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

NCT02067741 | Terminated Phase 2

• 2 other identifiers: SAKK 21/12SNCTP000000389
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 13

Brief 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.

Conditions

Metastatic Breast Adenocarcinoma; Breast Cancer

Keywords

Post-menopausal women; topical application CR1447; endocrine responsive-HER2neg breast cancer; triple negative-androgen receptor positive breast cancer

Outcome Measures

Primary Outcomes (1)

• Disease control at 24 weeks (DC24)

  DC24 is obtained in a patient who achieves complete response (CR) or partial response (PR) within the first 24 ± 2 weeks of treatment or stable disease (SD) for at least 24 weeks after treatment start according to the RECIST 1.1 criteria. For patients without CR or PR and no PD before 24 weeks: * If the tumor assessment at 24 ± 2 weeks is missing but a later assessment shows SD, the patient will be counted as obtaining DC24. * If the tumor assessment at 24 ± 2 weeks is missing and there are no further tumor assessments or the subsequent assessment shows PD, the patient will be counted as not obtaining DC24. Tumor assessments showing CR or PR have to be confirmed after 4 weeks.

  at 24 weeks

Secondary Outcomes (7)

• Adverse events

  30 days after treatment discontinuation and thereafter monthly until all adverse events related to the trial drug have resolved

• PK analysis of CR1447

  at baseline, 3 and 6 months of treatment

• Estradiol levels during treatment

  at baseline, 3 and 6 months of treatment

• mRNA expression signature of downstream target genes of the ERα, ERβ, PR, AR and angiogenesis in biopsies

  measured at baseline (day 0) and at treatment and within the third week of treatment

• Ki67 expression

  measured at baseline (day 0) and at treatment and within the third week of treatment

Study Arms (2)

Stratum A - HER2neg BC RD - CR1447

EXPERIMENTAL

Stratum A - patients with endocrine responsive-HER2neg BC

Drug: CR1447

Stratum B - ARpos B - CR1447

EXPERIMENTAL

Stratum B - patients with triple-negative and confirmed ARpos BC

Drug: CR1447

Interventions

CR1447 DRUG

400 mg, corresponding to two 4 g stick packs applications twice daily

Also known as: 4-OHT

Stratum A - HER2neg BC RD - CR1447; Stratum B - ARpos B - CR1447

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Swiss Cancer Institute: lead

Study Sites (13)

Kantonsspital Aarau

Aarau, CH-5001, Switzerland

Location

Kantonsspital Baden

Baden, CH-5404, Switzerland

Location

Universitätsspital Basel

Basel, CH-4031, Switzerland

Location

Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli

Bellinzona, CH-6500, Switzerland

Location

Oncocare / Klinik Engeried

Bern, 3012, Switzerland

Location

Inselspital Bern

Bern, CH-3010, Switzerland

Location

Kantonsspital Graubünden

Chur, CH-7000, Switzerland

Location

Kantonsspital Frauenfeld / Brustzentrum Thurgau

Frauenfeld, CH-8501, Switzerland

Location

Luzerner Kantonsspital

Lucerne, CH-6000, Switzerland

Location

Kantonsspital St. Gallen

Sankt Gallen, CH-9007, Switzerland

Location

Spital STS AG

Thun, CH-3600, Switzerland

Location

Kantonsspital Winterthur

Winterthur, CH-8401, Switzerland

Location

Onkozentrum - Klinik im Park

Zurich, CH-8002, Switzerland

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

4,17 beta-dihydroxy-4-androstene-3-one

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Marcus Vetter, MD

  Universitätsspital Basel

  STUDY CHAIR

• Beat Thürlimann, Prof

  Cantonal Hospital of St. Gallen

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 11, 2014
• First Posted: February 20, 2014
• Study Start: June 14, 2016
• Primary Completion: August 2, 2018
• Study Completion: October 24, 2022
• Last Updated: June 27, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

CH (13)