cervical carcinoma treated with LN-145
Cohort 5 ? To explore the efficacy and safety profile for re-treated patients with recurrent,
metastatic, or persistent cervical carcinoma treated with LN-145 in Cohorts 1 and 2;Secondary Objective: Cohort 1 and 2: To evaluate the efficacy parameters of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma by assessing duration of response, disease control rate and progression-free survival as assessed by the IRC per RECIST v1.1; to evaluate ORR, DOR, DCR, and PFS as assessed by the Investigator per RECIST v1.1; to evaluate overall survival (OS) in patients; to characterize the safety profile of LN-145
Cohort 3: To evaluate the efficacy of LN-145 in combination with pembrolizumab in patients with recurrent,
metastatic, or persistent cervical carcinoma by assessing ORR, DOR, DCR, and PFS per RECIST 1.1, as assessed by the Investigator; to evaluate OS in patients;Primary end point(s): ? Cohort 1 and 2: ORR as assessed by the IRC per RECIST v1.1

? Cohort 3: Incidence of Grade = 3 treatment-emergent adverse events (TEAEs)
? Cohorts 4 and 5: Because of the small sample size, results will be reported as appropriate by descriptive statistics.;Timepoint(s) of evaluation of this end point: Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months (ICTRP)

Secondary end point(s): Cohort 1 and 2
? DOR, DCR, and PFS as assessed by the IRC per RECIST v1.1
? ORR, DOR, DCR, and PFS as assessed by the Investigator per RECIST v1.1
? OS
? Incidence of severity, seriousness, relationship to study treatment, and characteristics of treatment-emergent adverse events (TEAEs), including serious AEs (SAEs), therapyrelated AEs, and AEs leading to early discontinuation from treatment or withdrawal from the Assessment Period or death
Cohort 3
? ORR, DOR, DCR, and PFS as assessed by the Investigator per RECIST v1.1
? OS
Cohorts 4 and 5
? Because of the small sample size, results will be reported as appropriate by descriptive statistics.;Timepoint(s) of evaluation of this end point: Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months;
OS: Time Frame: Unitl death or up to 60 months;
Adverse Events: Time Frame: Maximum 60 months (ICTRP)

Data di registrazione
14.09.2017 (ICTRP)

Inclusione del primo partecipante
23.05.2018 (ICTRP)

Sponsor secondari
non disponibile

Contatti aggiuntivi
Kenny Jones, c14504.cervical@iovance.com, +1650260 7120, Iovance Biotherapeutics, Inc. (ICTRP)

ID secondari
C-145-04, NCT03108495, 16819, 2016-003447-11-GB (ICTRP)

Risultati-Dati individuali dei partecipanti
non disponibile

Ulteriori informazioni sullo studio
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003447-11 (ICTRP)