CR1447 in Endocrine Responsive-HER2neg and TN-ARpos Breast Cancer

• Status: Active, not recruiting
• Trial end date: 2027-06-01
• Target enrollment: 0
• Participant gender: Female

Summary

SAKK 21/12 is a stratified, multicenter Phase II first in-human trial with transdermal CR1447 (4-OH-testosterone) and is directed to patients with endocrine responsive-HER2neg and TN-ARpos metastatic or locally advanced breast cancer.

The trial will be conducted in Switzerland with max. 90 patients. CR1447 has a very good safety and tolerability profile and combines two mechanisms of action, interaction with the AR and the aromatase enzyme may have a higher activity than drugs with a single mechanism and might offer the possibility of non-chemotherapy based endocrine therapy to the limited treatment options in TN-ARpos BC. Transdermal application of CR1447 might have the advantage to continuously release of 4-OHT into the blood stream, thus omitting a first pass effect.

In Phase II the main objective is to assess activity and to determine the efficacy and tolerability of CR1447. Phase II will consist of two strata, into which patients will be stratified according to their hormonal receptor status: Stratum A for patients with endocrine responsive-HER2neg disease, regardless of their AR status and Stratum B for patients with triple-negative and determined ARpos disease. Patients with triple-negative disease tested negative for AR will be excluded from the trial.

In both strata patients will be treated with 400 mg of CR1447 until disease progression, patients' wish or physicians' decision to end treatment. Biopsies of one defined metastatic lesion in those patients who gave informed consent will be performed at baseline and within the third week of treatment with CR1447.

Measurement of AR expression, expression of downstream targets of ERα, ERβ, PR, AR, angiogenesis and other translational studies as described in this protocol should help confirming the hypothesis of an increased benefit of CR1447 due to its dual action, efficacy of topical application, tolerability and in deciding whether one should proceed to a large randomized trial.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Swiss Group for Clinical Cancer Research
• Treatments: Androgens

Criteria

Inclusion Criteria:

• Patient must give written informed consent before registration.

• Post-menopausal women

• Locally advanced or metastatic, histologically confirmed breast adenocarcinoma requiring therapy and not suitable for local treatment.

• Stratum A: endocrine responsive-HER2neg BC, specifically: ERpos (≥1%), PRpos (≥1%), HER2neg; or ERpos(≥1%), PRneg, HER2neg

• Stratum B: triple negative BC (ERneg (<1%), PRneg (<1%), HER2neg) and ARpos (>0%).

• Positive AR of the most recent formalin-fixed paraffin-embedded (FFPE) biopsy determined by central pathology (Stratum B only). Note: TNBC patients with only locally assessed ARpos (>0%) status are not allowed to enter the trial in Phase II.

• Stratum A: Patients had 1 line of prior endocrine treatment for advanced disease with a treatment duration of ≥6 months and no evidence of progression at 6 months. No previous chemotherapy for advanced disease is allowed.

• Stratum B: TN-ARpos BC patients had ≤2 lines of prior chemotherapy treatment for advanced disease.

• Patient is suitable for endocrine treatment.

• Presence of ≥1 measurable or evaluable lesion according to RECIST 1.1.

• Tumor assessment to be performed within 28 days before or on registration.

• Baseline PRO questionnaire (FACT-ES) has been completed (Phase II only).

• WHO performance status 0-1.

• Age ≥ 18 years.

• Adequate hematological values: hemoglobin ≥100 g/L, ANC ≥1.5x109/L, platelets ≥100x109/L.

• Adequate hepatic function: total bilirubin ≤1.5xULN, ALT ≤2.5xULN (except for liver metastases ≤5xULN).

• Adequate renal function: serum creatinine ≤1.5xULN.

Exclusion Criteria:

• Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer.

• Uncontrolled central nervous system (CNS) metastases, pulmonary carcinomatous lymphangiosis (i.e., >50% invasion), or liver metastases on >1/3 of the liver on ultrasound or computed tomography (CT).

• Unsuitable for endocrine therapy (e.g. due to rapidly progressing disease or impending 6.2.3complication).

• Indication for chemotherapy.

• Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, filling out PRO forms, or interfering with compliance for oral drug intake.

• Concurrent treatment with other experimental drugs in a clinical trial within 30 days prior to trial treatment start or other anti-cancer therapy within 14 days. Treatment with bisphosphonates/denosumab is allowed. Bisphosphonates/denosumab treatment had to be started at least 3 months before registration.

• Any serious underlying medical condition (at the judgment of the investigator) which could impair the ability of the patient to participate in the trial (e.g. active autoimmune disease, uncontrolled diabetes).

• Known hypersensitivity to trial drug(s) or hypersensitivity to any other component of the trial drugs.

• Local tumor relapse only that is amenable to surgical treatment.

• Previous treatment with formestane (4-OHA).

• Radiotherapy (RT) within 4 weeks prior to treatment start .

• Concurrent estrogen or progestin therapy in any formulation.

• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow-up.