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

This study has been terminated.
(low accrual)
Sponsor:
Collaborator:
Celgene Corporation
Information provided by (Responsible Party):
Matthew Galsky, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier:
NCT01342172
First received: April 21, 2011
Last updated: November 26, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Metastatic Urothelial Carcinoma
Drug: Lenalidomide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Multi-Center Phase Ib/II Trial of Gemcitabine, Cisplatin, Plus Lenalidomide as First-line Therapy for Patients With Metastatic Urothelial Carcinoma

Resource links provided by NLM:


Further study details as provided by Mount Sinai School of Medicine:

Primary Outcome Measures:
  • Phase I: To determine the recommended phase II dose of the combination of gemcitabine, cisplatin, plus lenalidomide [ Time Frame: Day 1 of each 21 day cycle ] [ Designated as safety issue: Yes ]
    Safety as measured by the frequency and type of adverse event as per the NCI Common Terminology for Adverse Events (CTCAE) version 4 on Day 1 of each cycle (Cycle is 21 days).

  • Phase II: Progression-free survival at 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To determine the objective response rate to treatment with gemcitabine, cisplatin, plus lenalidomide [ Time Frame: After every 2 cycles (a cycle is 21 days) ] [ Designated as safety issue: No ]
    The objective response rate as determined by Response Evaluation Criteria in Solid Tumors (RECIST). Restaging CT scans will be performed after every 2 cycles (after cycles 2, 4, and 6). Each cycle is 21 days.

  • To determine the safety of combination therapy with gemcitabine, cisplatin, and lenalidomide [ Time Frame: Day 1 and Day 8 of each treatment cycle; 21 days after the last dose of Lenalidomide ] [ Designated as safety issue: Yes ]
    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.

  • To evaluate lenalidomide as maintenance treatment in patients achieving an objective response or stable disease following completion of 6 cycles of combination therapy. [ Time Frame: 168 days ] [ Designated as safety issue: No ]
  • To determine the impact of treatment on peripheral blood immune cell subsets [ Time Frame: Day 1 of Cycle 0 and Day 1 of Cycle 2 (each Cycle is 21 days) ] [ Designated as safety issue: No ]
    We plan 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 [ Time Frame: Day 1 of Cycles 0, 1 and 2 (each Cycle is 21 days) ] [ Designated as safety issue: No ]
    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.


Enrollment: 9
Study Start Date: March 2011
Study Completion Date: June 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lenalidomide
capsules for oral administration
Drug: Lenalidomide
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.
Other Name: Revlimid

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. Age > 18 years at the time of consent.
  3. Karnofsky Performance Status of ≥ 70%.
  4. 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.
  5. Measurable disease according to RECIST or unresectable disease (cT4b).
  6. All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
  7. 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, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.
  8. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).
  9. 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:

      • Males: (140 - Age in years) × Actual Body Weight in kg

        72 × Serum Creatinine (mg/dL)

      • Females: Estimated creatinine clearance for males × 0.85
    • Bilirubin < 1.5 x ULN
    • Aspartate aminotransferase (AST, SGOT) < 1.5 X ULN (< 5 X ULN if patient has hepatic metastases)

FCBP* A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Exclusion Criteria:

  1. 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)
  2. Has received prior lenalidomide.
  3. Has had major surgery within 30 days of starting the study treatment
  4. 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
  5. Has active CNS metastases. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis.

    i) NOTE: A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic

  6. Has a history of a prior malignancy with the exception of: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, clinically localized prostate cancer treated with definitive local therapy and without evidence of recurrent disease without the need for androgen deprivation therapy, or other cancer for which the subject has been disease-free for at least 5 years.
  7. Has received anticancer therapy, radiation, or any investigational agent within 30 days prior to being registered for protocol therapy.
  8. Pregnant or breastfeeding.
  9. Has a clinically significant infection as judged by the treating investigator.
  10. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01342172

Locations
United States, Maryland
National Cancer Institute
Bethesda, Maryland, United States, 20892
United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
United States, Utah
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
Mount Sinai School of Medicine
Celgene Corporation
Investigators
Principal Investigator: Matthew Galsky, MD Mount Sinai School of Medicine
  More Information

No publications provided

Responsible Party: Matthew Galsky, Principal Investigator, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier: NCT01342172     History of Changes
Obsolete Identifiers: NCT01441050
Other Study ID Numbers: GCO 10-1339
Study First Received: April 21, 2011
Last Updated: November 26, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Mount Sinai School of Medicine:
Bladder Cancer
Urothelial Cancer
Chemotherapy
First-line
Metastatic

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Lenalidomide
Cisplatin
Thalidomide
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Leprostatic Agents
Anti-Bacterial Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on July 26, 2014