Metastatic Breast Cancer, Solid Tumors
Conditions
Keywords
MLN0128, Dual TORC1/2 Inhibitor, MLN8237, Aurora A inhibitor, Alisertib, Triple-Negative Breast Cancer
Brief summary
This is a phase Ib study designed to evaluate the safety and toxicity of the combination of Alisertib and MLN0128 in patients with advanced solid tumors with an expansion cohort in patients with previously treated metastatic TNBC.
Detailed description
The purpose of this study is to evaluate the combination of Alisertib and MLN0128 in patients with advanced solid tumors refractory to standard treatment followed by an expansion cohort of patients with metastatic TNBC with exploratory correlative studies.
Interventions
DRUGAlisertib
Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.
DRUGMLN0128
Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study.
Sponsors
University of Colorado, Denver
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 101 Years
Healthy volunteers
No
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 1. Male or female patients 18 years or older. 2. Dose Escalation Cohort: Patients must have a diagnosis of a histologically confirmed solid tumor that is incurable and refractory to standard therapy or for which no standard therapy exists. 3. Dose Expansion Cohort Group 1 and 2: Patients must have a diagnosis of histologically confirmed metastatic TNBC defined as negative for estrogen receptor, progesterone receptor and HER2. Patients must have received either adjuvant or first line chemotherapy for metastatic disease. Negative for Estrogen and Progesterone Receptor includes the following: * Local Pathology report classifies them as negative * Allred Score of 2 or below * \<1% positive staining Subjects with solid tumor types other than TNBC may also be enrolled after discussion with the Sponsor. These subjects must have a diagnosis of a histologically confirmed solid tumor that is incurable and refractory to standard therapy or for which no standard therapy exists. 4. Pancreatic Cancer Cohort: Patients must have a diagnosis of locally advanced or metastatic pancreatic adenocarcinoma previously treated with or not a candidate for standard of care systemic therapy. Dose Expansion Cohort Group 1 and 2: At least one tumor lesion amenable to repeat core needle biopsy or punch biopsy without unacceptable risk of a major procedural complication. 5. Dose Expansion Cohort Group 1 and 2: At least one tumor lesion amenable to repeat core needle biopsy or punch biopsy without unacceptable risk of a major procedural complication. 6. Eastern Cooperative Oncology Group (ECOG) performance status \< 1 (See Appendix 1) 7. Three weeks or 5 half-lives (whichever is shorter) from previous systemic anticancer therapy; at least 4 weeks from major surgery and recovered; at least 2 weeks from palliative radiation and recovered. No more than 450 mg/m2 cumulative dose of doxorubicin or equivalent anthracycline dose is allowed. 8. All acute treatment-related toxicities from prior therapy must have resolved to Grade \< 1 prior to study entry excluding alopecia. 9. For women: * Postmenopausal for at least 1 year before the screening visit, OR * Surgically sterile, OR * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (Periodic abstinence \[e.g, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception. For men, even if surgically sterilized (ie, status post-vasectomy), they must: * Agree to practice effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (Periodic abstinence \[e.g, calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception * Agree not to donate sperm during the course of this study or 120 days after receiving their last dose of study drug 10. Screening clinical laboratory values as specified below: 1. Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL. Values must be obtained without the need for myeloid growth factor support, platelet or PRBC transfusion support within 14 days. 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 \< 1.5 X ULN or creatinine clearance ≥ 50 mL/min based either on Cockroft-Gault estimate or based on urine collection (12 or 24 hour)(Appendix 2); 4. Metabolic: Glycosylated hemoglobin (HbA1c)\<7.0%, fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL; 5. For patients undergoing serial tumor biopsies, INR and activated partial thromboplastin time (PTT) must be within 1.5 X the upper limit of normal. 11. Left ventricular ejection fraction (LVEF) \> LLN of the institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks prior to first study drug administration. 12. Ability to swallow oral medications. 13. 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. 14. 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 ≥ 4 weeks or hemorrhage after treatment 3. Off-treatment with dexamethasone for 2 weeks before administration of the first dose of MLN0128 4. No ongoing requirement for dexamethasone or anti-epileptic drugs.
Exclusion criteria
Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Maximum Tolerated Dose (MTD) in the Combination of MLN0128 and Alisertib in Patients With Advanced Solid Tumors Measured by Treatment Adverse Events as Assessed by the CTCAE v4.03 | Up to 28 days | The maximum tolerated dose (MTD) will be defined as the highest dose level evaluated in which 0 or 1 patient out of 6 patients experiences dose limiting toxicity (DLT) in the combination of MLN0128 and Alisertib. Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Safety Profile and Tolerability of the Combination of MLN0128 and Alisertib in Adult Patients With Advanced Solid Tumors. | At least 30 days after the last dose of MLN0128 or alisertib | Adverse events will be tabulated by type and grade according to the NCI CTCAE v.4.03. Please see adverse events section. |
Countries
United States
Participant flow
Pre-assignment details
This study had a dose escalation cohort followed by expansion cohorts. We had 65 patients consented and 18 patients were not eligible due to not meeting inclusion exclusion criteria. 1 subject withdrew by choice, 1 withdrew per Physician discretion..
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1: Alisertib 30 mg/MLN0128 1 mg This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 30 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 1 mg given by mouth (PO) once daily with continuous dosing.
Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.
MLN0128: Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study. | 3 |
| Dose Level 2: Alisertib 30 mg/MLN0128 2 mg This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 30 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 1 mg given by mouth (PO) once daily with continuous dosing.
Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.
MLN0128: Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study. | 4 |
| Dose Level 3: Alisertib 40 mg/MLN0128 2 mg This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 30 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 1 mg given by mouth (PO) once daily with continuous dosing.
Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.
MLN0128: Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study. | 6 |
| Dose Level 3: Alisertib 40 mg/MLN0128 3 mg This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 30 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 1 mg given by mouth (PO) once daily with continuous dosing.
Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.
MLN0128: Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study. | 2 |
| Dose-Expansion of Alisertib and MLN0128: Group 1 This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. In cycle 1, single agent Alisertib will be administered at the MTD on days 1-7 and MLN0128 will be administered on days 8-21. In cycle 2 and beyond, dosing with both agents will begin on day 1, with Alisertib administered days 1-7 and MLN0128 administered days 1-21.
Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.
MLN0128: Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study. | 10 |
| Dose-Expansion of Alisertib and MLN0128: Group 2 This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. In cycle 1, MLN0128 will be administered at the MTD days 1-28 and Alisertib will be administered at the MTD on days 8-15. In cycle 2 and beyond, dosing with both agents will begin on day 1, with Alisertib administered days 1-7 and MLN0128 administered days 1-21.
Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.
MLN0128: Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study. | 9 |
| Pancreatic Cancer Cohort This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. On each cycle, Alisertib will be administered on days 1-7, while MLN0128 will be administered continuously on days 1-21.
Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.
MLN0128: Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study. | 11 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Dose Level 1: Alisertib 30 mg/MLN0128 1 mg | Dose Level 2: Alisertib 30 mg/MLN0128 2 mg | Dose Level 3: Alisertib 40 mg/MLN0128 2 mg | Dose Level 3: Alisertib 40 mg/MLN0128 3 mg | Dose-Expansion of Alisertib and MLN0128: Group 1 | Dose-Expansion of Alisertib and MLN0128: Group 2 | Pancreatic Cancer Cohort | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 4 Participants | 1 Participants | 4 Participants | 5 Participants | 2 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 6 Participants | 4 Participants | 9 Participants | 26 Participants |
| Age, Continuous | 63.7 years | 64.8 years | 64.5 years | 65.5 years | 61.7 years | 61.9 years | 56.9 years | 61.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 4 Participants | 2 Participants | 9 Participants | 8 Participants | 8 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 3 participants | 4 participants | 6 participants | 2 participants | 10 participants | 9 participants | 11 participants | 45 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 5 Participants | 2 Participants | 8 Participants | 6 Participants | 2 Participants | 29 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 9 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 4 | 0 / 7 | 0 / 2 | 7 / 10 | 9 / 10 | 8 / 11 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 7 / 7 | 2 / 2 | 10 / 10 | 10 / 10 | 11 / 11 |
| serious Total, serious adverse events | 1 / 3 | 0 / 4 | 2 / 7 | 2 / 2 | 3 / 10 | 4 / 10 | 6 / 11 |
Outcome results
Primary
The Maximum Tolerated Dose (MTD) in the Combination of MLN0128 and Alisertib in Patients With Advanced Solid Tumors Measured by Treatment Adverse Events as Assessed by the CTCAE v4.03
The maximum tolerated dose (MTD) will be defined as the highest dose level evaluated in which 0 or 1 patient out of 6 patients experiences dose limiting toxicity (DLT) in the combination of MLN0128 and Alisertib. Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03.
Time frame: Up to 28 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose-Escalation of Alisertib and MLN0128 | The Maximum Tolerated Dose (MTD) in the Combination of MLN0128 and Alisertib in Patients With Advanced Solid Tumors Measured by Treatment Adverse Events as Assessed by the CTCAE v4.03 | alisertib | 30 mg |
| Dose-Escalation of Alisertib and MLN0128 | The Maximum Tolerated Dose (MTD) in the Combination of MLN0128 and Alisertib in Patients With Advanced Solid Tumors Measured by Treatment Adverse Events as Assessed by the CTCAE v4.03 | TAK228 | 2 mg |
Secondary
The Safety Profile and Tolerability of the Combination of MLN0128 and Alisertib in Adult Patients With Advanced Solid Tumors.
Adverse events will be tabulated by type and grade according to the NCI CTCAE v.4.03. Please see adverse events section.
Time frame: At least 30 days after the last dose of MLN0128 or alisertib
Population: Number of participants with at least one adverse event.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose-Escalation of Alisertib and MLN0128 | The Safety Profile and Tolerability of the Combination of MLN0128 and Alisertib in Adult Patients With Advanced Solid Tumors. | 3 Participants |
| Dose Level 2: Alisertib 30 mg/MLN0128 2 mg | The Safety Profile and Tolerability of the Combination of MLN0128 and Alisertib in Adult Patients With Advanced Solid Tumors. | 4 Participants |
| Dose Level 3: Alisertib 40 mg/MLN0128 2 mg | The Safety Profile and Tolerability of the Combination of MLN0128 and Alisertib in Adult Patients With Advanced Solid Tumors. | 7 Participants |
| Dose Level 4: Alisertib 40 mg/MLN0128 3 mg | The Safety Profile and Tolerability of the Combination of MLN0128 and Alisertib in Adult Patients With Advanced Solid Tumors. | 2 Participants |
| Dose-Expansion of Alisertib and MLN0128: Group 1 | The Safety Profile and Tolerability of the Combination of MLN0128 and Alisertib in Adult Patients With Advanced Solid Tumors. | 10 Participants |
| Dose Expansion of Alisertib and MLN0128: Group 2 | The Safety Profile and Tolerability of the Combination of MLN0128 and Alisertib in Adult Patients With Advanced Solid Tumors. | 10 Participants |
| Pancreatic Cancer Cohort | The Safety Profile and Tolerability of the Combination of MLN0128 and Alisertib in Adult Patients With Advanced Solid Tumors. | 11 Participants |