An open-label, phase I/II multicenter clinical trial of NECVAX-NEO1 as add-on to first-line neoadjuvant anti-PD-1 monoclonal antibody therapy in patients with triple-negative breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

NEC Bio Therapeutics GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Nov 2024 → ongoing

Decision date (initial)

2024-08-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Therapy

To assess Safety and tolerability of NECVAX-NEO1, at the dose level of 10^7 CFU for Cohort 1 and 10^8 CFU for Cohort 2, in addition to programmed cell death protein 1 (PD-1) inhibitor therapy

Secondary objectives 5

1. Antitumor activity, using molecular response as quantified by circulating tumor DNA (ctDNA) assessment.
2. Clinical efficacy as determined by response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) and iRECIST and Residual cancer burden (RCB).
3. (Exploratory) Effect of NECVAX-NEO1 in addition to PD-1 inhibitor on immuno- and biomarkers in tumor tissue and blood samples compared to pre-treatment
4. (Exploratory) To further assess clinical efficacy and OS of treatment with NECVAX-NEO1 in addition to PD-1 inhibitor
5. (Exploratory) Overall survival (OS)

Conditions and MedDRA coding

Triple negative breast cancer (TNBC)

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut, State Medicines Control Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patients able to understand and follow instructions during the trial.
2. Patients able and willing to give written informed consent, signed and dated.
3. Female and male patients. Inclusion criteria to check only at Screening not needed to be checked again at Baseline
4. Patients aged at least 18 years old at the time of ICF signature. Inclusion criteria to check only at Screening not needed to be checked again at Baseline
5. cT2-4 N0 or any N-positive (stage II-III) triple-negative breast cancer patients diagnosed as candidates for first-line neoadjuvant anti-PD1 monoclonal antibody and chemotherapy epirubicin/cyclophosphamide and nab-paclitaxel therapy. Inclusion criteria to check only at Screening not needed to be checked again at Baseline
6. Patients with tumor accessible for biopsy and surgery. Inclusion criteria to check only at Screening not needed to be checked again at Baseline
7. Patients with adequate bone marrow function at Screening, confirmed at Baseline, including: a. ANC ≥ 1.5 × 10^9/L; patients with documented benign cyclical neutropenia are eligible if white blood cell count is ≥ 1.5 × 10^9/L, with ANC ≥ 1.0 × 10^9/L, leukocytes ≥ 4.0 × 10^9/L, and lymphocytes ≥ 0.6 × 10^9/L; b. platelets ≥ 100 × 10^9/L; patients with platelets ≥ 75 × 109/L (CTCAE v5.0 Grade 1) are eligible at Baseline; c. hemoglobin ≥ 9 g/dL (may have been transfused);
8. International Normalized Ratio (INR) < 1.5×Upper Limit of Normal (ULN); patients treated with vitamin K antagonist are eligible if INR < 3.
9. Patients with adequate hepatic function at Screening, confirmed at Baseline, defined by a. total bilirubin level ≤1.5×ULN; patients with documented Gilbert disease are allowed if total bilirubin ≤3×ULN; b. aspartate aminotransferase (AST) level ≤2.5×ULN, and alanine aminotransferase (ALT) level ≤2.5×ULN, or, for patients with documented metastatic disease to the liver, AST and ALT levels ≤5×ULN; patients with AST or ALT level >2.5xULN and <3xULN (CTCAE v5.0 Grade 1) are eligible at Baseline.
10. Patients with adequate renal function at Screening, confirmed at Baseline, defined by eGFR ≥ 30 mL/min using 2021 CKD-EPI creatinine equation.
11. Patients must be able to undergo MRI or CT scan for tumor follow-up.
12. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
13. Life expectancy of at least 12 months according to the Investigator’s judgement.

Exclusion criteria 24

1. Patients with a history of any disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, based on the Investigator’s judgement, provides a reasonable suspicion of a disease or condition that contraindicates the use of the IMP or that might affect the interpretation of the trial results or render the patient at high risk for treatment complications.
2. Patients with CTCAE v 5.0 not referred on the Inclusion Criteria #7, #8, #9 and #10 Grade 3 or higher at Screening or before Baseline not having resolved to Grade 1 at Baseline
3. Patients with an active infection requiring systemic therapy with antibiotics (at both Screening and Baseline).
4. Patients with a known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome or multi-drug resistant gram-negative bacteria.
5. Patients with CTCAE v 5.0 Grade 3 or higher not having resolved to Grade 1 within 6 weeks before Baseline.
6. Patients with any significant co-morbidity which, according to the Investigator’s judgement, makes patient compliance to trial conditions unlikely.
7. Patients with previous malignant disease (other than the tumor disease for this trial) within the last five (5) years (except adequately treated non-melanoma skin cancers and carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete remission without further recurrence was achieved at least two (2) years prior to Screening, and the patient is deemed to have been cured with no additional therapy required or anticipated to be required.
8. Patients who underwent prior organ transplantation, including allogeneic stem cell transplantation.
9. Patients with congenital or any other immunodeficiency syndromes, or any active autoimmune disease that might deteriorate when receiving an immunostimulatory agent, except for: a. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment, are eligible. b. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation), is acceptable.
10. Patients with a history of uncontrolled intercurrent illness, including but not limited to uncontrolled hypertension (high blood pressure defined as BPD>=140 mmHg or BPS >=90 mmHg despite of combination therapy with diuretic/CCB/ACE or ARB) etc. and uncontrolled diabetes (e.g., hemoglobin A1c ≥ 8%).
11. Patients with a known prior hypersensitivity to the IMP or any component in its formulations or any other drug scheduled or likely to be given during the trial, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3).
12. Patients with severe acute or chronic medical conditions, including: a. Immune colitis b. Inflammatory bowel disease c. History of severe vomiting or diarrhea not having resolved to Grade 1 at Baseline d. Immune pneumonitis e. Pulmonary fibrosis f. Psychiatric conditions including recent (within the last year) or active suicidal ideation or behavior. g. Laboratory abnormalities that may increase the risk associated with trial participation or trial treatment administration or may interfere with the interpretation of trial results and, in the judgement of the Investigator, would make the patient inappropriate for entry into this trial.
13. Patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at Screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody Screening test positive).
14. Women who are pregnant or breastfeeding, or women of childbearing potential not willing to use acceptable methods of birth control.
15. Patients with a known history of drug/substance abuse.
16. Patients who received any live vaccines within 30 days prior to trial treatment.
17. Patients participating in any other clinical trial within 30 days before Screening.
18. Patients receiving any other treatment that, in the opinion of the Investigator, might interfere with the trial.
19. Patients receiving treatment with other experimental medicinal products in any other clinical trial medication within 30 days before Screening.
20. Patients receiving chronic concurrent therapy within two (2) weeks before the trial treatment or expected therapy during the trial treatment period with: a. Corticosteroids (except systemic corticosteroids up to 10 mg prednisolone or equivalent daily dose). b. Immunosuppressive agents. c. Antibiotics. d. Any other anticancer therapy or concurrent anticancer treatment except the neoadjuvant chemotherapy / anti-PD1 checkpoint inhibitor standard of care background therapy as per study protocol.
21. Patients unable to understand the protocol requirements, instructions and trial-related restrictions, the nature, scope, and possible consequences of the trial
22. Patients who are unlikely to comply with the Protocol requirements, instructions and trial-related restrictions, e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of completing the trial.
23. Patients with legal incapacity or limited legal capacity.
24. Patients with any condition which results in an undue risk for the patient during the trial participation according to the Investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Reported adverse events (AEs) and serious adverse events (SAEs)
2. Changes from Baseline in laboratory parameters (hematology, biochemistry, coagulation, and urinalysis), physical examinations, vital signs, and electrocardiograms (ECGs) during the Treatment and Follow-up periods.

Secondary endpoints 11

1. Pathological complete response (pCR), defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0/Tis ypN0 in the current American Joint Committee on Cancer (AJCC) system)
2. Residual cancer burden (RCB) as a determinant of the extent of residual disease in post-surgery. Six variables are included in the formula. An RCB index value can also be calculated and involves the categorization into one of four RCB classes (RCB 0 or pCR, RCB I or near pCR, RCB II, RCB III)
3. Changes in ctDNA assessments compared to pre-treatment
4. Event-free survival (EFS), defined as the time from first dose of NECVAX-NEO1 to any of the following events: progression of disease that precludes surgery, local or distant recurrence, or death due to any cause up to the end of the safety follow-up at 24 months
5. Invasive disease-free survival (iDFS), defined as the time from first dose of NECVAX-NEO1 until local or distant recurrence or death due to any cause up to the end of the safety follow-up at 24 months
6. (Exploratory) Tumor tissue evaluations at Baseline, and at surgery (Week 12) compared to Screening, including effector T-cell infiltration, regulatory T-cells (Treg), Myeloid Derived Suppressor Cells (MDSC), PD-1, and mutational burden
7. (Exploratory) Correlation between ctDNA and clinical efficacy/OS endpoints
8. (Exploratory) Intestinal microbiome evaluation at Week 12, Week 24 and Week 36 (in case of optional prolongation) compared to Baseline
9. (Exploratory) Clinical efficacy and OS endpoints, using pre-treatment as a reference date for changes, where applicable. Treatment response will also be assessed based on changes in tumor burden
10. (Exploratory) Overall survival (OS), defined as the time from first NECVAX-NEO1 administration to death
11. (Exploratory) Clinical efficacy based on available RECIST 1.1 and iRECIST assessments: Objective response rate (ORR): proportion of patients having a best overall response (BOR) of complete response (CR) or partial response (PR) relative to assessment at the Screening visit

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

NEC Bio Therapeutics GmbH

Sponsor organisation

NEC Bio Therapeutics GmbH

Address

Landteilstrasse 24, Lindenhof Lindenhof

City

Mannheim

Postcode

68163

Country

Germany

Scientific contact point

Organisation

NEC Bio Therapeutics GmbH

Contact name

Heinz Lubenau

Public contact point

Organisation

NEC Bio Therapeutics GmbH

Contact name

Heinz Lubenau

Third parties 1

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications