Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Transitional Cell

Carcinoma, Renal Cell

Urinary Bladder Neoplasms

Kidney Neoplasms

Urethral Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Kidney Diseases

Urethral Diseases

Transitional Cell Carcinoma

Renal Cell Carcinoma

All Drugs and Chemicals

Amino Acids

Tyrosine Kinase Inhibitors

Tyrosine

Administered orally at a dose of 60 mg once daily on each day of a 28-day cycle.

60 mg by mouth (PO) daily each 28 day cycle. Treatment continues until toxicity or disease progression.

Cabozantinib

Andrea B Apolo, M.D.

Background:

- Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It is approved for medullary thyroid cancer. However, studies have shown that prostate and ovarian tumors respond to it. Researchers want see if cabozantinib can be a safe and effective treatment for urothelial cancer.

Objectives:

- To test the safety and effectiveness of cabozantinib for advanced urothelial cancer.

Eligibility:

- Individuals at least 18 years of age who have advanced urothelial cancer that has not responded to standard treatments.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Tumor tissue samples will also be collected. Imaging studies will also be performed.
* Participants will take cabozantinib by mouth once per day on each day of a 28-day cycle.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Participants will continue to take the study drug for as long as their cancer does not worsen and side effects are not too severe.

Background:

* In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common malignancy in men and the ninth most common in women with an estimated 69,250 new cases and 14,990 deaths in the year 2011
* There is no Food and Drug Administration (FDA)-approved second line drug for patients with metastatic Urothelial Cancer (UC)
* Multiple lines of evidence support targeting angiogenesis in UC
* In human bladder cancer, overexpression of tyrosine-protein kinase (c-Met)/Axl/platelet derived growth factor receptor- (PDGFR)-alpha or c-Met alone showed significant correlation with poor survival
* Cabozantinib is a new chemical entity that inhibits multiple receptor tyrosine kinases with growth-promoting and angiogenic properties.
* The primary targets of cabozantinib are mesenchymal epithelial transition factor (MET), vascular endothelial factor receptor 2 (VEGFR2), and rearranged during transfection (RET)

Objectives:

- To determine the response rate of cabozantinib in patients with progressive urothelial cancer who have received prior cytotoxic chemotherapy

Eligibility:

* Patients in cohort 1 must have a histologically confirmed diagnosis of metastatic, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.
* Patients in cohort 2 must have a histologically confirmed diagnosis of bone only metastatic, urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.
* Patients in cohort 3 must have a histologically confirmed diagnosis of non-transitional cell carcinoma cancer (including but not limited to squamous cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid) of the bladder, urethra, ureter, or renal pelvis.
* Patients must have been previously treated, as defined by treatment with at least one prior cytotoxic chemotherapy regimen or agent. Patients may have received any number of prior cytotoxic agents.
* 18 years of age or older.

Design:

* A maximum of 71subjects will be enrolled in this open label, non-randomized, phase II trial of 60 mg each day of cabozantinib. Up to 50 patients will be accrued to cohort 1 (metastatic, progressive urothelial cancer. The remainder will be enrolled on exploratory cohorts 2 \& 3, bone only metastatic urothelial disease and non transitional cell carcinoma (TCC) bladder cancer respectively, during the time the study is accruing patients for cohort 1. Note: Patients who tolerate cabozantinib at 60 mg daily during the first 2 cycles (first restaging time period) without (Bullet) grade 2 toxicity may undergo dose escalation to 80 mg daily at the discretion of the Principal Investigator.
* A Simon 2 stage design with alpha=0.05 and beta = 0.10 as acceptable error probabilities. Initially 21 subjects will be enrolled and followed for progression. If 2 or more of cohort 1 subjects experiences a response, enrollment will continue until a total of 41 evaluable subjects with progressive urothelial cancer have been entered. 2-3 patients per month may enroll on this trial; thus, 2 to 3 years is anticipated as the accrual period.
* Each patient will undergo response evaluation assessments with chest abdomen pelvis computed tomography (CAP CT) (or magnetic resonance imaging (MRI)) with or without 18F-Sodium Fluoride (Na18F) positron emission tomography (PET CT) every 8 weeks while on active protocol therapy starting at baseline. Patients will undergo investigational Fludeoxyglucose, (FDG) PET/CT and PET/MRI (optional) at baseline, week 4 and week 8.

Cabozantinib for Advanced Urothelial Cancer

A Phase II Study of Cabozantinib (XL184) in Patients With Advanced/Metastatic Urothelial Carcinoma

Complete Response (CR) or Partial Response (PR) to Cabozantinib (XL184) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure the timing from the study start until death.

Measure the timing of maintaining stable disease or partial response until disease progression assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest um diameters while on study.

Grade 4 toxicity hypomagnesium experienced by participants related to Cabozantinib. Grade 4 toxicity is life-threatening consequences; urgent intervention indicated.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

National Cancer Institute (NCI)

Principal Investigator

All serious and non-serious adverse events are reported regardless of attribution. We did not group the adverse events by cohort because we did not expect the cohorts to experience different adverse events as they were all getting the same medication at the same dose. And 68/69 participants were analyzed because one participant was enrolled and deemed ineligible prior to treatment.

Cohort 1 - (urothelial progressive disease) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.

Cohort 2 (Bone-only) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.

Cohort 3 (Rare histologies) Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.

All Participants

Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.

Cohort 1 - (Urothelial Progressive Disease)

Cohort 2 (Bone-only)

Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.

Cohort 3 (Rare Histologies)

Total

Age, Continuous

Sex: Female, Male

White

African American

Asian

Unknown

Race/Ethnicity was not captured for one participant.

Race/Ethnicity, Customized

United States

Region of Enrollment

Bladder

Upper tract:renal pelvis or ureter

Bladder & upper tract

Primary Tumor Site

Age, Categorical is not reported because it was not captured by cohorts.

Dr. Andrea Apolo

42/50 were analyzed in cohort 1 because 5 participants withdrew, 2 were taken off study for adverse events and 1 was ineligible. In cohort 2, 5/6 patients were analyzed because 1 withdrew; and in cohort 3, 10/13 patients were analyzed because 1 withdrew and 2 were taken off study due to adverse events.

Percentage of Participants With Overall Response

Overall Survival

Progression Free Survival

We did not group the adverse events by cohort because we did not expect the cohorts to experience different adverse events as they were all getting the same medication at the same dose. And 68/69 participants were analyzed because one participant was enrolled and deemed ineligible prior to treatment.

Number of Participants With Grade 4 Toxicity Hypomagnesium Related to Cabozantinib

Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution

Overall Study

Ureteral Neoplasms

Ureteral Diseases

Antineoplastic Agents

Paclitaxel

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

TOCOSOL Paclitaxel

Phase 2B, multicenter study evaluating the safety and efficacy of weekly TOCOSOL Paclitaxel in taxane-naive patients receiving second line chemotherapy for metastatic or locally advanced, unresectable transitional cell carcinoma of the urothelium

TOCOSOL(TM) Paclitaxel in Metastatic or Locally Advanced Unresectable Transitional Cell Carcinoma of the Urothelium

A Phase 2 Multicenter Evaluation of the Safety and Efficacy of TOCOSOL(TM) Paclitaxel (S-8184 Paclitaxel Injectable Emulsion) in Patients With Metastatic or Locally Advanced, Unresectable Transitional Cell Carcinoma of the Urothelium

Achieve Life Sciences

Crizotinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Crizotinib was administered orally at 250mg twice daily

Earle Burgess, MD

This is a single arm two-stage phase II study with crizotinib (Xalkori®) in the treatment of subjects with metastatic urothelial cancer of the bladder, upper (ureter or renal pelvis) or lower (urethra) urinary tracts. The purpose of this study is to see if this experimental drug has a potential benefit in subjects with stage 4 urothelial cancer.

This study tests crizotinib used alone in subjects with urothelial cancer, previously treated with chemotherapy, and whose tumors have certain proteins. Proteins are complex natural substances essential to the structure and function of all living cells. These proteins, c-MET or RON, may trigger molecular pathways that are involved in the growth and spread of bladder or upper urinary tract cancer. Crizotinib is a drug taken by mouth that blocks these pathways. Early laboratory research suggests that crizotinib may benefit patients with urothelial and other cancers with these molecular pathways.

This is a single arm two-stage phase II study designed to evaluate the objective response rate in subjects with metastatic urothelial cancer demonstrating c-MET or RON overexpression who have received prior therapy with a cisplatin or carboplatin containing regimen.

Subjects will be recruited at Levine Cancer Institute (LCI) and other participating sites.

Immunohistochemistry will be utilized to define tumor sample c-MET and RON protein expression patterns for assignment into molecular cohorts as described in section 12.1.

In the first stage of this study, subjects will be enrolled in parallel to three molecularly defined cohorts as follows:

1. c-MET high (\>50%), RON null (0-9%) (n = 14 subjects)
2. c-MET-positive (10-100%), RON-positive (10-100%) (n = 7 subjects)
3. c-MET null (0-9%), RON-positive (10-100%) (n = 7 subjects)

All enrolled subjects will continue with study treatment until criteria for treatment discontinuation has been met.

If Stage 1 response criteria are met in a cohort, the cohort may be considered for expansion, and additional subjects (16 in Cohort 1 or 25 in Cohorts 2 or 3) may then be enrolled into that cohort in Stage 2. An expansion cohort will be defined by the Sponsor- Investigator following review of all available trial data which will be conducted after the first Stage 1 cohort has completed accrual and at least every six months thereafter until all Stage 1 cohorts have completed accrual.

If more than one cohort meets Stage 1 response criteria (2 responses out of 14 subjects for Cohort 1 or 1 response out of 7 subjects for each of Cohorts 2 and 3), then the cohort showing the highest response rate will be given highest consideration for expansion.

LCI-GU-URO-CRI-001: Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer

LCI-GU-URO-CRI-001: A Phase II Study of Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer

Overall response will be determined as the best treatment response for each patient as a binary variable indicating whether or not the patient achieved a Complete Response (CR) or Partial Response (PR) as determined by RECIST v1.1 criteria. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1):Complete Response (CR) is the disappearance of all lesions (target and non target); Partial Response (PR) is at least 30% decrease in the sum of the diameters of target lesions from baseline and no new lesions or unequivocal progression in non target lesions from baseline; Stable Disease (SD) is neither sufficient shrinkage in target lesions to qualify for PR (less than 30% decrease) nor sufficient increase in target lesions (versus smallest sum of diameters) to qualify for PD (less than 20% increase), with no new lesions or unequivocal progression in non target lesions from baseline. For the purposes of response determination, confirmatory scan for CR and PR is required.

Overall survival was defined as the duration from enrollment date to the date of death from any cause. Subjects who were alive or lost to follow-up at the time of the analysis were censored at the last known date they were alive.

PFS was defined as duration of time from enrollment to the study to time of progression or death. Disease progression (PD) can be objectively determined as per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors, where PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in non-target lesion, or the appearance of new lesions) or progression can be subjective as determined by the investigator. Evidence for subjective progressions must be documented in medical records. For surviving subjects who do not have documented PD, PFS will be censored at last radiologic assessment. For subjects who receive subsequent anti-cancer therapy prior to documented PD, PFS will be censored at last radiologic assessment prior to commencement of subsequent therapy. Subjects who experience a PFS event following an interval equal to two or more scheduled assessments will be censored at date of last assessment prior to first missed assessment.

Pfizer

Wake Forest University Health Sciences

Note, as there were no subjects enrolled in Cohort 2, the number of participants at risk for All-Cause Mortality, Serious Adverse Events, and Adverse Events in Cohort 2 is zero.

c-MET high (\> 50%), RON null (0-9%)

Crizotinib: All arms will receive crizotinib.

Cohort 1

c-MET + (10-100%), RON + (10-100%)

Crizotinib: All arms will receive crizotinib.

Cohort 2

c-MET null (0-9%), RON + (10-100%)

Crizotinib: All arms will receive crizotinib.

Cohort 3

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Measure Description: ECOG Scale of Performance Status, developed by the Eastern Cooperative Oncology Group, where 0 indicates subject is fully active, able to carry on all pre-disease performance without restriction and where 1 indicates subject is restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.

ECOG at Baseline

c-MET protein expression was assessed by immunohistochemistray as percent of tumor cells staining positive.

c-MET Expression, %

RON protein expression was assessed by immunohistochemistray as percent of tumor cells staining positive.

RON Expression, %

Note, there were no subjects enrolled to cohort 2 as no subjects were enrolled who were c-MET + and RON+. Therefore, no baseline results are available for Cohort 2.

Chair of Biostatistics Department

This group contains all subjects enrolled on the study, who received crizotinib, pooling the subjects in the three molecularly defined cohorts.

Total Enrolled Study Cohort

Study was designed to evaluate objective response rate overall for all enrolled subjects and not separately by molecular cohorts. Efficacy analyses were conducted on the population of subjects who began crizotinib treatment. Analysis of overall response rate was conducted on those patients in the efficacy population with measurable disease present at baseline.

Overall Response

Study was designed to evaluate outcomes overall for all enrolled subjects and not separately by molecular cohorts. Efficacy analyses were conducted on the population of subjects who began crizotinib treatment.

c-MET + (10-100%), RON + (10-100%)

Crizotinib was administered orally at 250 mg twice daily.

c-MET null (0-9%), RON + (10-100%)

Crizotinib was administered orally at 250 mg twice daily.

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Gland and Hormone Related Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Pancreatic Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Pancreatic Cancer

Ovarian Cancer

Ovarian Epithelial Cancer

Urethral Cancer

Gemcitabine

Carboplatin

Lenalidomide

Antimetabolites

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Standard of Care plus escalating doses of Lenalidomide

Lenalidomide Lead for 14 days + standard of care + lenalidomide MTD

Escalating Doses starting at 2.5 po daily up to 25 mg po daily until MTD is reached.

Background:

- Gemcitabine and carboplatin are chemotherapy drugs used to treat several types of cancer, including cancer of the pancreas, bladder, ovaries, and lung. Lenalidomide, a drug that prevents the growth of new blood vessels in tumors, has been approved for treatment of certain blood cancers, but it has not yet been approved for use in combination with gemcitabine and carboplatin. Researchers are interested in determining the safest and most effective dose of this combined form of chemotherapy for solid tumors, particularly for urothelial cancer (tumors of the bladder, urethra, ureter, or renal pelvis).

Objectives:

* To evaluate the safety and effectiveness of combined lenalidomide, gemcitabine, and carboplatin as a treatment for solid tumor cancers.
* To evaluate the safety and effectiveness of combined lenalidomide, gemcitabine, and carboplatin as a treatment for urothelial (bladder) cancer.

Eligibility:

* Individuals at least 18 years of age who have been diagnosed with solid tumors that have not responded to standard treatments.
* Individuals at least 18 years of age who have been diagnosed with urothelial cancer that has not responded to standard treatments.

Design:

* Participants will be screened with a physical examination, medical history, blood tests, and tumor imaging studies.
* Participants with urothelial cancer will receive lenalidomide alone for the first 14 days of a 21-day cycle before starting the first full treatment cycle.
* All participants will receive gemcitabine on days 1 and 8, and carboplatin on day 1 only, of every 21-day treatment cycle. Lenalidomide will be taken daily at home for the first 14 days of each cycle. Participants will be asked to take aspirin or other medications to prevent the possibility of blood clots.
* Participants may receive up to six cycles of treatment with this combination. If after six cycles the cancer has not grown or has shrunk, participants may continue to take lenalidomide alone for an additional 6 months (total of 12 months of therapy) or until the cancer recurs.
* Participants will be monitored with blood samples, physical examinations, and tumor imaging studies through the cycles of treatment.
* After the end of the last treatment cycle, participants will have followup visits every 3 months for the next 18 months, then every 6 months for another 18 months, and then yearly.

BACKGROUND:

* Gemcitabine plus carboplatin is an accepted first-line therapy in patients unfit for cisplatin chemotherapy with metastatic urothelial carcinoma or other solid tumor malignancies.
* Both non-clinical and clinical data support targeting angiogenesis in urothelial carcinoma and other solid tumors.
* Both non-clinical and clinical data support targeting the immune system in urothelial carcinoma and other solid tumors.
* Lenalidomide has both anti-angiogenic and potent immunomodulatory properties.
* Lenalidomide has been safely coadministered with cytotoxic therapy in patients with solid tumors and non-clinical studies demonstrate possible synergy with gemcitabine.

OBJECTIVES:

Primary

- To establish the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of lenalidomide which can be safely combined with gemcitabine and carboplatin in patients with advanced/metastatic UC and other solid tumors that are unfit for cisplatin.

Secondary

* To preliminarily evaluate the progression free survival, response rate and overall survival in patients with advanced/metastatic UC and other solid tumors treated with the combination of lenalidomide, gemcitabine, and carboplatin.
* To determine the effects of treatment on a set of 4 laboratory parameters (including Treg, sIL-2R, VEGF and CTC.) in the expansion cohort of patients with bladder cancer treated at the MTD.

ELIGIBILITY:

* Adult patients with histologic documentation of an advanced solid tumor with unresectable or metastatic disease.
* Urothelial cancer patients should be ineligible for cisplatin based on one or more of the following:
* Calculated creatinine clearance of \< 60 mL/min (but greater than or equal to 30 mL/min)
* Solitary kidney
* Karnofsky Performance Status \< 80%
* No prior combination systemic chemotherapy for metastatic disease allowed for patients with UC, except single agent radiosensitizing chemotherapy (not considered prior systemic therapy), or prior neoadjuvant or adjuvant systemic chemotherapy (including cisplatin-based) is allowed provided if it was completed (Bullet) 6 months prior to diagnosis of metastatic disease; or prior intravesical therapy is permitted. Up to 1 line of chemotherapy in the metastatic setting is permitted for non UC patients.
* Laboratory evaluation must meet safety requirements, including a creatinine clearance greater than 30 using the Cockroft-Gault formula; may not be pregnant or breast-feeding.

DESIGN:

* This is a single-institution phase I study of gemcitabine (1000 mg/m2 on days 1 and 8) and carboplatin (AUC 5 on day 1) plus escalating doses of lenalidomide (GCL) in patients with advanced/metastatic UC and other solid tumors ineligible for cisplatin therapy. Lenalidomide will be administered once daily on days 1 through 14 every 21 days at escalating dose. An expansion cohort at the MTD of an additional 15 patients with bladder cancer will be enrolled in order to determine whether there are differences between pre-treatment and post-treatment levels of the following parameters: Treg, sIL- 2R, VEGF and CTC.
* Patients will receive a total of 6 cycles of gemcitabine and carboplatin in combination with lenalidomide unless disease progression or unacceptable toxicity occurs. Patients who achieve stable disease, a partial response, or a complete response after completion of 6 cycles will be eligible to continue lenalidomide alone at the same dose and schedule until disease progression. Restaging evaluations will occur after every 3 cycles of treatment (approximately 9 weeks).
* Based on a standard 3+3 design with 4 dose levels per cohort, a maximum of 24 patients, with the potential for an additional 3 patients with CrCl\>60 mL/min, may need to be evaluated to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of lenalidomide in this combination therapy. With an expansion cohort of 15 patients at MTD, a total of 42 subjects may be enrolled over 1.5 -3 years.

Gemcitabine, Carboplatin, and Lenalidomide for Treatment of Advanced/Metastatic Urothelial Cancer and Other Solid Tumors

A Phase I Study of Gemcitabine, Carboplatin and Lenalidomide (GCL) for Treatment of Patients With Advanced/Metastatic Urothelial Carcinoma (UC) and Other Solid Tumors

.All IPD recorded in the medical record will be shared with intramural investigators upon request

any grade 3 or 4 toxicity with exceptions listed in protocol; MTD is one dose level below the dose that induces DLT in more than 1/6 patients

Percentage of patients whose cancer shrinks or disappears after treatment

time during which a patient shows no signs or symptoms of the growth or the spreading of a tumor

The length of time from the start of treatment that patients are still alive

determine the effects of treatment on a set of 5 laboratory parameters (including Treg, sIL-2R, VEGF, CTC and CEC in the expansion cohort of patients with bladder cancer treated at the MTD

Pelvic Neoplasms

Pembrolizumab

Antibodies

Cisplatin

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Dose Escalation: Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days

Enfortumab vedotin on days 1 and 8 plus pembrolizumab on day 1 every 21 days

Enfortumab vedotin on days 1 and 8 plus cisplatin on day 1 every 21 days

Enfortumab vedotin on days 1 and 8 plus carboplatin on day 1 every 21 days

Enfortumab vedotin and gemcitabine on days 1 and 8 every 21 days

Enfortumab vedotin on days 1 and 8 plus cisplatin or carboplatin on day 1 plus pembrolizumab on day 1 every 21 days

Enfortumab vedotin on days 1 and 8 every 21 days

Enfortumab vedotin on days 1 and 8 and every 21 days

Intravenous (IV) infusion on days 1 and 8 every 21 days

enfortumab vedotin (EV)

pembrolizumab

cisplatin

carboplatin

IV infusion on days 1 and 8 every 21 days

gemcitabine

Changting Meng, MD

Jason Lukas, MD, PhD

This study will test an experimental drug (enfortumab vedotin) alone and with different combinations of anticancer therapies. Pembrolizumab is an immune checkpoint inhibitor (CPI) that is used to treat patients with cancer of the urinary system (urothelial cancer). This type of cancer includes cancer of the bladder, renal pelvis, ureter or urethra. Some parts of the study will look at locally advanced or metastatic urothelial cancer (la/mUC), which means the cancer has spread to nearby tissues or to other areas of the body. Other parts of the study will look at muscle-invasive bladder cancer (MIBC), which is cancer at an earlier stage that has spread into the muscle wall of the bladder. This study will look at the side effects of enfortumab vedotin alone and with other anticancer therapies. A side effect is a response to a drug that is not part of the treatment effect. This study will also test if the cancer shrinks with the different treatment combinations.

This study will examine the safety and anticancer activity of enfortumab vedotin (EV) given intravenously as monotherapy and in combination with other anticancer therapies as first line (1L) and second line (2L) treatment for patients with urothelial cancer. The primary goal of the study is to determine the safety, tolerability, and efficacy of enfortumab vedotin alone and in combination with pembrolizumab and/or chemotherapy. The study will be conducted in multiple parts:

Locally advanced or metastatic urothelial cancer:

* Dose escalation
* Expansion

  * Part 1: Cohorts A and Optional B
  * Part 2: Cohorts D, E, and Optional F
  * Part 3: Cohort G.
* Randomized Cohort K

  * EV Monotherapy Arm
  * EV Combination Arm

Muscle invasive bladder cancer:

* Cohort H
* Optional Cohort J
* Cohort L

multi-cohort, open-label, multicenter study, global

A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer

A Study of Enfortumab Vedotin (ASG-22CE) as Monotherapy or in Combination With Other Anticancer Therapies for the Treatment of Urothelial Cancer

Descriptive statistics will be used to summarize results.

The proportion of patients with confirmed complete response (CR) or partial response (PR) according to RECIST 1.1

The proportion of patients with absence of viable tumor tissue at the time of radical cystectomy.

Incidence of DLTs (dose-escalation expansion Cohorts D, E, F, and the first 6 patients of Cohort G).

The proportion of patients with confirmed CR or PR according to RECIST 1.1.

The proportion of patients with confirmed CR or PR according to RECIST 1.1

The proportion of patients with confirmed CR or PR according to iRECIST.

Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1.

Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1

Proportion of patients with CR, PR, or SD according to iRECIST.

The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD per RECIST 1.1) or to death due to any cause, whichever comes first.

The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD per RECIST 1.1 or to death due to any cause, whichever comes first

The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD per iRECIST or to death due to any cause, whichever comes first.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cabozantinib for Advanced Urothelial Cancer	NCT01688999	Urothelial Carc... Urethral Neopla... Urinary Bladder... Kidney Neoplasm...	Cabozantinib	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
TOCOSOL(TM) Paclitaxel in Metastatic or Locally Advanced Unresectable Transitional Cell Carcinoma of the Urothelium	NCT00077688	Bladder Neoplas... Ureteral Neopla... Urethral Neopla... Carcinoma, Tran...	TOCOSOL Paclita...	18 Years -	Achieve Life Sciences
LCI-GU-URO-CRI-001: Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer	NCT02612194	Urinary Bladder... Ureteral Neopla... Urethral Neopla...	Crizotinib	18 Years -	Wake Forest University Health Sciences
Gemcitabine, Carboplatin, and Lenalidomide for Treatment of Advanced/Metastatic Urothelial Cancer and Other Solid Tumors	NCT01352962	Urethral Neopla... Neoplasms, Uret... Cancer of the U... Urethral Cancer	Gemcitabine Carboplatin Lenalidomide	18 Years -	National Institutes of Health Clinical Center (CC)
A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer	NCT03288545	Carcinoma, Tran... Urinary Bladder... Urologic Neopla... Renal Pelvis Ne... Urothelial Canc... Ureteral Neopla... Urethral Neopla...	enfortumab vedo... pembrolizumab cisplatin carboplatin gemcitabine	18 Years -	Astellas Pharma Inc
Gemcitabine, Carboplatin, and Lenalidomide for Treatment of Advanced/Metastatic Urothelial Cancer and Other Solid Tumors	NCT01352962	Urethral Neopla... Neoplasms, Uret... Cancer of the U... Urethral Cancer	Gemcitabine Carboplatin Lenalidomide	18 Years -	National Institutes of Health Clinical Center (CC)
LCI-GU-URO-CRI-001: Crizotinib in Patients With c-MET or RON-Positive Metastatic Urothelial Cancer	NCT02612194	Urinary Bladder... Ureteral Neopla... Urethral Neopla...	Crizotinib	18 Years -	Wake Forest University Health Sciences

Spots Global Cancer Trial Database for urethral neoplasms