Triple Negative Breast Cancer
Conditions
Brief summary
This study evaluates efficacy of TAK- 228 and TAK- 117 followed by cisplatin and nab paclitaxel 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 the oral combination of TAK-228 and TAK-117 (PIKTOR) will inhibit NHEJ in metastatic TNBC, leading at the time of disease progression to metastases that are HR-deficient and sensitive to cisplatin plus nab paclitaxel therapy.
Interventions
DRUGTak-228 & Tak-117
Patients will receive 4mg oral TAK-228 and 200mg TAK-117 tablets until disease progression.
DRUGCisplatin & Nab Paclitaxel
following Tak-228 & Tak-117 standard nab paclitaxel 175-220 mg/m2 plus cisplatin 60-75 mg/m2 infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion
Sponsors
Takeda
Joyce O'Shaughnessy
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 TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female patients 18 years or older. 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. 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. Androgen receptor-negative (less than 10% positive nuclei) on standard IHC performed at the local pathology laboratory. 5. Have locoregional (eg, breast, chest wall, regional lymphatic) or pulmonary or hepatic metastatic disease that is amenable to core needle biopsy. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (See Appendix I) 7. Female patients who: 1. Are postmenopausal for at least 1 year before the screening visit, OR 2. Are surgically sterile, OR 3. If they are of childbearing potential, agree to practice 1 effective methods of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer as mandated by local labeling \[eg, USPI, SmPC, etc,\]) after the last dose of study drug, OR 4. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) 8. Screening clinical laboratory values as specified below: 1. Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 10\^9; platelet count ≥ 100 x 10\^9; hemoglobin ≥ 9 g/dL without transfusion within 1 week preceding study drug administration 2. Hepatic: total bilirubin ≤ 1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present); 3. Renal: creatinine clearance ≥60 mL/min based either on cockroft-Gault estimate or based on urine collection (12 or 24 hour); 4. Metabolic: Glycosylated hemoglobin (HbA1c)\<7.0%, fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL 9. Ability to swallow oral medications. 10. Must be able to fast for glucose monitoring throughout PIKTOR treatment. 11. 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. No evidence of disease progression for ≥2 months before the first dose of study drug. 3. No hemorrhage after treatment 4. Off-treatment with dexamethasone for 3 weeks before administration of the first dose of PIKTOR 5. No ongoing requirement for dexamethasone or anti-epileptic drugs 12. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
Exclusion criteria
Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy (Objective Response Rate) | Through study completion, up to 2 years 8 months | To assess the objective response rate associated with sequential treatment of the oral combination TAK 228 and 117 followed by nab-paclitaxel plus cisplatin in metastatic TNBC. 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) | Through study completion, up to 2 years 8 months | To assess duration of response associated with sequential treatment of the oral combination Tak 228 and 117 followed by nab-paclitaxel plus cisplatin. Duration of response is measured as prolonged clinical benefit; clinical benefit is defines as progression free survival on study therapy for at least 6 months. |
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0. | For up to 30 days following last dose, approximately 7 months | To assess safety associated with sequential treatment of the oral combination Tak 228 and 117 followed by nab-paclitaxel plus cisplatin |
| Number of Treatment-Emergent Adverse Events (Safety and Tolerability) | For up to 30 days following last dose, approximately 7 months | To assess safety associated with sequential treatment of the oral combination TAK 228 and TAK 117 followed by nab-paclitaxel plus cisplatin per CTCAE v4.0 criteria. |
Countries
United States
Participant flow
Pre-assignment details
Two patients are not included in the results as they screen failed before begin assigned to a study group.
Participants by arm
| Arm | Count |
|---|---|
| Tak + Cisplatin and Nab Paclitaxel Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion.
Tak-228 & Tak-117: Patients will receive oral TAK-228 and TAK-117 tablets until disease progression.
Cisplatin & Nab Paclitaxel: following Tak-228 & Tak-117 standard nab paclitaxel plus cisplatin infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 6 |
Baseline characteristics
| Characteristic | Tak + Cisplatin and Nab Paclitaxel |
|---|---|
| Age, Continuous | 52 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 8 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 | 6 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 4 / 10 |
Outcome results
Primary
Efficacy (Objective Response Rate)
To assess the objective response rate associated with sequential treatment of the oral combination TAK 228 and 117 followed by nab-paclitaxel plus cisplatin in metastatic TNBC. 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, up to 2 years 8 months
Population: All participants who received at least one dose of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tak + Cisplatin and Nab Paclitaxel | Efficacy (Objective Response Rate) | 1 Participants |
Secondary
Efficacy (Duration of Response)
To assess duration of response associated with sequential treatment of the oral combination Tak 228 and 117 followed by nab-paclitaxel plus cisplatin. Duration of response is measured as prolonged clinical benefit; clinical benefit is defines as progression free survival on study therapy for at least 6 months.
Time frame: Through study completion, up to 2 years 8 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tak + Cisplatin and Nab Paclitaxel | Efficacy (Duration of Response) | 28 weeks |
Secondary
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0.
To assess safety associated with sequential treatment of the oral combination Tak 228 and 117 followed by nab-paclitaxel plus cisplatin
Time frame: For up to 30 days following last dose, approximately 7 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tak + Cisplatin and Nab Paclitaxel | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0. | 10 Participants |
Secondary
Number of Treatment-Emergent Adverse Events (Safety and Tolerability)
To assess safety associated with sequential treatment of the oral combination TAK 228 and TAK 117 followed by nab-paclitaxel plus cisplatin per CTCAE v4.0 criteria.
Time frame: For up to 30 days following last dose, approximately 7 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tak + Cisplatin and Nab Paclitaxel | Number of Treatment-Emergent Adverse Events (Safety and Tolerability) | 64 adverse events |