Phase II Study of Paclitaxel and TAK-228 in metastatic urothelial carcinoma (UC) and the impact of PI3K-mTOR pathway genomic alterations
- Conditions
- Metastatic urothelial carcinoma (UC)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2017-004486-27-ES
- Lead Sponsor
- Associació Per a la Recerca Oncològica(APRO)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 22
1.Male or female patients 18 years or older.
2.Patients must have a diagnosis of metastatic or advanced histologically confirmed UC (urothelial cancer). Mixed histologies are allowed.
3.Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
4.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., USPI, 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
5.Screening clinical laboratory values as specified below:
•Bone marrow reserve consistent with: absolute neutrophil count (ANC) = 1.5 x 109/L; platelet count = 100 x 109/L; hemoglobin = 9 g/dL without transfusion within 1 week preceding study drug administration.
•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);
•Renal: creatinine clearance =50 mL/min based either on Cockroft-Gault estimate or based on urine collection (12 or 24 hour);
•Metabolic: Glycosylated hemoglobin (HbA1c) <7.0%, fasting serum glucose (= 130 mg/dL) and fasting triglycerides = 300 mg/dL.
6.Ability to swallow oral medications.
7.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.
8.Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:
•Brain metastases which have been treated.
•No evidence of disease progression for =3 months before the first dose of study drug.
•No hemorrhage after treatment.
•Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228.
•No ongoing requirement for dexamethasone or anti-epileptic drugs.
9.Patients having received prior systemic chemotherapy treatment for UC, with no limit for number of prior syste
1.Prior treatment with paclitaxel for UC (in any setting – neoadjuvant, adjuvant or for metastatic disease). Patients treated with prior docetaxel are eligible.
2.Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1 inhibitors.
3.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.
4.Poorly controlled diabetes mellitus defined as HbA1c > 7%; subjects with a history of transient glucose intolerance due to corticosteroid administration are allowed in this study if all other inclusion/exclusion criteria are met.
5.Presence of central nervous system metastasis, except for those matching requirements detailed per inclusion criterion 8.
6.Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator’s opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol.
7.History of any of the following within the last 6 months prior to study entry:
•Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
•Ischemic cerebrovascular event, including TIA 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 (See Appendix C)
•Pulmonary embolism.
8.Significant active cardiovascular or pulmonary disease at the time of study entry, including:
•Uncontrolled high blood pressure (i.e., systolic blood pressure >180 mm Hg, diastolic blood pressure > 95 mm Hg). Use of anti-hypertensive agents to control hypertension before Cycle 1 Day 1 is allowed.
•Pulmonary hypertension.
•Uncontrolled asthma or O2 saturation < 90% by ABG (Arterial Blood Gas) analysis or pulse oximetry on room air.
•Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement.
•Medically significant (symptomatic) bradycardia.
•History of arrhythmia requiring an implantable cardiac defibrillator.
•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).
9.History of arrhythmia (multifocal premature ventricular contractions (PVCs), bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation), which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia.
10.Controlled atrial fibrillation such as with medication or cardioversion is not excluded.
11.Treatment with systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy, i.e., prednisone =10mg or its equivalent) within 1 week before administration of the first dose of study drug.
12.Women who are currently pregnant or breast feeding.
13.Receipt of any investigational agent, chemotherapy or radiation therapy within 21 days prior to Study Day 1.
14.Any unresolved non-hematologic toxici
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To evaluate the efficacy of TAK-228 (orally administered 3 days each week) in combination with weekly IV paclitaxel as assessed by objective response rate in patients with metastatic, previously treated urothelial carcinoma (UC).;Primary end point(s): Objective Response Rate;Timepoint(s) of evaluation of this end point: During treatment and follow-up period.;Secondary Objective: •To assess the efficacy of TAK-228 in combination with paclitaxel in terms of progression free survival (PFS) and overall survival (OS).<br>•To assess the safety and tolerability of TAK-228 in combination with paclitaxel in terms of the incidence and nature of Grade 3, 4 and serious adverse events (AEs).
- Secondary Outcome Measures
Name Time Method Secondary end point(s): •To assess the safety of TAK-228 in combination with paclitaxel in patients with metastatic, previously treated transitional cell carcinoma.<br>•To evaluate the tolerability of TAK-228 in combination with paclitaxel in patients with metastatic, previously treated transitional cell carcinoma.<br>•To assess the efficacy of TAK-228 in combination with paclitaxel in terms of progression free survival (PFS).<br>•To assess the efficacy of TAK-228 in combination with paclitaxel in terms of overall survival (OS).;Timepoint(s) of evaluation of this end point: During treatment and follow-up period.