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A Pharmacokinetic and Randomized Trial of Neoadjuvant Treatment With Anastrozole Plus AZD0530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer

NCT01216176

Description:

The investigators propose to conduct a Phase I/randomized Phase II study design in order to test the tolerability and efficacy of AZD0530 when used together with anastrozole in therapy for ER+ and/or PR+, postmenopausal breast cancer. The Phase I pharmacokinetic (PK) cohort of the study (cohort A) in postmenopausal women with metastatic breast cancer 2008-2009 showed initial safety,tolerability and good bioavailability of both drugs and determined the doses for use in the ongoing Phase II trial. In the randomized Phase II cohort of the study (cohort B), postmenopausal women with newly diagnosed, previously untreated ER+, HER2 negative breast cancer that is at least 2 cm or more in diameter by clinical exam or radiology will be randomized to either neoadjuvant treatment with anastrozole plus placebo, or anastrozole in combination with AZD0530. The Phase II cohort will permit extended assays of tolerability, initial estimates of efficacy, and the investigation of molecular predictors of drug efficacy.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Pharmacokinetic and Randomized Trial of Neoadjuvant Treatment With Anastrozole Plus AZD0530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer
  • Official Title: A Phase I Pharmacokinetic and Randomized Phase II Trial of Neoadjuvant Treatment With Anastrozole Plus AZD0530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 20080325
  • SECONDARY ID: SCCC-2008002
  • NCT ID: NCT01216176

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
AnastrozolePhase 1 - Cohort A
AZD0530Phase 1 - Cohort A
PlaceboPhase 2 - Cohort B [Anastrozole + Placebo]

Purpose

The investigators propose to conduct a Phase I/randomized Phase II study design in order to test the tolerability and efficacy of AZD0530 when used together with anastrozole in therapy for ER+ and/or PR+, postmenopausal breast cancer. The Phase I pharmacokinetic (PK) cohort of the study (cohort A) in postmenopausal women with metastatic breast cancer 2008-2009 showed initial safety,tolerability and good bioavailability of both drugs and determined the doses for use in the ongoing Phase II trial. In the randomized Phase II cohort of the study (cohort B), postmenopausal women with newly diagnosed, previously untreated ER+, HER2 negative breast cancer that is at least 2 cm or more in diameter by clinical exam or radiology will be randomized to either neoadjuvant treatment with anastrozole plus placebo, or anastrozole in combination with AZD0530. The Phase II cohort will permit extended assays of tolerability, initial estimates of efficacy, and the investigation of molecular predictors of drug efficacy.

Trial Arms

NameTypeDescriptionInterventions
Phase 1 - Cohort AExperimentalDual treatment with 1 mg anastrozole orally once daily together with AZD0530 175 mg orally once daily, or as specified per protocol, until disease progression for treatment of metastatic breast cancer
  • Anastrozole
  • AZD0530
Phase 2 - Cohort B [Anastrozole + AZD0530]Active ComparatorDual treatment with 1 mg anastrozole orally once daily together with AZD0530 175 mg orally once daily, or as specified per protocol, until disease progression or 4-6 months of treatment completed.
  • Anastrozole
  • AZD0530
Phase 2 - Cohort B [Anastrozole + Placebo]Placebo ComparatorDual treatment with 1 mg anastrozole orally once daily together with Placebo orally once daily, or as specified per protocol, until disease progression or4-6 months of treatment completed.
  • Anastrozole
  • Placebo

Eligibility Criteria

        Inclusion Criteria - Phase 1 (Cohort A):

          -  Female patient ≥ 18 years

          -  Patient must be postmenopausal, verified by 1 of the following:

               -  Bilateral surgical oophorectomy

               -  No spontaneous menses > 1 year

               -  No menses for < 1 year with FSH and estradiol levels in postmenopausal range

          -  Postmenopausal women with primary invasive breast cancer, histologically confirmed by
             core needle (or incisional biopsy), whose tumors are estrogen (ER) and/or progesterone
             (PgR) positive. Estrogen- and/or progesterone-receptor positive disease based on 10%
             or more nuclear staining of the invasive component of the tumor

          -  Stage IV disease (as defined by the AJCC Staging Manual, 6th Edition, 2002); or
             locally relapsed, unresectable disease

          -  Measurable or evaluable disease according to RECIST criteria (see appendix VII)

          -  Both HER2-positive and HER2-negative disease (as defined by IHC or by fluorescence in
             situ hybridization [FISH]). HER2+ must have had prior treatment with trastuzumab
             and/or lapatinib.

          -  ECOG performance status 0-2 (see appendix VI)

          -  Patients are suitable candidates for treatment with anastrozole (patients may have had
             any prior endocrine therapy or prior chemotherapy for treatment of their disease,
             either as adjuvant therapy, or as treatment for advanced disease). There is no
             restriction on the number of prior regimens in the phase I cohort A.

          -  Patient is accessible and willing to comply with treatment and follow-up

          -  Patient is willing to provide written informed consent prior to the performance of any
             study-related procedures

          -  Required laboratory values

               -  Absolute neutrophil count ≥ to 1.5 x 10^9/L

               -  Hemoglobin ≥ to 9.0 g/dL

               -  Platelet count ≥ to 100 x 10^9/L

               -  Creatinine ≤ 1.5 mg/dL

               -  Total bilirubin ≤ 1.0 x upper limit of normal (ULN)

               -  Alkaline phosphatase and AST/ALT within protocol parameters. In determining
                  eligibility, the more abnormal of the two values (AST or ALT) should be used.

        Inclusion Criteria - Phase 2 (Cohort B):

          -  Female patient ≥ 18 years

          -  Patient must be postmenopausal, verified by 1 of the following:

               -  Bilateral surgical oophorectomy

               -  No spontaneous menses ≥ 1 year

               -  No menses for < 1 year with FSH and estradiol levels in postmenopausal range

          -  Postmenopausal women with primary invasive breast cancer, histologically confirmed by
             core needle (or incisional biopsy), whose tumors are estrogen (ER) and/or progesterone
             (PgR) positive. Estrogen- and/or progesterone-receptor positive disease based on 10%
             or more nuclear staining of the invasive component of the tumor. Patients may have
             bilateral or multifocal invasive breast cancers. The patient may have concurrent DCIS
             in either breast but the DCIS will not be measured as part of the study endpoints.

          -  Tumor size ≥ 2 cm

          -  Tumor measurable either by clinical examination, mammography, MRI, or ultrasound

          -  HER2-negative disease (as defined by fluorescence in situ hybridization [FISH] or by
             IHC)

          -  ECOG performance status 0-1 (see Appendix VI)

          -  Patient is accessible and willing to comply with treatment and follow-up

          -  Patient is willing to provide written informed consent prior to the performance of any
             study-related procedures

          -  Required laboratory values

               -  Absolute neutrophil count ≥ 1.5 x 10^9/L

               -  Hemoglobin ≥ 9.0 g/dL

               -  Platelet count ≥ 70 x 10^9/L

               -  Creatinine ≤ 1.5 mg/dL

          -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

          -  Alkaline phosphatase and AST/ALT ≤ 1.5 x upper limit of normal (ULN)

        Exclusion Criteria - Phase 1 (Cohort A):

          -  Concurrent therapy with any other non-protocol anti-cancer therapy

               -  Any agent with estrogenic or putatively estrogenic properties, including herbal
                  preparations, must be stopped at least one week prior to registration.

               -  Ongoing, chronic administration of bisphosphonate therapy is allowed so long as
                  such treatment was ongoing at the time of study entry.

          -  Current therapy with hormone replacement therapy, or any hormonal agent such as
             raloxifene, tamoxifen, or other selective estrogen receptor modulators (agents must be
             stopped prior to randomization)

          -  Presence of neuropathy ≥ grade 2 (NCI-CTC version 3.0) at baseline

          -  History of any other malignancy within the past 5 years, with the exception of
             non-melanoma skin cancer or carcinoma-in-situ of the cervix

          -  Clinically significant cardiovascular disease (e.g., hypertension [BP > 150/100],
             history of myocardial infarction or stroke within 6 months, unstable angina), New York
             Heart Association (NYHA) Grade II or greater congestive heart failure, or serious
             cardiac arrhythmia requiring medication

          -  Active, uncontrolled infection requiring parenteral antimicrobials

          -  A history of a severe hypersensitivity reaction to anastrozole, or AZD0530 or their
             excipients

          -  Evidence of bleeding diathesis or coagulopathy.

          -  Resting EKG with measurable QTc interval of >480msec at 2 or more time points within a
             24 hr period.

          -  Since AZD0530 is a substrate and inhibitor of CYP3A4, patients requiring medication
             with drugs listed in Appendix XI should be excluded from study.

          -  Any evidence of severe or uncontrolled systemic medical or psychiatric conditions
             (e.g. Severe hepatic impairment, interstitial lung disease [bilateral, diffuse,
             parenchymal lung disease]) or current unstable or uncompensated respiratory or cardiac
             conditions which make it undesirable for the patient to participate in the study or
             which could jeopardize compliance with the protocol

          -  Evidence of underlying pulmonary dysfunction as evidenced by oxygen saturation <90% by
             pulse oximetry, interstitial pulmonary infiltrates on high resolution CT scan prior to
             study entry and/or symptomatic pulmonary (pleural or parenchymal) metastasis.

        Exclusion Criteria - Phase 2 (Cohort B):

          -  Prior chemotherapy, endocrine therapy or radiotherapy for the presenting breast
             cancer. Prior incidence and treatment of contralateral invasive or non-invasive breast
             cancer is not an exclusion criterion.

          -  Inflammatory breast cancer, clinically defined as the presence of erythema or
             induration involving one-third or more of the breast, or pathologically defined as
             dermal lymphatic invasion

          -  Prior excisional biopsy or complete resection of the primary invasive tumor (prior
             sentinel node biopsy allowed)

          -  Prior ipsilateral radiation therapy for invasive or non-invasive breast cancer

          -  Distant metastasis is an exclusion criterion - Isolated ipsilateral supraclavicular
             node involvement and/or direct invasion of the primary tumor into skin is allowed

          -  Concurrent therapy with any other non-protocol anti-cancer therapy

          -  Any agent with estrogenic or putatively estrogenic properties, including herbal
             preparations, must be stopped at least one week prior to registration

          -  Current therapy with hormone replacement therapy, or any hormonal agent such as
             raloxifene, tamoxifen, or other selective estrogen receptor modulators (agents must be
             stopped for one week prior to randomization)

          -  Presence of neuropathy ≥ grade 2 (NCI-CTC AE version 3.0) at baseline

          -  History of any other malignancy within the past 5 years, with the exception of
             non-melanoma skin cancer or carcinoma-in-situ of the cervix

          -  Clinically significant cardiovascular disease (e.g. history of myocardial infarction
             or stroke within 6 months, unstable angina), New York Heart Association (NYHA) Grade
             II or greater congestive heart failure, or serious cardiac arrhythmia requiring
             medication

          -  Active, uncontrolled infection requiring parenteral antimicrobials

          -  A history of a severe hypersensitivity reaction to anastrozole, or AZD0530 or their
             excipients

          -  Evidence of bleeding diathesis or coagulopathy

          -  Resting EKG with measurable QTc interval of >480msec at 2 or more time points within a
             24 hr period.

          -  AZD0530 is a substrate and inhibitor of CYP3A4. Since concurrent administration of
             AZD0530 with other CYP3A4 substrates has been shown to be well tolerated, continuation
             or initiation of medically indicated drugs that are substrates of CYP3A4 is permitted
             at MD discretion. Drugs listed in Appendix XI that are known to strongly induce or
             inhibit CYP3A4 activity should be discontinued prior to study entry and should not be
             initiated during protocol treatment.

          -  Any evidence of severe or uncontrolled systemic psychiatric or medical conditions (eg.
             Severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal
             lung disease]) or current unstable or uncompensated respiratory or cardiac conditions
             which make it undesirable for the patient to participate in the study or which could
             jeopardize compliance with the protocol

          -  Evidence of underlying pulmonary dysfunction as evidenced by oxygen saturation <90% by
             pulse oximetry prior to study entry and/or symptomatic pulmonary (pleural or
             parenchymal) disease.

          -  Subjects unwilling or unable to undergo breast MRI as required by protocol will be
             excluded from study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I Cohort A: To determine if a well tolerated dose of AZD0530 can be used in combination with anastrozole for postmenopausal women with ER+/PR+ metastatic breast cancer
Time Frame:Cycle 1: Days 1 - 28
Safety Issue:
Description:Clinical response is defined as percentage change/reduction in tumor size calculated from bi-dimensional clinical tumor measurement at diagnosis and on completion of neoadjuvant treatment.

Secondary Outcome Measures

Measure:Phase I - Cohort A: To test the effects of giving AZD0530 and Anastrozole together on pharmacokinetics of both drugs
Time Frame:Cycle 1: 0 hrs, 6 hrs, 12 hrs, 24hrs, 48 hrs, 72 hrs, 7 days, 14 days, 21 days after first dose of AZD0530
Safety Issue:
Description:Blood draws at protocol-specified timepoints to determine pharmacokinetics of AZD0530 and Anastrozole.
Measure:Phase II - Cohort B: Evaluation of pathologic complete response (pCR)
Time Frame:At the end of neoadjuvant therapy and after definitive surgery
Safety Issue:
Description:Evaluation of tumor specimen in patients undergoing mastectomy or breast-conserving procedure to determine response (pCR)
Measure:Phase II - Cohort B: Clinical Benefit (complete (CR), or partial (PR) responses or stable disease (SD))
Time Frame:At the end of neoadjuvant therapy
Safety Issue:
Description:Based on physician measurement of tumor size and by MRI measurements of tumor volume at diagnosis and prior to surgery.
Measure:Phase II - Cohort B: Qualitative and Quantitative Toxicities
Time Frame:Baseline, 4-6 treatment cycles and up to 4-6 weeks after surgery or after therapy/withdrawal or until resolution of any toxicity
Safety Issue:
Description:Patients who have tumor removal breast surgery after neoadjuvant therapy will be assessed up to 2 months after surgery. In the event the tumor is not-operable, toxicity will evaluated by patient interview and examination for the last time 4-6 weeks after discontinuing therapy or when toxicity is resolved.
Measure:Phase II - Cohort B: To identify molecular/biologic correlates as indicators of treatment response
Time Frame:At the end of neoadjuvant therapy and after definitive surgery
Safety Issue:
Description:Evaluation of biomarkers including Ki67 and p27, EGFR, Her2, Src, Akt and MAPK Levels, localization and phosphorylation as assayed by immunohistochemistry. Other biomarkers may be considered pending initial IHC results.
Measure:Phase II cohort B: Evaluation of clinical response defined as percentage change/reduction in tumor size by comparison of serial MRI
Time Frame:Baseline , 10 weeks from study start date and pre-operative
Safety Issue:
Description:MRI will be used to compare tumor size prior to drug therapy , at 10 weeks after start of treatment and prior to surgery after completion of study medication

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Joyce Marie Slingerland

Trial Keywords

  • Breast Cancer
  • Postmenopausal
  • Metastatic Phase I ONLY
  • AZD0530
  • Anastrozole
  • Phase I for metastatic disease
  • Phase II for newly diagnosed breast cancer
  • Pharmacokinetic
  • PK
  • Hormone Receptor
  • Estrogen Receptor
  • Progesterone Receptor
  • ER+
  • PR+
  • HER negative
  • Aromatase Inhibitors

Last Updated

July 19, 2017