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JOURNAL ONKOLOGIE – STUDIE

NeoTIL in Advanced Solid Tumors

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NCT-Nummer:
NCT04643574

Studienbeginn:
November 2020

Letztes Update:
25.11.2020

Wirkstoff:
Cyclophosphamide, Fludarabine, Interleukin-2

Indikation (Clinical Trials):
Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
Centre Hospitalier Universitaire Vaudois

Collaborator:
-

Studienleiter

George Coukos, MD, PhD
Principal Investigator
Centre Hospitalier Universitaire Vaudois

Kontakt

Studienlocations (1 von 1)

Studien-Informationen

Detailed Description:

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

tomotherapy.

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.

Ein-/Ausschlusskriterien

Inclusion Criteria:

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

cancer

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).

9. Hematology

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.

10. Coagulation

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.

11. Chemistry:

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

anti-angiogenic antibodies

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:

- Fatigue

- Alopecia

- 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.

Exclusion Criteria:

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

corticosteroid treatment.

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

origin)

6. History of recent myocardial infarction or unstable angina, either within six months

of enrolment

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

chemotherapy.

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

chemotherapy.

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

this study.

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

the study.

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.

Studien-Rationale

Primary outcome:

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

Secondary outcome:

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

Geprüfte Regime

  • NeoTIL:
    Adoptive transfer of ex vivo expanded Autologous Tumor-Infiltrating Lymphocytes enriched for tumor antigen specificity (NeoTIL)
  • Cyclophosphamide:
    Cyclophosphamide will be administered as an intravenous (IV) infusion for two days.
  • Fludarabine:
    Fludarabine will be administered as an intravenous (IV) infusion for five days.
  • Interleukin-2:
    After TIL infusion, IL-2 (optional) will be started as a bolus administration every eight hours, for a maximum of eight doses.
  • Radiotherapy:
    Low-dose irradiation (1Gy) will be administered using tomotherapy to tumor lesions once before NeoTIL infusion.

Quelle: ClinicalTrials.gov


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