Breast Cancer
Conditions
Keywords
Breast Cancer
Brief summary
This research study is studying a drug called Abemaciclib as a possible treatment for have metastatic triple-negative type of breast cancer.
Detailed description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved abemaciclib as a treatment for any disease. Some triple-negative breast cancers show expression of the Rb protein and are referred to as "Rb-positive." The Rb protein is important because it controls the way that cancer cells divide and grow. Drugs like abemaciclib work by changing the way that Rb functions. This can potentially stop cancer cells from dividing, and can also potentially lead to cancer cell death. In this research study, the investigators are are looking to see how safe abemaciclib is and how well it will work to help people with triple-negative breast cancer that is Rb-positive.
Interventions
DRUGAbemaciclib
Abemaciclib (LY2835219) has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4 and CDK6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation.
Sponsors
Dana-Farber Cancer Institute
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically or cytologically confirmed invasive breast cancer, which is recurrent, locally advanced, unresectable or metastatic. * Patients must have at least one lesion that is not within a previously radiated field and that is measurable on computerized tomography (CT) or magnetic resonance imaging (MRI) scans per RECIST version 1.1. Bone lesions are not considered measurable. * Either the primary tumor and/or metastatic tumor must be triple-negative on the most recent sample as defined below: * Hormone receptor status: the invasive tumor must be ER- and PR-negative, or staining present in \<1% by immunohistochemistry (IHC) * HER2 status: the invasive tumor must be Human Epidermal Growth Factor Receptor 2 Negative (HER2-negative) by the ASCO CAP guidelines * Either the primary tumor and/or the metastatic tumor must be RB positive as defined below: --RB status: the invasive tumor must have greater than 50% of tumor cells staining positive for RB. * Prior Chemotherapy: * Patients may have received 1-3 prior systemic therapies for metastatic disease (note: for patients who have first developed recurrent/metastatic disease within 12 months of completing any (neo)-adjuvant therapy for triple-negative breast cancer, the (neo)-adjuvant therapy is counted as a prior line of therapy). * Patients must have been off treatment with myelosuppressive chemotherapy for at least 21 days or nonmyelosuppressive agents for 14 days before registration. Patients should also be adequately recovered (to baseline or grade 1) from acute toxicities of prior treatment except for residual alopecia and peripheral neuropathy. * Prior biologic therapy: Patients must have discontinued all biologic therapy at least 21 days before registration. * Prior radiation therapy: Patients may have received prior radiation therapy in either the metastatic or early-stage setting. Radiation therapy must be completed at least 14 days prior to study registration. * Patients on bisphosphonates or RANK-L inhibitors may continue receiving these therapies during study treatment. There is no washout period required between the last dose of these therapies and the start of abemaciclib. * The patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Patients must have normal organ and marrow function as defined below: * Absolute neutrophil count ≥1500/mm3 * Platelets ≥100,000/mm3 * Hemoglobin ≥8 g/dL * Total Bilirubin ≤1.5x the upper limit of normal (ULN) * Serum creatinine ≤1.5 mg/dL OR calculated GFR ≥60mL/min * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 times the upper limit of normal. For patients with documented liver metastases, AST/ALT ≤ 5.0 times the upper limit of normal. * Female subjects of childbearing potential must have a negative serum pregnancy test at screening. Women of childbearing potential are defined as those who have not been surgically sterilized and have had a menstrual period in the past year * The patient must be ≥18 years old * Capable of understanding and complying with the protocol and has signed the informed consent document. * Able to swallow study drug. * Sexually active patients (male and female) must use medically acceptable methods of contraception during the course of the study and for 3 months after completion of study treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately. While on the study and for 3 months after final drug administration, women may not breast-feed. * Confirmed availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue * Patients with tumor that is felt to be accessible to biopsy must be willing to provide tissue from a newly obtained core biopsy of a tumor lesion at baseline. Biopsies will be obtained up to 1 week (7 days) prior to initiation of treatment on Cycle 1, Day 1. Patients who undergo an attempted research biopsy procedure for the purpose of this protocol, and in whom inadequate tissue is obtained, are not required to undergo a repeat biopsy in order to continue on protocol.
Exclusion criteria
* Received a prior CDK4/6 inhibitor. * Undergone major surgery within 14 days of the initial dose of study drug * Received another investigational agent (defined as any agent/device that has not received regulatory approval for any indication) within 14 days of the first dose of study drug for a nonmyelosupressive agent, or 21 days of the first dose of study drug for a myelosuppressive agent. * Has any severe concurrent disease, infection, or comorbid condition that renders the patient inappropriate for enrollment in the opinion of the investigator. * Has an active bacterial, fungal, and/or known viral infection. Patients with known HIV infection are excluded given the potential for interactions between antiretroviral agents and abemaciclib, and the potential for increased risk of life-threatening infection with therapy that is myelosuppressive. Patients with known Hepatitis B or Hepatitis C infection are excluded only if there is evidence of active infection (detectable Hepatitis B surface antigen, detectable Hepatitis C RNA) * Documented brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to trial registration, are neurologically stable, and have recovered from effects of radiotherapy or surgery. * Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥2 weeks before the first study drug. * Treatment for brain metastases may have included whole brain radiotherapy, radiosurgery, or a combination as was deemed appropriate by the treating physician. * Patients who meet the above criteria and are clinically stable on anti-convulsant medication are eligible only if their anti-convulsant does not alter hepatic cytochrome P450 activity in a way that might interfere with metabolism of abemaciclib. * Pregnant women are excluded from this study because of the potential for teratogenic effects. * Lactating women are excluding from the study. * Individuals with a history of a second malignancy are ineligible except for the following circumstances: individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if they are diagnosed and have completed treatment within the past 5 years: cervical cancer in situ, and non-melanoma cancer of the skin. Patients with other cancers diagnosed within the past 5 years and felt to be at low risk of recurrence should be discussed with the principle investigator to determine eligibility. * Have received any live vaccination within 28 days of first dose of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 2 years | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; Overall Response Rate(ORR) = (CR + PR)/sample size. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Baseline to the earlier of progression (per Response Evaluation Criteria in Solid Tumors 1.1), date of death due to any cause, or date of last disease evaluation. Participants will be followed up up to 16.5 months. | Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression (per Response Evaluation Criteria in Solid Tumors 1.1) or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Overall Survival | Baseline to date of death due to any cause, or at date last known alive.Participants will be followed once every 6 months until death.Those removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization. | Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. |
| Disease Control Rate | 2 years | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage (compared to baseline) to qualify for partial or complete response (CR or PR) nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD); Disease control rate is defined as CR + PR + SD ≥ 16weeks |
| Clinical Benefit Rate | 2 years | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage (compared to baseline) to qualify for partial or complete response (CR or PR) nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD); Clinical benefit rate is defined as CR+PR+SD ≥ 24weeks |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSara Tolaney, MD, MPH
Dana-Farber Cancer Institute
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Abemaciclib -Abemaciclib was administered orally, twice daily on days 1 to 28
Abemaciclib: Abemaciclib (LY2835219) has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4 and CDK6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | Abemaciclib |
|---|---|
| Age, Continuous | 61 years |
| Age, Customized Age at enrollment Less than 50 years old | 5 Participants |
| Age, Customized Age at enrollment Over 50 years old | 22 Participants |
| BRCA1 or BRCA2 Mutation Absent | 19 Participants |
| BRCA1 or BRCA2 Mutation Not reported | 4 Participants |
| BRCA1 or BRCA2 Mutation Present | 4 Participants |
| (Neo)adjuvant therapy No | 5 Participants |
| (Neo)adjuvant therapy Yes | 22 Participants |
| Number of metastatic sites | 7 sites |
| Number of patients recurred within 12 months of their adjuvant systemic therapy | 15 Participants |
| Number of prior lines of systemic therapy for metastatic disease 0 | 2 Participants |
| Number of prior lines of systemic therapy for metastatic disease 1 | 4 Participants |
| Number of prior lines of systemic therapy for metastatic disease 2 | 14 Participants |
| Number of prior lines of systemic therapy for metastatic disease 3 | 7 Participants |
| Prior chemotherapies in any setting Anthracycline | 18 participants |
| Prior chemotherapies in any setting Eribulin | 4 participants |
| Prior chemotherapies in any setting Taxane | 22 participants |
| Prior immune therapy for early stage or metastatic disease | 12 Participants |
| Race/Ethnicity, Customized Race Black | 2 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants |
| Race/Ethnicity, Customized Race White | 24 Participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 0 Participants |
| Site of metastasis --Bone | 15 Participants |
| Site of metastasis --Brain | 6 Participants |
| Site of metastasis --Liver | 8 Participants |
| Site of metastasis --Lung | 12 Participants |
| Site of metastasis --Lymph node | 23 Participants |
| Site of metastasis --Skin | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 24 / 27 |
| other Total, other adverse events | 27 / 27 |
| serious Total, serious adverse events | 10 / 27 |
Outcome results
Primary
Objective Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; Overall Response Rate(ORR) = (CR + PR)/sample size.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abemaciclib | Objective Response Rate | 0 Participants |
95% CI: [0, 0.247]
Secondary
Clinical Benefit Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage (compared to baseline) to qualify for partial or complete response (CR or PR) nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD); Clinical benefit rate is defined as CR+PR+SD ≥ 24weeks
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abemaciclib | Clinical Benefit Rate | 4 Participants |
95% CI: [0.042, 0.337]
Secondary
Disease Control Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage (compared to baseline) to qualify for partial or complete response (CR or PR) nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD); Disease control rate is defined as CR + PR + SD ≥ 16weeks
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abemaciclib | Disease Control Rate | 6 Participants |
95% CI: [0.086, 0.423]
Secondary
Overall Survival
Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.
Time frame: Baseline to date of death due to any cause, or at date last known alive.Participants will be followed once every 6 months until death.Those removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abemaciclib | Overall Survival | 8.44 months |
Secondary
Progression Free Survival
Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression (per Response Evaluation Criteria in Solid Tumors 1.1) or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Baseline to the earlier of progression (per Response Evaluation Criteria in Solid Tumors 1.1), date of death due to any cause, or date of last disease evaluation. Participants will be followed up up to 16.5 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Abemaciclib | Progression Free Survival | 1.94 months |