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

• ClinicalTrials.gov Identifier: NCT04503278
• Recruitment Status: Recruiting
• First Posted: August 7, 2020
• Last Update Posted: January 5, 2023
• Sponsor: BioNTech Cell & Gene Therapies GmbH
• Information provided by (Responsible Party): BioNTech SE ( BioNTech Cell & Gene Therapies GmbH )

Tracking Information

• First Submitted Date: July 28, 2020
• First Posted Date: August 7, 2020
• Last Update Posted Date: January 5, 2023
• Actual Study Start Date: September 16, 2020
• Estimated Primary Completion Date: August 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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 (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: A Trial to Evaluate the Safety and Efficacy of CLDN6 CAR-T +/- CLDN6 RNA-LPX
• Official Title: 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: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumor

Intervention

• 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

• 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

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 25, 2022): 96
• Original Estimated Enrollment (submitted: August 4, 2020): 36
• Estimated Study Completion Date: September 2036
• Estimated Primary Completion Date: August 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: BioNTech clinical trials patient information; +49 6131 9084 ext 0; patients@biontech.de

• Listed Location Countries: Germany, Netherlands

Administrative Information

• NCT Number: NCT04503278
• Other Study ID Numbers: 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

• Plan to Share IPD: No

• Current Responsible Party: BioNTech SE ( BioNTech Cell & Gene Therapies GmbH )
• Original Responsible Party: Same as current
• Current Study Sponsor: BioNTech Cell & Gene Therapies GmbH
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: BioNTech Responsible Person; BioNTech SE

• PRS Account: BioNTech SE
• Verification Date: January 2023