Study of TAK-228 (MLN0128) in Soft Tissue Sarcomas

This is an open-label phase II study of TAK-228 for patients ≥ 18 years of age with complex genomic sarcomas exhibiting Phosphoinositide-3 Kinase (PI3K) pathway dysregulation. Patients must have surgically unresectable or metastatic disease that is refractory to at least one prior line of therapy (not including neoadjuvant or adjuvant therapy in a curative setting). Patients disease must also have evidence of progression prior to enrollment. The purpose of this study is to determine the antitumor activity in this group of patients. Patients must meet all eligibility criteria as detailed in section 10. A total of up to 33 patients will be included in the study. Patients will undergo screening evaluations to determine eligibility within 28 days of the first dose. All patients will be required to submit baseline tumor samples for analysis. Patients who have had their tumors tested commercially for PI3K/ AKT/mechanistic Target of Rapamycin (mTOR) alterations will be assessed on a case by case basis for eligibility and for determination as to whether additional tissue is required.

TAK-228 will be administered orally at 3 mg daily for a 21 day cycle. Clinical and laboratory assessments will be made on day 1 of each cycle. Disease will be assessed by comparing unidimensional tumor measurements on pre and peritreatment imaging (CT or MRI) after weeks 6, 12, 18 and every 12 weeks thereafter. Response will be assessed according to RECIST 1.1. Therapy will continue until disease progression or unacceptable toxicity or withdrawal of consent.


Eligibility Criteria:
Inclusion Criteria:

* This trial has two step inclusion criteria.

Step 1 Inclusion Criteria

1. Male or female patients 18 years or older.
2. Patients must have a diagnosis of a locally advanced or metastatic sarcoma that is progressing. The following subtypes (considered genomically complex) will be eligible: leiomyosarcoma (well differentiated or poorly differentiated), undifferentiated pleomorphic sarcoma, myxofibrosarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, malignant peripheral nerve sheath tumor, angiosarcoma or extraskeletal osteosarcoma. Other potentially genomically complex Soft Tissue Sarcomas (STS) subtypes may be included on a case-by-case basis after discussion with the principal investigator.
3. Measurable disease by RECIST 1.1 criteria (at least one target lesion outside of previous radiation fields or progressed within a previous radiation field), described in detail in section 15.
4. Progression of disease by radiographic imaging (10% increase in size by RECIST v1.1 within 6 months of registration) or presence of new lesions.
5. Must have received at least 1 prior systemic therapy for advanced disease (does not include adjuvant/neoadjuvant therapy in a curative setting).
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
7. Adequate contraception as follows:

   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 1 effective method of contraception, and 1 additional (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling \[eg. United Surgical Partners Internationals (USPI), Summary of Product Characteristics (SmPC), etc;\]) 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, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

   Highly effective methods:

   Intra-uterine devices (IUD) Hormonal (birth control pills/oral contraceptives, injectable contraceptives, contraceptive patches, or contraceptive implants)

   Other effective Methods:

   Latex Condoms Diaphragm with spermicide; Cervical cap;Sponge

   For men, even if surgically sterilized (ie, status post-vasectomy), they must:

   Agree to practice highly 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, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)

   Agree not to donate sperm during the course of this study or 120 days after receiving their last dose of study drug
8. Screening clinical laboratory values as specified below:

   a) Bone marrow reserve consistent with: i. absolute neutrophil count (ANC) ≥ 1.5 x 10(9)/L; ii. platelet count ≥ 100 x 10(9)/L; iii. hemoglobin ≥ 9 g/dL without transfusion within 1 week preceding study drug administration b) Hepatic: i. total bilirubin ≤ 1.5 x upper limit of normal (ULN), ii. 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); c) Renal: creatinine clearance ≥ 50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour); d) Metabolic: i. Glycosylated hemoglobin (HbA1c) ≤ 7.0%, ii. fasting serum glucose ≤ 130 mg/dL iii. fasting triglycerides ≤ 300 mg/dL
9. Ability to swallow oral medications.
10. 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.
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 ≥ 3 months or hemorrhage after treatment
    3. Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228
    4. No ongoing requirement for dexamethasone or anti-epileptic drugs

Step 2 Inclusion Criteria: Must be met after meeting step1inclusion and exclusion criteria.

1. Tumor must have dysregulation of the PI3K/AKT/mTOR pathway. For the purposes of this study, patients must have either PTEN protein or genomic loss, or phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA)/ Phosphatase and tensin homolog (PTEN) mutation. Patients must be willing to provide sufficient archival tissue. If this is not available fresh tumor for biopsy is required. In the event that a patient has had tumor analyzed for PTEN/PIK3CA status through commercial means, their eligibility and need for additional tissue will be determined on a case by case basis by the principle investigator.

Exclusion Criteria:

* Step 1 Exclusion Criteria

  1. Any 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. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
  4. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  5. 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.
  6. Breast feeding or pregnant.
  7. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK-228. In addition, patients with enteric stomata are also excluded.
  8. Treatment with any investigational products, radiation therapy, surgery, tumor embolization, chemotherapy or immunotherapy within 21 days before the first dose of the study drug. For biologic or hormonal therapy treatment within 14 days or five half-lives of a drug (whichever is longer) before the first dose of study drug.
  9. 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
     6. Pulmonary embolism
  10. 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)
  11. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) \>7% ; patients with a history of transient glucose intolerance due to corticosteroid administration or gestational diabetes may be enrolled in this study if all other inclusion/exclusion criteria are met.
  12. Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, CYP2C19 or CYP2C9 within 1 week preceding the first dose of study drug.
  13. 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.
  14. 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.