PD 0332991 and Anastrozole for Stage 2 or 3 Estrogen Receptor Positive and HER2 Negative Breast Cancer
This phase II trial studies palbociclib isethionate together with anastrozole and to see how well they work in treating patients with estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) stage II or III breast cancer. Palbociclib isethionate may stop tumor growth by blocking an enzyme needed for cell division and growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole may fight breast cancer by lowering the amount of estrogen the body makes. Giving palbociclib isethionate together with anastrozole may be an effective treatment for ER+ HER2- breast cancer.
Inclusion Criteria
- PIK3CA WILD TYPE AND MUTANT COHORT (closed 03/17/2016): Patients who were pre-registered to National Cancer Institute (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 NCI 9170 open, or after completion of enrollment to NCI 9170 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
- ENDOCRINE RESISTANT 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 Eligibility Inclusion Criteria for the PIK3CA Mutant Cohort (closed 03/17/2016)
- Clinical T2-T4c, any N, M0 invasive ER+ (Allred score of 6-8) and HER2 negative (0 or 1+ by immunohistochemistry [IHC] or fluorescent in situ hybridization [FISH] negative for amplification) breast cancer, by American Joint Committee on Cancer (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 ductal carcinoma in situ (DCIS) in the contralateral breast the patient are eligible
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- Life expectancy > 4 months
- If premenopausal, patient must be willing to comply with pregnancy requirements
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< upper normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/ and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit normal
- Creatinine =< upper normal institutional limits
- Able to understand and willing to sign an Institutional Review Board (IRB)-approved written informed consent document
- PIK3CA MUTANT COHORT (closed 03/17/2016): Tumor PIK3CA mutation present
- PIK3CA MUTANT COHORT (closed 03/17/2016): In premenopausal women, serum estradiol level in postmenopausal range =< 7 days prior to registration
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): 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
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): 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
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): ECOG performance status of 0, 1 or 2
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): Life expectancy > 4 months
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): If premenopausal, patient must be willing to comply with pregnancy requirements
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): Leukocytes >= 3,000/mcL
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): Absolute neutrophil count >= 1,500/mcL
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): Platelets >= 100,000/mcL
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): Total bilirubin =< upper normal institutional limits
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): AST(SGOT)/ and ALT(SGPT) =< 2.5 X institutional upper limit normal
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): Creatinine =< upper normal institutional limits
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): In premenopausal women, serum estradiol level in postmenopausal range =< 7 days prior to registration
- PIK3CA WILD TYPE COHORT (closed 03/17/2016): Able to understand and willing to sign an IRB-approved written informed consent document
- ENDOCRINE RESISTANT AND ADJUVANT COHORT: ECOG performance status of 0, 1 or 2
- ENDOCRINE RESISTANT AND ADJUVANT COHORT: Leukocytes >= 3,000/mcL
- ENDOCRINE RESISTANT AND ADJUVANT COHORT: Absolute neutrophil count >= 1,500/mcL
- ENDOCRINE RESISTANT AND ADJUVANT COHORT: Platelets >= 100,000/mcL
- ENDOCRINE RESISTANT AND ADJUVANT COHORT: Total bilirubin =< upper normal institutional limits
- ENDOCRINE RESISTANT AND ADJUVANT COHORT: AST(SGOT)/ and ALT(SGPT) =< 2.5 X institutional upper limit normal
- ENDOCRINE RESISTANT COHORT: 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 positive (pos), HER2 negative (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
- 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; 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 identification (ID)# can be assigned prior to shipment of the slides * 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
- ENDOCRINE RESISTANT COHORT: 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
- ENDOCRINE RESISTANT COHORT: Creatinine =< upper normal institutional limits
- ADJUVANT COHORT: 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
- ADJUVANT COHORT: If premenopausal, patient must be willing to comply with pregnancy requirements
- ADJUVANT COHORT: At least 4 weeks post completion of adjuvant chemotherapy and radiation therapy if indicated
- ADJUVANT COHORT: 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 initiation of adjuvant hormonal therapy.
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 cyclin-dependent kinase (Cdk) 4 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 human immunodeficiency virus (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 0332991or other agents used in the study
- Corrected QT (QTc) interval > 470 msec
- PIK3CA MUTANT AND WILD TYPE COHORT (closed 03/17/2016): Current use or anticipated need for food or drugs that are known strong cytochrome P450, family 3, subfamily A, polypeptide 4 (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 MUTANT AND WILD TYPE COHORT (closed 03/17/2016): Evidence of inflammatory cancer (clinical presentation of skin erythema involving more than one third of the breast or pathological evidence of dermal lymphatic involvement)
- ENDOCRINE RESISTANT COHORT: Prior treatment of this cancer including: * Surgery * Radiation therapy * Chemotherapy
Additional locations may be listed on ClinicalTrials.gov for NCT01723774.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To determine the rate of complete cell cycle arrest, defined by Ki67 =< 2.7%, following 2 weeks (cycle [C]1 day [D]15) of neoadjuvant palbociclib isethionate (PD 0332991) in combination with anastrozole in women with clinical stage II or III ER+/HER2- breast cancer without PIK3CA hot spot mutation (PIK3CA Wild Type Cohort).
II. To determine the rate of complete cell cycle arrest, defined by Ki67 =< 2.7%, following 2 weeks (C1D15) of neoadjuvant PD 0332991 in combination with anastrozole in women with clinical stage II or III ER+/HER2- endocrine-resistant breast cancer.
SECONDARY OBJECTIVES:
I. To determine the rate of complete cell cycle arrest, defined by Ki67 =< 2.7%, following 2 weeks (C1D15) of neoadjuvant PD 0332991 in combination with anastrozole in women with clinical stage II or III ER+/HER2- breast cancer with PIK3CA hot spot mutation.
II. To determine the rate of complete cell cycle arrest, defined by Ki67 =< 2.7%, following 2 weeks (C1D15) of neoadjuvant PD 0332991 in combination with anastrozole in women with clinical stage II or III ER+/HER2- endocrine-resistant breast cancer.
The following objectives will be assessed in PIK3CA mutant cohort and in PIK3CA wild type (WT) cohort combined or separately, and assessed separately in the endocrine resistant cohort.
III. To compare the rate of complete cell cycle arrest between C1D1 and C1D15.
IV. To assess Ki67 level on serially collected tumor specimens (baseline, C1D1, C1D15, and surgery).
V. To determine the rate of Preoperative Endocrine Prognostic Index (PEPI) 0 score with the study drug therapy.
VI. To determine the pathologic complete response (pCR) rate of study drug therapy.
VII. To assess the rate of clinical response and radiologic response in the neoadjuvant setting.
VIII. To determine the safety profile (on therapy and post 30 days of therapy completion) of the study therapy during 4 months of neoadjuvant therapy.
IX. To determine the safety profile of the study therapy during 2 years of adjuvant therapy.
X. To assess the long term outcomes of patients treated in this trial.
EXPLORATORY OBJECTIVES:
The following objectives will be assessed in PIK3CA mutant cohort and in PIK3CA WT cohort combined or separately, and assessed separately in the endocrine resistant cohort.
I. To assess tumor cell apoptosis index and senescence markers on serially collected tumor specimens.
II. To examine the pharmacodynamic effect of PD 0332991 in combination with anastrozole using serially collected tumor specimens (baseline, C1D1, 2 weeks on combination therapy, and surgery).
III. To explore molecular mechanisms which could affect tumor response to the combination PD 0332991 and anastrozole by tumor genomic, transcriptomic, and proteomic analysis.
IV. To document pathologic staging (tumor size, lymph node status) following neoadjuvant chemotherapy in patients who had tumor Ki67 > 10% on C1D15 and elected to receive neoadjuvant chemotherapy.
V. To explore circulating markers predictive of cancer recurrence.
VI. To assess the concentrations of anastrozole prior to and 90 minutes following anastrozole (without PD 0332991) on cycle 1 day 1 and to compare these concentrations to the concentrations of anastrozole prior to and 90 minutes following both anastrozole and PD 0332991 on cycle 1 day 15.
VII. To assess the concentration of PD 0332991 prior to and 90 minutes following both anastrozole and PD 0332991 on cycle 1 day 15.
OUTLINE:
Patients receive palbociclib isethionate orally (PO) daily on days 1-21 of a 28 day cycle. Patients also receive anastrozole PO daily on days 1-28 and goserelin acetate subcutaneously (SC) on day 1 (premenopausal patients only). Treatment continues for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo a 5th cycle comprising palbociclib isethionate PO daily and anastrozole PO daily for 10-12 days. On the day after completion of treatment cycle 5, patients undergo surgery.
After completion of study treatment, patients are followed up annually for 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorCynthia Xiuguang Ma
- Primary ID201301106
- Secondary IDsNCI-2012-02202
- ClinicalTrials.gov IDNCT01723774