JOURNAL ONKOLOGIE – STUDIE

A Clinical Study of the Safety and Effectiveness of an Investigational Cell Therapy Given With and Without an Investigational RNA-based Vaccine in Patients With Organ Tumors

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT04503278

Studienbeginn:
September 2020

Letztes Update:
03.04.2024

Wirkstoff:
CLDN6 CAR-T, CLDN6 uRNA-LPX/CLDN6 modRNA-LPX

Indikation (Clinical Trials):
Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
BioNTech Cell & Gene Therapies GmbH

Collaborator:
-

Studienleiter

BioNTech Responsible Person
Study Director
BioNTech SE

Kontakt

BioNTech clinical trials patient information
Kontakt:
Phone: +49 6131 9084
E-Mail: patients@biontech.de» Kontaktdaten anzeigen

Studienlocations
(3 von 12)

Charité - Universitätsmedizin Berlin - Campus Benjamin Franklin
12200 Berlin
(Berlin)
GermanyRekrutierend» Google-Maps

Universitätsklinikum Erlangen - Hämatologie & Intrinsische Onkologie - Medizinische Klinik 5
91054 Erlangen
(Bayern)
GermanyRekrutierend» Google-Maps

Universitätsklinikum Hamburg Eppendorf - II Medizinische Klinik und Poliklinik
20246 Hamburg
(Hamburg)
GermanyRekrutierend» Google-Maps

Medizinische Hochschule Hannover - Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation
30625 Hannover
(Niedersachsen)
GermanyRekrutierend» Google-Maps

Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg
69120 Heidelberg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps

Universitätsklinikum Köln AÖR-Centrum für Integrierte Onkologie (CIO)-Studienzentrum der Klinik I für Innere Medizin (CTU Cologne)
50937 Köln
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps

Universitätsmedizin Mainz - III Medizinische Klinik und Poliklinik
55131 Mainz
(Rheinland-Pfalz)
GermanyRekrutierend» Google-Maps

Universitätsklinikum Regensburg - Klinik und Poliklinik für Innere Medizin III
93053 Regensburg
(Bayern)
GermanyRekrutierend» Google-Maps

Peter MacCallum Cancer Centre
3000 Melbourne
AustraliaRekrutierend» Google-Maps

He Nederlands Kanker Instituut (The Netherlands Cancer Institute) - Antoni van Leeuwenhoek Ziekenhuis (NKI-AVL)
1066 Amsterdam
NetherlandsRekrutierend» Google-Maps

Erasmus MC - Universitair Medisch Centrum - Medical oncology
3015 Rotterdam
NetherlandsRekrutierend» Google-Maps

Karolinska Comprehensive Cancer Center Cancerstudieenheten Huddinge Karolinska Universitetssjukhuset
14186 Stockholm
SwedenRekrutierend» Google-Maps

Alle anzeigen

Studien-Informationen

Detailed Description:

CLDN6 CAR-T is used as a general term to refer to CLDN6 CAR-T cells from the manual and

automated manufacturing processes.

The trial consists of two parts.

The trial began using a manual CLDN6 CAR-T production process.

Part 1 is a CLDN6 CAR-T dose escalation in lymphodepleted patients until the maximum

tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of CLDN6 CAR-T are defined.

Dose escalation with CLDN6 CAR-T cells from the automated manufacturing process follows an

accelerated titration design, as opposed to the classical 3+3 trial design used for the dose

escalation with CLDN6 CAR-T manufactured with the manual process.

In addition, an optional de-escalation dose level may be explored to further evaluate

clinical safety and efficacy of CLDN6 CAR-T manufactured with the automated process.

Part 2 is a vaccine-modulated dose escalation using a bifurcated design until the MTD and/or

RP2D of CLDN6 CAR-T + CLDN6 RNA-LPX are defined.

The trial started with a CLDN6 encoding uridine containing RNA formulated in lipoplexes

(CLDN6 uRNA-LPX). In order to optimize CAR-T cell persistence in patients, an alternative

RNA-LPX, CLDN6 modRNA-LPX, will be tested once the RP2D dose for CLDN6 CAR-T ± CLDN6 RNA-LPX

is identified.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Each patient enrolled in the trial must have CLDN6-positive tumor regardless of tumor

histology defined as ≥ 50% of tumor cells expressing ≥ 2+ CLDN6 protein using a

semi-quantitative immunohistochemistry (IHC) assay in a central laboratory for

specific detection of CLDN6 protein expression in formalin-fixed, paraffin-embedded

(FFPE) neoplastic tissues.

- Availability of a FFPE tumor tissue sample. FFPE can be from an archival tumor tissue

sample, and it should be from the most recent tumor tissue obtained. If this is not

available, patient must be biopsied for CLDN6 staining.

- Must have histological documentation of the original primary tumor via a pathology

report.

- Must have measurable disease per RECIST 1.1 (except for germ cell tumors, where

patients can be evaluated according to Cancer-Antigen (CA)-125, Alpha-fetoprotein or

human chorionic gonadotropin [as applicable] or ovarian cancer, where patients can be

evaluated according to CA-125. The pre-treatment sample must be at least twice the

upper limit of normal).

- Must have a histologically confirmed solid tumor that is metastatic or unresectable

and for which there is no available standard therapy likely to confer clinical

benefit, or patient who is not a candidate for such available therapy.

- Must be ≥ 18 years of age at the time the pre-screening informed consent is signed.

- Must sign an informed consent form (ICF) indicating that he or she understands the

purpose of and procedures required for the trial and are willing to participate in the

trial prior to any trial-related assessments or procedures.

- Must have an Eastern Cooperative Oncology Group performance status of 0 to 1.

- Must have adequate coagulation function at screening as defined in the protocol.

- Must have adequate hematologic function at screening as defined in the protocol.

- Must have adequate hepatic function at screening as defined in the protocol.

- Must have adequate renal function at screening as defined in the protocol.

- Must be able to attend trial visits as required by the protocol.

- Women of childbearing potential (WOCBP) must have a negative serum (beta-human

chorionic gonadotropin) test/value at screening. Patients who are post-menopausal or

permanently sterilized can be considered as not having reproductive potential.

- WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted

reproduction during the entire trial and thereafter.

- WOCBP and men that are sexually active with a WOCBP and have not had a vasectomy must

agree to use highly effective birth control method(s), as defined in the protocol.

True abstinence is an acceptable alternative to the use of contraception.

- Men must agree not to father a child or donate sperm, and WOCBP must agree not to

become pregnant during the trial and for at least 12 months after the CLDN6 CAR-T

infusion or CLDN6 RNA-LPX treatment.

For Part 2 only:

- Histologically or cytologically confirmed solid tumor fulfilling inclusion criteria

1-4 that is metastatic or unresectable, and for whom there is no available standard

therapy likely to confer clinical benefit, or patient who is not a candidate for such

available therapy.

Exclusion Criteria:

- Has received prior CAR-T therapy, except CLDN6 CAR-T therapy.

- Has received vaccination with live virus vaccines within 6 weeks prior to the start of

lymphodepletion (LD).

- Receives concurrent systemic (oral or i.v.) steroid therapy > 10 mg prednisolone

daily, or its equivalent, for an underlying condition.

- Has side effects of any prior therapy or procedures for any medical condition not

recovered to national cancer institute common terminology criteria for adverse events

(CTCAE v.5) Grade ≤ 1.

Medical conditions:

- Current evidence of new or growing brain or spinal metastases during screening.

Patients with known brain or spinal metastases may be eligible if they:

1. Have had radiotherapy or another appropriate therapy for the brain or spinal

metastases,

2. Have no neurological symptoms,

3. Have stable brain or spinal disease on the computer tomography or magnetic

resonance imaging scan within 4 weeks before signing of the ICF,

4. Are not undergoing acute corticosteroid therapy or steroid taper. Chronic steroid

therapy is acceptable provided that the dose is stable for the last 14 days prior

to screening (≤ 10 mg prednisolone daily or equivalent),

5. Do not require steroid therapy within 7 days before the first dose of CLDN6

CAR-T,

6. Do not have anticipated imminent fracture or cord compression due to spinal bone

metastases.

- Has history of epilepsy. Isolated seizures in the past or febrile seizures in

childhood are permitted; has a history of a cerebrovascular accident or transient

ischemic attack less than 6 months ago.

- Pericardial effusion requiring any drainage is excluded.

- Has an active autoimmune disease including but not limited to inflammatory bowel

disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or

multiple sclerosis. Has any active immunologic disorder requiring immunosuppression

with steroids or other immunosuppressive agents with the exception of patients with

isolated vitiligo, resolved childhood asthma or atopic dermatitis, controlled

hypoadrenalism or hypopituitarism, and euthyroid patients with a history of Grave's

disease. Patients with controlled hyperthyroidism must be negative for thyroglobulin,

thyroid peroxidase antibodies, and thyroid-stimulating immunoglobulin prior to trial

drug administration.

- Seropositivity for human immunodeficiency virus.

- Known history/positive serology for hepatitis B requiring active antiviral therapy

(unless immune due to vaccination or resolved natural infection or unless passive

immunization due to immunoglobulin therapy). Patients with positive serology must have

hepatitis B virus viral load below the limit of quantification.

- Active hepatitis C virus (HCV) infection; patients who have completed curative

antiviral treatment with HCV viral load below the limit of quantification are allowed.

- Has a known hypersensitivity to a component of CLDN6 CAR-T or CLDN6 RNA-LPX cancer

vaccine drug product, or another similar compound.

- Only for patients recruited for Part 2 with LD chemotherapy (CLDN6 CAR-T + CLDN6

RNA-LPX with LD chemotherapy): history of severe immediate hypersensitivity reaction

to LD chemotherapy consisting of cyclophosphamide or fludarabine.

- Has a history of another primary cancer within the 2 years prior to enrollment except

for the following: Non-melanoma skin cancer, cervical carcinoma in situ, superficial

bladder cancer, prostate cancer with currently undetectable prostate specific antigen,

or other non-metastatic carcinoma that has been in complete remission without

treatment for more than 2 years.

- Receipt of allogenic stem cell transplantation in the 5 years prior to enrollment into

the trial.

- Patients with acute or chronic graft versus host disease.

Other comorbidities:

- Has abnormal electrocardiograms that are clinically significant, such as QT

prolongation.

- In the opinion of the Investigator, has any concurrent conditions that could pose an

undue medical hazard or interfere with the interpretation of the trial results; these

conditions include, but are not limited to:

1. Ongoing or active infection requiring antibiotic/antiviral/antifungal therapy

2. Concurrent congestive heart failure (New York Heart Association Functional

Classification Class III or IV)

3. Concurrent unstable angina

4. Concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial

fibrillation)

5. Acute coronary syndrome within the previous 6 months

6. Significant pulmonary disease (shortness of breath at rest or on mild exertion)

for example due concurrent severe obstructive pulmonary disease.

- Has a cognitive, psychological or psychosocial impediment that would impair the

ability of the patient to receive therapy according to the protocol or adversely

affect the ability of the patient to comply with the informed consent process,

protocol, or protocol-required visits and procedures.

- Is pregnant or breastfeeding.

Studien-Rationale

Primary outcome:

1. Occurrence of treatment-emergent adverse events (TEAEs) including ≥ Grade 3, serious, fatal TEAEs by relationship (Time Frame - up to 25 months)

2. Occurrence of dose reduction and discontinuation of investigational medicinal product (IMP) due to TEAEs (Time Frame - up to 25 months)

3. Occurrence of dose-limiting toxicity (DLT) during the DLT evaluation period (Time Frame - Day 1 to day 28)

Secondary outcome:

1. Change from baseline in the levels and kinetics of soluble immune factors measured by cytokine multiplex assay (Time Frame - Baseline up to 25 months):
Systemic effects in patients will be assessed (e.g., tumor necrosis factor, interferon (IFN)-γ, interleukin (IL)-2, soluble IL-2Rα, interferon-gamma-induced- protein (IP)-10, IL-12, IFN-α, IL-6, soluble IL-6R).

2. Objective response rate (ORR) defined as the proportion of patients in whom a complete response (CR) or partial response (PR) (per response evaluation criteria in solid tumors [RECIST 1.1]) is observed as best overall response (Time Frame - up to 25 months)

3. Disease control rate (DCR) defined as the proportion of patients in whom a CR or PR or stable disease (SD) (per RECIST 1.1, SD assessed at least 6 weeks after the first dose) is observed as best overall response (Time Frame - up to 25 months)

4. Duration of response (DOR) defined as the time from first objective response (CR or PR per RECIST 1.1) to first occurrence of objective progressive disease (PD) per RECIST 1.1/recurrence or death from any cause, whichever occurs first (Time Frame - up to 25 months)

Studien-Arme

Experimental: Part 1 - CLDN6 CAR-T
Dose escalation in lymphodepleted patients until the MTD and/or RP2D.
Experimental: Part 2 Vaccine-modulated - CLDN6 uRNA-LPX/CLDN6 modRNA-LPX
Dose escalation until the MTD and/or RP2D.

Geprüfte Regime

CLDN6 CAR-T:
administered as an intravenous (i.v.) infusion.
CLDN6 uRNA-LPX/CLDN6 modRNA-LPX:
administered as an i.v. injection at protocol-specified intervals.

Quelle: ClinicalTrials.gov

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