Randomized Discontinuation Study of Lapatinib Versus Placebo in Subjects With Documented Tumor Progression After Chemotherapy, or Where no Approved Therapy Exists

Study Overview
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Brief Summary
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This study will examine the efficacy and safety of lapatinib in patients with ErbB2 positive ovarian, gastric/esophageal adenocarcinoma, uterine serous papillary, or bladder cancers.

Official Title
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A Phase II, Placebo Controlled, Double-Blind, Randomized, Discontinuation Study of Lapatinib Administered Orally to Subjects With ErbB2 Positive Ovarian, Gastric/Esophageal Adenocarcinoma, Uterine Serous Papillary, or Bladder Cancer

Conditions
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Cancer

Intervention / Treatment
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* Drug: Oral lapatinib tablets or placebo tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent. Age >= 18 years old. Life expectancy of at least 12 weeks. Have histologically confirmed ovarian, gastric/esophageal adenocarcinoma, uterine serous papillary, or bladder cancer. Have ErbB2-positive cancer as determined by Fluorescence In Situ Hybridization (FISH) assay. Have documented tumor progression after receiving all standard/approved chemotherapies per National Comprehensive Cancer Network (NCCN) guidelines (V1) for their specific cancer and no approved therapy exists. Have one or more tumors measurable by medical imaging and assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Have archived tumor tissue available for biomarker analysis. Have a negative serum pregnancy test if female of childbearing potential. Any chemotherapy, major surgery, or irradiation must have been completed at least 3 weeks prior to receiving study drug (6 weeks for mitomycin-C or nitrosourea) and subject must have recovered from all toxicities incurred as a result of previous therapy. Have a gastrointestinal tract intact enough to swallow and assure absorption of the drug. Women of childbearing potential must have a negative serum pregnancy test at screening and must use an approved contraceptive method, if appropriate (for example, intrauterine device, birth control pills, or barrier device) beginning 2 weeks before the first dose of investigational product and for 28 days after the final dose of investigational product. Males able to father a child must practice adequate methods of birth control or practice complete abstinence from intercourse from the first dose of investigational treatment until one week after the final dose of investigational treatment. Have a cardiac ejection fraction within institutional range of normal as measured by either echocardiogram or multigated acquisition scans. The same method of cardiac evaluation must be used consistently throughout the study. Subjects must have adequate organ function: Hematologic: absolute neutrophil count >1.5 x 109/L hemoglobin >9 g/dL platelets >75 x 109/L Hepatic: albumin >2.5 g/dL serum bilirubin <1.25 x upper limit of normal aspartate aminotransferase/alanine aminotransferase <3 x ULN if no documented liver metastases aspartate aminotransferase/alanine aminotransferase <5 x ULN with documented liver metastases Renal: serum creatinine <2.0 mg/dL OR - calculated creatinine clearance1 >40 mL/min Exclusion Criteria: Have New York Heart Association Class III or IV, cardiac disease, myocardial infarction within past 6 months, unstable arrhythmia or evidence of ischemia on electrocardiogram. Subjects who have had chemotherapy or radiotherapy within 3 weeks prior to entering the study or who have unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment. Concurrent treatment with an investigational agent or participation in another treatment clinical trial. Prior lapatinib therapy. ECOG Performance Status 2 or greater. Subjects receiving concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy (including an ErbB1 and/or ErbB2 inhibitor), or hormonal therapy for treatment of their cancer. Concurrent treatment with bisphosphonates is allowed. History of allergic reactions attributed to compounds of similar chemical composition (quinazolines) to lapatinib. Concurrent treatment with prohibited medications. Malabsorption syndrome, resection of the small bowel or active, uncontrolled ulcerative colitis. Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical or psychiatric disorder that would interfere with the subject's safety. Uncontrolled infection. Pregnant or lactating females.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib Oral Tablets<br> | Drug: Oral lapatinib tablets or placebo tablets<br>* Subjects administered open label lapatinib, 1500 mg to be taken orally once a day, for 12 weeks. After 12 weeks, subjects with a partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST) will continue to receive open label lapatinib (1500 mg/day orally) until disease progression. Subjects who maintain stable disease will be randomized in a 1:1 ratio to enter stage 2 of the study and receive double blind therapy of either lapatinib 1500 mg/day orally or placebo. Subjects who progress on placebo will have the option to receive lapatinib 1500 mg/day orally until further progression. Those who progress on lapatinib will be withdrawn from the study.<br>|
| Placebo Comparator: Placebo Control<br> | Drug: Oral lapatinib tablets or placebo tablets<br>* Subjects administered open label lapatinib, 1500 mg to be taken orally once a day, for 12 weeks. After 12 weeks, subjects with a partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST) will continue to receive open label lapatinib (1500 mg/day orally) until disease progression. Subjects who maintain stable disease will be randomized in a 1:1 ratio to enter stage 2 of the study and receive double blind therapy of either lapatinib 1500 mg/day orally or placebo. Subjects who progress on placebo will have the option to receive lapatinib 1500 mg/day orally until further progression. Those who progress on lapatinib will be withdrawn from the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Tumor Response at 12 Weeks From First Dose | Per Response Evaluation Criteria In Solid Tumors (RECIST): Complete response (CR), disappearance of all lesions; partial response (PR), >=30% decrease in the measurements of the largest lesions; stable disease (SD), insufficient shrinkage to qualify for PR or insufficient increase to qualify for progressive disease (PD); PD, >=20% increase in measurements of lesions or appearance of new lesions. Data were not fully analyzed due to early study termination. | Week 12 | 
| Percentage of Participants Who Remained Progression-free 12 Weeks After Randomization | The percentage of participants who did not show signs of progressive disease 12 weeks after receiving lapatinib or placebo in Stage 2 of the study (participants who maintained SD in Stage 1 were randomized to either lapatinib or placebo) was measured. Formal statistics for treatment comparison were not performed, due to early study termination. The percentage of participants displayed below includes those with CR + PR + SD. | Week 12 after randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Duration of response was calculated as the time from first documented partial response (PR; >=30% decrease in the measurements of the largest lesions) or complete response (CR; disappearance of all lesions) until disease progression, the time when the participant began a new anti-cancer therapy, or death. Data were not analyzed due to early study termination. | (assessments every 12 weeks until death for withdrawn participants and every 3 weeks for participants continuing on lapatinib) | 
| Progression-free Survival (PFS) | Progression-free survival was calculated as the time from the start of treatment until disease progression or death. For participants who did not have disease progression or did not die, the date on which alternative anti-cancer therapy began was used, or the date of last contact (if sooner). The word used for such participants was censored. Data were not analyzed due to early study termination. | From start of treatment to disease progression/death (assessments every 12 weeks until death for withdrawn participants and every 3 weeks for participants continuing on lapatinib) | 
| Time to Disease Progression (TTP) | Time to disease progression was calculated as the time from the start of treatment to disease progression or death due to disease progression. For participants who did not progress, the date of last contact was used and for those who died due to other causes, the date of death was used. The word used for such participants was censored. As the median value in the placebo arm was not reached (2 participants were censored and 2 were ongoing), results for the placebo arm are not displayed in the table below. | From start of treatment to disease progression/death (up to 83.3 weeks) | 
| Number of Participants With the Indicated Change in Cancer Antigen-125 (CA-125) Levels From Day 1 | CA-125 is a tumor marker, found in greater concentration in tumor cells than other cells of the body. In particular, CA-125 is present in greater concentration in ovarian cancer cells than in other cells. A decreasing level generally indicates that therapy has been effective, whereas an increasing level indicates tumor recurrence. | Pre-dose and every 6 weeks until withdrawal (up to 84.1 weeks) | 
| Incidence of MET Amplification in Gastric Cancer | The number of gastric cancer participants with MET amplification (determined by fluorescence in situ hybridization [FISH] assay) compared to the total number of gastric cancer participants screened was to be recorded. Amplification of the MET gene has been reported to be related to carcinogenesis, progression of gastric cancer, and poor prognosis. Data were not analyzed due to early study termination. | Performed on archived tissue collected at screening. | 
| Incidence of ErbB2-positive Participants | The number of ErbB2-positive participants (determined by FISH assay) compared to the total number of participants screened was to be recorded. Over-expression of ErbB2 has been correlated with an overall poor prognosis. Data were not analyzed, due to early study termination. | Screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian Cancer, Bladder Cancer, ErbB2 positive, Lapatinib, Gastric/Esophageal Cancer, Uterine Serous Papillary Cancer