Primary Objective: To assess the safety profile (AEs, SAEs) on combined treatment with tamoxifen and testosterone.Secondary Objectives:• AR to ER ratio on baseline FES- and FDHT-PET imaging (assessed per lesion and per patient by quantitative…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety profile, defined as the number of AEs and SAEs that occur while on
tamoxifen and testosterone treatment.
Secondary outcome
• AR to ER ratio on baseline FES- and FDHT-PET imaging (assessed per lesion and
per patient by quantitative analysis using standardized uptake values (SUV))
and/or tumor tissue (assessed by percentage of ER and AR expression).
• Treatment response on 8 weeks FDG-PET/CT (assessed per lesion and per patient
by quantitative analysis using standardized uptake values (SUV).
• Relation between baseline imaging and tumor characteristics to treatment
response.
• Difference in adverse events between the two testosterone dosages.
Background summary
Male breast cancer (BC) is rare and usually shows favorable characteristics
with expression of the estrogen-, progesterone- and androgen receptor (ER, PR
and AR), but not the human epidermal growth factor-2 receptor (HER2). In ER+
BC, contrary to triple negative BC, the AR appears to function as tumor
suppressor. Recently, in preclinical ER+ BC models growth inhibition was shown
when an androgen agonist was combined with standard ER modulator tamoxifen.
Therefore, this could potentially be a rational treatment option for patients
with ER+ BC as well. However, earlier studies in female BC patients showed
considerable side effects due to virilization, and treatment with androgen
agonists was subsequently abandoned. No data exist in male BC patients, but it
is highly conceivable that virilization is not as concerning in male BC
patients and could potentially even be considered as beneficial. Recent data
suggest that the ratio of AR to ER in the tumor is relevant for response to AR
and ER targeting treatments. Assessment in tumor tissue however can only
reflect one part of one tumor lesion. Whole body ER and AR expression can be
visualized using 16α-[18F]fluoro-17βoestradiol (FES) positron emission
tomography (PET) and [18F]fluoro-dihydrotestosterone (FDHT) PET. These scans
potentially allow fine-tuning of combined treatment with an androgen agonist
and tamoxifen. Ultimately, this could lead to a new, additional combined
endocrine approach in the treatment of male BC patients. Particularly regarding
the expected favorable (side) effects of this combination in men, this could
contribute to improved quality of life in male BC patients.
Study objective
Primary Objective: To assess the safety profile (AEs, SAEs) on combined
treatment with tamoxifen and testosterone.
Secondary Objectives:
• AR to ER ratio on baseline FES- and FDHT-PET imaging (assessed per lesion and
per patient by quantitative analysis using standardized uptake values (SUV)
and/or tumor tissue (assessed by percentage of ER and AR expression).
• Treatment response on 8 weeks FDG-PET/CT.
• Relation between baseline imaging and tumor characteristics to treatment
response.
• Difference in adverse events between the two testosterone dosages.
• Increase in free testosterone levels, related to treatment response and
toxicity.
• Monitoring of blood hematocrite, related to testosterone treatment.
• CtDNA for ER mutation analysis and CTCs (for ER and AR expression) at
baseline, prior to cycle 2 and 3, related to response and FES- and FDHT PET
imaging.
Study design
This is a concise single arm, feasibility study, which will be executed in the
University Medical Center Groningen, The Netherlands. Male patients with
metastatic BC (n=6) are eligible for this study after at least 1 line of
conventional endocrine therapy.
Intervention
After the baseline imaging with FES- and FDHT-PET is completed, tamoxifen 20mg
1dd1 (standard dosage) plus testosterone (Androgel®) will be started. The first
3 patients will receive 25mg testosterone once daily (half the standard
starting dosage for male hypogonadism). If this is well tolerated after 3
weeks, the dosage will be increased to 50mg once daily. Out of precaution, the
safety profile of the 50mg dosage in the first 3 patients will be evaluated
after all 3 patients have received 50mg testosterone for 8 weeks, prior to
proceeding to the next 3 patients. Patients will be treated with tamoxifen and
testosterone until disease progression or unacceptable toxicity.
Study burden and risks
At baseline two additional visits for FES- and FDHT PET imaging are required.
FES- and FDHT PET imaging, with a standard 3 Mbq/kg injection dose, lead to an
additional radiation exposure of 4.6 and 3.6 mSv respectively. This is
comparable to a standard FDG PET for each scan. Further participation will be
embedded in standard care, meaning no additional drawing of blood, site visits
or physical examinations will be required in addition to those already required
for standard care. Tamoxifen is part of the standard treatment strategy in male
BC and is known to induce toxicity such as hot flashes and loss of libido.
Testosterone is known to induce virilization. Based on the well-known safety
profile of tamoxifen and testosterone separately in men, and the previous data
of combined tamoxifen and AR agonists in female BC patients, showing no
additional toxicity other than expected based on the separate compounds, no
unexpected toxicity of the combination is expected in male BC patients.
Furthermore, it is conceivable that the combined treatment is better tolerated
(and possibly more effective) than standard tamoxifen alone in men with BC.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
1. Male
2. A history of proven ER+ (>10% of cells), AR+ (>10% of cells), and HER2-
metastatic BC
3. Tumor progression after at least one line of conventional endocrine therapy
(tamoxifen, AI, fulvestrant, CDK4/6, ±LHRH analogue).
4. Age >= 18 years
5. Adequate hematological, renal and liver function as follows:
• Absolute neutrophil count > 1.5 x 109/L
• Platelet count >100 x 109/L
• White blood cell count >3 x 109/L
• AST and ALT <2.5 or <5.0 in case of liver metastases x upper limit of normal
(ULN)
• Creatinine clearance >50mL/min
• Prothrombin time, partial thromboplastin time and INR <1.5 x ULN
6. Written informed consent
Exclusion criteria
1. History of prostate, testicular or liver cancer
2. Patients already using testosterone supplements
3. Patients using medication with anti-androgenic effects (e.g. spironolactone)
4. Elevated PSA (>4µg/L) or severe urinary tract problems (as defined with a
Prostate Symptom Score >19). Patients with known BRCA mutation and PSA *3 µg/L
will be referred to the urologist for prostate cancer screening, and can
participate if they have no signs of prostate cancer.
5. Hematocrit >50%
6. Patients with uncontrolled hypertension, diabetes mellitus or other
significant cardiovascular morbidity.
7. Patients with recent history of coronary artery disease or trombo-embolic
events within 6 months prior to screening
8. Severe concurrent disease, infection, co morbid condition that, in the
judgment of the investigator would make the patient inappropriate for
enrollment
9. Visceral crisis and/or rapid progression necessitating chemotherapy
10. Previous allergic reaction to androgen agonists
11. Contra-indication for PET imaging
12. Tamoxifen or fulvestrant treatment <5 weeks prior to FES-PET.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-002170-72-NL |
| CCMO | NL79433.042.22 |
| Other | volgt |