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Gemcitabine, Cisplatin, Plus Lenalidomide as First-line Therapy for Patients With Metastatic Urothelial Carcinoma

Primary Purpose

Urinary Bladder Neoplasms

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Lenalidomide

About this trial

This is an interventional treatment trial for Urinary Bladder Neoplasms focused on measuring Bladder Cancer, Urothelial Cancer, Chemotherapy, First-line, Metastatic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
Age > 18 years at the time of consent.
Karnofsky Performance Status of ≥ 70%.
Histological or cytological proof of transitional cell carcinoma of the urothelial tract. The primary site may include: urethra, bladder, ureters, and renal pelvis. Patients with mixed histologies may be enrolled provided that transitional cell carcinoma is the predominant histology.
Measurable disease according to RECIST or unresectable disease (cT4b).
All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control.
Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).
Adequate organ function as determined by the following laboratory values:
- Hemoglobin (Hgb) > 9 g/dL
- Platelets > 100 x 1,000,000,000/L
- Absolute neutrophil count (ANC) > 1.5 x 1,000,000,000/L
- Calculated creatinine clearance of > 60 cc/min using the Cockcroft-Gault formula
- Bilirubin < 1.5 x ULN
- Aspartate aminotransferase (AST, SGOT) < 1.5 X ULN (< 5 X ULN if patient has hepatic metastases)

Exclusion Criteria:

Has had prior treatment with systemic chemotherapy for metastatic disease (prior intravesical therapy is permitted; prior neoadjuvant/adjuvant chemotherapy permitted if completed ≥ 1 year from study entry)
Has received prior lenalidomide.
Has had major surgery within 30 days of starting the study treatment
Has had any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism
Has active CNS metastases. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis.
Has a history of a prior malignancy
Has received anticancer therapy, radiation, or any investigational agent within 30 days prior to being registered for protocol therapy.
Pregnant or breastfeeding.
Has a clinically significant infection as judged by the treating investigator.
Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).

Sites / Locations

National Cancer Institute
Icahn School of Medicine at Mount Sinai
Huntsman Cancer Institute/University of Utah

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lenalidomide

Arm Description

capsules for oral administration

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD) of Lenalidomide

MTD was determined by testing planned increasing doses up to 25 mg daily dose on days 1-14, starting at 10mg. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in > 33% of participants. DLTs were defined as any lenalidomide-related Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0) Grade 3 or 4 adverse events

Phase II: Progression-free Survival at 1 Year

Secondary Outcome Measures

The Objective Response Rate to Treatment With Gemcitabine, Cisplatin, Plus Lenalidomide

The objective response rate as determined by Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) Disappearance of all target lesions for a period of at least one month. Partial Response (PR) At least a 30% decrease in the sum of the longest diameter of measures lesions (target lesions), taking as reference the baseline sum of the longest diameter. Stable Disease (NR/SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since the treatment started. Progressive Disease (PD) A 20% or greater increase in the sum of the longest diameter of measured lesions (target lesions), taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions

Number of Grade >=3 Adverse Events

Number of grade >=3 adverse events to assess the safety of combination therapy with gemcitabine, cisplatin plus lenalidomide as determined by the frequency and severity of adverse events as per the NCI Common Terminology for Adverse Events (CTCAE) version 4.0.

Best Overall Response

Best Overall Response to evaluate lenalidomide as maintenance treatment in patients achieving an objective response of either complete response or partial response following completion of 6 cycles of combination therapy. Complete Response (CR) - CR of target lesions and no new lesions Partial Response (PR) -PR of target lesions and no new lesions Stable Disease (SD) - SD of target lesions and no new lesions Progression Disease (PD) - any status of target lesions and new lesions

To Determine the Impact of Treatment on Peripheral Blood Immune Cell Subsets

To determine the changes in cellular immunity with lenalidomide in peripheral blood mononuclear cells including Tregs, NK, NKT cells (Berg et al JCO 2010), sIl-2R, TNF alpha (Bartlett et al BJC 2004) and markers indicative of activation, i.e. CD107a. These analyses will only be done in the phase II portion of the protocol.

To Determine the Impact of Treatment on Circulating Tumor Cells

Circulating epithelial tumor cells (CTC) will be investigated as an experimental endpoint using immunofluorescence techniques and CTC identification by positive expression of epithelial markers and a viability marker and negative expression of hematopoietic markers. These analyses will only be done in the phase II portion of the protocol.

Full Information

NCT ID

NCT01342172

First Posted

April 21, 2011

Last Updated

April 19, 2019

Sponsor

Icahn School of Medicine at Mount Sinai

Collaborators

Celgene

1. Study Identification

Unique Protocol Identification Number

NCT01342172

Brief Title

Gemcitabine, Cisplatin, Plus Lenalidomide as First-line Therapy for Patients With Metastatic Urothelial Carcinoma

Official Title

Multi-Center Phase Ib/II Trial of Gemcitabine, Cisplatin, Plus Lenalidomide as First-line Therapy for Patients With Metastatic Urothelial Carcinoma

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Terminated

Why Stopped

low accrual

Study Start Date

March 2011 (undefined)

Primary Completion Date

June 2013 (Actual)

Study Completion Date

June 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Icahn School of Medicine at Mount Sinai

Collaborators

Celgene

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The primary objectives of this study are (Phase 1) to determine in subjects with unresectable or metastatic bladder cancer who have never had chemotherapy, the dose of lenalidomide that is well-tolerated when given in combination with gemcitabine plus cisplatin and (Phase 2) to study this recommended dose in subjects to evaluate progression-free survival at 1 year. The secondary objectives will be to determine the objective response rate to treatment, and the safety of combination therapy with gemcitabine, cisplatin and lenalidomide as well as to evaluate lenalidomide as maintenance treatment in subjects achieving objective response or stable disease.

Detailed Description

Urothelial carcinoma of the urinary bladder is the second most common genitourinary malignancy. Based on the results of a large randomized study comparing MVAC with gemcitabine plus cisplatin, the latter regimen became a treatment standard based on improved tolerability. While the tolerability of chemotherapy for patients with advanced urothelial carcinoma has improved, there have been no significant improvements in efficacy since the advent of MVAC in the 1980's and novel approaches are clearly needed. The current study will explore the safety and activity of lenalidomide in combination with gemcitabine plus cisplatin as first line chemotherapy in subjects with metastatic urothelial carcinoma. The primary objective of the phase Ib portion will be to determine the recommended phase II dose of the combination of gemcitabine, cisplatin, plus lenalidomide in patients with advanced/metastatic urothelial carcinoma. The primary objective of the phase II portion will be the progression-free survival at 1 year. The secondary objectives are to evaluate the activity (as determined by objective response rate); and to determine the safety (per the Common Terminology for Adverse Events version 4.0) of combination therapy with gemcitabine, cisplatin plus lenalidomide; to evaluate lenalidomide as maintenance treatment in patients achieving an objective response or stable disease following completion of 6 cycles of combination therapy and; to determine the impact of treatment on peripheral blood immune cell subsets and circulating tumor cells. Patients will receive gemcitabine 1000 mg/m2 IV on days 1 + 8 and cisplatin 70 mg/m2 IV on day 1 of each 21 day cycle. Lenalidomide will be given orally on days 1-14 and the dose will be escalated in successive cohorts during the phase Ib portion to define the recommended phase II dose. Patients will continue gemcitabine, cisplatin, plus lenalidomide for up to 6 cycles, in the absence of disease progression or prohibitive toxicity. After completion of 6 cycles of therapy, patients who have achieved at least "stable disease" will proceed with "maintenance" lenalidomide given orally on days 1-21 of each 28-day cycle. Treatment will continue, in the absence of prohibitive toxicity, until the time of disease progression.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Urinary Bladder Neoplasms

Keywords

Bladder Cancer, Urothelial Cancer, Chemotherapy, First-line, Metastatic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

9 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Lenalidomide

Arm Type

Experimental

Arm Description

capsules for oral administration

Intervention Type

Drug

Intervention Name(s)

Lenalidomide

Other Intervention Name(s)

Revlimid

Intervention Description

Patients will receive gemcitabine 1000 mg/m2 IV on days 1 + 8 and cisplatin 70 mg/m2 IV on day 1 of each 21 day cycle. Lenalidomide will be given orally on days 1-14 and the dose will be escalated in successive cohorts during the phase Ib portion to define the recommended phase II dose. Patients will continue gemcitabine, cisplatin, plus lenalidomide for up to 6 cycles, in the absence of disease progression or prohibitive toxicity. After completion of 6 cycles of therapy, patients who have achieved at least "stable disease" will proceed with "maintenance" lenalidomide given orally on days 1-21 of each 28-day cycle. Treatment will continue, in the absence of prohibitive toxicity, until the time of disease progression.

Primary Outcome Measure Information:

Title

Maximum Tolerated Dose (MTD) of Lenalidomide

Description

Time Frame

after 1 cycle (each cycle is 21 days)

Title

Phase II: Progression-free Survival at 1 Year

Time Frame

1 year

Secondary Outcome Measure Information:

Title

The Objective Response Rate to Treatment With Gemcitabine, Cisplatin, Plus Lenalidomide

Description

Time Frame

After 2 cycles (a cycle is 21 days)

Title

Number of Grade >=3 Adverse Events

Description

Time Frame

Day 1 and Day 8 of each treatment cycle; 21 days after the last dose of Lenalidomide

Title

Best Overall Response

Description

Time Frame

168 days

Title

To Determine the Impact of Treatment on Peripheral Blood Immune Cell Subsets

Description

Time Frame

Day 1 of Cycle 0 and Day 1 of Cycle 2 (each Cycle is 21 days)

Title

To Determine the Impact of Treatment on Circulating Tumor Cells

Description

Time Frame

Day 1 of Cycles 0, 1 and 2 (each Cycle is 21 days)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Age > 18 years at the time of consent. Karnofsky Performance Status of ≥ 70%. Histological or cytological proof of transitional cell carcinoma of the urothelial tract. The primary site may include: urethra, bladder, ureters, and renal pelvis. Patients with mixed histologies may be enrolled provided that transitional cell carcinoma is the predominant histology. Measurable disease according to RECIST or unresectable disease (cT4b). All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®. Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin). Adequate organ function as determined by the following laboratory values: Hemoglobin (Hgb) > 9 g/dL Platelets > 100 x 1,000,000,000/L Absolute neutrophil count (ANC) > 1.5 x 1,000,000,000/L Calculated creatinine clearance of > 60 cc/min using the Cockcroft-Gault formula Bilirubin < 1.5 x ULN Aspartate aminotransferase (AST, SGOT) < 1.5 X ULN (< 5 X ULN if patient has hepatic metastases) Exclusion Criteria: Has had prior treatment with systemic chemotherapy for metastatic disease (prior intravesical therapy is permitted; prior neoadjuvant/adjuvant chemotherapy permitted if completed ≥ 1 year from study entry) Has received prior lenalidomide. Has had major surgery within 30 days of starting the study treatment Has had any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism Has active CNS metastases. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. Has a history of a prior malignancy Has received anticancer therapy, radiation, or any investigational agent within 30 days prior to being registered for protocol therapy. Pregnant or breastfeeding. Has a clinically significant infection as judged by the treating investigator. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Matthew Galsky, MD

Organizational Affiliation

Icahn School of Medicine at Mount Sinai

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Cancer Institute

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

Facility Name

Icahn School of Medicine at Mount Sinai

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

Facility Name

Huntsman Cancer Institute/University of Utah

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84112

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

25052451

Citation

Agarwal N, Apolo AB, Tsao CK, Lee KM, Godbold JH, Soto R, Poole A, Gimpel-Tetra K, Lowe N, Oh WK, Galsky MD. Phase Ib/II trial of gemcitabine, cisplatin, and lenalidomide as first-line therapy in patients with metastatic urothelial carcinoma. Oncologist. 2014 Sep;19(9):915-6. doi: 10.1634/theoncologist.2014-0153. Epub 2014 Jul 22.

Results Reference

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Gemcitabine, Cisplatin, Plus Lenalidomide as First-line Therapy for Patients With Metastatic Urothelial Carcinoma

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