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

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ClinicalTrials.gov Identifier: NCT02067741
Recruitment Status : Active, not recruiting
First Posted : February 20, 2014
Last Update Posted : September 26, 2018
Sponsor:
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research

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.


Condition or disease Intervention/treatment Phase
Metastatic Breast Adenocarcinoma Breast Cancer Drug: CR1447 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 29 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Stratified, Multicenter Phase II Trial of Transdermal CR1447 (4-OH-testosterone) in Endocrine Responsive-HER2 Negative and Triple Negative-androgen Receptor Positive Metastatic or Locally Advanced Breast Cancer
Actual Study Start Date : June 14, 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : June 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Stratum A - HER2neg BC RD - CR1447
Stratum A - patients with endocrine responsive-HER2neg BC
Drug: CR1447
400 mg, corresponding to two 4 g stick packs applications twice daily
Other Name: 4-OHT

Experimental: Stratum B - ARpos B - CR1447
Stratum B - patients with triple-negative and confirmed ARpos BC
Drug: CR1447
400 mg, corresponding to two 4 g stick packs applications twice daily
Other Name: 4-OHT




Primary Outcome Measures :
  1. Disease control at 24 weeks (DC24) [ Time Frame: at 24 weeks ]

    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.



Secondary Outcome Measures :
  1. Adverse events [ Time Frame: 30 days after treatment discontinuation and thereafter monthly until all adverse events related to the trial drug have resolved ]
  2. PK analysis of CR1447 [ Time Frame: at baseline, 3 and 6 months of treatment ]
  3. Estradiol levels during treatment [ Time Frame: at baseline, 3 and 6 months of treatment ]
  4. mRNA expression signature of downstream target genes of the ERα, ERβ, PR, AR and angiogenesis in biopsies [ Time Frame: measured at baseline (day 0) and at treatment and within the third week of treatment ]
  5. Ki67 expression [ Time Frame: measured at baseline (day 0) and at treatment and within the third week of treatment ]
  6. Disease control at 12 weeks (DC12) [ Time Frame: at 12 ± 1 weeks ]
  7. Change in tumor size at 12 weeks [ Time Frame: at 12 weeks ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02067741


Locations
Switzerland
Kantonsspital Aarau
Aarau, Switzerland, CH-5001
Kantonsspital Baden
Baden, Switzerland, CH-5404
Universitätsspital Basel
Basel, Switzerland, CH-4031
Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
Bellinzona, Switzerland, CH-6500
Oncocare / Klinik Engeried
Bern, Switzerland, 3012
Inselspital Bern
Bern, Switzerland, CH-3010
Kantonsspital Graubünden
Chur, Switzerland, CH-7000
Kantonsspital Frauenfeld / Brustzentrum Thurgau
Frauenfeld, Switzerland, CH-8501
Luzerner Kantonsspital
Luzern, Switzerland, CH-6000
Kantonsspital St. Gallen
St. Gallen, Switzerland, CH-9007
Spital STS AG
Thun, Switzerland, CH-3600
Kantonsspital Winterthur
Winterthur, Switzerland, CH-8401
Onkozentrum - Klinik im Park
Zurich, Switzerland, CH-8002
Sponsors and Collaborators
Swiss Group for Clinical Cancer Research
Investigators
Study Chair: Marcus Vetter, MD Universitätsspital Basel
Study Chair: Beat Thürlimann, Prof Cantonal Hospital of St. Gallen

Responsible Party: Swiss Group for Clinical Cancer Research
ClinicalTrials.gov Identifier: NCT02067741     History of Changes
Other Study ID Numbers: SAKK 21/12
SNCTP000000389 ( Other Identifier: SNCTP )
First Posted: February 20, 2014    Key Record Dates
Last Update Posted: September 26, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Swiss Group for Clinical Cancer Research:
Post-menopausal women
topical application CR1447
endocrine responsive-HER2neg breast cancer
triple negative-androgen receptor positive breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Adenocarcinoma
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs