Phase 1b Study of PD-0332991 in Combination With T-DM1(Trastuzumab-DM1)

NCT01976169

Last updated date
Study Location
UT Southwestern Medical Center
Dallas, Texas, 75390, United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Advanced Breast Cancer
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18-90 years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- 1.All subjects must be informed about the study and have signed a current IRB (Institutional Review Board) approved informed consent.

2. All subjects must have recurrent or metastatic HER2-positive breast cancer. diagnosed by biopsy.

3. All subjects must have previously received trastuzumab or other HER2 targeted therapies.

4.Tumor must be HER2-positive and RB-proficient. RB (Retinoblastoma protein)-proficiency is determined by tumor biopsy demonstrating RB normal and p16in4a low by immunohistochemistry. RB proficiency means that there is an intact RB pathway indicative of responsiveness to PD-0332991. RB staining is scored on an absent (no nuclear staining), weak (nuclear staining less than observed in endothelial cells and stromal cells surrounding the tumor), positive (nuclear staining at or above surrounding tissue) (0, 0.5, 1 respectively). P16ink4a is a routine clinical stain that is scored using absent, weak, positive, strong (0,1,2,3 respectively). Tumors will be scored using [p16]/[RB], where a score of less than 3 is required for inclusion. RB loss is expected to occur in less than 15% of cases.

5. Subjects must have a performance status of ≤ 2 on the ECOG (Eastern Cooperative Oncology Group)Performance scale.

6. Subjects must have bilirubin <1.5 mg/dl, transaminases <2.5x upper limit of normal, albumin >3gm/dl, creatinine <1.3mg/dl, adequate cardiac reserve (EF>50%), ANC (Absolute neutrophil count) >1,000/mcL (microliter), and Platelets >100,000/mcL.

7. Must be willing to be treated at the University of Texas Southwestern Hospital, University of Pennsylvania and affiliated clinics.

8. Subjects must be willing to use an approved form of birth control while on this study and for 90 days after completion.

9. Age > 18 years. 10. Subject must be able to swallow capsules and have no surgical or anatomic condition that will preclude the subject from swallowing and absorbing oral medications on an ongoing basis.

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 1. Chemotherapy, radiotherapy or hormonal therapy within 3 weeks ( 6 weeks for
nitrosoureas, mitomycin C or bevacizumab), or who have not recovered from the adverse
events to < grade 2 due to previous agents administered more than 4 weeks prior to
Study Day 1.


2. Subjects less than 4 weeks post major surgery. 3. Known active CNS metastases or
carcinomatous meningitis. Subjects with CNS (Central Nervous System) metastases
including brain metastases who have completed a course of radiotherapy are eligible
for the study provided they are clinically stable. However, oral corticosteroids for
control of CNS symptoms are not allowed.


4. Known documented or suspected hypersensitivity to the components of the study
drug(s) or analogs.


5. Uncontrolled systemic illness, including but not limited to ongoing or active
infection.


6. Symptomatic congestive heart failure, unstable angina pectoris, stroke or
myocardial infarction within 3 months.


7. Baseline neuropathy >grade 1. 8. Known positive for human immunodeficiency virus
(HIV). Baseline HIV screening is not required.


9. Pregnant or breast-feeding subjects. 10. Subjects who are unable or unwilling to
abide by the study protocol or to cooperate fully with the investigator or designee.

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Advanced Information
Descriptive Information
Brief Title  ICMJE Phase 1b Study of PD-0332991 in Combination With T-DM1(Trastuzumab-DM1)
Official Title  ICMJE Phase 1B Study of PD-0332991 in Combination With T-DM1 in the Treatment of Patients With Advanced HER2 (Human Epidermal Growth Factor Receptor 2)-Positive Breast Cancer
Brief Summary

Standard of care:

Treatment with Trastuzumab

Experimental:

21-Day Cycle of Combination therapy with T-DM1 intravenously on Day 1 and oral PD-0332991 on Days 5-18

Study Design and Methodology:

This is a phase 1B inter-patient dose escalation study of PD-0332991 in combination with T-DM1 in patients with recurrent or metastatic HER2-positive breast cancer after prior trastuzumab or other HER2-directed therapies.

The subjects will be administered T-DM1 by intravenous infusion at 3.6 mg/kg for 90 minutes on day 1 of each 21 day cycle. Infusion timing may vary from 30-90 minutes depending on how well the subject tolerates the treatment.

A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts.The dosing of PD-0332991 will be divided into 3 cohorts, the subjects will receive PD-0332991 on days 5-18 of each 21 day cycle.

Cohort 1 : PD-0332991 - 100 mg daily (oral) Cohort 2 : PD-0332991 - 150 mg daily (oral) Cohort 3 : PD-0332991 - 200 mg daily (oral)

The 3+3 design entails that if one patient out of the first three patients has a DLT, up to three additional patients will be entered at that dose level

Treatment cycles will continue until disease progression or withdrawal from study.

Detailed Description

This is a phase 1B inter-patient dose escalation study of PD-0332991 in combination with T--DM1 in patients with recurrent or metastatic HER2-positive breast cancer after prior trastuzumab or other HER2-directed therapies. A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts. The 3+3 design entails that if one patient out of the first three patients has a dose-limiting toxicity (DLT), three additional patients will be entered at that dose level. The PD-0332991 dose levels will start at 100 mg po daily; the second cohort will receive 150mg po daily; the third cohort 200mg po daily. Patients receive PD-0332991 on days 5-18 of each 21 day cycle. T-DM1 will be given intravenously at 3.6 mg/kg on day 1 of each 21 day cycle.

Toxicity will be assessed using the Common Terminology Criteria of Adverse Events (CTCAE) version 4.0 grading scale. Dose- limiting toxicity-DLT is defined as any drug-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity lasting >28 days after the last day of therapy. If two patients experience drug-related DLT, the maximal tolerated dose (MTD) for the combination in HER2-positive breast cancer patients has been exceeded, enrollment to that dose will stop, and the next lower dose will be designated the MTD. An additional 15 patients will be treated at the MTD or the maximal 200mg po daily PD-0332991 dose in combination with T-DM1 to confirm safety. Treatment cycles will continue until disease progression or withdrawal from study.

Study End-points:

  1. To evaluate and assess Dose Limiting Toxicities (DLT).
  2. To determine the toxicity profile.
  3. To determine the clinical response rate.
  4. To determine the duration of response.
  5. To evaluate baseline HER2 positivity biomarkers by analyzing pretreatment tumor Ki67, phospho-RB, cleaved caspase 3, phospho-histone H3, cycline E, MCM7, HER2, p27Kip1.
  6. To evaluate post-treatment Ki67, phospho-RB, cleaved caspase 3, phospho-histone H3, cyclin E, MCM7, HER2, p27Kip1, Rb, p16ink4c, CDK4, CDK6 in order to establish biomarker response to treatment.
  7. To evaluate pharmacokinetic (PK) parameters for PD-0332991 and T-DM1 including Cmax, AUC, t1/2
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Breast Cancer
Intervention  ICMJE Drug: PD-0332991 and T-DM1

The subjects will be administered T-DM1 by intravenous infusion at 3.6 mg/kg for 90 minutes on day 1 of each 21 day cycle. Infusion timing may vary from 30-90 minutes depending on how well the subject tolerates the treatment.

A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts.The dosing of PD-0332991 will be divided into 3 cohorts, the subjects will receive PD-0332991 on days 5-18 of each 21 day cycle.

Cohort 1 : PD-0332991 - 100 mg daily (oral) Cohort 2 : PD-0332991 - 150 mg daily (oral) Cohort 3 : PD-0332991 - 200 mg daily (oral)

Other Names:
  • KADCYLA=T-DM1
  • Palbociclib=PD-0332991
Study Arms  ICMJE Experimental: PD-0332991 and T-DM1

The subjects will be administered T-DM1 by intravenous infusion at 3.6 mg/kg for 90 minutes on day 1 of each 21 day cycle. Infusion timing may vary from 30-90 minutes depending on how well the subject tolerates the treatment.

A standard 3+3 trial design will be used for PD-0332991 dose escalation cohorts.The dosing of PD-0332991 will be divided into 3 cohorts, the subjects will receive PD-0332991 on days 5-18 of each 21 day cycle.

Cohort 1 : PD-0332991 - 100 mg daily (oral) Cohort 2 : PD-0332991 - 150 mg daily (oral) Cohort 3 : PD-0332991 - 200 mg daily (oral)

Intervention: Drug: PD-0332991 and T-DM1
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: March 13, 2020)
28
Original Estimated Enrollment  ICMJE
 (submitted: October 29, 2013)
17
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 1.All subjects must be informed about the study and have signed a current IRB (Institutional Review Board) approved informed consent.

    2. All subjects must have recurrent or metastatic HER2-positive breast cancer. diagnosed by biopsy.

    3. All subjects must have previously received trastuzumab or other HER2 targeted therapies.

    4.Tumor must be HER2-positive and RB-proficient. RB (Retinoblastoma protein)-proficiency is determined by tumor biopsy demonstrating RB normal and p16in4a low by immunohistochemistry. RB proficiency means that there is an intact RB pathway indicative of responsiveness to PD-0332991. RB staining is scored on an absent (no nuclear staining), weak (nuclear staining less than observed in endothelial cells and stromal cells surrounding the tumor), positive (nuclear staining at or above surrounding tissue) (0, 0.5, 1 respectively). P16ink4a is a routine clinical stain that is scored using absent, weak, positive, strong (0,1,2,3 respectively). Tumors will be scored using [p16]/[RB], where a score of less than 3 is required for inclusion. RB loss is expected to occur in less than 15% of cases.

    5. Subjects must have a performance status of ? 2 on the ECOG (Eastern Cooperative Oncology Group)Performance scale.

    6. Subjects must have bilirubin <1.5 mg/dl, transaminases <2.5x upper limit of normal, albumin >3gm/dl, creatinine <1.3mg/dl, adequate cardiac reserve (EF>50%), ANC (Absolute neutrophil count) >1,000/mcL (microliter), and Platelets >100,000/mcL.

    7. Must be willing to be treated at the University of Texas Southwestern Hospital, University of Pennsylvania and affiliated clinics.

    8. Subjects must be willing to use an approved form of birth control while on this study and for 90 days after completion.

    9. Age > 18 years. 10. Subject must be able to swallow capsules and have no surgical or anatomic condition that will preclude the subject from swallowing and absorbing oral medications on an ongoing basis.

Exclusion Criteria:

  • 1. Chemotherapy, radiotherapy or hormonal therapy within 3 weeks ( 6 weeks for nitrosoureas, mitomycin C or bevacizumab), or who have not recovered from the adverse events to < grade 2 due to previous agents administered more than 4 weeks prior to Study Day 1.

    2. Subjects less than 4 weeks post major surgery. 3. Known active CNS metastases or carcinomatous meningitis. Subjects with CNS (Central Nervous System) metastases including brain metastases who have completed a course of radiotherapy are eligible for the study provided they are clinically stable. However, oral corticosteroids for control of CNS symptoms are not allowed.

    4. Known documented or suspected hypersensitivity to the components of the study drug(s) or analogs.

    5. Uncontrolled systemic illness, including but not limited to ongoing or active infection.

    6. Symptomatic congestive heart failure, unstable angina pectoris, stroke or myocardial infarction within 3 months.

    7. Baseline neuropathy >grade 1. 8. Known positive for human immunodeficiency virus (HIV). Baseline HIV screening is not required.

    9. Pregnant or breast-feeding subjects. 10. Subjects who are unable or unwilling to abide by the study protocol or to cooperate fully with the investigator or designee.

Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01976169
Other Study ID Numbers  ICMJE STU 042013-042
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party University of Texas Southwestern Medical Center
Study Sponsor  ICMJE University of Texas Southwestern Medical Center
Collaborators  ICMJE
  • Pfizer
  • University of Pennsylvania
Investigators  ICMJE
Principal Investigator:Barbara Haley, MDInternal Medicine Hematology Oncology
PRS Account University of Texas Southwestern Medical Center
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP