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Trial record 1 of 1 for:    NCT01723774
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PD 0332991 and Anastrozole for Stage 2 or 3 Estrogen Receptor Positive and HER2 Negative Breast Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2015 by Washington University School of Medicine
Information provided by (Responsible Party):
Washington University School of Medicine Identifier:
First received: November 6, 2012
Last updated: January 30, 2015
Last verified: January 2015

A Phase II study to investigate the potential utility of PD 0332991 in the treatment of early stage ER+ Human epidermal growth factor receptor 2 (HER2)- breast cancer, to investigate whether the combination of PD 0332991 and anastrozole is able to: 1) improve the pathologic complete response rate when compared to the historical control of single agent aromatase inhibitors, 2) result in fewer patients with on therapy Ki67>10% compared to historical control.

Condition Intervention Phase
Breast Neoplasms
Drug: PD0332991
Drug: Anastrozole
Drug: Goserelin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Neoadjuvant PD 0332991, a Cyclin-Dependent Kinase (Cdk) 4/6 Inhibitor, in Combination With Anastrozole in Women With Clinical Stage 2 or 3 Estrogen Receptor Positive and HER2 Negative Breast Cancer

Resource links provided by NLM:

Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Complete cell cycle arrest in women without PIK3CA hotspot mutation [ Time Frame: 2 weeks (C1D15) ] [ Designated as safety issue: No ]
    Complete cell cycle arrest is defined as Ki67 < 2.7% following 2 weeks of neoadjuvant PD 0332991

Secondary Outcome Measures:
  • PEPI 0 score [ Time Frame: 30 days following the last day of study treatment. ] [ Designated as safety issue: No ]
  • Clinical response and radiologic response [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

    Physical examination: Prior cycle 0 and at the end of each neoadjuvant treatment cycle cycles (that is, at the end of cycles 0-4) the longest axis and the perpendicular axis of the measurable lesion should be measured and recorded in metric notation by tape, ruler or caliper technique on the case report forms.

    Radiographic evaluation of tumor size: Mammogram and ultrasound imaging will be performed prior to cycle 0 and at the end of cycle 4 combination therapy for bidimensional measurement of the tumor.

    WHO criteria will be used to assess clinical response:

  • Ki67 level post 2 weeks of PD 332991 [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]

    Following the approach of Dowsett et al., the percent change in the Ki67 level from baseline will be determined on the log scale. A 95% t-confidence interval for the mean percent change in the Ki67 level from baseline will be constructed (if appropriate).

    Logistic regression modeling will be used to examine which baseline patient and/or tumor characteristics are associated with the likelihood of a Ki67 being at or below 10%.

  • concentration of PD 0332991 [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    Blood will be drawn for PKs on Cycle 1 Day 15. At each time point, blood will be drawn prior to drug administration and 90 minutes following drug administration. This will be done in the first 16 patients in the PIK3CA wild type cohort only.

  • Complete cell cycle arrest rate at C1D1 and C1D15 [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    Compare rate of complete cell cycle (defined as Ki67 < 2.7%) arrest between C1D1 and C1D15

  • Ki67 level of tumor specimens [ Time Frame: 5 months ] [ Designated as safety issue: No ]
    To assess Ki67 level on serially collected tumor specimens (baseline, C1D1, C1D15, and time of surgery)

  • Pathologic complete response (pCR) rate [ Time Frame: 5 months ] [ Designated as safety issue: No ]
  • concentration of anastrozole [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    Blood will be drawn for PKs prior to initiation of PD 0332991 but after patients have taken anastrozole alone or in combination with goserelin for at least 2 weeks (this could be done on Cycle 1 Day 1) and again on Cycle 1 Day 15. At each time point, blood will be drawn prior to drug administration and 90 minutes following drug administration. This will be done in the first 16 patients in the PIK3CA wild type cohort only.

  • Safety of PD 0332991 in combination in anastrozole [ Time Frame: 15 weeks ] [ Designated as safety issue: Yes ]
    The maximum grade for each type of adverse event will be recorded for each patient using the NCI-CTCAE v4.0 coding scheme, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

  • Complete cell cycle arrest in women with PIK3CA hotspot mutation [ Time Frame: 2 weeks (C1D15) ] [ Designated as safety issue: No ]
    Complete cell cycle arrest is defined as Ki67 < 2.7% following 2 weeks of neoadjuvant PD 0332991

Estimated Enrollment: 29
Study Start Date: June 2013
Estimated Study Completion Date: February 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PD0332991+ Anastrozole

PD0332991 125 mg orally Days 1-21 of each 28 day cycle.

Anastrozole 1 mg orally on Days 1-28 of each cycle.

If premenopausal Goserelin 3.6 mg SC on Day 1.

Treatment with PD 0332991 combined with anastrozole (and goserelin if premenopausal) is for a maximum of 4 28-day cycles prior to surgery.

Anastrozole is to be continued until the day of surgery. The last dose is on the day before surgery.

Drug: PD0332991 Drug: Anastrozole
Other Name: Arimidex®
Drug: Goserelin
Other Names:
  • Zoladex®
  • Decapeptide I


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Patients who were pre-registered to NCI 9170 trial (Phase II Trial of Neoadjuvant MK-2206 in Combination with either Anastrozole if Postmenopausal or Anastrozole and Goserelin if Premenopausal in Women with Clinical Stage 2 or 3 PIK3CA Mutant Estrogen Receptor Positive and HER2 Negative Invasive Breast Cancer), started anastrozole (or anastrozole plus goserelin if premenopausal) < 6 weeks, and were found negative for PIK3CA hotspot mutations are eligible to be screened for the wild type cohort. In institutions without NCI9170 open, or after completion of enrollment to NCI9170 in institutions where it is open, patients will be pre-registered to this trial and those with PIK3CA mutations will be enrolled to the PIK3CA mutant cohort. Pre-registration is not required for patients to be enrolled in the endocrine resistant cohort, as PIK3CA mutation status will not be assessed.

Pre-Registration Inclusion Criteria:

-Clinical T2-T4c, any N, M0 invasive ER+ (Allred Score of 6-8) and HER2 negative (0 or 1+ by IHC or FISH negative for amplification) breast cancer, by AJCC 7th edition clinical staging, with the goal being surgery to completely excise the tumor in the breast and the lymph node.

Note: Patients with invasive ER+ (Allred score of 6-8) HER2- breast cancer or DCIS in the contralateral breast the patient are eligible

  • Female ≥18 years of age.
  • ECOG performance status of 0, 1 or 2.
  • Life expectancy > 4 months.
  • If premenopausal, patient must be willing to comply with pregnancy requirements
  • Adequate organ and marrow function as defined below:

    • leukocytes ≥ 3,000/mcL
    • absolute neutrophil count ≥ 1,500/mcL
    • platelets ≥ 100,000/mcL
    • total bilirubin ≤ upper normal institutional limits
    • AST(SGOT)/ and ALT(SGPT) ≤ 2.5 X institutional upper limit normal
    • Creatinine ≤ upper normal institutional limits
  • Able to understand and willing to sign an IRB-approved written informed consent document.

Pre-Registration Exclusion Criteria:

  • Prior treatment of this cancer including:

    • Surgery
    • Radiation therapy
    • Chemotherapy
    • Biotherapy
    • Hormonal therapy
    • Investigational agent prior to study entry.
  • Receiving any other investigational agents.
  • Prior therapy with any Cdk4 inhibitor.
  • Any of the following in the previous 6 months:

    • myocardial infarction
    • severe/unstable angina
    • coronary/peripheral artery bypass graft
    • symptomatic congestive heart failure
    • cerebrovascular accident
    • transient ischemic attack
    • symptomatic pulmonary embolism.
  • Uncontrolled intercurrent illness including, but not limited to:

    • ongoing or active infection
    • symptomatic congestive heart failure
    • unstable angina pectoris
    • uncontrolled symptomatic cardiac arrhythmia,
    • psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant/nursing.
  • Unwilling to employ adequate contraception.
  • Known HIV-positive on combination antiretroviral therapy.

NOTE: HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with PD 0332991. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.

  • Evidence of inflammatory cancer (clinical presentation of skin erythema involving more than one third of the breast or pathological evidence of dermal lymphatic involvement)
  • Known metastatic disease.
  • Current use of anticoagulation therapy.
  • Previous excisional biopsy of the breast cancer or sentinel lymph node biopsy.
  • Any condition that impairs patient's ability to swallow PD 0332991 tablets (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption)
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to PD 0332991 or other agents used in the study.
  • Corrected QT (QTc) interval > 470 msec.

Registration Inclusion Criteria

The criteria below must be met for registration onto the study in addition to the pre-registration criteria, except treatment with endocrine therapy for this cancer is allowed prior to registration.

  • For the PIK3CA mutant cohort: tumor PIK3CA mutation present
  • For the PIK3CA wild type cohort: tumor PIK3CA mutation absent.

Note that if a patient did not have sufficient tissue for PIK3CA sequencing at pre-registration or if PIK3CA sequencing result is delayed, she could be registered and enrolled on this trial without assigning to a particular cohort at the time of enrollment. PIK3CA sequencing will be performed in the future on tumors collected at subsequent time points to assign the treatment cohort or when the PIK3CA sequencing data is available.

  • In premenopausal women, serum estradiol level in postmenopausal range ≤ 7 days prior to registration.
  • For the endocrine resistant cohort: Ki67 > 10% by central testing at Washington University AMP laboratory from a tumor biopsy performed after at least 2 weeks on neoadjuvant endocrine therapy.

    • Note that prior neoadjuvant endocrine therapy could include any endocrine therapy (including aromatase inhibitor, tamoxifen, fulvestrant) alone or in combination, or endocrine therapy in combination with any investigational agent that is not a Cdk 4/6 inhibitor.
    • Patients who had a Day 17 Ki67 > 10% from the NCI9170 trial are eligible for the endocrine resistant cohort.
    • Note that enrollment to the endocrine resistant cohort will depend on the funding availability. Please contact the study chair before enrolling patients to this cohort.

Registration Exclusion Criteria

The criteria below must be met for registration onto the study in addition to the pre-registration criteria.

  • Receiving medications (within the last 7 days prior to registration) that have the potential of prolonging the QT interval.
  • Current use or anticipated need for food or drugs that are known strong CYP3A4 inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, posaconazole, erythromycin, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone, diltiazem, and delavirdine) or inducers (i.e. dexamethasone, glucocorticoids, progesterone, rifampin, phenobarbital, St. John's wort).
  • Receiving medications that are proton pump inhibitors.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01723774

Contact: Cynthia Ma, M.D., Ph.D. 314-362-9383

United States, Alabama
University of Alabama Recruiting
Birmingham, Alabama, United States, 35233
Contact: Andres Forero, M.D.    205-934-7167   
United States, Arizona
Mayo Clinic - Scottsdale Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Donald W Northfelt, M.D.    480-301-8000   
Principal Investigator: Donald W Northfelt, M.D.         
United States, Minnesota
Mayo Clinic - Rochester Recruiting
Rochester, Minnesota, United States, 55905
Contact: Matthew Goetz, M.D.    507-284-2511   
Principal Investigator: Matthew Goetz, M.D.         
Sub-Investigator: Tina Hieken, M.D.         
United States, Missouri
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63122
Contact: Cynthia Ma, M.D., PH.D.    314-362-9383   
Principal Investigator: Cynthia Ma, M.D., Ph.D.         
Sub-Investigator: Julie Margenthaler, M.D.         
Sub-Investigator: Souzan Sanati, M.D.         
Sub-Investigator: Hussam Al-Kateb, M.Sc, Ph.D.         
United States, Texas
Baylor College of Medicine Not yet recruiting
Houston, Texas, United States, 77030
Contact: Matthew Ellis, M.B.   
Sponsors and Collaborators
Washington University School of Medicine
Principal Investigator: Cynthia Ma, M.D., Ph.D. Washington University School of Medicine
  More Information

Additional Information:
No publications provided

Responsible Party: Washington University School of Medicine Identifier: NCT01723774     History of Changes
Other Study ID Numbers: 201301106
Study First Received: November 6, 2012
Last Updated: January 30, 2015
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Additional relevant MeSH terms:
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses processed this record on March 03, 2015