Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

All Conditions

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Ovarian Cancer

Ovarian Epithelial Cancer

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Paclitaxel

Albumin-Bound Paclitaxel

Lapatinib

Tubulin Modulators

Antimitotic Agents

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Patients in this group will receive Lapatinib (500mg PO BID) and Paclitaxel (80mg/m2).

Patients in this group will receive Lapatinib (750mg PO BID) and Paclitaxel (80mg/m2).

Patients in this group will receive Lapatinib (1500mg PO BID) and Paclitaxel (80mg/m2).

Patients in this group will receive Lapatinib (2000mg PO BID) and Paclitaxel (80mg/m2).

Participants will receive twice-daily Lapatinib, beginning two days prior to Paclitaxel treatment.

Lapatinib and Paclitaxel

Frederick Ueland, MD

This trial will be a phase I dose-escalation study of lapatinib and paclitaxel for platinum-resistant ovarian cancer, which will establish the phase II dose for subsequent efficacy trials.

While ABCB1 (P-glycoprotein 1) upregulation after paclitaxel administration is well known, there is currently no clinically available method for preventing or overcoming it. To develop a therapy able to prevent ABCB1 upregulation and paclitaxel resistance, several ABCB1 inhibitors have been evaluated in combination with paclitaxel in preclinical model systems. Pulsed-dose lapatinib and paclitaxel are synergistic and inhibition of ABCB1 by lapatinib increases sensitivity to paclitaxel. Lapatinib is FDA approved, orally available, and previously studied in combination with weekly paclitaxel for breast cancer at doses of 1000mg to 1250mg daily (7000-8250mg per week). This trial will use twice-daily dosing of lapatinib at a starting dose of 750 mg for 2 days (1500mg a day and 3000mg weekly dose), which is less than half of the continuous dose and has been shown to achieve plasma concentrations at 48 hours that are associated with synergy. Therefore, these findings can be translated into a novel, well-tolerated, and convenient combination regimen with significant potential for clinical activity. This trial will be a phase I dose-escalation study of lapatinib and paclitaxel for platinum-resistant ovarian cancer, which will establish the phase II dose for subsequent efficacy trials.

Dose Escalation of Lapatinib With Paclitaxel in Ovarian Cancer

A Phase I Dose-Escalation Study on the Safety of Lapatinib With Dose-Dense Paclitaxel in Patients With Platinum-Resistant Ovarian Cancer

Levels of ABCB1 expression (cell-free RNA) will be measured using Nanostring sequencing.

Proportion of patients with progression-free survival at one year.

Dose limiting toxicity (DLT) is calculated as the total number of patients experiencing DLTs divided by the total number treated.

Plasma concentrations of lapatinib will be measured on days 1, 8 and 15.

National Cancer Institute (NCI)

Frederick R. Ueland, M.D.

Professor

Urinary Bladder Neoplasms

Urologic Neoplasms

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

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.

Ajjai S. Alva, M.D.

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.

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.

Trial of Lapatinib and Weekly Paclitaxel for Advanced Urothelial Cancer

Phase II Trial of Lapatinib and Weekly Paclitaxel for Advanced Platinum Refractory Urothelial Cancer

The frequency of circulating tumor cells (CTCs) expressing HER2 and EGFR at baseline and at progression.

Expression of phospho-HER3, PTEN, pS6k and p53 by IHC in metastatic tumor tissue if available or alternatively, primary tumor tissue at baseline.

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.

Safety of combination lapatinib and weekly paclitaxel.

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 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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Dose Escalation of Lapatinib With Paclitaxel in Ovarian Cancer	NCT04608409	Ovarian Cancer	Lapatinib and P...	18 Years - 100 Years	University of Kentucky
Trial of Lapatinib and Weekly Paclitaxel for Advanced Urothelial Cancer	NCT01700010	Urothelial Canc... Bladder Cancer	Lapatinib and P...	18 Years -	University of Michigan Rogel Cancer Center

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