Trial of Lapatinib and Weekly Paclitaxel for Advanced Urothelial Cancer

This study has been withdrawn prior to enrollment.
(Funding issues.)
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
University of Michigan Cancer Center
ClinicalTrials.gov Identifier:
NCT01700010
First received: October 2, 2012
Last updated: January 15, 2013
Last verified: January 2013
  Purpose

This study will involve subjects who have advanced urothelial cancer who are platinum refractory (platinum based chemotherapies that are not effective in treating the cancer), and who are over-expressing EGFR and/or HER2, or do not over-express EGFR and HER2. Genetic expression is a process that takes inherited information in genes (like DNA sequence), and from that information makes a specific functional product (sometimes called a gene product) such as RNA (ribonucleic acid) or protein. Normal tissue cells have a particular genetic expression, which changes when they turn into cancer. EGFR and HER2 are involved in the process by which normal cells are transformed into cancer cells.

The main purpose of the study is to look at the proportion of subjects, who over-express EGFR and/or HER2, who do not progress (cancer gets worse) after 16 weeks of study treatment with daily lapatinib and weekly paclitaxel. The study will also look at the safety and effectiveness of this therapy in all subjects.

Another part of this study will look at blood and tissue samples. Blood samples will be collected to see how many cells express EGFR and HER2 before study treatment and at the time the cancer gets worse. Tumor tissue will be analyzed to look at the expression of certain genes in advanced urothelial cancer. Some gene expression tests can reveal how cancer cells are different from normal cells and the results might lead to more accurate diagnosis and treatment.


Condition Intervention Phase
Urothelial Cancer
Bladder Cancer
Drug: Lapatinib and Paclitaxel
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: Phase II Trial of Lapatinib and Weekly Paclitaxel for Advanced Platinum Refractory Urothelial Cancer

Resource links provided by NLM:


Further study details as provided by University of Michigan Cancer Center:

Primary Outcome Measures:
  • Progression free [ Time Frame: 16 weeks after participant study therapy ] [ Designated as safety issue: No ]
    The proportion of patients with platinum refractory advanced urothelial cancer over-expressing EGFR and/or HER2 who do not progress after 16 weeks of therapy with lapatinib and weekly paclitaxel.


Secondary Outcome Measures:
  • Number of participants with adverse events [ Time Frame: 5.5 years ] [ Designated as safety issue: Yes ]
    Safety of combination lapatinib and weekly paclitaxel.

  • The overall response proportion [ Time Frame: Up to 12 months after the last subject comes off study treatment. ] [ Designated as safety issue: No ]
    The overall response proportion (complete response + partial response) in patients with platinum refractory urothelial cancer treated with lapatinib and weekly paclitaxel whose tumors over-express EGFR and/or HER2; whose tumors over-express only EGFR or only HER2; and whose tumors over-express neither EGFR nor HER2.

  • Median progression free survival [ Time Frame: Up to 12 months after the last subject comes off study treatment. ] [ Designated as safety issue: No ]
    Median progression free survival in patients with platinum refractory urothelial cancer treated with lapatinib and weekly paclitaxel whose tumors over-express EGFR and/or HER2; whose tumors over-express only EGFR or only HER2; and whose tumors over-express neither EGFR nor HER2.

  • Overall survival [ Time Frame: Up to 12 months after the last subject comes off study treatment. ] [ Designated as safety issue: No ]
    The overall survival in patients with platinum refractory urothelial cancer treated with lapatinib and weekly paclitaxel whose tumors over-express EGFR and/or HER2; whose tumors over-express only EGFR or only HER2; and whose tumors over-express neither EGFR nor HER2.


Other Outcome Measures:
  • Frequency of circulating tumor cells (CTCs) expressing HER2 and EGFR [ Time Frame: 6.5 years ] [ Designated as safety issue: No ]
    The frequency of circulating tumor cells (CTCs) expressing HER2 and EGFR at baseline and at progression.

  • Expression of phospho-HER3, PTEN, pS6k and p53 [ Time Frame: 6.5 years ] [ Designated as safety issue: No ]
    Expression of phospho-HER3, PTEN, pS6k and p53 by IHC in metastatic tumor tissue if available or alternatively, primary tumor tissue at baseline.


Enrollment: 0
Study Start Date: November 2012
Estimated Study Completion Date: January 2019
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lapatinib and Paclitaxel

Lapatinib comes in tablet form and is taken by mouth at a dose of 1,000 mg every day. Paclitaxel will be given through the vein (IV) at a dose of 80 mg/m2 on days 1, 8, and 15 at each 28 day cycle. If cancer does not progress and study treatment can be tolerated after 6 cycles of paclitaxel and lapatinib, paclitaxel will be stopped and lapatinib will continue until disease progression, side effects cannot be tolerated, participant is removed from or withdraws from study, or for other reasons.

Subjects with locally advanced disease who respond to treatment and are felt to be appropriate for local therapy may proceed to receive local therapy as deemed appropriate by the managing physician after a minimum of 6 cycles or upon achieving complete remission followed by an additional 2 cycles. Subjects who proceed to receive local therapy will be removed from protocol therapy. Subjects who elect not to receive or are not candidates for local therapy may continue treatment on protocol.

Drug: Lapatinib and Paclitaxel

Lapatinib comes in tablet form and is taken by mouth at a dose of 1,000 mg every day. Paclitaxel will be given through the vein (IV) at a dose of 80 mg/m2 on days 1, 8, and 15 at each 28 day cycle. If cancer does not progress and study treatment can be tolerated after 6 cycles of paclitaxel and lapatinib, paclitaxel will be stopped and lapatinib will continue until disease progression, side effects cannot be tolerated, participant is removed from or withdraws from study, or for other reasons.

Subjects with locally advanced disease who respond to treatment and are felt to be appropriate for local therapy may proceed to receive local therapy as deemed appropriate by the managing physician after a minimum of 6 cycles or upon achieving complete remission followed by an additional 2 cycles. Subjects who proceed to receive local therapy will be removed from protocol therapy. Subjects who elect not to receive or are not candidates for local therapy may continue treatment on protocol.


Detailed Description:

Bladder cancer caused 14,680 deaths in 2010 in the US. In advanced bladder cancer, MVAC (methotrexate, vinblastine, adriamycin and cisplatin) and GC (gemcitabine, cisplatin) combination chemotherapy demonstrate comparable efficacy with response rates of 45%- 50%. Despite the reasonable initial response to platinum based chemotherapy, median time to progression on first line therapy is only 7 months and median survival approximately 15 months. There is no standard second line therapy after platinum based chemotherapy in the US and no survival benefit has been noted with any agent. Median progression free survival (PFS) is around 2 months in platinum refractory urothelial cancer (PRUC) and overall survival (OS) is 6 - 8 months with single agent second line therapy. Combination chemotherapy does not prolong overall survival. Given the dire prognosis in PRUC and the lack of efficacy of conventional chemotherapy, preclinical investigations and clinical research have focused on identification of novel molecular targets.

Lapatnib is approved by the FDA for the treatment of breast cancer. Paclitaxel is approved by the FDA for the treatment of sarcoma, breast and lung cancers. Lapatinib and paclitaxel are not approved for advanced urothelial cancer; however, the FDA allows the use of these drugs in this study for research purposes.

  Eligibility

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

Inclusion Criteria:

  • Male and female patients must be at least 18 years of age.
  • Diagnosis of urothelial carcinoma that is locally advanced, recurrent or metastatic is required.
  • Patients must have progressed on prior regimens (1-2 allowed) of systemic chemotherapy for any stage of urothelial carcinoma (including peri-operative chemotherapy alone in which case they must have progressed within 12 months of peri-operative chemotherapy), with one of the regimens including a platinum agent.
  • Patients must have adequate tumor tissue (primary or metastatic tumor; fresh or archived) available for EGFR and HER2 expression analysis at baseline as determined by the study pathologist.
  • EGFR and HER2 status by Immunohistochemistry of a potential patient's urothelial tumor must be determined at baseline before registration or therapy. A potential patient's eligibility will depend on his/her tumor's EGFR and HER2 category AND the available open slots in that category at that time.
  • Patients must be able to care for themselves and must be up and about more than 50% of waking hours.
  • Patients must have measurable disease.
  • Prior chemotherapy or radiation therapy must have been completed prior to registration (at least 4 weeks prior for chemotherapy and at least 2 weeks prior for radiation). Patients must have recovered from any reversible side effects and must not have had more than 25% of the bone marrow irradiated.
  • Ability of the heart to pump blood must be adequate for this study. This will be determined by a screening test.
  • Patients must have adequate organ and marrow function as determined by screening tests.
  • All patients must be informed of the investigational nature of this study and must sign an informed consent document.
  • Both men and women and members of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

  • No prior use of anti-HER2 (including trastuzumab) or anti-EGFR (including erlotinib, gefitinib, cetuximab) therapy, paclitaxel, nanoparticle bound paclitaxel or docetaxel for any reason.
  • Must not have history of or known spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease. Patients with known brain metastases would be excluded from this clinical trial.
  • Known HIV positive patients may not participate.
  • No malignancy for which systemic therapy, surgery or radiation is ongoing or anticipated within the next 3 months as assessed by the investigator.

    • In situ carcinoma of any site including CIS of the urothelial tract [or] adequately treated basal cell or squamous cell skin cancer is allowed.
    • Patients with history of non-metastatic prostate cancer who have a PSA <2 ng/mL with or without androgen deprivation therapy are eligible.
  • Patients with serious cardiac illness or medical conditions are excluded.
  • Patients must not receive treatment on another therapeutic clinical trial. Supportive care trials and non-interventional trials, e.g. quality of life (QOL) trials are allowed..
  • Herbal medications or supplements are not allowed.
  • Female patients must be surgically sterile or be postmenopausal as per the investigator's discretion, or must agree to use effective contraception during the period of therapy. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to registration. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy.
  • Must not have malabsorption syndrome, any disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, or unable to swallow oral medication.
  • No history of allergic reactions to compounds of similar chemical or biologic composition to lapatinib.
  • Use of strong CYP3A4 inhibitors or inducers is prohibited on study.
  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: NCT01700010

Locations
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
University of Michigan Cancer Center
GlaxoSmithKline
Investigators
Principal Investigator: Ajjai S. Alva, M.D. University of Michigan
  More Information

No publications provided

Responsible Party: University of Michigan Cancer Center
ClinicalTrials.gov Identifier: NCT01700010     History of Changes
Other Study ID Numbers: UMCC 2012.045, HUM00062889
Study First Received: October 2, 2012
Last Updated: January 15, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Michigan Cancer Center:
Urothelial
Bladder
Cancer

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Paclitaxel
Lapatinib
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 24, 2014