Phase I Study of MLN0128 and MLN8237 in Patients With Advanced Solid Tumors and Metastatic Triple-negative Breast Cancer
Condition: Metastatic Breast Cancer; Solid Tumors
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Intervention: Alisertib; MLN0128
Intervention description: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.; Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 47.0
Sex: All
Minimum age: 18 Years
Maximum age: 101 Years
Healthy volunteers: No
Keywords: MLN0128; Dual TORC1/2 Inhibitor; MLN8237; Aurora A inhibitor; Alisertib; Triple-Negative Breast Cancer

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.
    

Eligibility criteria:

        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 exclusion criteria are not to be enrolled in the
        study:

          1. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease,
             active central nervous system disease, active infection, or any other condition that
             could compromise the patient's participation in the study.

          2. Known human immunodeficiency virus infection.

          3. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is
             considered to be over 25%.

          4. Known history of uncontrolled sleep apnea syndrome and other conditions that could
             result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
             disease; requirement for supplemental oxygen.

          5. Systemic infection requiring IV antibiotic therapy within 14 days preceding the first
             dose of study drug, or other severe infection.

          6. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C
             infection.

          7. Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of treatment according to this protocol.

          8. Diagnosed or treated for another malignancy within 2 years before administration of
             the first dose of study drug, or previously diagnosed with another malignancy and have
             any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma
             in situ of any type are not excluded if they have undergone complete resection.

          9. Breast feeding or pregnant.

         10. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI
             disease, or for an unknown reason that may alter the absorption of MLN0128. In
             addition, patients with enteric stomata are also excluded.

         11. Treatment with any investigational products within 3 weeks before the first dose of
             study drug.

         12. History of any of the following within the last 6 months before administration of the
             first dose of the drug:

               1. Ischemic myocardial event, including angina requiring therapy and artery
                  revascularization procedures

               2. Ischemic cerebrovascular event, including transient ischemic attack and artery
                  revascularization procedures

               3. Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)
                  cardiac arrhythmia (including atrial flutter/fibrillation, ventricular
                  fibrillation or ventricular tachycardia)

               4. Placement of a pacemaker for control of rhythm

               5. New York Heart Association (NYHA) Class III or IV heart failure (See Appendix 3)

               6. Pulmonary embolism

         13. Significant active cardiovascular or pulmonary disease including:

               1. Uncontrolled hypertension (i.e., systolic blood pressure >180 mm Hg, diastolic
                  blood pressure > 95 mm Hg). Use of anti-hypertensive agents to control
                  hypertension before Cycle1 Day 1 is allowed.

               2. Pulmonary hypertension

               3. Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis or
                  pulse oximetry on room air

               4. Significant valvular disease; severe regurgitation or stenosis by imaging
                  independent of symptom control with medical intervention, or history of valve
                  replacement

               5. Medically significant (symptomatic) bradycardia

               6. History of arrhythmia requiring an implantable cardiac defibrillator

               7. Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated
                  demonstration of QTc interval > 480 milliseconds, or history of congenital long
                  QT syndrome, or torsades de pointes)

         14. Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, CYP2C19
             or CYP2C19 within 1 week preceding the first dose of study drug.

         15. Patients receiving systemic corticosteroids (either IV or oral steroids, excluding
             inhalers or low-dose hormone replacement therapy) within 1 week before administration
             of the first dose of study drug.

         16. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within
             7 days before receiving the first dose of study drug.

         17. For patients undergoing serial tumor biopsies, known bleeding diathesis or history of
             abnormal bleeding or require anti-coagulation therapy which cannot be interrupted for
             biopsy.