Trial Title:
NEODOXy: Targeting Breast Cancer Stem Cells With Doxycycline
NCT ID:
NCT06452394
Condition:
Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Doxycycline
Conditions: Keywords:
early ER+/HER2- breast cancer
NEODOXy
Doxycycline
Human Epidermal Growth Factor Receptor 2 negative
Estrogen Receptor
Breast Cancer
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
A prospective, single arm, open label
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Doxycyclin
Description:
Belongs to the class of tetracyclines. It has bacteriostatic activity against a broad
range of gram-positive and gram-negative bacteria. Its mechanism of action lies in the
binding to the 30S ribosomal subunit
Arm group label:
NEOadjuvant DOXYcycline
Other name:
Doxyclin
Summary:
Despite modern surgical and medical treatments, breast cancer can re-occur and lead 20%
of patients to death. During the last 20 years, pre-clinical studies have shown that
treatment failures may be due to the presence of a sub-type of cancer cells, the cancer
stem cells, which are resistant to chemotherapy and radiotherapy. By chance, doxycycline,
an old, inexpensive and safe molecule seems to target effectively these cancer stem
cells. This study proposes to check for the clinical efficacy of doxycycline to target
the cancer stem cells and improve the response to neoadjuvant chemotherapy in ER+/HER2-
breast cancers.
Detailed description:
Patients with early stage ER+/HER2- breast cancer (BC) have a low pathologic complete
response (pCR) rate of less than 15%. Over the past 20 years, studies have identified a
subset of cancer cells with tumorigenic and stem-like properties, known as cancer stem
cells (CSCs), that are involved in tumour initiation, metastasis, relapse and resistance
to treatment. Cancer cells with stem-like properties are known to possess cellular
plasticity that not only enables self-renewal capacity, but also exhibits high
tumourigenic potential and resistance to oncological therapies such as chemotherapy
and/or radiotherapy.
CSCs can arise from normal adult breast stem cells through mutations or directly from
differentiated tumor cells. Tumour hypoxia has been shown to be one of the major factors
promoting and maintaining the stemness phenotype. The metabolism of CSCs in hypoxia
relies on a delicate balance between reduced energy requirements through reduced
proliferation and an altered balance between mitochondrial oxidative phosphorylation
("OXPHOS") and cytosolic glycolysis, while maintaining mitochondrial redox homeostasis to
control reactive oxygen species (ROS) levels. Any slight imbalance in mitochondrial redox
homeostasis in CSCs, leading to transient effects on ROS, may promote their
differentiation towards their non-stem tumour cell counterparts. Consequently, specific
drugs targeting mitochondrial metabolism, leading to increased ROS levels, may
destabilise CSCs.
This study proposes to check for the clinical efficacy of doxycycline to target the
cancer stem cells and improve the response to neoadjuvant chemotherapy in ER+/HER2-
breast cancers. The change in the stemness marker, ALDH1, assessed before and after
treatment and the effect of doxycycline on the pathological response will be studied.
The translational work will be to better define these stem cells and to grow organoid
cultures to study the effects of the different drugs in vitro. This study also aims to
address a number of translational research questions using a tumor sample obtained from
an additional core biopsy prior to treatment initiation and using a fresh tumor sample
from the surgical specimen in the case of residual tumor after neoadjuvant treatment:
- Quantify and characterise the effects of doxycycline on tumors
- Identify factors that facilitate or prevent the effects of doxycycline
- Estimate the effect of doxycycline compared to other CSC-targeting drugs
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Written informed consent according to Swiss law and ICH GCP E6(R2) regulations
before registration and prior to any trial specific procedures.
- Histologically confirmed ER+/HER2- primary invasive breast cancer, according to
ASCO/CAP Guideline1,2, defined as ER expression rate ≥ 1%.
- Patient candidate for curative surgery and with a tumor size of at least 2 cm and
nodal classification cN0-3 according to the 8th edition, January 2017 of the
anatomic TNM classification3.
- Patients with multiple synchronous ipsilateral tumors are allowed, as long as all
lesions are ER+/HER2-. Only one target lesion will be considered for ALDH1 primary
endpoint, and the target lesion has to be the largest lesion.
- Patients are planned for neoadjuvant chemotherapy according to the local standards.
- Patients accept standard curative surgery after neoadjuvant chemotherapy with 4
cycles of epirubicin and cyclophosphamide (EC) followed by 12 doses of weekly
paclitaxel (or nab-paclitaxel).
- Diagnostic tumor tissue is available for the mandatory central pathology
examinations; or an additional biopsy is planned in case of lack of remaining
material from the diagnostic biopsy, provided that the patient has consented to the
optional TR-project.
- Patients with a prior malignancy and treated with curative intention are eligible if
all treatment of that malignancy was completed at least 2 years before registration
in this trial and the patient has no evidence of disease at registration. Less than
2 years is acceptable for adequately treated cervical carcinoma in situ or localized
non-melanoma skin cancer.
- Male or female patients age ≥ 18 years.
- ECOG performance status 0-1.
- Adequate bone marrow function:
- neutrophil count ≥ 1.5 x 10^9/L,
- platelet count ≥ 100 x 10^9/L,
- hemoglobin ≥ 90 g/L.
- Adequate hepatic function:
- total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease max.
3.0 x ULN),
- AST and ALT ≤ 2.5 x ULN.
- Adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 50
mL/min/1.73 m2 (according to CKD-EPI formula).
- No known cardiac dysfunction contraindicating the planned neoadjuvant chemotherapy
with 4 cycles of EC followed by 12 doses of weekly paclitaxel.
- Women of childbearing potential must use highly effective, are not pregnant or
lactating and agree not to become pregnant during trial treatment and until 12
months after the last dose of investigational drug. A negative pregnancy test before
inclusion into the trial is required for all women of childbearing potential.
- Men agree not to donate sperm or to father a child during trial treatment and until
12 months after the last dose of investigational drug.
- Patient is able and willing to swallow trial drug as whole tablet.
Exclusion Criteria:
- Patients with 2 synchronous breast cancers or more of different subtypes (other than
ER+/HER2-).
- Metastatic patients.
- Patients having received or planned to undergo neoadjuvant endocrine therapy or
other investigational therapies before surgery.
- Concomitant or recent (within 30 days of registration) treatment with any other
experimental drug.
- Concomitant use of drugs contraindicated with doxycycline according to the
Swissmedic-approved product information or contraindicated according to the trial
protocol.
- Use of dietary supplements, natural therapies, phytotherapy or complementary and
integrative medicines (homeopathy, spagyric remedies, etc) without approval of the
sponsor.
- Concomitant use of other anti-cancer drugs or radiotherapy.
- Patients having received doxycycline or other antibiotics of the cyclin family
within 28 days before registration.
- Known hypersensitivity to cyclin group of substances, including tetracyclines,
doxycycline or to any component of the trial drug.
- Any other serious underlying medical, psychiatric, psychological, familial or
geographical condition, which in the judgment of the investigator may interfere with
the planned staging, treatment and follow-up, affect patient compliance or place the
patient at high risk from treatment-related complications.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Kantonsspital Graubünden
Address:
City:
Chur
Zip:
7000
Country:
Switzerland
Contact:
Last name:
Sophie Reinhart, M.D.
Phone:
+41 81 256 66 46
Email:
sophie.reinhart@ksgr.ch
Facility:
Name:
Kantonsspital St.Gallen
Address:
City:
St. Gallen
Zip:
9007
Country:
Switzerland
Contact:
Last name:
Jens Huober, M.D.
Phone:
+41 71 494 18 88
Email:
jens.huober@kssg.ch
Facility:
Name:
Clinique de Genolier
Address:
City:
Genolier
Zip:
1272
Country:
Switzerland
Contact:
Last name:
Magdalena Kohlik, M.D.
Phone:
+41 22 362 60 00
Email:
mkohlik@genolier.net
Facility:
Name:
Kantonsspital Winterthur
Address:
City:
Winterthur
Zip:
8401
Country:
Switzerland
Facility:
Name:
Tumor Zentrum Aarau
Address:
City:
Aarau
Zip:
5000
Country:
Switzerland
Facility:
Name:
Centre Hospitalier Universitaire Vaudois (CHUV)
Address:
City:
Lausanne
Zip:
CH-1011
Country:
Switzerland
Facility:
Name:
Tumor- und Brustzentrum Ostschweiz
Address:
City:
Saint Gallen
Zip:
9016
Country:
Switzerland
Start date:
January 1, 2025
Completion date:
December 31, 2028
Lead sponsor:
Agency:
Swiss Group for Clinical Cancer Research
Agency class:
Other
Source:
Swiss Group for Clinical Cancer Research
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06452394
