| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent, metastatic, or persistent Cervical Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cervical cancer that has come back, spread to other places in the body, or has not improved |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008229 |
| E.1.2 | Term | Cervical cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma using the objective response rate (ORR). |
|
| E.2.2 | Secondary objectives of the trial |
To characterize the safety profile of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma.
To evaluate efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma such as complete response (CR) rate, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must be ≥18 years of age at the time of consent.
2. Must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
3. Must be able and willing to comply to the study visit schedule and protocol requirements.
4. Must have metastatic, recurrent or persistent squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix, which is not amenable to curative treatment with surgery and/or radiation therapy.
5. Must have at least 1 lesion that is resectable for TIL generation. The prosected TIL generating lesion(s) should be least 1.5 cm in diameter post-prosection, and can be surgically removed with minimal morbidity (defined as any operation for which expected hospitalization is ≤ 3 days). If the lesion is within a previously irradiated field, the irradiation must have occurred at least 3 months prior to Screening. An aggregate of ≥ 1.5 cm in diameter from multiple lesions is permitted.
6. Must have a remaining measurable target lesion as defined by RECIST 1.1 following the surgical resection. If measurable target lesion(s) are in previously irradiated areas, irradiation must have occurred at least 3 months prior to Screening and the lesions must have demonstrated evidence of progression since radiation.
7. Must have had at least 1 prior systemic immunotherapy or chemotherapeutic treatment for cervical carcinoma. Patients must have either progressive disease or no response (i.e., no PR or CR) while receiving or after the completion of the most recent prior treatment.
8. Any prior therapy directed at the malignant tumor, including radiation therapy, chemotherapy, biologic/targeted agents and immunologic agents must be discontinued at least 28 days prior to tumor resection.
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 > 9.0 g/dL
• Platelet count > 100,000/mm3
• ALT/SGPT and AST/SGOT < 3.0 x the upper limit of normal (ULN)
o Patients with liver metastases may have LFT ≥ 3.0 x ULN)
• Serum creatinine ≥ 1.5 mg/dL
• Total bilirubin ≤ 2.0 mg/dL
o Patients with Gilbert’s Syndrome must have a total bilirubin ≤ 3.0 mg/dL.
11. Patients must be seronegative for the HIV antibody, hepatitis B antigen, and hepatitis C antibody or antigen.
• Note: Patients with a positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus (HCV antibody) indicating acute or chronic infection may be enrolled if the viral load by PCR is undetectable with/without active treatment.
12. Patients of childbearing potential must be willing to practice an approved method of birth control starting at the time of informed consent and for 1 year after the completion of all study treatment regimen.
• Approved methods of birth control are as follows:
o combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
• oral; intravaginal; transdermal
o progestogen-only hormonal contraception associated with inhibition of ovulation:
• oral; injectable; implantable
o intrauterine device (IUD)
o intrauterine hormone-releasing system (IUS)
o bilateral tubal occlusion
o vasectomized partner
o sexual abstinence |
|
| E.4 | Principal exclusion criteria |
1. Patients who have received prior cell transfer therapy, which includes non-myeloablative or myeloablative chemotherapy regimen.
2. Patients who are on a systemic steroid therapy (> 10 mg of prednisone or equivalent daily).
• Note: A short course of higher dose steroid therapy is allowed in cases of exacerbation of known disease or for treatments of new acute symptoms.
3. Patients who currently have prior therapy-related toxicities greater than Grade 1 according to NCI-CTCAE v4.03; except for peripheral neuropathy, alopecia or vitiligo prior to enrollment/resection.
• If toxicities have resolved to Grade 1 or less, a minimum of 4 weeks must elapse prior to enrollment (tumor resection).
• Note: Patients may have undergone pre-planned procedures if not within 2-3 weeks prior to the start of nonmyeloablative lymphodepletion.
4. Patients with documented Grade 2 or greater diarrhea or colitis due to previous immunotherapy (e.g., ipilimumab, tremelimumab, anti-PD-1 or anti-PD-L1 within six months from Screening.
• Note: Patients that have been asymptomatic for at least 6 months or had a normal colonoscopy post anti-PD-1/anti-PD-L1 treatment, with uninflamed mucosa by visual assessment are not excluded.
5. Patients with history of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, IL-2, or aminoglycosides (e.g., gentamicin or streptomycin).
6. Patients with active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, including evidence in the medical history of a positive thallium stress test, myocardial infarction, cardiac arrhythmia, or obstructive or restrictive pulmonary disease, or other conditions that in the opinion of the Investigator would increase the risk of participation.
7. Patients with symptomatic and/or untreated brain metastases (of any size and any number).
• Patients with definitive treated brain metastases may be considered for enrollment after discussion with the Sponsor’s Medical Monitor/Designee, and must be stable for 2-4 weeks and asymptomatic prior to the start of treatment (nonmyeloablative lymphodepletion).
8. Patients who have any form of primary immunodeficiency, such as severe combined immunodeficiency disease or acquired immune deficiency syndrome (AIDS).
9. Patients who have a diagnosis of end-stage renal disorder requiring hemodialysis.
10. Patients who have a left ventricular ejection fraction (LVEF) < 45%. Patients >60 years of age must have had an echocardiogram within the previous 60 days of Screening.
11. Patients who have a FEV1 (forced expiratory volume in one second) of less than or equal to 60% of predicted normal.
12. Patients who have had another primary malignancy within the previous 3 years (except for curatively treated localized malignancy that has not required treatment for greater than 1 year, and in the judgment of the investigator, does not pose a significant risk of recurrence including, but not limited to, non-melanoma skin cancer or bladder cancer).
13. Patients who are pregnant or breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Response Rate (ORR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After last patient complete treatment and reach the 6-month tumor assessment, and final analysis at end of 2-year post-treatment follow up. |
|
| E.5.2 | Secondary end point(s) |
• Incidence of treatment-emergent AEs (TEAEs), including SAEs, therapy-related AEs, AEs leading to early discontinuation of treatment or withdrawal from post-treatment follow-up or death
• Complete Response (CR) rate
• Duration of Response (DOR)
• Disease Control Rate (DCR)
• Progression-Free Survival (PFS)
• Overall Survival (OS)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After last patient complete treatment and reach the 6-month tumor assessment, and final analysis at end of 2-year post-treatment follow up. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Spain |
| Switzerland |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| 3 years after the last patient completes the post-treatment follow-up, the time point all patients have exited the study for any reasons, or study termination at the Sponsor’s discretion, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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