Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Digestive System Diseases

Gland and Hormone Related Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Pancreatic Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Urethral Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urethral Diseases

Urologic Diseases

Male Urogenital Diseases

Pancreatic Cancer

Ovarian Cancer

Ovarian Epithelial Cancer

Transitional Cell Carcinoma

Urethral Cancer

Antineoplastic Agents

All Drugs and Chemicals

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.

Andrea B Apolo, M.D.

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

National Cancer Institute (NCI)

Symptoms and General Pathology

Ureteral Neoplasms

Disease Progression

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Ureteral Diseases

TRC105

Background:

- Urothelial cancer (tumors of the bladder, urethra, ureter, or renal pelvis) often responds initially to standard chemotherapy treatments, but frequently recurs and can often spread to other parts of the body. TRC105, an experimental drug that blocks the development of the new blood vessels needed for tumor growth, may be able to shrink or stabilize urothelial cancer tumors. TRC105 has been given previously to individuals with other types of cancer, and researchers are interested in determining its safety and effectiveness in treating urothelial cancer.

Objectives:

- To determine the safety and effectiveness of TRC105 as a treatment for metastatic urothelial cancer that has not responded to standard treatments.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with urothelial cancer that has spread to other parts of the body and has not responded to standard chemotherapy.

Design:

* Participants will be screened with a physical examination, medical history, blood tests, and tumor imaging studies.
* Participants will receive TRC105 intravenously once every 2 weeks on days 1 and 15 of a 28-day treatment cycle. The first dose of TRC105 will be given over a 4-hour period; participants who do not have side effects may receive the next dose over 2 hours. If the second dose is tolerated, subsequent doses can be given over at least 1 hour.
* To help prevent known side effects of TRC105, participants will take two doses (one in the morning and one in the evening) of the steroid dexamethasone on the day before each infusion is scheduled. Participants may have additional dexamethasone 30 minutes before infusion, and may have the infusion slowed or stopped to adjust for side effects.
* Participants will be monitored with blood samples, physical examinations, and tumor imaging studies through the cycles of treatment.
* Participants will continue to take TRC105 for as long as the treatment is effective against the cancer and as long as the side effects are not severe enough to stop treatment.

BACKGROUND:

* In the United States, urothelial carcinoma (UC) of the bladder is the 4th most common malignancy in men and the 9th most common in women with an estimated 70,980 new cases and 14,330 deaths in the year 2009. Although it is chemosensitive with response proportions of over 50% with conventional cytotoxic regimens, the response durations are short and the median survival of patients with metastatic disease is approximately 14 months.
* TRC105 is a genetically engineered human/murine chimeric monoclonal antibody that inhibits angiogenesis and tumor growth via endothelial cell growth inhibition and apoptosis. TRC105 is directed against human CD105 (endoglin), an angiogenic membrane protein that is highly expressed on proliferating vasculature in solid tumors and up-regulated following anti-VEGF (vascular endothelial growth factor) therapy. Clinical studies in bladder cancer with anti-angiogenic agents have shown anti-tumor activity.
* TRC105 targets a unique mechanism for tumor angiogenesis, through modification of CD105 signaling. In patients with advanced bladder cancer that have progressed through standard chemotherapy and have no further life prolonging therapeutic options, use of this novel angiogenesis inhibitor may improve outcomes.

OBJECTIVES:

* To measure PFS (progression free survival) of TRC105 as determined by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1
* To determine the safety and toxicity of TRC105 in this patient population.
* In addition, in a preliminary fashion, response rate and overall survival of patients with metastatic urothelial carcinoma of the bladder treated with TRC105 will be estimated.

ELIGIBILITY:

* Adults with progressive advanced/metastatic urothelial carcinoma that have progressed despite treatment with prior cytotoxic chemotherapy.
* Subjects must have received at least one prior cytotoxic agent (which must have included at least one of the following: cisplatin, carboplatin, paclitaxel, docetaxel, or gemcitabine).

DESIGN:

* TRC105 will be administered at a dose of 15 mg/kg intravenously every two weeks, on days 1 and 15 of each 28 day cycle.
* Patients may continue on study as long as they are tolerating therapy and are free of disease progression.
* The study will be conducted as a two-stage optimal design (Simon 1989). With alpha=0.10 and beta=0.10 as acceptable error probabilities, the trial will target 30% as the desirable proportion of patients who are still without progression by radiographic criteria at approximately 6 months (p1=0.30), and will be considered inadequate if only a fraction consistent with 10% are without progression by the same evaluation time (p0=0.10). Initially 12 patients will be enrolled and followed for progression. If 2 or more of the first 12 patients reach 6 months without progression, then enrollment will continue until a total of 35 evaluable patients (37 total patients to allow for a small number of inevaluable patients) have been entered.

TRC105 in Adults With Advanced/Metastatic Urothelial Carcinoma

A Phase II Study of TRC105 in Adults With Advanced/Metastatic Urothelial Carcinoma

Time interval from start of treatment to documented evidence of disease progression. Progressive disease 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 progression).-

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Objective response is defined as the number of participants who meet the criteria for a complete response (CR) or a partial response (PR) per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Date of on-study to the date of death from any cause or last follow up.

Adverse events by grade, (e.g. 1 is mild, 2 is moderate, 3 is severe and 4 is life threatening) related to TRC-105.

Principal Investigator

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously

Single Arm-TRC105 in Urothelial Carcinoma

Age, Categorical

Age, Continuous

Gender

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Median Age (Range)

Karnofsky Performance Scale: 60 - requires occasional assistance, but is able to care for most of his/her needs; 70 - cares for self, unable to carry on normal activity or to do active work; 80 - normal activity with effort; some signs or symptoms of disease; 90 - able to carry on normal activity; minor signs or symptoms of disease.

Karnofsky Performance Status

Bladder

Upper urinary tract

Primary Tumor Site

Lung

Liver

Bone

Any visceral metastases

Lymph node only

Metastatic Sites of Disease

Number of Previous Therapies for Metastatic Disease

Dr. Andrea Apolo

Progression Free Survival

Number of Participants With Adverse Events

Complete response

Partial response

Objective Response

Median Overall Survival

Anemia

Anorexia

Cough

Edema (Limbs)

Epistaxis

Fatigue

Gum bleeding

Headache

Hematuria

Hypoalbuminemia

Hypophosphatemia

Increased Alanine Aminotransferase

Infusion-Related Reaction

Maculopapular Rash

Nasal Congestion

Nausea

Proteinuria

Skin Infection

Telangiectasia

Vomiting

Xerostomia

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously

Adverse events grades 1-4 (mild, moderate, severe and life threatening).

TRC105 in Urothelial Carcinoma - Adverse Events - All Grades

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously Grade 1 (mild) adverse events.

TRC105 in Urothelial Carcinoma - Adverse Events - Grade 1

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously Grade 2 (moderate) adverse events.

TRC105 in Urothelial Carcinoma - Adverse Events - Grade 2

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously Grade 3 (severe) adverse events.

TRC105 in Urothelial Carcinoma - Adverse Events - Grade 3

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously Grade 4 (life threatening) adverse events.

TRC105 in Urothelial Carcinoma - Adverse Events - Grade 4

Incidence of TRC-105-Related Adverse Events

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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)
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)
TRC105 in Adults With Advanced/Metastatic Urothelial Carcinoma	NCT01328574	Urothelial Carc... Ureteral Neopla... Ureter Cancer Neoplasm, Urete... Cancer of the U...	TRC105	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for cancer of the renal pelvis