PRIMARY OBJECTIVE:
I. To determine the safety and tolerability of the combination of sapanisertib (TAK-228
[MLN0128]) plus paclitaxel, when given with carboplatin, and to determine the optimal dose
triplet, or maximum tolerated dose (MTD), in patients with advanced cancers refractory to
standard therapy.
SECONDARY OBJECTIVES:
I. To assess the clinical tumor response of this combination. II. To assess toxicity of this
combination. III. To assess progression free survival. IV. To assess molecular signatures
predictive of sensitivity and resistance.
OUTLINE: This is a dose escalation study.
Patients receive sapanisertib orally (PO) once daily (QD) on days 2-4, 9-11, and 16-18,
paclitaxel intravenously (IV) over 3 hours on days 1, 8, and 15, and carboplatin IV over 60
minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of
disease progression or unacceptable toxicity. Patients then receive sapanisertib PO QD on
days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up periodically.
Inclusion Criteria:
- Patients must have a diagnosis of a solid tumor malignancy and is refractory to
standard therapies who have relapsed after standard therapy, or whose cancers have no
standard therapy.
- Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
status =< 1.
- Female patients who: Are postmenopausal for at least 1 year before the screening
visit, OR are surgically sterile, OR if they are of childbearing potential, agree to
practice 1 effective method 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 [e.g., United Surgical Partners
International (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], withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception. Female and male
condoms should not be used together.)
- Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: 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], 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
within 120 days after receiving their last dose of study drug.
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.
- Platelet count >= 100 x 10^9/L.
- Hemoglobin >= 9 g/dL without transfusion within 1 week preceding study drug
administration.
- 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).
- Creatinine clearance >= 50 mL/min based either on Cockcroft-Gault estimate or based on
urine collection (12 or 24 hour).
- Glycosylated hemoglobin (HbA1c) < 7%.
- Fasting serum glucose =< 130 mg/dL.
- Fasting triglycerides =< 300 mg/dL.
- Ability to swallow oral medications.
- 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.
- Patients who have a history of brain metastasis are eligible for the study provided
that all the following criteria are met: a) Brain metastases which have been treated
b) No evidence of disease progression for >= 3 months before the first dose of study
drug. c) No hemorrhage after treatment d) Off-treatment with dexamethasone for 4 weeks
before administration of the first dose of TAK-228 e) No ongoing requirement for
dexamethasone or anti-epileptic drugs.
- Patients must have evaluable or measurable disease by Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 criteria.
- Patients must be 4 weeks beyond previous treatment of any chemotherapy or
radiotherapy, and must have recovered to =< grade 1 or previous baseline for each
toxicity. Exception: Patients may have received palliative low dose radiotherapy to
the limbs 1-4 weeks before this therapy provided pelvis, sternum, scapulae, vertebrae,
or skull were not included in the radiotherapy field. Patients who have received
non-chemotherapeutic biological agents will need to wait at least 5 half-lives or 4
weeks, whichever is shorter, from the last day of treatment of non-chemotherapeutic
biological agents.
Exclusion Criteria:
- Carboplatin or paclitaxel exposure within past 6 months.
- Central nervous system (CNS) metastasis.
- 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.
- Known history of human immunodeficiency virus infection.
- Known history of hepatitis B surface antigen-positive, or known or suspected active
hepatitis C infection.
- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.
- 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.
- Breast feeding or pregnant.
- Treatment with any investigational products within 4 weeks before the first dose of
study drug.
- Previous treatment with dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1
inhibitors.
- 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.
- History of any of the following within the last 6 months before administration of the
first dose of the drug: a) Ischemic myocardial event, including angina requiring
therapy and artery revascularization procedures b) Ischemic cerebrovascular event,
including transient ischemic attack and artery revascularization procedures c)
Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or
ventricular tachycardia) d) Placement of a pacemaker for control of rhythm e) New York
Heart Association (NYHA) class III or IV heart failure f) Pulmonary embolism.
- Significant active cardiovascular or pulmonary disease including: a) Uncontrolled
hypertension (i.e., systolic blood pressure > 150 mm Hg, diastolic blood pressure > 90
mm Hg). Use of anti-hypertensive agents to control hypertension before cycle 1 day 1
is allowed. b) Pulmonary hypertension c) Uncontrolled asthma or oxygen (O2) saturation
< 90% by arterial blood gas analysis or pulse oximetry on room air d) Significant
valvular disease; severe regurgitation or stenosis by imaging independent of symptom
control with medical intervention, or history of valve replacement e) Medically
significant (symptomatic) bradycardia f) History of arrhythmia requiring an
implantable cardiac defibrillator g) 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).
- Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%;
patients with a history of transient glucose intolerance due to corticosteroid
administration may be enrolled in this study if all other inclusion/exclusion criteria
are met.
- 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.
- 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.
- Patients with hypersensitivity or other allergic reaction to platinum chemotherapy.
- Patients with hypersensitivity or other allergic reaction to taxanes.
