JOURNAL ONKOLOGIE – STUDIE
NeoTIL in Advanced Solid Tumors
Cyclophosphamide, Fludarabine, Interleukin-2
Indikation (Clinical Trials):
Centre Hospitalier Universitaire Vaudois
Centre Hospitalier Universitaire Vaudois
E-Mail: email@example.com» Kontaktdaten anzeigen
The objective of the trial is to define the feasibility, safety, and efficacy of NeoTIL-ACT
in combination with LDI in patients with advanced, recurrent or metastatic solid tumors, as
categorized in two molecularly defined cohorts.
Study treatment will begin with intravenous (IV) non-myeloablative (NMA) lymphodepleting
chemotherapy composed by fludarabine and cyclophosphamide. Both treatments will be started on
the same day. Fludarabine will be administered from for five days, and cyclophosphamide ffor
two days. Low-dose irradiation (LDI) will be administered once, to tumor lesions using
Patients will receive NeoTIL infusion intravenously followed by high dose IL-2 administration
every eight hours, for a maximum of eight doses. Supportive care will be given as needed
during the whole treatment period.
Patients achieving a stable disease, partial response or complete response after NeoTIL-ACT
treatment will then enter a clinical follow-up period for 5 years.
1. Patients with advanced (not radically treatable), recurrent or metastatic solid tumors
of any histology with the exception of primary central nervous system tumors, who have
received, and then progressed or been intolerant to at least one standard therapy
regimen in the advanced or metastatic setting if such a therapy exists, and have been
considered for all other potentially efficacious therapies prior to enrollment. If the
participant refuses, or is not eligible for these regimens in the opinion of the
investigator, the reason must be documented in the medical record.
2. Patients who have previously undergone tumor resection or biopsy and for whom
pre-Rapid Expansion Protocol (REP) NeoTIL cultures are ongoing or completed.
3. At least one lesion accessible to biopsy for translational research (TR) at baseline
and D30, without putting the patient at unusual risk.
4. Male or female age ≥ 18 to ≤ 70 years at the time of informed consent. Patients aged
>70 will be evaluated by the investigator, and decision will be made according to
patient's status, upon agreement with the PI.
5. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) of 0 to 2.
6. Life expectancy of greater than 12 weeks.
7. Radiologically measurable disease (as per Response Evaluation Criteria in Solid
Tumours [RECIST] v1.1).
1. Modified RECIST should be used for mesothelioma
2. Prostate Cancer Working Group 3 (PCWG3) criteria should be used for prostate
8. Adequate serology defined by the following laboratory results:
1. Negative test for Human Immunodeficiency Virus (HIV)
2. Patients with active or chronic hepatitis B (defined as having a positive
hepatitis B surface antigen [HBsAg] test at pre-screening) are not eligible.
- Patients with past/resolved Hepatitis B virus (HBV) infection (defined as
having a negative HBsAg test and a positive antibody to hepatitis B core
antigen (anti-HBc) antibody test) are eligible, if HBV deoxyribonucleic acid
(DNA) test is negative.
- HBV DNA must be obtained in patients with positive hepatitis B core antibody
prior start of study treatment.
3. Patients with active hepatitis C are not eligible. Patients positive for
Hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction
(PCR) is negative for HCV ribonucleic acid (RNA).
1. Absolute neutrophil count ≥ 1.0 x 109 cell/L without the support of granulocyte
colony stimulating factor (G-CSF).
2. Platelet count ≥ 100 x109 cell/L
3. Hemoglobin ≥ 80 g/L. Subjects may be transfused to reach this cut-off.
a. International normalization ratio (INR) ≤1.5 times the upper limit of normal (x
ULN) unless the subject is receiving anticoagulant.
i) Exception: for patients with hepatocellular carcinoma (HCC), the INR may be up to
2.2, as long as the Child-Pugh score is A6 maximum.
b. Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤
1.5 x ULN unless the subject is receiving anticoagulant therapy.
1. Serum alanine transaminase (ALT) / aspartate aminotransferase (AST) ≤ to 3 x ULN
i) Exception: ALT/AST considered related to liver metastasis ≤ to 5 x ULN ii)
Exception: for patients with HCC serum ALT/AST ≤ to 5 x ULN
2. Total bilirubin ≤1.5 x ULN i) Exception: in patients with Gilbert's syndrome who
must have a total bilirubin ≤2.5 x ULN ii) Exception: total bilirubin considered
related to liver metastasis ≤3 x ULN iii) Exception: for patients with HCC total
bilirubin ≤2.3 x ULN, as long as the Child-Pugh score is A6 maximum
3. Creatinine clearance by Cockcroft-Gault formula ≥ 40 ml/min
12. Adequate cardiovascular function, with documented left ventricular ejection fraction
(LVEF) ≥ 45%. This parameter must be documented within 12 weeks before registration
13. Adequate respiratory function with forced expiratory volume in 1 second (FEV1) ≥ 50%
predicted, forced vital capacity (FVC) ≥ than 50% predicted and diffusing capacity for
carbon monoxide (DLCO) ≥ than 50% predicted corrected. Patients with lung cancer or
mesothelioma and values slightly under these limits (but >30% of predicted) can be
enrolled after discussion and approval by the PI. These parameters must be documented
within 12 weeks before registration
14. At the time the patient receives the NMA chemotherapy regimen (D-7):
1. ≥14 days or 5 half-lives must have elapsed from any chemotherapeutic cytotoxic
drug, whichever is shorter.
2. ≥28 days must have elapsed from bevacizumab, aflibercept and other
3. ≥28 days or 5 half-lives (whichever is shorter) must have elapsed from a
non-cytotoxic drug including but not limited to trastuzumab, pertuzumab, and
other molecular targeted therapy (such as tyrosine kinase inhibitors, etc…) i)
Note: In case of probable tumor flare upon stopping of the non-cytotoxic drug,
the investigator may decide to shorten this delay, upon agreement of the
Principal Investigator (PI), in a case-by-case approach.
4. ≥21 days must have elapsed from the last antibody therapy that could affect an
anti-cancer immune response, including but not limited to anti-Cytotoxic
T-lymphocyte-associated protein 4 (CTLA4), anti-Programmed cell death protein 1
(PD-1), anti-Programmed death-ligand 1 (PD-L1), anti-Tumor Necrosis Factor
Receptor Superfamily, member 4 (OX-40), or anti-Lymphocyte-activation gene 3
(LAG3) antibody therapy or their combination
5. Exceptions: denosumab and biphosphonates are permitted (and will be administered
as standard of care [SOC]).
6. Exceptions: androgen-deprivation therapy (ADT) for prostate cancer and hormonal
therapy for breast cancer are permitted (and will be administered as SOC).
15. Patients' toxicities from previous therapies must have recovered to at least grade 1
according to National Cancer Institute Common Terminology Criteria for Adverse v5.0
(NCI CTCAE v5.0), except for toxicities described below, as long as they do not put at
risk the patient's condition and do not require systemic immunosuppressive steroids at
immunosuppressive doses, including but not limited to:
- Skin disorders
- Stable neuropathy
- Endocrinopathies requiring replacement treatment Note: For other medical
conditions, or for any other toxicity with a higher grade but controlled by
adequate treatment, prior discussion and agreement with the PI is mandatory.
Note: Patients may have undergone surgical procedures within the past 3 weeks, as long
as all toxicities have recovered to grade 1 or less.
16. For women of childbearing potential (WOCBP: sexually mature women who have not
undergone a hysterectomy and/or bilateral oophorectomy, have not been naturally
post-menopausal for at least 12 consecutive months or have a serum
follicle-stimulating hormone (FSH) < 40 milli-International Unit [mIU]/ml):
1. Agreement to follow instructions for method(s) of contraception for the couple,
from screening until month 6 post start of NMA chemotherapy of the study.
2. Negative pregnancy test (urine or serum) during screening
17. For men participating in the trial and their female partners: agreement to follow
instructions for method(s) of contraception for the couple from screening until month
6 post start of NMA chemotherapy of the study.
1. Patients with an active second malignancy, except for
1. non-melanoma skin cancer that has been apparently cured or successfully resected
2. carcinoma in situ as long as they have been adequately treated
3. Any malignancy that can be adequately managed expectantly without compromising
prognosis, and after PI agreement.
Patients who have a history of malignancy are not considered to have an active
malignancy if they have completed therapy since at least 2 years and are considered by
their treating investigator to be at ≤ 30% risk for relapse.
2. Patients with symptomatic and/or untreated brain metastases. Patients with
definitively-treated brain metastases will be considered for enrollment after
agreement with PI, as long as lesions are stable for ≥ 14 days prior to beginning the
chemotherapy, there are no new brain lesions, and the patient does not require ongoing
3. Patients with known peritoneal metastases who have a recent history of intermittent
bowel obstruction (even partial), unless such obstruction has been resolved. Agreement
with the PI is mandatory.
4. Patients with leptomeningeal carcinomatosis
5. History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any
6. History of recent myocardial infarction or unstable angina, either within six months
7. Documented Child-Pugh score of B or C for hepatocellular carcinoma patients with known
underlying liver dysfunction
8. Active severe systemic infections within four weeks prior to beginning of NMA
9. Patient requiring regular systemic immunosuppressive therapy (for example for organ
transplantation, chronic rheumatologic disease); all immunosuppressive medications
including but not limited to steroids, mycophenolate mofetil, azathioprine,
methotrexate, thalidomide, and anti-tumor necrosis factor-alpha (TNF-alpha) agents
must have been discontinued within the last two weeks prior to starting NMA
1. Note: Use of inhaled or topical steroids or corticosteroid use for radiographic
procedures is permitted
2. Note: The use of physiologic corticosteroid replacement therapy is permitted.
10. History of severe immediate hypersensitivity reaction to any of the agents used in
11. Women who are pregnant or breastfeeding because of the potentially dangerous effects
of the treatment on the fetus or infant.
12. Subjects for whom there are concerns that they will not reliably comply with the
requirements for contraception should not be enrolled into the study.
13. Any serious underlying medical condition that could interfere with study medication
and potential adverse events.
14. Any mental or other impairment that may compromise compliance with the requirements of
15. Patient participation in any other study currently receiving treatment. If the patient
is in the follow-up period, he/she may be enrolled, as far as the elapsed time since
the last previous treatment administration and the preparative regimen (NMA
chemotherapy) is respected according to Inclusion Criteria n°14.
16. Participation in a research project using radiation sources exceeding an effective
dose of 5 millisievert (mSv) with no direct benefit within the 12 last months.
1. Evaluation of the number of patients who successfully receive NeoTIL-ACT in combination with LDI (feasibility) (Time Frame - Evaluated for each patient at day 0):
Defined as: Planned NMA chemotherapy regimen Planned LDI At least partial NeoTIL infusion No minimum IL-2 requirement
2. Toxicity of NeoTIL-ACT in combination with LDI (Time Frame - Treatment limiting toxicity (TLT) period: from day starting NMA chemotherapy to day 30 post NeoTIL infusion):
Number of patients with adverse events as assessed by CTCAE version 5.0
3. Objective response rate (ORR; efficacy of NeoTIL-ACT in combination with LDI) (Time Frame - Up to 6 months):
Defined as best overall response (complete response or partial response) accross all assessment time points, according to RECIST 1.1, mRECIST for mesothelioma or PCWG3 for prostate cancer
1. Disease Control Rate (DCR) (Time Frame - 1, 3, 6, 9,12 months):
Achievement of complete response, partial response or stable disease
2. Objective response rate (ORR) (Time Frame - 1, 3, 6, 9, 12 months):
Best overall response
3. Progression free survival (PFS) (Time Frame - 5 years):
Time from enrollment until objective tumor progression or death
4. Overall survival (OS) (Time Frame - 5 years):
Time from enrollment until death from any cause
Adoptive transfer of ex vivo expanded Autologous Tumor-Infiltrating Lymphocytes enriched for tumor antigen specificity (NeoTIL)
Cyclophosphamide will be administered as an intravenous (IV) infusion for two days.
Fludarabine will be administered as an intravenous (IV) infusion for five days.
After TIL infusion, IL-2 (optional) will be started as a bolus administration every eight hours, for a maximum of eight doses.
Low-dose irradiation (1Gy) will be administered using tomotherapy to tumor lesions once before NeoTIL infusion.