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

NCT01216176 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 20080325SCCC-2008002
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 2

Brief Summary

The investigators propose to conduct a Phase I/randomized Phase II study design in order to test the tolerability and efficacy of AZD0530 (also called saracatinib) 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 (saracatinib). The Phase II cohort will permit extended assays of tolerability, initial estimates of efficacy, and the investigation of molecular predictors of drug efficacy.

Conditions

Breast Cancer

Keywords

Breast Cancer; Postmenopausal; Metastatic Phase I ONLY; AZD0530 (saracatinib); 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

Outcome Measures

Primary Outcomes (2)

• Phase I Cohort A: Maximum Tolerated AZD0530 Daily Dose Used in Combination With Daily Oral Anastrozole

  To identify a well tolerated dose of AZD0530 (saracatinib) that can be used together with anastrozole in the Phase 2 trial with tolerable toxicity and PK, subjects were followed as AEs recorded and evaluated and drug concentrations were in the therapeutic range.

  Cycle 1: Days 1 - 28

• Phase II - Cohort B: Compare Treatment Groups (AZD0530 + Anastrozole Versus Anastrozole With Placebo) With Respect to Clinical Response

  Clinical response is defined as percentage change in tumor size calculated from bi-dimensional clinical tumor measurement at diagnosis and on completion of neoadjuvant treatment. The mean reduction in tumor size ( +/-SD) will be derived form the change in largest tumor dimension ( RECIST) and by calculated tumor volume

  Baseline, cycle 6

Secondary Outcomes (7)

• Phase I - Cohort A: Plasma Concentrations of AZD0530 (Saracatinib) and Anastrozole

  0 hrs, 6 hrs, 12 hrs, 24hrs, 48 hrs, 72 hrs, 8 days, 15 days, 22 days after first dose of AZD0530

• Phase 1-Cohort A: Peak Concentration of Each Study Drug ( AZD0530 (Saracatinib) and Anastrozole)

  0 hrs, 6 hrs, 12 hrs, 24hrs, 48 hrs, 72 hrs, 7 days, 14 days, 21 days after first dose of AZD0530

• Phase II Cohort B: Change in Tumor Size by Comparison of Serial MRI

  Baseline to 10 weeks;and baseline to 6 months

• Phase II - Cohort B: Number of Participants With Pathologic Complete Response (pCR)

  At completion of 4-6 cycles of therapy or after disease progression

• Phase II - Cohort B: The Number of Participants Achieving Clinical Benefit Defined as Complete Response (CR), or Partial Response (PR) or Stable Disease (SD)

  At the end of neoadjuvant therapy

Study Arms (3)

Phase 1 - Cohort A

EXPERIMENTAL

Dual treatment with 1 mg anastrozole orally once daily together with AZD0530 (saracatinib) 175 mg orally once daily, or as specified per protocol, until disease progression for treatment of metastatic breast cancer

Drug: Anastrozole; Drug: AZD0530 (saracatinib)

Phase 2 - Cohort B [Anastrozole + AZD0530]

ACTIVE COMPARATOR

Dual treatment with 1 mg anastrozole orally once daily together with AZD0530 (saracatinib) 175 mg orally once daily, or as specified per protocol, until disease progression or 4-6 months of treatment completed.

Drug: Anastrozole; Drug: AZD0530 (saracatinib)

Phase 2 - Cohort B [Anastrozole + Placebo]

PLACEBO COMPARATOR

Dual 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.

Drug: Anastrozole; Drug: Placebo

Interventions

Anastrozole DRUG

Phase 1 - Cohort A; Phase 2 - Cohort B [Anastrozole + AZD0530]; Phase 2 - Cohort B [Anastrozole + Placebo]

AZD0530 (saracatinib) DRUG

Phase 1 - Cohort A; Phase 2 - Cohort B [Anastrozole + AZD0530]

Placebo DRUG

Phase 2 - Cohort B [Anastrozole + Placebo]

Eligibility Criteria

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

You may qualify if:

• 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. If a study subject under the age of 60 reports prior surgery in which the ovaries were removed and if the operative report cannot be obtained to confirm bilateral salpingo-oophorectomy, the subject will have serum estradiol, LH and FSH drawn to confirm menopausal status prior to study entry
• 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

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Joyce Marie Slingerland, MD: lead
• Stanford University: collaborator

Study Sites (2)

Stanford University

Palo Alto, California, 94304, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Anastrozole; saracatinib

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Joyce Slingerland MD PhD FCRP(C)
• Organization: University of Miami

jslingerland@med.miami.edu

305-243-7265

Study Officials

• Joyce Slingerland, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 5, 2010
• First Posted: October 7, 2010
• Study Start: October 21, 2008
• Primary Completion: February 7, 2018
• Study Completion: February 7, 2018
• Last Updated: January 8, 2025
• Results First Posted: July 31, 2019

Record last verified: 2024-12

Locations

US (2)