Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Paclitaxel and TAK-228 in Urothelial Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03745911
Recruitment Status : Recruiting
First Posted : November 19, 2018
Last Update Posted : November 19, 2018
Sponsor:
Collaborators:
Takeda
Pivotal S.L.
Information provided by (Responsible Party):
Associació per a la Recerca Oncologica, Spain

Tracking Information
First Submitted Date  ICMJE January 9, 2018
First Posted Date  ICMJE November 19, 2018
Last Update Posted Date November 19, 2018
Actual Study Start Date  ICMJE May 4, 2018
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 15, 2018)
Objective Response Rate (ORR) [ Time Frame: 34 months ]
Objective response rate (ORR), defined as the sum of the complete and partial responses (CR+PR), with the goal of increasing the rate from 10% to 26%. Response rates will be measured using RECIST 1.1 criteria
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: November 15, 2018)
  • Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 34 months ]
    To assess the safety and evaluate the tolerability of TAK-228 in combination with paclitaxel in patients with metastatic, previously treated transitional cell carcinoma.
  • Progression-Free Survival (PFS) [ Time Frame: 34 months ]
    Time from the first day of therapy to the first evidence of progression as defined by RECIST, or death from any cause, whichever is first. Patients who die without a reported prior progression will be considered to have progressed on the day of their death. Patients alive and without disease progression will be censored at the time of the last objective tumor assessment. Patients who do not progress and are subsequently lost to follow-up will have their data censored at the day of their last objective tumor assessment.
  • Overall Survival (OS) [ Time Frame: 34 months ]
    Time from the first day of therapy to the date of death from any cause. If the patient is alive at the end of the follow-up period or is lost to follow-up, OS will be censored on the last date the patient is known to be alive.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: November 15, 2018)
  • Characterization of PI3K/ AKT/ mTOR pathway mutations [ Time Frame: 34 months ]
    Patient tumors samples will be analyzed for genetic alterations within the PI3K/AKT/mTOR pathway to determine if alterations within this pathway correlate with response rate, in patients with UC
  • Characterization of PI3K/ AKT/ mTOR pathway mutations [ Time Frame: 34 months ]
    Patient tumors samples will be analyzed for genetic alterations within the PI3K/AKT/mTOR pathway to determine if alterations within this pathway correlate with PFS, in patients with UC
  • Characterization of PI3K/ AKT/ mTOR pathway mutations [ Time Frame: 34 months ]
    Patient tumors samples will be analyzed for genetic alterations within the PI3K/AKT/mTOR pathway to determine if alterations within this pathway correlate with OS, in patients with UC
  • To discover biomarkers in the serum or plasma (pre and post treatment) of subjects that may predict response to therapy. [ Time Frame: 34 months ]
    Findings suggest S2481 phosphorylation could be a marker for activity of mTORC2. S2481 has the potential to be a prognostic, predictive, and pharmacodynamic marker: • Characterize the phosphorylation of S2481 of mTOR in UC tumor tissue
  • To discover biomarkers in the serum or plasma (pre and post treatment) of subjects that may predict response to therapy. [ Time Frame: 34 months ]
    Findings suggest S2481 phosphorylation could be a marker for activity of mTORC2. S2481 has the potential to be a prognostic, predictive, and pharmacodynamic marker: Evaluate whether basal levels of mTOR S2481 phosphorylation correlate with prognosis and/or are predictive of clinical outcomes of the study patients treated with the combination
  • To discover biomarkers in the serum or plasma (pre and post treatment) of subjects that may predict response to therapy. [ Time Frame: 34 months ]
    Findings suggest S2481 phosphorylation could be a marker for activity of mTORC2. S2481 has the potential to be a prognostic, predictive, and pharmacodynamic marker: Assess for changes in tumoral phospho-S2481 after treatment in the biopsy subset of patients.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Paclitaxel and TAK-228 in Urothelial Carcinoma
Official Title  ICMJE Phase II Study of Paclitaxel and TAK-228 in Metastatic Urothelial Carcinoma (UC) and the Impact of PI3K-mTOR Pathway Genomic Alterations
Brief Summary Phase II Multicentre, single arm, open label study of Paclitaxel and TAK-228 in metastatic urothelial carcinoma (UC) and the impact of PI3K-mTOR pathway genomic alterations
Detailed Description

The PI3K/AKT/mTOR pathway has been shown to be altered in a large percentage of metastatic urothelial carcinoma (UC) tumors. Within this pathway, the PI3 kinase alpha subunit (PIK3CA) is frequently mutated in muscle invasive bladder cancer (MIBC) (15-20%) and PTEN is inactivated in another 30%.

Due to TAK-228's effects on the PI3K/AKT/mTOR pathway in preclinical studies and the frequency of pathway alterations in UC tumors, TAK-228 is a rational therapy for bladder cancer.

This clinical investigation may also reveal how alterations in the PI3K/AKT/mTOR pathway correlate with treatment response. In preclinical bladder cell line models and xenografts done in our lab, synergistic effect has been seen with the combination with paclitaxel.

The primary end-point is objective response rate (ORR) with the goal of increasing the rate from 10% to 26%. Response rates will be measured using RECIST 1.1 criteria. PFS and OS will be measured from the start date of treatment with TAK-228 and paclitaxel. Grade 3, 4 or serious adverse events will be collected and compared to the catalogued events in the phase II trial in breast cancer (NCT01351350). Patient tumors will be analyzed for genetic alterations within the PI3K/AKT/mTOR pathway to determine if alterations within this pathway correlate with response rate, PFS, or OS.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Urothelial Cancer
Intervention  ICMJE Combination Product: Paclitaxel and TAK-228
Treatment with TAK-228 oral (D2, 3 and 4 of each week) and paclitaxel (D1 of each week) on Days 1, 8 and 15 for each 28-days cycle until disease progression or unacceptable toxicity. If paclitaxel is stopped, TAK-228 may be continued
Study Arms  ICMJE Experimental: Paclitaxel plus TAK-228
  • Paclitaxel will be given on days 1, 8, and 15 of each 28 day cycle intravenously (every Monday or first day of business week if holiday), the day before the first TAK-228 dose. It should be given over approximately one hour.
  • TAK-228 will be given orally on Days 2-4, 9-11, 16-18 and 23-25 of each 28-day cycle.
Intervention: Combination Product: Paclitaxel and TAK-228
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 15, 2018)
52
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2020
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  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 systemic chemotherapeutic or investigational treatment regimens. Specifically, subjects must meet one or more of the following criteria:

    • Progression after treatment with a regimen that includes a platinum salt (e.g. - carboplatin or cisplatin) for Stage IV disease.

    OR

    • Disease recurrence within one years from the date of last dose of chemotherapy or surgery until day the informed consent is signed) after neoadjuvant or adjuvant treatment with a regimen that includes a platinum salt.

  10. Measurable disease, as defined by RECIST v.1.1. If all sites of measurable disease have been irradiated, one site must have demonstrated growth after irradiation.
  11. Normal (or within 5% of lower limit) left ventricular ejection fraction

Exclusion Criteria:

  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 toxicity greater than CTCAE grade 1 from previous anti-cancer therapy (other than alopecia).
  15. Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy
  16. Grade 2 or greater peripheral neuropathy
  17. 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.
  18. 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.
  19. Known human immunodeficiency virus infection
  20. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
  21. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
  22. Patients who are taking proton pump inhibitors (PPIs) within 7 days of the first dose of study drug or who require treatment with PPIs throughout the trial or those who are taking H2 receptor antagonists within 24 hours of the first dose of study drug.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Joaquím Bellmunt, MD/PhD +34 932 483 860 jbellmunt@imim.cat
Contact: Inmaculada Musté +34 932 274 760 oncologia.apro@gmail.com
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03745911
Other Study ID Numbers  ICMJE X31005
2017-004486-27 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Associació per a la Recerca Oncologica, Spain
Study Sponsor  ICMJE Associació per a la Recerca Oncologica, Spain
Collaborators  ICMJE
  • Takeda
  • Pivotal S.L.
Investigators  ICMJE
Principal Investigator: Joaquín Bellmunt, MD/PhD Hospital del Mar
Principal Investigator: Alejo Rodríguez-Vida, MD/PhD Hospital del Mar
PRS Account Associació per a la Recerca Oncologica, Spain
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP