- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03047213
Sapanisertib in Treating Patients With Locally Advanced or Metastatic Bladder Cancer With TSC1 and/or TSC2 Mutations
An Open Label, Multicenter, Single Arm Phase II Study to Evaluate the Activity and Tolerability of the Novel mTOR Inhibitor, MLN0128 (TAK-228), in Patients With Locally Advanced or Metastatic Transitional Cell Carcinoma of the Urothelial Tract Whose Tumors Harbor a TSC1 and/or a TSC2 Mutation
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
PRIMARY OBJECTIVE:
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 or TSC2 mutation.
II. To evaluate progression free survival (PFS) and overall survival (OS).
EXPLORATORY 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. Cycles 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 and every 6 months thereafter.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Locations
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California
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Los Angeles, California, United States, 90033
- USC / Norris Comprehensive Cancer Center
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Los Angeles, California, United States, 90033
- Los Angeles General Medical Center
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Pasadena, California, United States, 91105
- Keck Medical Center of USC Pasadena
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Sacramento, California, United States, 95817
- University of California Davis Comprehensive Cancer Center
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-
Connecticut
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New Haven, Connecticut, United States, 06520
- Yale University
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New Haven, Connecticut, United States, 06510
- Smilow Cancer Center/Yale-New Haven Hospital
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-
Illinois
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Chicago, Illinois, United States, 60611
- Northwestern University
-
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Kansas
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Fairway, Kansas, United States, 66205
- University of Kansas Clinical Research Center
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-
Maryland
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Baltimore, Maryland, United States, 21287
- Johns Hopkins University/Sidney Kimmel Cancer Center
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-
Massachusetts
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Boston, Massachusetts, United States, 02215
- Dana-Farber Cancer Institute
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Boston, Massachusetts, United States, 02115
- Brigham and Women's Hospital
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Michigan
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Ann Arbor, Michigan, United States, 48109
- University of Michigan Comprehensive Cancer Center
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Nebraska
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Bellevue, Nebraska, United States, 68123
- Nebraska Medicine-Bellevue
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Omaha, Nebraska, United States, 68198
- University of Nebraska Medical Center
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Omaha, Nebraska, United States, 68118
- Nebraska Medicine-Village Pointe
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North Carolina
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Chapel Hill, North Carolina, United States, 27599
- UNC Lineberger Comprehensive Cancer Center
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Pennsylvania
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Pittsburgh, Pennsylvania, United States, 15232
- University of Pittsburgh Cancer Institute (UPCI)
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Tennessee
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Nashville, Tennessee, United States, 37232
- Vanderbilt University/Ingram Cancer Center
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Nashville, Tennessee, United States, 37204
- Vanderbilt Breast Center at One Hundred Oaks
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Utah
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Salt Lake City, Utah, United States, 84112
- Huntsman Cancer Institute/University of Utah
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- Must have a histologically confirmed transitional cell carcinoma (TCC, also known as urothelial carcinoma), locally advanced or metastatic
- Patient must have TCCs tumors harboring a TSC1 or TSC2 mutation identified by a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory
- Unless the pre-screening was performed at Yale Clinical Molecular Pathology Lab (YCMPL), 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) along with a buccal swab; if the number of slides is less than 10, a biopsy should be considered; if a biopsy is deemed unsafe, the case may be discussed with the study principal investigator (PI) and approval must be given for eligibility
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 x institutional upper limit of normal (ULN) and =< 5 ULN if liver metastases are present
- Creatinine =< 1.5 x upper normal institutional limits (UNL) OR creatinine clearance >= 40 mL/min based either on Cockcroft-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 or less, and patients whose FBS can be brought in this range with medical therapy are eligible for trial inclusion
The effects of MLN0128 (TAK-228) on the developing human fetus are unknown; fertility and developmental studies with MLN0128 (TAK-228) have not been conducted; on the basis of potential hazard of other mTOR inhibitors (i.e., rapamycin and other rapalogs) on the developing fetus, 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., United States product insert [USPI], summary of product characteristics [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, immunotherapy, or investigational therapy, within 4 weeks (6 weeks for nitrosoureas or mitomycin C), or palliative radiotherapy within 2 weeks prior to the first dose of the study drug
- Patients who have not recovered from adverse events due to prior anti-cancer therapy to grade 1 or baseline; patients with stable, controlled grade 2 adverse events (AEs) such as peripheral neuropathy, hypothyroidism, hypertension, adrenal insufficiency or alopecia are allowed after discussing with the PI
Patients with known symptomatic, untreated central nervous system (including brain, spinal cord); patients who have a history of brain/central nervous system (CNS) metastasis are eligible for the study provided that all the following criteria are met:
- Brain/CNS 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
- 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 (excluding rate controlled atrial fibrillation/flutter), or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant and breastfeeding women are excluded from this study because fertility and developmental studies with MLN0128 (TAK-228) have not been conducted and there is a potential risk for adverse events including teratogenicity and risk of abortion; 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 because of the potential for pharmacokinetic interactions with MLN0128 (TAK-228); however, HIV patients treated with regimens that have low CYP450 inhibition may be allowed as long as the patient's general health and CD4 counts are within acceptable levels
- 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)
- 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
- New York Heart Association (NYHA) class III or IV heart failure
- Placement of a pacemaker for control of rhythm
- 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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (sapanisertib)
Patients receive sapanisertib PO QD on days 1-28.
Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
|
Given PO
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Overall response rate (TSC1 patients)
Time Frame: Up to 4 weeks after last dose of study treatment
|
Up to 4 weeks after last dose of study treatment
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of toxicity (TSC1 patients)
Time Frame: Up to 4 weeks after last dose of study treatment
|
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
|
Progression-free survival (PFS) (TSC1 patients)
Time Frame: Time from start of treatment to date of progression or death, whichever occurs first, assessed up to 1 year
|
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 1 year
|
Overall survival (OS) (TSC1 patients)
Time Frame: Time from start of treatment to time of death from any cause, assessed up to 1 year
|
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 1 year
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall response rate (TSC2 patients)
Time Frame: Up to 4 weeks after last dose of study treatment
|
Up to 4 weeks after last dose of study treatment
|
|
Incidence of toxicity (TSC2 patients)
Time Frame: Up to 4 weeks after last dose of study treatment
|
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
|
Progression-free survival (TSC2 patients)
Time Frame: Time from start of treatment to date of progression or death, whichever occurs first, assessed up to 1 year
|
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 1 year
|
Overall survival (TSC2 patients)
Time Frame: Time from start of treatment to time of death from any cause, assessed up to 1 year
|
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 1 year
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Joseph W Kim, Yale University Cancer Center LAO
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Urologic Neoplasms
- Urogenital Neoplasms
- Neoplasms by Site
- Urologic Diseases
- Neoplasms, Glandular and Epithelial
- Urinary Bladder Diseases
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Male Urogenital Diseases
- Carcinoma
- Urinary Bladder Neoplasms
- Carcinoma, Transitional Cell
Other Study ID Numbers
- NCI-2015-00121 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- UM1CA186689 (U.S. NIH Grant/Contract)
- 9767 (Other Identifier: CTEP)
- 1505015958
- 2000021268
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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