Paclitaxel and TAK-228 in Urothelial Carcinoma

Phase 2

• Conditions: Metastatic Urothelial Cancer
• Interventions: Combination Product: Paclitaxel and TAK-228

• Registration Number: NCT03745911
• Lead Sponsor: Associació per a la Recerca Oncologica, Spain

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 Timeline

• Study First Submitted: 2018-01-09
• Study Start: 2018-05-04
• Status Verified: 2018-11
• Study First Submitted QC: 2018-11-15
• Last Update Submitted: 2018-11-15
• Study First Posted: 2018-11-19
• Last Update Posted: 2018-11-19
• Primary Completion: 2020-11
• Study Completion: 2020-11

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 52

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Paclitaxel plus TAK-228	Paclitaxel and 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.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	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

Secondary Outcome Measures

Name	Time	Method
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	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.
Overall Survival (OS)	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.
Progression-Free Survival (PFS)	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.

Trial Locations

Locations (5)

Hospital General Universitario de Elche; 🇪🇸 Elche, Alicante, Spain

Parc Taulí Hospital Universitario; 🇪🇸 Sabadell, Barcelona, Spain

Clínica Universitaria de Navarra; 🇪🇸 Pamplona, Navarra, Spain

Hospital del Mar; 🇪🇸 Barcelona, Spain

Hospital de la Santa Creu i Sant Pau; 🇪🇸 Barcelona, Spain