Clinical Trials /

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

NCT02067741

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CR1447 in Endocrine Responsive-HER2neg and TN-ARpos Breast Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: SAKK 21/12
  • SECONDARY ID: SNCTP000000389
  • NCT ID: NCT02067741

Conditions

  • Metastatic Breast Adenocarcinoma
  • Breast Cancer

Interventions

DrugSynonymsArms
CR14474-OHTStratum A - HER2neg BC RD - CR1447

Purpose

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.

Detailed Description

      Breast cancer is the most frequently diagnosed cancer and a heterogeneous disease and tumor
      categorization based on molecular characteristics beyond the currently used markers such as
      the estrogen receptor (ER), progesterone receptor (PR), and HER2, makes tumor categorization
      and treatment a demanding task.

      The treatment and prevention of relapses of breast cancer is mainly based on I) surgery of
      primary tumors, II) radiotherapy, III) chemotherapy, IV) endocrine therapy, and V) specific
      interventions. Although there have been advances in breast cancer therapy with three out of
      four women with breast cancer now being cured, one out of four patients will relapse or
      present with metastatic disease at the time of first diagnosis and hence be incurable and die
      of their disease.

      The endocrine responsive breast cancer is defined by the immunohistochemical detection of the
      ER (estrogen receptor) and/or the PR (progesterone receptor) on at least 1% of tumor cells on
      the tissue sample to a variable degree and offers the possibility of treatment using
      endocrine strategies in about 80% of patients. Endocrine responsive breast cancers may also
      express HER2. The triple negative breast cancer (TNBC) is defined by the lack of expression
      of ER, PR, and HER2. The analysis is made on the pathological tumor tissue sample. While for
      ER and PR, the threshold is less than 1% of tumor cells expressing both receptors, HER2
      negativity is defined as immunohistochemical scores of 0/1+ or tumors with scores of 0/1+ or
      2+ that are lacking HER2 gene amplification after in situ hybridization. Approximately 15% of
      all breast cancers are found to be triple-negative. However, due to the biologically more
      aggressive behavior of these tumors, the patient group suffering from this type of disease
      are overrepresented within the first five years after initial diagnosis.

      Recently, androgen receptor (AR) targeted therapies gained new interest due to the fact that
      the AR is the most abundantly expressed sex hormone receptor in breast cancer (approx. 70% of
      all breast tumors) and, importantly, in about 20% (range 10% to 50% depending on the
      respective reference) of triple-negative breast tumors. The threshold for ARpos breast cancer
      is that >0% of tumor cells expresses the AR. In addition, a significant association was found
      between AR expression and longer overall survival of breast cancer patients. Androgens can
      induce proliferative changes in breast cancer cell lines, and testosterone acts as a tumor
      promoter in several animal models of breast cancer.

      Endocrine responsive breast cancer Anti-estrogen therapy includes ovariectomy, to remove the
      primary source of female sex hormone in premenopausal women, and the application of
      luteinizing hormone releasing hormone (LHRH) agonists, to decrease the release of LH and
      prevent gonadal estrogen synthesis. These therapies induce a postmenopausal status. The
      hormonal treatment of choice for premenopausal women with ER positive metastatic breast
      tumors is the use of ER antagonists such as tamoxifen. Tamoxifen and aromatase inhibitors,
      preventing the final conversion of androgens to estrogens, are the main endocrine treatment
      options for postmenopausal women with metastatic breast cancer. The persisting estrogen
      levels in postmenopausal women are mainly due to aromatase activity in extragonadal sources
      such as breast tissue, skeletal muscle and adipose tissue. Thus, both ER blockade by
      tamoxifen and inhibition of estrogen synthesis inhibit the growth signal for breast cancer
      cells expressing ER.

      Aromatase, the key enzyme of estrogen production in women, is expressed in and around breast
      tumors, in ovaries, and in skeletal muscle and adipose tissue in postmenopausal women.
      Several aromatase inhibitors (AI) have been developed. The first generation aromatase
      inhibitors include testolactone and aminogluthetimide that were replaced by the more potent
      second generation inhibitors fadrazole and formestane (4-hydroxy-4-androstenedione, 4-OHA),
      and later on by the even more potent third generation inhibitors exemestane, letrozole and
      anastrozole. 4OHA and exemestane are steroidal AI and irreversibly block aromatase while the
      non-steroidal AI letrozole and anastrozole are reversible inhibitors. Importantly, there
      seems to exist no cross-resistance between the two aromatase inhibitor classes, and 4-OHA or
      exemestane may still show efficacy after relapse upon letrozole/anastrozole treatment.

      In summary, there is a great demand for novel and improved therapeutic strategies, especially
      to overcome resistance to chemotherapy or presently available endocrine therapy in
      postmenopausal women.

      While patients with ER and/or PR positive tumors can be treated with endocrine therapies and
      patients with HER2pos disease with treatments directed against HER2 such as trastuzumab,
      lapatinib, and trastuzumab/pertuzumab combination therapy, no endocrine or targeted anti-HER2
      directed therapy exists for patients suffering from triple negative disease.

      For these patients, only chemotherapy is a therapeutic option. Unfortunately, these tumors
      tend to be aggressive and quickly growing with a high relapse rate even after intensive
      adjuvant chemotherapy. Due to the absence of estrogen receptors, endocrine therapy based on
      anti-estrogen intervention strategies must fail.

      There are currently no suitable treatment options for patients with metastatic
      triple-negative breast tumors whose disease has failed to respond to chemotherapy. Thus,
      there is a great demand for novel and improved therapeutic strategies in this patient group
      and in all patients with acquired resistance to combat breast cancer.

      Testosterone was already used extensively between the 1930s and 1960s for breast cancer
      treatment, with anecdotal tumor responses (especially bone metastases) seen in up to 20% of
      treated women. Side effects such as hirsutism and aggressive behavior as signs of
      virilization in treated women and the evidence that testosterone may be easily be converted
      to estrogens in the body led to the discontinuation of its use.

      CR1447 (4-hydroxytestosterone [4-OHT]) is a steroidal small molecule which has two distinct
      properties, acting as a steroidal aromatase inhibitor (AI) and binding to the AR with high
      affinity (IC50 4.4 nM). In vitro studies indicate that human breast cancer cell lines are
      inhibited by CR1447 in their growth if they express the androgen receptor, while knock out of
      the AR abolishes this effect. A significant proportion of 4-OHT is converted to 4-OHA
      (4-hydroxyandrostenedione, formestane). In vivo 4-OHT and 4-OHA, form a redox system. 4-OHA
      is the 17-beta-oxidized isoform of CR1447. 4-OHA had previously been approved as an aromatase
      inhibitor for the treatment of BC via intramuscular (i.m.) injection (Formestane, Lentaron®)
      injection, but was discontinued by Novartis due to the development of oral aromatase
      inhibitors. Unlike testosterone, both compounds, 4-OHA and 4-OHT, are not converted to
      estrogens in vivo. Due to a high first pass effect after oral dosing, 4-OHA had to be
      administered parentally e.g. as an intramuscular injection. While this regimen was clinically
      effective, local side effects were a dose limiting issue.

      A clinical feasibility study of transdermally applied 4-OHA showed that significant amounts
      of 4-OHA are absorbed by the skin. Intramuscular and transdermally (twice daily) applied
      4-OHA achieved comparable the same plasma levels from day 3 on.
    

Trial Arms

NameTypeDescriptionInterventions
Stratum A - HER2neg BC RD - CR1447ExperimentalStratum A - patients with endocrine responsive-HER2neg BC
  • CR1447
Stratum B - ARpos B - CR1447ExperimentalStratum B - patients with triple-negative and confirmed ARpos BC
  • CR1447

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease control at 24 weeks (DC24)
Time Frame:at 24 weeks
Safety Issue:
Description: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

Measure:Adverse events
Time Frame:30 days after treatment discontinuation and thereafter monthly until all adverse events related to the trial drug have resolved
Safety Issue:
Description:
Measure:PK analysis of CR1447
Time Frame:at baseline, 3 and 6 months of treatment
Safety Issue:
Description:
Measure:Estradiol levels during treatment
Time Frame:at baseline, 3 and 6 months of treatment
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Ki67 expression
Time Frame:measured at baseline (day 0) and at treatment and within the third week of treatment
Safety Issue:
Description:
Measure:Disease control at 12 weeks (DC12)
Time Frame:at 12 ± 1 weeks
Safety Issue:
Description:
Measure:Change in tumor size at 12 weeks
Time Frame:at 12 weeks
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Swiss Group for Clinical Cancer Research

Trial Keywords

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

Last Updated

December 20, 2017