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RNA-Immunotherapy of IVAC_W_bre1_uID and IVAC_M_uID (TNBC-MERIT)

Primary Purpose

Breast Cancer (Triple Negative Breast Cancer (TNBC))

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
IVAC_W_bre1_uID
IVAC_W_bre1_uID/IVAC_M_uID
Sponsored by
BioNTech SE
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer (Triple Negative Breast Cancer (TNBC)) focused on measuring TNBC, Breast Cancer, Warehouse, Mutanome, RNA, Vaccine

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Histologically confirmed invasive adenocarcinoma triple negative breast cancer (TNBC), pT1cN0M0 - anyTanyNM0 confirmed by physical examination or imaging

  • Triple negative breast cancer is defined as:

    • HER2 negative
    • IHC 0-1+
    • IHC 2+ and FISH negative (ratio < 2.0 or < 4 gene copies / cell, as per new ASCO guideline)
    • ER and PR negative confirmed< 1%
  • For patients with surgery of primary tumor followed by adjuvant chemotherapy, treatment with IVAC_W_bre1_uID will be initiated after completion of the adjuvant chemotherapy. The adjuvant chemotherapy should contain anthracyclines and taxanes - except for patients with contraindications for treatment with one or both substances.
  • For patients with neoadjuvant chemotherapy according to local standard followed by surgery of primary tumor, treatment with IVAC_W_bre1_uID will be initiated after the surgery. The neoadjuvant chemotherapy should contain anthracyclines and taxanes - except for patients with contraindications for treatment with one or both substances.
  • Patients with planned radiotherapy (as per local policy) are eligible and should be irradiated in parallel to the vaccination cycles
  • Patients after completion of standard of care therapy e. g. surgery and/or chemotherapy and/or radiotherapy (as per local policy) are eligible at the discretion of the investigator after no clinical sings of recurrence and/or metastasis, if the treatment with IVAC_W_bre1_uID starts within one year after completion of the radiotherapy.

  • Adequate organ function (hematopoietic, hepatic and renal function):

    • Hemoglobin ≥ 9 g/dl
    • ANC ≥ 1500/µl
    • Platelet count ≥ 100,000/mm³
    • ALT/AST <2 x ULN
    • Serum creatinine ≤ 1.5 ULN
  • Expression of at least two tumor-specific antigens of the WAREHOUSE_bre1 confirmed by RT-qPCR on FFPE tumor tissue for ARM1 and ARM3
  • Female patients, ≥ 18 years of age
  • Written informed consent
  • ECOG performance status (PS) 0-1
  • Recovered pre-existing toxicities < grade 2 according to NCI CTCAE 4.03, except alopecia
  • Negative pregnancy test (measured by β-HCG) for females of childbearing age
  • Not pregnant or nursing

Exclusion Criteria:

  • Patients with stage pT1a,bN0M0 and anyTanyNM1disease are excluded
  • Patients with recurrence of breast cancer prior to the start of study treatment with IVAC_W_bre1_uID
  • Any serious local infection (e. g. cellulitis, abscess) or systemic infection (e. g. pneumonia, septicemia, viral or fungal infection) which requires systemic treatment with antibiotics or corticoid therapy within two weeks prior to the first dose of study medication
  • Previous splenectomy
  • Concurrence of a second malignancy other than squamous or basal cell carcinoma or cervical carcinoma in situ within 5 years prior to the start of study treatment
  • Known hypersensitivity to the active substance or to any of the excipients
  • Prior solid organ transplantation or hematopoietic stem cell transplantation
  • Positive test for acute Hepatitis A, acute or chronic active Hepatitis B or C infection
  • Clinically relevant active autoimmune disease

  • Systemic immune suppression:

    • HIV disease
    • Use of chronic oral or systemic steroid medication (topical or inhalational steroids are permitted)
    • Other clinically relevant systemic immune suppression
  • Symptomatic congestive heart failure (NYHA 3 or 4)
  • Unstable angina pectoris
  • Adjuvant chemotherapy within 14 days before the first treatment of IVAC_W_bre1_uID
  • Other major surgeries within 28 days before the first treatment
  • Other investigational agents within 28 days or 5 half-lives depending on what gives the longer range before the first treatment
  • Ongoing participation in another clinical study (except of Follow-Up observation)
  • Fertile females who are unwilling to use a highly effective method of birth control (less than 1% per year, e.g. birth control pills, injections, patches, intrauterine device, or intrauterine hormone-releasing system) during study treatment and until End of Trial visit (EOT) at day 120
  • Presence of a severe concurrent illness or another condition (e. g. psychological, family, sociological, or geographical circumstances) that does not permit adequate Follow-Up and compliance with the protocol

Sites / Locations

  • Johannes Gutenberg University
  • National Center for Tumor Diseases (NCT)
  • Dr. Horst Schmidt-Kliniken Wiesbaden
  • Uppsala University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

ARM1 IVAC_W_bre1_uID

ARM2 IVAC_W_bre1_uID/IVAC_M_uID

ARM3 IVAC_W_bre1_uID + RBLTet.1

Arm Description

Patients enrolled in ARM1 will receive a treatment with four RNAs. This includes two to three variant RNAs selected from the WAREHOUSE plus p53 RNA. The selection process of RNAs from the warehouse is based on RT-PCR-based profiling of RNA extracted from patient tumor sample specimens, pre-defined cut-offs and algorithms to select the three relevant RNAs for a given patient.

Patients enrolled in ARM2 will optionally receive the WAREHOUSE treatment as described above followed by the personalized IVAC® MUTANOME immunotherapy. The mutation selection process constitutes a multi-step process including identification of somatic mutations by NGS, mutation confirmation and prioritization, selection, and on demand manufacturing.

Patients enrolled in ARM3 will receive a treatment with four RNAs. This includes two to three variant RNAs selected from the WAREHOUSE plus p53 RNA. The selection process of RNAs from the warehouse is based on RT-PCR-based profiling of RNA extracted from patient tumor sample specimens, pre-defined cut-offs and algorithms to select the three relevant RNAs for a given patient. RBLTet.1 RNA will be added to each RNA applied.

Outcomes

Primary Outcome Measures

Number of Adverse Events as a Measure of Safety and Tolerability of IVAC_W_bre1_uID
Assessment of AEs
Number of Adverse Events as a Measure of Safety and Tolerability of IVAC_W_bre1_uID plus IVAC_M_uID
Assessment of AEs, End of treatment visit is depending on treatment schedule

Secondary Outcome Measures

Change of induced T-cell responses for IVAC_W_bre_uID change from Visit 1 to V10
Vaccine induced T-cell responses assessed by immuno assays in peripheral blood
Change of induced T-cell responses for IVAC_M_uID change from Visit 18 to Follow-up Visit
Vaccine induced T-cell responses assessed by immuno assays in peripheral blood

Full Information

First Posted
November 21, 2014
Last Updated
July 18, 2023
Sponsor
BioNTech SE
Collaborators
Seventh Framework Programme
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1. Study Identification

Unique Protocol Identification Number
NCT02316457
Brief Title
RNA-Immunotherapy of IVAC_W_bre1_uID and IVAC_M_uID
Acronym
TNBC-MERIT
Official Title
First-in-human Clinical Study With RNA-Immunotherapy Combination of IVAC_W_bre1_uID and IVAC_M_uID for Individualized Tumor Therapy in Triple Negative Breast Cancer Patients
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
October 2016 (Actual)
Primary Completion Date
May 13, 2020 (Actual)
Study Completion Date
May 17, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
BioNTech SE
Collaborators
Seventh Framework Programme

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The Mutanome Engineered RNA Immuno-Therapy (MERIT) study introduces a novel concept for Individualized Cancer Immunotherapy (IVAC®) to treat each patient with the relevant and immunogenic RNA vaccines for a given patient's tumor. The TNBC-MERIT trial uses two complementary strategies, the WAREHOUSE and the IVAC® MUTANOME concept, resulting in two custom-made IVAC® investigational medicinal products (IMPs) (IVAC_W_bre1_uID and IVAC_M_uID) for each individual patient.
Detailed Description
The WAREHOUSE concept is based on RNA drug products shelved in a warehouse and targeting shared tumor-associated antigens (TAAs). The BioNTech Group (henceforward the "company") has identified a set of target antigens commonly expressed in TNBC. The selected breast cancer-associated antigens have been shown by immunogenicity testing to constitute suitable targets for immunotherapy and form the basis for the development of a novel RNA-based immunotherapy approach. The IVAC® MUTANOME concept is based on the identification of tumor-specific mutations by next-generation sequencing (NGS) and on-demand RNA manufacturing for use in single patients to target multiple neo-antigens derived from mutated epitopes. The novel therapeutic concept is supported by a series of research projects and high level publications that have led to a broad acceptance that mutation-specific T cells bear enormous potential to confer anti-tumoral activity in cancer patients. The TNBC-MERIT study will introduce the novel therapeutic concept for the individualized treatment of breast cancer that is based on (i) treatment with a patient-specific liposome complexed RNA tailored to the antigen-expression profile of any given patient's tumor (WAREHOUSE immunotherapy - IVAC_W_bre1_uID) and (ii) on treatment with de novo synthesized RNAs targeting up to 20 individual tumor mutations (IVAC® MUTANOME immunotherapy - IVAC_M_uID) following optional treatment with WAREHOUSE. The scientific rationale for the combination of the two IVAC® approaches is based on the assumption that immunotherapies that (1) acknowledge tumor heterogeneity on a single-patient level and (2) target the whole range of antigens selectively expressed on tumors ("cancer antigenome"), including immunogenic shared and unique antigens, bear the highest potential to constitute an effective treatment of tumors.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer (Triple Negative Breast Cancer (TNBC))
Keywords
TNBC, Breast Cancer, Warehouse, Mutanome, RNA, Vaccine

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
42 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ARM1 IVAC_W_bre1_uID
Arm Type
Experimental
Arm Description
Patients enrolled in ARM1 will receive a treatment with four RNAs. This includes two to three variant RNAs selected from the WAREHOUSE plus p53 RNA. The selection process of RNAs from the warehouse is based on RT-PCR-based profiling of RNA extracted from patient tumor sample specimens, pre-defined cut-offs and algorithms to select the three relevant RNAs for a given patient.
Arm Title
ARM2 IVAC_W_bre1_uID/IVAC_M_uID
Arm Type
Experimental
Arm Description
Patients enrolled in ARM2 will optionally receive the WAREHOUSE treatment as described above followed by the personalized IVAC® MUTANOME immunotherapy. The mutation selection process constitutes a multi-step process including identification of somatic mutations by NGS, mutation confirmation and prioritization, selection, and on demand manufacturing.
Arm Title
ARM3 IVAC_W_bre1_uID + RBLTet.1
Arm Type
Experimental
Arm Description
Patients enrolled in ARM3 will receive a treatment with four RNAs. This includes two to three variant RNAs selected from the WAREHOUSE plus p53 RNA. The selection process of RNAs from the warehouse is based on RT-PCR-based profiling of RNA extracted from patient tumor sample specimens, pre-defined cut-offs and algorithms to select the three relevant RNAs for a given patient. RBLTet.1 RNA will be added to each RNA applied.
Intervention Type
Biological
Intervention Name(s)
IVAC_W_bre1_uID
Intervention Description
vaccination
Intervention Type
Biological
Intervention Name(s)
IVAC_W_bre1_uID/IVAC_M_uID
Intervention Description
vaccination
Primary Outcome Measure Information:
Title
Number of Adverse Events as a Measure of Safety and Tolerability of IVAC_W_bre1_uID
Description
Assessment of AEs
Time Frame
day 120
Title
Number of Adverse Events as a Measure of Safety and Tolerability of IVAC_W_bre1_uID plus IVAC_M_uID
Description
Assessment of AEs, End of treatment visit is depending on treatment schedule
Time Frame
up to day 246
Secondary Outcome Measure Information:
Title
Change of induced T-cell responses for IVAC_W_bre_uID change from Visit 1 to V10
Description
Vaccine induced T-cell responses assessed by immuno assays in peripheral blood
Time Frame
up to 78 days
Title
Change of induced T-cell responses for IVAC_M_uID change from Visit 18 to Follow-up Visit
Description
Vaccine induced T-cell responses assessed by immuno assays in peripheral blood
Time Frame
up to 78 days

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically confirmed invasive adenocarcinoma triple negative breast cancer (TNBC), pT1cN0M0 - anyTanyNM0 confirmed by physical examination or imaging Triple negative breast cancer is defined as: HER2 negative IHC 0-1+ IHC 2+ and FISH negative (ratio < 2.0 or < 4 gene copies / cell, as per new ASCO guideline) ER and PR negative confirmed< 1% For patients with surgery of primary tumor followed by adjuvant chemotherapy, treatment with IVAC_W_bre1_uID will be initiated after completion of the adjuvant chemotherapy. The adjuvant chemotherapy should contain anthracyclines and taxanes - except for patients with contraindications for treatment with one or both substances. For patients with neoadjuvant chemotherapy according to local standard followed by surgery of primary tumor, treatment with IVAC_W_bre1_uID will be initiated after the surgery. The neoadjuvant chemotherapy should contain anthracyclines and taxanes - except for patients with contraindications for treatment with one or both substances. Patients with planned radiotherapy (as per local policy) are eligible and should be irradiated in parallel to the vaccination cycles Patients after completion of standard of care therapy e. g. surgery and/or chemotherapy and/or radiotherapy (as per local policy) are eligible at the discretion of the investigator after no clinical sings of recurrence and/or metastasis, if the treatment with IVAC_W_bre1_uID starts within one year after completion of the radiotherapy. Adequate organ function (hematopoietic, hepatic and renal function): Hemoglobin ≥ 9 g/dl ANC ≥ 1500/µl Platelet count ≥ 100,000/mm³ ALT/AST <2 x ULN Serum creatinine ≤ 1.5 ULN Expression of at least two tumor-specific antigens of the WAREHOUSE_bre1 confirmed by RT-qPCR on FFPE tumor tissue for ARM1 and ARM3 Female patients, ≥ 18 years of age Written informed consent ECOG performance status (PS) 0-1 Recovered pre-existing toxicities < grade 2 according to NCI CTCAE 4.03, except alopecia Negative pregnancy test (measured by β-HCG) for females of childbearing age Not pregnant or nursing Exclusion Criteria: Patients with stage pT1a,bN0M0 and anyTanyNM1disease are excluded Patients with recurrence of breast cancer prior to the start of study treatment with IVAC_W_bre1_uID Any serious local infection (e. g. cellulitis, abscess) or systemic infection (e. g. pneumonia, septicemia, viral or fungal infection) which requires systemic treatment with antibiotics or corticoid therapy within two weeks prior to the first dose of study medication Previous splenectomy Concurrence of a second malignancy other than squamous or basal cell carcinoma or cervical carcinoma in situ within 5 years prior to the start of study treatment Known hypersensitivity to the active substance or to any of the excipients Prior solid organ transplantation or hematopoietic stem cell transplantation Positive test for acute Hepatitis A, acute or chronic active Hepatitis B or C infection Clinically relevant active autoimmune disease Systemic immune suppression: HIV disease Use of chronic oral or systemic steroid medication (topical or inhalational steroids are permitted) Other clinically relevant systemic immune suppression Symptomatic congestive heart failure (NYHA 3 or 4) Unstable angina pectoris Adjuvant chemotherapy within 14 days before the first treatment of IVAC_W_bre1_uID Other major surgeries within 28 days before the first treatment Other investigational agents within 28 days or 5 half-lives depending on what gives the longer range before the first treatment Ongoing participation in another clinical study (except of Follow-Up observation) Fertile females who are unwilling to use a highly effective method of birth control (less than 1% per year, e.g. birth control pills, injections, patches, intrauterine device, or intrauterine hormone-releasing system) during study treatment and until End of Trial visit (EOT) at day 120 Presence of a severe concurrent illness or another condition (e. g. psychological, family, sociological, or geographical circumstances) that does not permit adequate Follow-Up and compliance with the protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
BioNTech Responsible Person
Organizational Affiliation
BioNTech SE
Official's Role
Study Director
Facility Information:
Facility Name
Johannes Gutenberg University
City
Mainz
State/Province
RLP
ZIP/Postal Code
55131
Country
Germany
Facility Name
National Center for Tumor Diseases (NCT)
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
Dr. Horst Schmidt-Kliniken Wiesbaden
City
Wiesbaden
ZIP/Postal Code
65199
Country
Germany
Facility Name
Uppsala University Hospital
City
Uppsala
ZIP/Postal Code
75185
Country
Sweden

12. IPD Sharing Statement

Links:
URL
http://www.biontech.de
Description
BioNTech SE

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RNA-Immunotherapy of IVAC_W_bre1_uID and IVAC_M_uID

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