Clinical trial NCT01723774: PD 0332991 and Anastrozole for Stage 2 or 3 Estrogen Receptor Positive and HER2 Negative Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Breast Neoplasms
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2012-11-08
Enrollment: 84
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Pre-registration PIK3CA Mutant Inclusion

* 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
* Premenopausal, patient must be willing to comply with pregnancy requirements
* Adequate organ and marrow function

  * leukocytes ≥ 3,000/mcL
  * absolute neutrophil count ≥ 1,500/mcL
  * platelets ≥ 100,000/mcL
  * total bilirubin ≤ ULN
  * AST(SGOT)/ and ALT(SGPT) \< 2.5 X ULN
  * Creatinine ≤ ULN
* Able to understand and willing to sign an IRB-approved written informed consent document

Exclusion

* Prior treatment of this cancer including: surgery, radiation, chemotherapy, biotherapy, hormonal therapy, investigational agent prior to study entry
* Receiving any 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
* Evidence of inflammatory cancer
* 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 interval \>470 msec

Registration PIK3CA Mutant Inclusion The criteria below must be met in addition to the pre-registration criteria, except treatment with endocrine therapy for this cancer is allowed prior to registration

* PIK3CA mutant cohort: tumor PIK3CA mutation present
* Premenopausal women, serum estradiol level in postmenopausal range ≤ 7 days prior to registration

Exclusion Criteria below must be met in addition to the pre-registration criteria -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)

PIK3CA Wild Type Inclusion

* 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
* For the PIK3CA wild type cohort: tumor PIK3CA mutation absent. Note that if a patient did not have sufficient research tissue for PIK3CA sequencing at pre-registration or if PIK3CA sequencing result is delayed, she could be registered and enrolled on the PD991 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
* 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
* 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:

  * leukocytes ≥ 3,000/mcL
  * absolute neutrophil count ≥ 1,500/mcL
  * platelets ≥ 100,000/mcL
  * total bilirubin ≤ ULN
  * AST(SGOT)/ and ALT(SGPT) \< 2.5 X ULN
  * Creatinine ≤ ULN
* In premenopausal women, serum estradiol level in postmenopausal range ≤ 7 days prior to registration.
* Able to understand and willing to sign an IRB-approved written informed consent document

Exclusion

* 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
* Evidence of inflammatory cancer
* 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 interval \>470 msec
* 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)

Endocrine Resistant Inclusion

* Clinical T2-T4c at diagnosis or screening, any N, M0 invasive ER+ (Allred Score at least 3 or \> 1% ER positivity) and HER2 negative (0 or 1+ by IHC or FISH negative or equivocal) 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 breast cancer that is ER pos, HER2 neg or equivocal or DCIS in the contralateral breast are eligible; multi-focal diseases are not excluded. The dominant lesion will be followed per protocol
* Ki67 \> 10% by central testing at Washington University AMP laboratory from a tumor biopsy performed after at least 2 weeks on neoadjuvant endocrine therapy. If Ki67 is \> 10% by local testing, the Ki67 slide and H\&E slide need to be reviewed by the study pathologist to confirm eligibility (discuss with Study Chair). For patients external to Washington University, please contact the Washington University coordinator by email so that a screening ID# can be assigned prior to shipment of the slides
* Female ≥ 18 years of age
* ECOG performance status of 0, 1 or 2
* Pre- or post-menopausal women are eligible. If premenopausal, patient must be willing to comply with pregnancy requirements and agrees with GnRH agonist therapy for ovarian suppression during the study
* Adequate organ and marrow function:

  * Leukocytes ≥ 3,000/mcL
  * Absolute neutrophil count ≥ 1,500/mcL
  * Platelets ≥ 100,000/mcL
  * Total bilirubin ≤ ULN
  * AST(SGOT)/ and ALT(SGPT) \< 2.5 X ULN
  * Creatinine ≤ ULN
* Able to understand and willing to sign an IRB-approved written informed consent document

Exclusion

* Prior treatment of this cancer including: Surgery, Radiation, Chemotherapy
* Receiving any other investigational agents
* Prior therapy with 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
* 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 interval \>470 msec
* 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)

Adjuvant Inclusion

* Derived benefit from PD 0332991 in the neoadjuvant setting in this trial. This includes the 26 patients who achieved complete cell cycle arrest only after the addition of PD 0332991 (C1D1 Ki67 \>2.7% and C1D15 Ki67 ≤ 2.7%) from the main study (PIK3CA WT, mutant, or unknown cohorts) as well as any patients who have a Ki67 ≤ 10% on C1D15 biopsy in the endocrine resistant cohort
* ECOG performance status of 0, 1 or 2
* Premenopausal, patient must be willing to comply with pregnancy requirements laid out
* Adequate organ and marrow function

  * leukocytes ≥ 3,000/mcL
  * absolute neutrophil count ≥ 1,500/mcL
  * platelets ≥ 100,000/mcL
  * total bilirubin ≤ ULN
  * AST(SGOT)/ and ALT(SGPT) ≤ 2.5 X ULN
  * Creatinine ≤ ULN
* Underwent surgery of the breast and axilla for curative intent
* At least 4 weeks post completion of adjuvant chemotherapy and radiation therapy if indicated
* Patients who already started on adjuvant hormonal therapy are eligible under the following conditions:

  * For the 26 patients who enrolled in the initial cohorts and derived benefit from neoadjuvant PD 0332991 (C1D1 Ki67 \>2.7% and C1D15 Ki67 ≤ 2.7%), adjuvant PD 0332991 should be initiated as soon as possible if adjuvant hormonal therapy has been initiated and the patient has completed radiation if indicated
  * For patients who enrolled in the endocrine resistant cohort and derived benefit from neoadjuvant PD 0332991 (C1D15 Ki67 ≤ 10%), adjuvant PD 0332991 should be initiated within 6 months or sooner after initation of adjuvant hormonal therapy
* Able to understand and willing to sign an IRB-approved written informed consent document

Exclusion

* 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, ssychiatric illness/social situations that would limit compliance with study requirements
* Pregnant/nursing
* Unwilling to employ adequate contraception
* Known HIV-positive on combination antiretroviral therapy. -Known metastatic disease
* 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 interval \>470 msec
* 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)

Primary outcomes:
measure: Number of Participants With Complete Cell Cycle Arrest at Cycle 1 Day 15 (PIK3CA Wild Type Cohort Only)
timeFrame: At cycle 1 day 15 (2 weeks)
measure: Number of Participants With Complete Cell Cycle Arrest at Cycle 1 Day 15 (Endocrine Resistant Cohort Only)
timeFrame: At cycle 1 day 15 (2 weeks)
Secondary outcomes:
measure: Number of Participants With Complete Cell Cycle Arrest at Cycle 1 Day 15 ( PIK3CA Mutant Type Cohort Only)
timeFrame: At cycle 1 day 15 (2 weeks)
measure: Number of Participants With Complete Cell Cycle Arrest
timeFrame: Cycle 1 day 1 and cycle 1 day 15 (2 weeks)
measure: Clinical Response Rate
timeFrame: 16 weeks
measure: Radiologic Response Rate
timeFrame: At the end of cycle 4 prior to surgery (estimated to be 16 weeks)
measure: Safety of PD 0332991 in Combination in Anastrozole as Measured by Frequency and Grade of Related Adverse Events
timeFrame: From start of treatment through 30 days after completion of an estimated 4 months of neoadjuvant therapy
measure: Number of Participants With a PEPI-0 Score
timeFrame: At the time of surgery (estimated to be 5 months)
measure: Change in Ki67 Level of Tumor Specimens
timeFrame: Pre-treatment and cycle 1 day 15
measure: Change in Ki67 Level of Tumor Specimens
timeFrame: Cycle 1 day 15 and at time of surgery (approximately 2-4 weeks post completion of cycle 4 - each cycle is 28 days)
measure: Number of Participants With Pathologic Complete Response (pCR)
timeFrame: At the time of surgery (estimated to be 5 months)
measure: Safety Profile of Study Therapy During Adjuvant Therapy as Measured by Frequency and Grade of Adverse Event
timeFrame: From start of adjuvant therapy through 30 days after completion of adjuvant therapy (estimated to be 2 years)
measure: Overall Survival
timeFrame: 5 years
measure: Relapse-free Survival
timeFrame: 5 years
measure: Local Recurrence Rate
timeFrame: 5 years
measure: Regional Recurrence Rate
timeFrame: 5 years
measure: Distant Recurrence Rate
timeFrame: 5 years
measure: Rate of Second Primary Breast Cancer
timeFrame: 5 years
measure: Rate of Second Primary Cancer (Non-breast)
timeFrame: 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic - Scottsdale
state: Arizona
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Cynthia X Ma, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bagegni N, Thomas S, Liu N, Luo J, Hoog J, Northfelt DW, Goetz MP, Forero A, Bergqvist M, Karen J, Neumuller M, Suh EM, Guo Z, Vij K, Sanati S, Ellis M, Ma CX. Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. Breast Cancer Res. 2017 Nov 21;19(1):123. doi: 10.1186/s13058-017-0913-7.