Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery

Protocol: OSU-14264

Full Title

Phase III study evaluating palbociclib (PD-0332991), a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor in patients with hormone-receptor-positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy

Purpose

The PENELOPEB study is designed to demonstrate that in the background of standard

anti-hormonal therapy palbociclib provides superior invasive disease-free survival (iDFS)

compared to placebo in pre- and postmenopausal women with HR-positive/HER2-normal early

breast cancer at high risk of relapse after showing less than pathological complete response

to neoadjuvant taxane- containing chemotherapy. Considering the high risk of recurrence in

patients after neoadjuvant chemotherapy and a high CPS-EG score, palbociclib appears to be

an attractive option with a favourable safety profile for these patients.

Study Objective

About one third of patients with hormone-receptor (HR)-positive, HER2- normal breast cancer

and residual disease after neoadjuvant chemotherapy have a substantial risk of relapse. The

clinical-pathologic stage - estrogen/grade (CPS-EG)1 combining clinical stage before

neoadjuvant treatment, pathological stage after neoadjuvant treatment, grading and

estrogen-receptor status can be used to identify these high-risk patients. The CPS-EG score

was additionally validated in 2454 patients with HRpositive/ HER2-normal tumors from the

German neoadjuvant studies' metadatabase. Patients who had a score of 3 or higher or Score 2

and ypN+ disease show a 3-years iDFS of 77% despite adequate local therapy and adjuvant

endocrine treatment. Cyclin dependent kinases (CDK), a group of serine/threonine kinases,

play a key role in regulating cell cycle progression by interacting with specific cyclin

proteins in luminal-type tumors.2,3 PD-0332991 (palbociclib) is an oral, highly selective

inhibitor of CDK4/6 kinase activity that prevents cellular DNA synthesis by prohibiting

progression of the cell cycle from G1 to S phase through blocking retinoblastoma (Rb)

phosphorylation.4 Preclinical studies identified luminal ER subtype, elevated expression of

cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to

palbociclib.

Are you eligible?

Inclusion Criteria:

Based on protocol E version 10 dated 12 April 2016

Inclusion Criteria

1. Written informed consent prior to beginning specific protocol procedures, including

expected cooperation of the patients for the treatment and follow-up, must be

obtained and documented according to the local regulatory requirements.

2. Willingness and ability to provide archived formalin fixed paraffin embedded tissue

block or a partial block from surgery after neoadjuvant chemotherapy and from

core-biopsy before start of neoadjuvant chemotherapy, which will be used for

centralized retrospective confirmation of hormone- and HER2-status and to evaluate

correlation between genes, proteins, and mRNAs relevant to the endocrine and cell

cycle pathways and sensitivity/resistance to the investigational agents. In case of

bilateral breast cancer, tumor tissue of both sides needs to be assessable.

3. Histologically confirmed unilateral or bilateral primary invasive carcinoma of the

breast.

4. Residual invasive disease post-neoadjuvant either in the breast or as residual nodal

invasion.

5. Centrally confirmed hormone-receptor-positive (≥1% ER and/or PR positive stained

cells) and HER2-normal (IHC score 0-1 or FISH negative (in-situ hybridization (ISH)

ratio) <2.0 status) assessed preferably on tissue from post-neoadjuvant residual

invasive disease or core biopsy of the breast, or if no other tissue is available the

residual tumor of the lymphnode can be assessed.

In case of bilateral breast cancer hormonreceptor positivity and HER2-normal status

has to be centrally confirmed for both sides.

6. Centrally assessed Ki-67, pRB, and Cyclin D1 status assessed preferably on

post-neoadjuvant residual invasive disease of the breast, or if not possible, of

residual nodal invasion or core biopsy. In case of bilateral breast cancer, tumor

tissue of both sides needs to be assessable.

7. Patients must have received neoadjuvant chemotherapy of at least 16 weeks. This

period must include 6 weeks of a taxane -containing neoadjuvant therapy (Exception:

For patients with progressive disease that occurred after at least 6 weeks of

taxane-containing neoadjuvant treatment, a total treatment period of less than 16

weeks is also eligible).

8. Adequate surgical treatment including resection of all clinically evident disease and

ipsilateral axillary lymph node dissection. Histologically complete resection (R0) of

the invasive and ductal in situ tumor is required in case of breast conserving

surgery as the final treatment. No evidence of gross residual disease (R2) is

required after total mastectomy (R1 resection is acceptable). Axillary dissection is

not required in patients with a negative sentinel-node biopsy before (pN0, pN+(mic))

or after (ypN0, ypN+(mic) neoadjuvant chemotherapy.

9. Less than 16 weeks interval since the date of final surgery or less than 10 weeks

from completing radiotherapy (whichever occurs last) and date of randomization.

10. Completion of adjuvant radiotherapy according to standard guidelines (e.g. AGO Mamma,

NCCN) is strongly recommended. If radiotherapy is not performed the reason for this

needs to be documented in the eCRF.

11. No clinical evidence for locoregional or distant relapse during or after preoperative

chemotherapy. Local progression during chemotherapy is not an exclusion criterion.

12. A clinical-pathologic stage - estrogen/grade (CPS-EG) score of ≥3, or score 2 if

nodal status at surgery is ypN+, calculated using local estrogen receptor status and

grade assessed on either core biopsies taken before start of neoadjuvant treatment or

surgical specimen (see chapter 21.1).

13. Age at diagnosis at least 18 years.

14. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (see

Appendix 21.2).

15. Resolution of all acute toxic effects of prior anti cancer therapy or surgical

procedures to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not

considered a safety risk for the patient at investigator's discretion).

16. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast

cancer.

17. The patient must be accessible for scheduled visits, treatment and follow-up.

Patients registered on this trial must be treated at the participating center which

Exclusion Criteria:

Based on protocol E version 10 dated 12 April 2016

Inclusion Criteria

1. Written informed consent prior to beginning specific protocol procedures, including

expected cooperation of the patients for the treatment and follow-up, must be

obtained and documented according to the local regulatory requirements.

2. Willingness and ability to provide archived formalin fixed paraffin embedded tissue

block or a partial block from surgery after neoadjuvant chemotherapy and from

core-biopsy before start of neoadjuvant chemotherapy, which will be used for

centralized retrospective confirmation of hormone- and HER2-status and to evaluate

correlation between genes, proteins, and mRNAs relevant to the endocrine and cell

cycle pathways and sensitivity/resistance to the investigational agents. In case of

bilateral breast cancer, tumor tissue of both sides needs to be assessable.

3. Histologically confirmed unilateral or bilateral primary invasive carcinoma of the

breast.

4. Residual invasive disease post-neoadjuvant either in the breast or as residual nodal

invasion.

5. Centrally confirmed hormone-receptor-positive (≥1% ER and/or PR positive stained

cells) and HER2-normal (IHC score 0-1 or FISH negative (in-situ hybridization (ISH)

ratio) <2.0 status) assessed preferably on tissue from post-neoadjuvant residual

invasive disease or core biopsy of the breast, or if no other tissue is available the

residual tumor of the lymphnode can be assessed.

In case of bilateral breast cancer hormonreceptor positivity and HER2-normal status

has to be centrally confirmed for both sides.

6. Centrally assessed Ki-67, pRB, and Cyclin D1 status assessed preferably on

post-neoadjuvant residual invasive disease of the breast, or if not possible, of

residual nodal invasion or core biopsy. In case of bilateral breast cancer, tumor

tissue of both sides needs to be assessable.

7. Patients must have received neoadjuvant chemotherapy of at least 16 weeks. This

period must include 6 weeks of a taxane -containing neoadjuvant therapy (Exception:

For patients with progressive disease that occurred after at least 6 weeks of

taxane-containing neoadjuvant treatment, a total treatment period of less than 16

weeks is also eligible).

8. Adequate surgical treatment including resection of all clinically evident disease and

ipsilateral axillary lymph node dissection. Histologically complete resection (R0) of

the invasive and ductal in situ tumor is required in case of breast conserving

surgery as the final treatment. No evidence of gross residual disease (R2) is

required after total mastectomy (R1 resection is acceptable). Axillary dissection is

not required in patients with a negative sentinel-node biopsy before (pN0, pN+(mic))

or after (ypN0, ypN+(mic) neoadjuvant chemotherapy.

9. Less than 16 weeks interval since the date of final surgery or less than 10 weeks

from completing radiotherapy (whichever occurs last) and date of randomization.

10. Completion of adjuvant radiotherapy according to standard guidelines (e.g. AGO Mamma,

NCCN) is strongly recommended. If radiotherapy is not performed the reason for this

needs to be documented in the eCRF.

11. No clinical evidence for locoregional or distant relapse during or after preoperative

chemotherapy. Local progression during chemotherapy is not an exclusion criterion.

12. A clinical-pathologic stage - estrogen/grade (CPS-EG) score of ≥3, or score 2 if

nodal status at surgery is ypN+, calculated using local estrogen receptor status and

grade assessed on either core biopsies taken before start of neoadjuvant treatment or

surgical specimen (see chapter 21.1).

13. Age at diagnosis at least 18 years.

14. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (see

Appendix 21.2).

15. Resolution of all acute toxic effects of prior anti cancer therapy or surgical

procedures to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not

considered a safety risk for the patient at investigator's discretion).

16. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast

cancer.

17. The patient must be accessible for scheduled visits, treatment and follow-up.

Patients registered on this trial must be treated at the participating center which

Ovarian Cancer Gynecologic Cancers Breast Cancer