Metastatic Urothelial Cancer
Conditions
Keywords
Urothelial carcinoma
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.
Interventions
COMBINATION_PRODUCTPaclitaxel 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
Sponsors
Takeda
Pivotal S.L.
Associació per a la Recerca Oncologica, Spain
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Characterization of PI3K/ AKT/ mTOR pathway mutations | 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 |
| To discover biomarkers in the serum or plasma (pre and post treatment) of subjects that may predict response to therapy. | 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 |
Countries
Spain
Contacts
Primary ContactJoaquím Bellmunt, MD/PhD
Backup ContactInmaculada Musté
Outcome results
None listed