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A Trial to Evaluate the Safety and Efficacy of CLDN6 CAR-T +/- CLDN6 RNA-LPX

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04503278
Recruitment Status : Recruiting
First Posted : August 7, 2020
Last Update Posted : January 5, 2023
Sponsor:
Information provided by (Responsible Party):
BioNTech SE ( BioNTech Cell & Gene Therapies GmbH )

Tracking Information
First Submitted Date  ICMJE July 28, 2020
First Posted Date  ICMJE August 7, 2020
Last Update Posted Date January 5, 2023
Actual Study Start Date  ICMJE September 16, 2020
Estimated Primary Completion Date August 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 4, 2020)
  • Occurrence of treatment-emergent adverse events (TEAEs) within a patient including ≥ Grade 3, serious, fatal TEAEs by relationship [ Time Frame: up to 25 months ]
  • Occurrence of dose reduction and discontinuation of investigational medicinal product (IMP) within a patient due to TEAEs [ Time Frame: up to 25 months ]
  • Occurrence of dose-limiting toxicity (DLT) within a patient during the DLT evaluation period [ Time Frame: Day 1 to day 28 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 15, 2022)
  • 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., TNF, IFN-γ, IL-2, soluble IL-2Rα, IP-10, IL-12, IFN-α, IL-6, soluble IL-6R).
  • 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 ]
  • 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 ]
  • Duration of response (DOR) defined as the time from first objective response (CR or PR per RECIST 1.1) to first occurrence of objective tumor progression (Progressive disease (PD) per RECIST 1.1/recurrence) or death from any cause, whichever occurs first [ Time Frame: up to 25 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 4, 2020)
  • Change from baseline in the levels of soluble immune factors [ Time Frame: Baseline up to 25 months ]
    Systemic effects in patients will be assessed (e.g., TNF, IFN-γ, IL-2, soluble IL-2Rα, IP-10, IL-12, IFN-α, IL-6, soluble IL-6R).
  • 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 ]
  • 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 ]
  • Duration of response (DOR) defined as the time from first objective response (CR or PR per RECIST 1.1) to first occurrence of objective tumor progression (Progressive disease (PD) per RECIST 1.1) or death from any cause, whichever occurs first [ Time Frame: up to 25 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Trial to Evaluate the Safety and Efficacy of CLDN6 CAR-T +/- CLDN6 RNA-LPX
Official Title  ICMJE Phase I/IIa, First-in-human (FIH), Open-label, Dose Escalation Trial With Expansion Cohorts to Evaluate Safety and Preliminary Efficacy of CLDN6 CAR-T With or Without CLDN6 RNA-LPX in Patients With CLDN6-positive Relapsed or Refractory Advanced Solid Tumors
Brief Summary This is a Phase I/IIa, FIH, open-label, multicenter, dose escalation trial with expansion cohorts to evaluate safety and preliminary efficacy of CLDN6 CAR-T/CLDN6 CAR-T(A) with or without CLDN6 RNA-LPX in patients with CLDN6-positive relapsed or refractory advanced solid tumors.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumor
Intervention  ICMJE
  • Biological: CLDN6 CAR-T/CLDN6 CAR-T(A)
    administered as an i.v. infusion.
  • Biological: CLDN6 RNA-LPX
    administered as an i.v. injection at protocol-specified intervals.
Study Arms  ICMJE
  • Experimental: Part 1 CLDN6 CAR-T/CLDN6 CAR-T(A)
    Dose escalation in lymphodepleted patients until the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D).
    Intervention: Biological: CLDN6 CAR-T/CLDN6 CAR-T(A)
  • Experimental: Part 2 Vaccine-modulated
    Dose escalation until the MTD and/or RP2D.
    Interventions:
    • Biological: CLDN6 CAR-T/CLDN6 CAR-T(A)
    • Biological: CLDN6 RNA-LPX
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 25, 2022)
96
Original Estimated Enrollment  ICMJE
 (submitted: August 4, 2020)
36
Estimated Study Completion Date  ICMJE September 2036
Estimated Primary Completion Date August 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria: Phase 1 of the trial

  • 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 (AFP) or human chorionic gonadotropin (hCG) [as applicable] if they have a pre-treatment sample that is 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), such as barrier method of birth control, e.g., either condom with spermicidal foam/gel/film/cream/suppository for men; and/or for females occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; an intrauterine device; and/or hormone-based contraception, with established use of oral, injected, or implanted hormonal methods of contraception. 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/CLDN6 CAR-T(A) 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: Phase 1 of the trial

  • Has received prior CAR-T therapy, except CLDN6 CAR-T/CLDN6 CAR-T(A) 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 (NCI) 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 (CT) or magnetic resonance imaging (MRI) 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/CLDN6 CAR-T(A),
    6. 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 (HIV).
  • 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/CLDN6 CAR-T(A) 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 CAR-T(A) + 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 (ECGs) 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: BioNTech clinical trials patient information +49 6131 9084 ext 0 patients@biontech.de
Listed Location Countries  ICMJE Germany,   Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04503278
Other Study ID Numbers  ICMJE BNT211-01
2019-004323-20 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party BioNTech SE ( BioNTech Cell & Gene Therapies GmbH )
Original Responsible Party Same as current
Current Study Sponsor  ICMJE BioNTech Cell & Gene Therapies GmbH
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: BioNTech Responsible Person BioNTech SE
PRS Account BioNTech SE
Verification Date January 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP