Patient case: 49-year-old female with lung cancer; genetic feature: ERBB2

Clinical trial: Phase I Study of MLN0128 and MLN8237 in Patients With Advanced Solid Tumors and Metastatic 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.

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.

Eligibility: Inclusion Criteria:
  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. TNBC Dose Expansion Cohort: Patients must have a diagnosis of histologically confirmed metastatic TNBC defined as negative for estrogen receptor, progesterone receptor and human epidermal growth factor 2 (HER2). Patients must have received either adjuvant or first line chemotherapy for metastatic disease.
  4. Dose Expansion Cohort: At least one tumor lesion amenable to repeat core needle biopsy or punch biopsy without unacceptable risk of a major procedural complication.
  5. Eastern Cooperative Oncology Group (ECOG) performance status < 1.
  6. Three weeks or 5 half-lives from previous systemic anticancer therapy.
  7. All acute treatment-related toxicities from prior therapy must have resolved to Grade < 1 prior to study entry excluding alopecia.
  8. 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.
  For men:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug.
  9. Patients must meet screening laboratory values.
  10. Left ventricular ejection fraction (LVEF) > lower limit of normal (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.
  11. Ability to swallow oral medications.
  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.
  13. Patients who have a history of brain metastasis are eligible for the study provided they meet certain criteria.
  Exclusion Criteria:
  1. Other clinically significant co-morbidities.
  2. Known human immunodeficiency virus infection.
  3. Radiation therapy to more than 25% of the bone marrow.
  4. Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness.
  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.
  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 non-melanoma 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:
  -  Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
  -  Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures
  -  Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia)
  -  Placement of a pacemaker for control of rhythm
  -  New York Heart Association (NYHA) Class III or IV heart failure
  -  Pulmonary embolism
  13. Significant active cardiovascular or pulmonary disease.
  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 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.

Relevance to patient case: not relevant