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Metastatic Urothelial CancerPhase 2NCT03745911

Paclitaxel and TAK-228 in Urothelial Carcinoma

A Phase 2 study testing Paclitaxel and TAK-228 in people with Metastatic Urothelial Cancer, run by Associació per a la Recerca Oncologica, Spain at 5 sites in Spain.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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 Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Urothelial Cancer
What is being tested?
Paclitaxel and TAK-228
Could I receive a placebo?
No, everyone receives an active treatment
How many people
52 participants
Where
5 sitesSpain
Study dates
4 May 2018to Nov 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female patients 18 years or older.
  • Patients must have a diagnosis of metastatic or advanced histologically confirmed UC (urothelial cancer). Mixed histologies are allowed.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Female patients who:
  • Are postmenopausal for at least 1 year before the screening visit, OR
  • Are surgically sterile, OR
Show all 31Show fewer
  • 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
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • Normal (or within 5% of lower limit) left ventricular ejection fraction

Who cannot join

  • Prior treatment with paclitaxel for UC (in any setting - neoadjuvant, adjuvant or for metastatic disease). Patients treated with prior docetaxel are eligible.
  • Previous treatment with PI3K, AKT, 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.
  • 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.
  • Presence of central nervous system metastasis, except for those matching requirements detailed per inclusion criterion 8.
  • 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.
Show all 35Show fewer
  • 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.
  • 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).
  • 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.
  • Controlled atrial fibrillation such as with medication or cardioversion is not excluded.
  • 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.
  • Women who are currently pregnant or breast feeding.
  • Receipt of any investigational agent, chemotherapy or radiation therapy within 21 days prior to Study Day 1.
  • Any unresolved non-hematologic toxicity greater than CTCAE grade 1 from previous anti-cancer therapy (other than alopecia).
  • Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy
  • Grade 2 or greater peripheral neuropathy
  • 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.
  • 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 human immunodeficiency virus infection
  • Known 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
  • 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.

Trial locations and contacts

5 sites in 1 country.

Joaquím Bellmunt, MD/PhD contact

+34 932 483 860

jbellmunt@imim.cat

Inmaculada Musté contact

+34 932 274 760

oncologia.apro@gmail.com

5 sites in 1 country

Spain5 sites, 5 recruiting

  • Hospital del Mar

    Barcelona, 08003

    Alejo Rodríguez-Vida, MD/PhD, arodriguezvida@hospitaldelmar.cat

    Alejo Rodríguez-Vida, MD/PhD

    Recruiting

  • Hospital de la Santa Creu i Sant Pau

    Barcelona, 08041

    José Pablo Maroto Rey, MD/PhD, jmaroto@santpau.cat

    José Pablo Maroto Rey, MD/PhD

    Recruiting

  • Hospital General Universitario de Elche

    Elche, Alicante, 03203

    Federico J. Vázquez Mazón, MD/PhD, fvazquezmd@gmail.com

    Federico J. Vázquez Mazón, MD/PhD

    Recruiting

  • Clínica Universitaria de Navarra

    Pamplona, Navarre, 31008

    José Luis Pérez Gracia, MD/PhD, jlgracia@unav.es

    José Luis Pérez Gracia, MD/PhD

    Recruiting

  • Parc Taulí Hospital Universitario

    Sabadell, Barcelona, 08208

    Teresa Bonfilll, MD/PhD, terebonfill@gmail.com

    Teresa Bonfill, MD/PhD

    Recruiting

Other trials in Spain

About this study

Official title: Phase II Study of Paclitaxel and TAK-228 in Metastatic Urothelial Carcinoma (UC) and the Impact of PI3K-mTOR Pathway Genomic Alterations

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

Read the 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.

Being tested
Paclitaxel and TAK-228
Keywords
Urothelial carcinoma
Medical subject headings
Carcinoma, Transitional Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Paclitaxel and TAK-228Combination product

    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 groups in NCT03745911
Study groupRoleWhat they receive
Paclitaxel plus TAK-228Experimental* 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.
Receives: Combination Product: Paclitaxel and TAK-228

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Objective Response Rate (ORR)

    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

    Measured: 34 months

Secondary outcomes (3)

  1. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

    To assess the safety and evaluate the tolerability of TAK-228 in combination with paclitaxel in patients with metastatic, previously treated transitional cell carcinoma.

    Measured: 34 months

  2. Progression-Free Survival (PFS)

    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.

    Measured: 34 months

  3. Overall Survival (OS)

    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.

    Measured: 34 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Nov 2018
  2. Study start4 May 2018
  3. Primary completionNov 2020 (estimated)
  4. Study completionNov 2020 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
52 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03745911
Sponsor's protocol ID
X31005
Other IDs
2017-004486-27, 2017
Status last verified
Nov 2018
First submitted
9 Jan 2018
Last updated
19 Nov 2018
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Iyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV, Kim PH, Lin O, Weinhold N, Sander C, Zabor EC, Janakiraman M, Garcia-Grossman IR, Heguy A, Viale A, Bochner BH, Reuter VE, Bajorin DF, Milowsky MI, Taylor BS, Solit DB. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol. 2013 Sep 1;31(25):3133-40. doi: 10.1200/JCO.2012.46.5740. Epub 2013 Jul 29.

    PubMed 23897969

  • Guo Y, Chekaluk Y, Zhang J, Du J, Gray NS, Wu CL, Kwiatkowski DJ. TSC1 involvement in bladder cancer: diverse effects and therapeutic implications. J Pathol. 2013 May;230(1):17-27. doi: 10.1002/path.4176. Epub 2013 Mar 21.

    PubMed 23401075

  • Wagle N, Grabiner BC, Van Allen EM, Hodis E, Jacobus S, Supko JG, Stewart M, Choueiri TK, Gandhi L, Cleary JM, Elfiky AA, Taplin ME, Stack EC, Signoretti S, Loda M, Shapiro GI, Sabatini DM, Lander ES, Gabriel SB, Kantoff PW, Garraway LA, Rosenberg JE. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 2014 May;4(5):546-53. doi: 10.1158/2159-8290.CD-13-0353. Epub 2014 Mar 13.

    PubMed 24625776

  • Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 Jan;63(1):11-30. doi: 10.3322/caac.21166. Epub 2013 Jan 17.

    PubMed 23335087

  • Ortmann CA, Mazhar D. Second-line systemic therapy for metastatic urothelial carcinoma of the bladder. Future Oncol. 2013 Nov;9(11):1637-51. doi: 10.2217/fon.13.139.

    PubMed 24156324

  • Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. doi: 10.1200/JCO.2002.20.4.937.

    PubMed 11844814

  • von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. doi: 10.1200/JCO.2005.07.757.

    PubMed 16034041

  • Verdoorn BP, Kessler ER, Flaig TW. Targeted therapy in advanced urothelial carcinoma. Oncology (Williston Park). 2013 Mar;27(3):219-26.

    PubMed 23687793

  • Ching CB, Hansel DE. Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway. Lab Invest. 2010 Oct;90(10):1406-14. doi: 10.1038/labinvest.2010.133. Epub 2010 Jul 26.

    PubMed 20661228

  • Platt FM, Hurst CD, Taylor CF, Gregory WM, Harnden P, Knowles MA. Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res. 2009 Oct 1;15(19):6008-17. doi: 10.1158/1078-0432.CCR-09-0898. Epub 2009 Sep 29.

    PubMed 19789314

  • Bowles DW, Diamond JR, Lam ET, Weekes CD, Astling DP, Anderson RT, Leong S, Gore L, Varella-Garcia M, Vogler BW, Keysar SB, Freas E, Aisner DL, Ren C, Tan AC, Wilhelm F, Maniar M, Eckhardt SG, Messersmith WA, Jimeno A. Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies. Clin Cancer Res. 2014 Mar 15;20(6):1656-65. doi: 10.1158/1078-0432.CCR-13-2506. Epub 2014 Feb 3.

    PubMed 24493827

  • Bowles DW, Ma WW, Senzer N, Brahmer JR, Adjei AA, Davies M, Lazar AJ, Vo A, Peterson S, Walker L, Hausman D, Rudin CM, Jimeno A. A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br J Cancer. 2013 Sep 3;109(5):1085-92. doi: 10.1038/bjc.2013.474. Epub 2013 Aug 13.

    PubMed 23942080

  • Gomez-Pinillos A, Ferrari AC. mTOR signaling pathway and mTOR inhibitors in cancer therapy. Hematol Oncol Clin North Am. 2012 Jun;26(3):483-505, vii. doi: 10.1016/j.hoc.2012.02.014. Epub 2012 Mar 31.

    PubMed 22520976

  • Seront E, Rottey S, Sautois B, Kerger J, D'Hondt LA, Verschaeve V, Canon JL, Dopchie C, Vandenbulcke JM, Whenham N, Goeminne JC, Clausse M, Verhoeven D, Glorieux P, Branders S, Dupont P, Schoonjans J, Feron O, Machiels JP. Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers. Ann Oncol. 2012 Oct;23(10):2663-2670. doi: 10.1093/annonc/mds057. Epub 2012 Apr 3.

    PubMed 22473592

  • Milowsky, M.I., Final results of a multicenter, open-label phase II trial of dovitinib (TKI258) in patients with advanced urothelial carcinoma with either mutated or nonmutated FGFR3. 2013, J Clin Oncol 2013; 31(Suppl 6) [abstract: 255].

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Paclitaxel and TAK-228 in people with Metastatic Urothelial Cancer, run by Associació per a la Recerca Oncologica, Spain at 5 sites in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 31 inclusion and 35 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 19 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Joaquím Bellmunt, MD/PhD (+34 932 483 860, jbellmunt@imim.cat), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective Response Rate (ORR) (time frame: 34 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03745911, which also lists 31 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Nov 2018.

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