Clinical Trials Logo

Clinical Trial Details — Status: Not yet recruiting

Administrative data

NCT number NCT03108261
Other study ID # NCI-2015-00121
Secondary ID NCI-2015-0012115
Status Not yet recruiting
Phase Phase 2
First received April 5, 2017
Last updated April 5, 2017
Start date May 1, 2017
Est. completion date December 31, 2020

Study information

Verified date April 2017
Source Yale University
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This pilot phase II trial studies how well sapanisertib works in treating patients with bladder cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic) with tuberous sclerosis (TSC)1 and/or TSC2 mutations (changes in deoxyribonucleic acid [DNA]).Sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Description:

PRIMARY OBJECTIVES:

I. To determine the overall response rate (ORR) defined as complete response (CR) and partial response (PR) in patients with locally advanced or metastatic transitional cell carcinoma (TCC) harboring a TSC1 mutation.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of sapanisertib (MLN0128) (TAK-228) in patients with locally advanced or metastatic TCC harboring a TSC1 mutation.

II. To evaluate progression free survival (PFS) and overall survival (OS).

TERTIARY OBJECTIVES:

I. To determine the ORR in patients with locally advanced or metastatic TCC harboring a TSC2 mutation.

II. To evaluate toxicity, PFS, and OS in TSC2 mutation patients.

OUTLINE:

Patients receive sapanisertib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.


Recruitment information / eligibility

Status Not yet recruiting
Enrollment 209
Est. completion date December 31, 2020
Est. primary completion date December 31, 2018
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria:

- Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

- Eligible patients should have a histologically confirmed locally advance or metastatic TCC who progressed after standard therapy

- Patient must have TCCs tumors harboring a TSC1 or TSC2 mutation identified by a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory

- Patients must have TCC tumor tissue available for submission in a form of at least 10 unstained slides or formalin-fixed paraffin-embedded (FFPE) block (FFPE block highly recommended and preferred); if the tissue were previously sent to Yale Tumor Profiling Laboratory (TPL) for prescreening, additional tissue submission may not be required if sufficient remaining tissue is available; but, must first consult with the principle investigator

- Patient must have developed disease progression during or following treatment with at least one platinum- containing regimen (e.g., gemcitabine/cisplatin [GC], methotrexate-vinblastine-doxorubicin-cisplatin [MVAC], carboplatin, gemcitabine [CarboGem]) for inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence, or must be unfit or ineligible for cisplatin-based chemotherapy; there is no restriction on the number of prior lines of chemotherapeutics agents received

- Patients who progressed within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant regimen are considered second-line patients; therefore, these patients may be also eligible

- Patients who are unfit or ineligible for cisplatin-based chemotherapy as defined by any one of the following criteria are eligible for this trial:

- Eastern Cooperative Oncology Group (ECOG) performance score of 2

- Creatinine clearance < 60 mL/min

- A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies

- Grade >= 2 peripheral neuropathy

- ECOG performance status =< 2 (Karnofsky >= 60 %)

- Life expectancy of greater than 12 weeks

- Hemoglobin >= 9 g/dL

- Fasting serum glucose =< 130 mg/dL

- Glycosylated hemoglobin measurement (HbA1c) < 7.0%

- Fasting triglycerides =< 300 mg/dL

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × institutional upper limit of normal (ULN) and =< 5 ULN if liver metastases are present

- Creatinine within normal institutional limits OR creatinine clearance >= 50 mL/min based either on Cockroft-Gault estimate or based on urine collection (12 or 24 hour)

- Patients with controlled diabetes are allowed on study; controlled diabetes is defined as fasting blood sugar (FBS) < 130 mg/dL, and patients whose FBS can be brought in this range with medical therapy are eligible for trial inclusion

- Women of childbearing age should avoid becoming pregnant while taking any mTOR inhibitor including MLN0128 (TAK-228)

- Female patients must:

- Be postmenopausal for at least 1 year before the screening visit, OR

- Be surgically sterile, OR

- If they are of childbearing potential, agree to practice 1 highly 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; NOTE: 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 postvasectomy), must:

- 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 (NOTE: 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)

- AND agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug

- Ability to swallow oral medications

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients who are receiving any other investigational agents

- Patients with known untreated brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN0128 (TAK-228)

- Subjects who are on systemic corticosteroids (intravenous (IV) or oral steroids, excluding inhaled, topical or ophthalmic corticosteroids), or anti-epileptic drugs for treated brain metastasis

- Subjects taking strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, CYP2C19 or CYP2C9 within 1 week preceding the first dose of MLN0128 (TAK-228); if a subject requires treatment with strong inhibitors and/or inducers of CYP3A4, CYP2C19 and/or CYP2C9, alternative treatment must be considered; if no alternative is available, one such medication may be allowed after discussing with the study principle investigator

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

- Pregnant and breastfeeding women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MLN0128 (TAK-228)

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; however, HIV patients treated with regimens that have low cytochrome P450 (CYP450) inhibition may be allowed as long as the patient's general health and cluster of differentiation (CD)4 counts are within acceptable levels

- Patients with symptomatic/untreated central nervous system (CNS) metastases; patients with treated and stable brain metastasis are allowed

- Patients with impaired cardiac function or clinically significant cardiac disease; patients with 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) will not be allowed; no ischemic myocardial or cerebrovascular event, class III or IV heart failure, placement of pacemaker, or pulmonary embolism within six months of receiving first dose of MLN0128 (TAK-228)

- Patients with untreated or active hepatitis B or C infection

- 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)

- Pulmonary hypertension

- Uncontrolled asthma or oxygen (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

- Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128 (TAK-228)

- Concomitant administration of any proton pump inhibitor (PPI) is not permitted during the study; patients receiving PPI therapy before enrollment must stop using the PPI for 7 days before their first dose of study drugs

- 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 transient ischemic attack (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)

- Pulmonary embolism

- Subjects who have initiated treatment with bisphosphonates less than 30 days prior to the first administration of MLN0128 (TAK-228); concurrent bisphosphonate use is only allowed if the bisphosphonate was initiated at least 30 days prior to the first administration of MLN0128 (TAK-228)

- Patients who received prior PI3K, AKT or mTOR inhibitors are not allowed

- Patients who received radiation therapy within the last 4 weeks; radiation exposure may not exceed 30% of marrow area

Study Design


Related Conditions & MeSH terms


Intervention

Other:
Laboratory Biomarker Analysis
Correlative studies
Drug:
Sapanisertib
Given PO

Locations

Country Name City State
United States Beth Israel Deaconess Medical Center Boston Massachusetts
United States Brigham and Women's Hospital Boston Massachusetts
United States Dana-Farber Cancer Institute Boston Massachusetts
United States Massachusetts General Hospital Cancer Center Boston Massachusetts
United States UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina
United States Yale University New Haven Connecticut

Sponsors (2)

Lead Sponsor Collaborator
Yale University National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Other Incidence of toxicity (TSC2 patients) The occurrence rate of each specific type of toxicity at a certain severity grade will be described by point estimates and Wilson type 90% (2-sided) CIs. Up to 4 weeks after last dose of study treatment
Other Overall response rate (TSC2 patients) Up to 4 weeks after last dose of study treatment
Other Overall survival (TSC2 patients) The censored OS distributions will each be estimated by the K-M survivorship function. Point estimates and 90% (2-sided) CIs will be computed for all estimable summary statistics, e.g., the median, 6-month rate, 12-month rate, etc. Time from start of treatment to time of death from any cause, assessed up to 4 weeks after last dose of study treatment
Other Progression-free survival (TSC2 patients) The censored PFS distributions will each be estimated by the K-M survivorship function. Point estimates and 90% (2-sided) CIs will be computed for all estimable summary statistics, e.g., the median, 6-month rate, 12-month rate, etc. Time from start of treatment to date of progression or death, whichever occurs first, assessed up to 4 weeks after last dose of study treatment
Primary Overall response rate (TSC1 patients) Up to 4 weeks after last dose of study treatment
Secondary Incidence of toxicity (TSC1 patients) The occurrence rate of each specific type of toxicity at a certain severity grade will be described by point estimates and Wilson type 90% (2-sided) confidence intervals (CIs). Up to 4 weeks after last dose of study treatment
Secondary Overall survival (TSC1 patients) The censored OS distributions will each be estimated by the K-M survivorship function. Point estimates and 90% (2-sided) CIs will be computed for all estimable summary statistics, e.g., the median, 6-month rate, 12-month rate, etc. Time from start of treatment to time of death from any cause, assessed up to 4 weeks after last dose of study treatment
Secondary Progression-free survival (TSC1 patients) The censored PFS distributions will each be estimated by the Kaplan-Meier (K-M) survivorship function. Point estimates and 90% (2-sided) CIs will be computed for all estimable summary statistics, e.g., the median, 6-month rate, 12-month rate, etc. Time from start of treatment to date of progression or death, whichever occurs first, assessed up to 4 weeks after last dose of study treatment
See also
  Status Clinical Trial Phase
Completed NCT05700344 - SOGUG-AVELUMAB_RWD
Recruiting NCT04623502 - An Investigation of Kidney and Urothelial Tumor Metabolism in Patients Undergoing Surgical Resection and/or Biopsy N/A
Recruiting NCT05107674 - A Study of NX-1607 in Adults With Advanced Malignancies Phase 1
Recruiting NCT04953104 - Nivolumab for the Treatment of Patients With Metastatic Urothelial Cancer With ARID1A Mutation and Stratify Response Based on CXCL13 Expression Phase 2
Withdrawn NCT06050954 - A Pilot Study of Circulating Tumor DNA Adaptive Risk Maintenance Approach for Bladder Cancer (CARMA) Phase 2
Active, not recruiting NCT03534804 - Cabozantinib Plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced Urothelial Carcinoma Phase 2
Active, not recruiting NCT00365157 - Eribulin Mesylate in Treating Patients With Locally Advanced or Metastatic Cancer of the Urothelium and Kidney Dysfunction Phase 1/Phase 2
Withdrawn NCT06018116 - A Canadian Trial of Bicalutamide in Patients Receiving Maintenance Avelumab for Metastatic Urothelial Cancer. Phase 2
Recruiting NCT04936230 - Immunotherapy With or Without Radiation Therapy for Metastatic Urothelial Cancer Phase 2
Recruiting NCT05544552 - Safety and Preliminary Anti-Tumor Activity of TYRA-300 in Advanced Urothelial Carcinoma and Other Solid Tumors With FGFR3 Gene Alterations Phase 1/Phase 2
Active, not recruiting NCT04514484 - Testing the Combination of the Anti-cancer Drugs XL184 (Cabozantinib) and Nivolumab in Patients With Advanced Cancer and HIV Phase 1
Terminated NCT05052372 - Biomarker Research Study for Patients With FGFR-Mutant Bladder Cancer Receiving Erdafitinib
Terminated NCT03115801 - A Phase II Randomized Trial of Immunotherapy Plus Radiotherapy in Metastatic Genitourinary Cancers Phase 2
Active, not recruiting NCT03854474 - Testing the Addition of Tazemetostat to the Immunotherapy Drug, Pembrolizumab (MK-3475), in Advanced Urothelial Carcinoma Phase 1/Phase 2
Terminated NCT02693717 - Pemetrexed Disodium in Treating Patients With Previously Treated Metastatic Urothelial Cancer Phase 2
Recruiting NCT04848519 - Immune Checkpoint Inhibitors With or Without Propranolol Hydrochloride In Patients With Urothelial Carcinoma Phase 2
Active, not recruiting NCT04724018 - Sacituzumab Govitecan Plus EV in Metastatic UC Phase 1
Terminated NCT04003610 - Pemigatinib + Pembrolizumab vs Pemigatinib Alone vs Standard of Care for Urothelial Carcinoma (FIGHT-205) Phase 2
Recruiting NCT04383067 - A Phase 2, Single-Center, Open Label Study of Autologous, Adoptive Cell Therapy Following a Reduced Intensity, Non-myeloablative, Lymphodepleting Induction Regimen in Metastatic Urothelial Carcinoma Patients Phase 2
Recruiting NCT05733000 - CPI-613 (Devimistat) in Combination With Hydroxychloroquine and 5-fluorouracil or Gemcitabine in Treating Patients With Advanced Chemorefractory Solid Tumors Phase 2