Triple Negative Breast Cancer
Conditions
Brief summary
This study evaluates efficacy of LY3023414 and prexasertib in patients with metastatic triple negative breast cancer.
Detailed description
Seventy to eighty percent of breast cancers have a gene expression profile which is characterized by homologous recombination deficiency (HRD) and high proliferation. HRD leads to errors in DNA pathway \[non -homologous end joining (NHEJ)\] that repair DNA-breaks, a process required for metastatic triple negative breast cancer (TNBC) survival. The hypothesis of this pilot trial is that administration of LY3023414 and prexasertib will inhibit NHEJ in metastatic TNBC.
Interventions
COMBINATION_PRODUCTDrug 1: LY3023414; Drug 2: Prexasertib
Metastatic TNBC patients will consent to and undergo core needle biopsies of a metastatic lesion for NGS, RPPA, and other molecular analyses at study entry. Patients will then be treated with 150 mg LY3023414 PO BID and prexasertib 80 mg/m\^2 IV administered every 2 weeks until disease progression or unacceptable toxicity. Any time after the completion of Cycle 2 of the treatment combination, or at the physician's discretion, a second core needle biopsy of the same metastatic lesion (or different metastases if the initial metastasis has regressed) will be performed for RPPA and other molecular analyses. If a research biopsy from a patient's metastatic disease cannot be safely obtained, a skin biopsy is permitted. Treatment will be discontinued in patients who achieve a confirmed clinical complete response, and these patients will be followed to document the durability of the complete responses.
Sponsors
Eli Lilly and Company
Baylor Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients with metastatic TNBC who meet the enrollment criteria will receive LY3023414 and prexasertib until disease progression.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients ≥18 years of age. Patients must agree to use one highly effective (less than 1% failure rate) method of contraception or use a combination of two effective methods of contraception during treatment with study drug and for at least 12 weeks following the last dose of study drug. 2. Have a diagnosis of metastatic TNBC previously treated with standard anthracycline, cyclophosphamide, and taxane chemotherapy, unless there was a contraindication to doxorubicin, in which case prior treatment with this agent is not required. NOTE: TNBC defined as ER-negative tumors with ≤10% tumor nuclei immunoreactivity, or ER Low Positive as defined by the updated ASCO/CAP guidelines 2020. 3. Have not received more than 3 prior chemotherapy regimens for metastatic disease. Prior platinum and/or taxane therapy in the adjuvant or metastatic setting is permitted. 4. Have locoregional (eg, breast, chest wall, regional lymphatic) or pulmonary or hepatic metastatic disease that is amenable to core needle biopsy. If a research biopsy from a patient's metastatic disease cannot be safely obtained, a skin biopsy is permitted. If a skin biopsy cannot be safely obtained, patients may still be eligible, per physician discretion. 5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 6. Have adequate hematologic function, defined by: 1. Absolute neutrophil count (ANC) \>1500/mm\^3 2. Platelet count ≥100,000/mm\^3 3. Hemoglobin ≥9 g/dL 7. Have adequate liver function, defined by: 1. AST and ALT ≤2.5 x the upper limit of normal (ULN) or ≤5 x ULN in presence of liver metastases 2. Total bilirubin ≤1.5 x ULN 8. Have adequate renal function, defined by: a. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance of ≥60 ml/min 9. Have the ability to swallow oral medications 10. Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met: 1. Brain metastases which have been treated 2. Off-treatment with steroids for 2 weeks before administration of the first dose of LY3023414 and prexasertib 3. No ongoing requirement for dexamethasone or anti-epileptic drugs 4. No clinical or radiological evidence of progression of brain metastases 11. Patient must be accessible for treatment and follow-up. 12. All patients must be able to understand the investigational nature of the study and give written informed consent prior to study entry.
Exclusion criteria
1. Have a family history of long QT Syndrome and serious cardiac conditions. 2. Have QTcF interval of \>470 msec on screening electrocardiogram (ECG) as well as on pre-dose Cycle 1 Day 1 ECG 3. Have insulin-dependent diabetes mellitus. Patients with a type 2 diabetes mellitus are eligible if adequate control of blood glucose level is obtained by oral anti-diabetics as documented by HbA1c \<8%. Patients with type 1 diabetes mellitus are not eligible. 4. Previous radiotherapy for metastatic disease completed \<2 weeks prior to study treatment initiation. 5. Women who are pregnant or lactating. 6. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation such as: 1. severe impaired lung functions as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air 2. liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C). 3. viral hepatitis or HIV. 7. Concurrent use of CYP3A4 inhibitors and inducers from 72 hours prior to initiation of study treatment until the end of treatment. 8. History of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that might affect interpretation of the results of this study, or render the patient at high risk for treatment complications. 9. Patients who have received prior PI3K or CHK therapy. 10. Any other investigational or anti-cancer treatments while participating in this study 11. Any other active malignancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy (Objective Response Rate) | Through study completion, approximately 2 years and 8 months | To assess the objective response rate associated with LY3023414 and prexasertib in metastatic TNBC patients. Objective response is measured as prolonged clinical benefit; clinical benefit is defined as progression free survival on study therapy for at least 6 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy (Duration of Response) | From the time that 6 months of progression free survival on study therapy was first met until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year. | To assess duration of response to combination of LY3023414 and prexasertib in metastatic TNBC patients. Duration of response is measured as prolonged clinical benefit; clinical benefit is defined as progression free survival on study therapy for at least 6 months. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LY3023414 + Prexasertib Patients with metastatic TNBC who meet the enrollment criteria will receive LY3023414 and prexasertib until disease progression. Patients whose disease does not respond to the combination of LY3023414 and prexasertib may be treated with standard of care breast cancer therapies off study, at the recommendation of the treating physician.
Drug 1: LY3023414; Drug 2: Prexasertib Patients will be treated with 150 mg LY3023414 PO BID and prexasertib 80 mg/m\^2 IV administered every 2 weeks until disease progression or unacceptable toxicity. Treatment will be discontinued in patients who achieve a confirmed clinical complete response, and these patients will be followed to document the durability of the complete responses. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 6 |
Baseline characteristics
| Characteristic | LY3023414 + Prexasertib |
|---|---|
| Age, Continuous | 57.5 years |
| Primary Tumor Size | 14.5 mm STANDARD_DEVIATION 4.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 3 / 10 |
Outcome results
Primary
Efficacy (Objective Response Rate)
To assess the objective response rate associated with LY3023414 and prexasertib in metastatic TNBC patients. Objective response is measured as prolonged clinical benefit; clinical benefit is defined as progression free survival on study therapy for at least 6 months.
Time frame: Through study completion, approximately 2 years and 8 months
Population: All participants who received at least one dose of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY3023414 + Prexasertib | Efficacy (Objective Response Rate) | 3 Participants |
Secondary
Efficacy (Duration of Response)
To assess duration of response to combination of LY3023414 and prexasertib in metastatic TNBC patients. Duration of response is measured as prolonged clinical benefit; clinical benefit is defined as progression free survival on study therapy for at least 6 months.
Time frame: From the time that 6 months of progression free survival on study therapy was first met until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year.
Population: All participants who received at least one dose of treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LY3023414 + Prexasertib | Efficacy (Duration of Response) | 9 weeks |