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Treatment regimen selected by CO eXpression ExtrapolatioN (COXEN) model

One or combination of agents: Abiraterone, Arsenic Trioxide, Asparaginase Escherichia coli source, Axitinib, Azacitidine, Bendamustine, Bleomycin, Bortezomib, Busulfan, Carboplatin, Carfilzomib, Carmustine, Chlorambucil, Cisplatin, Cladribine, Clofarabine, Crizotinib, Cytarabine, Dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, Decitabine, Docetaxel, Doxorubicin, Epirubicin, Eribulin, Erlotinib, Estramustine, Etoposide, Exemestane, Floxuridine, Fludarabine, Fluorouracil, Gefitinib, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Irinotecan, Ixabepilone, Lapatinib, Lomustine, Mechlor, Melphalan, Mercapto, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Nilotinib, Oxaliplatin, Paclitaxel, Pazopanib, Pentostatin, Romidepsin, Ruxolitinib, Sorafenib, Streptozocin, Sunitinib, Tamoxifen, Temsirolimus, Teniposide, Thioguanine, Thiotepa, Topotecan, Toremifene, Tretinoin, Vandetanib, Vemurafenib, Vinblastine, Vincristine, Vismodegib, and/or Vorinostat

75 approved agents

The CO eXpression ExtrapolatioN (COXEN) algorithm will be used to determine the next best therapy from among 75 Food and Drug Administration (FDA) approved agents (single agent or combination) in patients that have progressed on at least one chemotherapy regimen.

COXEN

Andrea B Apolo, M.D.

Background:

Advanced urothelial cancer has no cure. But only a few chemotherapy drugs have been tested for it. The Co-eXpression ExtrapolatioN (COXEN) model predicts if cells respond to treatment. It may also help determine which drugs fight urothelial cancer based on the characteristics of a tumor. Researchers want to test if this model can choose the best therapy for advanced urothelial cancer within 3 weeks and how tumors respond to the next best therapy.

Objective:

To test if the COXEN model can choose the best therapy for advanced urothelial cancer within 3 weeks.

Eligibility:

People ages 18 and older whose urothelial cancer has spread after at least 1 line of chemotherapy

Design:

Participants will be screened with medical history, physical exam, blood and urine tests, and tumor scans.

Participants will provide a tumor sample from a previous surgery and a new biopsy. A needle will remove a small piece of tumor.

Participants will repeat screening tests, plus have an electrocardiogram (EKG) and scan. For the scan, they will get an injection of radioactive drug. They will lie in a machine that takes pictures.

Participants will take the drugs assigned by the COXEN model. They will have visits every 2-3 weeks. These will include blood and urine tests.

Participants will have tumor scans every 8-9 weeks.

Participants may have another biopsy.

Participants will take the drugs until they can't tolerate the side effects or their cancer worsens. They may be assigned to a second COXEN therapy.

Participants will have a follow-up visit 4-5 weeks after their last drug dose.

Participants will be contacted by phone every few months until death.

Background:

* Patients presenting de novo with metastatic bladder cancer, or developing visceral metastatic disease after local treatment, are incurable with currently available therapeutic modalities.
* Only a small number of chemotherapeutic agents have been tested and very few have some single agent activity in the treatment of metastatic urothelial carcinoma. However most (\>100) Food and Drug Administration (FDA) approved anticancer agents have yet to be tested in this disease.
* Novel approaches to the development of genomic predictors of chemosensitivity that do not require clinical trials for their identification are urgently needed in order to identify agents that are clinically effective when either repurposed or discovered de novo specifically for urothelial carcinoma. Such repurposing of an FDA approved anticancer agent in order to advance therapy from one cancer to another would require only minimal clinical development, saving billions of dollars and reducing the time required to reach routine clinical practice.
* Our established extramural-intramural National Cancer Institute (NCI) collaboration pulls together significant expertise in biomarker development and clinical trial design in bladder cancer. The innovation of this group lies not only in the novel scientific approaches i.e. CoeXpression ExtrapolatioN (COXEN) under investigation, but also in the successful creation of a cohesive multi-institutional research collaboration dedicated to improved clinical outcomes in bladder cancer patients.
* COXEN uses molecular profiles as a Rosetta Stone for translating drug sensitivities of one set of cancers into predictions for another completely independent set of cell lines or human tumors. The COXEN methodology has been scrutinized and deemed methodologically sound by peer review. The ability of COXEN to predict drug effectiveness in patients a priori, from purely in vitro assays, is unique as no other tool currently either in practice or in development provides similar results.

Objectives:

- To determine the feasibility of using the Co-eXpression ExtrapolatioN (COXEN) model in making a real-time treatment decision (within 3 weeks) in patients with advanced urothelial carcinoma.

Eligibility:

* Patients must have a histologically confirmed diagnosis of metastatic, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.
* Patients must have progressive metastatic disease defined as new or progressive lesions on cross-sectional imaging.
* Patients must have at least:

  * One measurable site of disease (according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria)
  * Or, appearance of one new bone lesion
* Patients must have been previously treated, as defined by treatment with at least one prior cytotoxic chemotherapy regimen or agent. Patients may have received any number of prior cytotoxic agents.
* Archival tumor tissue must be available for enrollment.
* Tumor amenable to biopsy will be mandatory for this study.
* 18 years of age or older
* Eastern Cooperative Oncology Group (ECOG) performance status \<2 (Karnofsky \>60%)

Design:

* This will be a pilot single-arm, open-label study using the COXEN score to select the best next therapy from a list of 75 FDA approved anti-neoplastic drugs, in patients with metastatic bladder cancer who have progressed despite treatment with cytotoxic chemotherapy. Combinations of the listed agents may also be utilized provided that phase 1 data are available.
* The COXEN algorithm requires a multi-step process (pathology, tissue processing, messenger ribonucleic acid (mRNA) profiling, bioinformatics, etc.) and is potentially labor intensive and time intensive.
* Given the disease state of patients eligible for this protocol, using this algorithm to select a treatment would only be a worthwhile process to undertake if it can be demonstrated that a very high fraction of patients are likely to obtain the benefit from the procedure.

Genomic Based Assignment of Therapy in Advanced Urothelial Carcinoma

A Pilot Clinical Trial of Genomic Based Assignment of Therapy in Advanced Urothelial Carcinoma

Participants were assigned a treatment combination by the co-expression extrapolation (COXEN) algorithm. The COXEN algorithm used a multi-step process that involved pathology, tissue processing, messenger ribonucleic acid (mRNA) profiling and bioinformatics, etc. to select a treatment regimen.

Progression Free Survival is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Radiological assessment per the Response Evaluation Criteria in Solid Tumors (RECIST) was done every 2 cycles to measure change in tumor size until tumors increased. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study; this includes the baseline sum if that is the smallest on study. The appearance of one or more new lesions is also considered progressions.

Objective Response is defined as a Complete Response and Partial Response and was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Amount of time subject survives without disease progression after treatment. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.

Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening or disabling, and Grade 5 is death.

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

National Cancer Institute (NCI)

Principal Investigator

Serious and Other (Not Including Serious) Adverse Events were not monitored for those participants who were enrolled but not treated. However, All-Cause Mortality was monitored for one participant in the Participants Who Were Enrolled But Not Treated Arm/Group.

All participants that received Doxorubicin 75mg/m\^2.

Doxorubicin 75mg/m^2

All participants that received Paclitaxel 100 mg/m\^2 and Erlotinib 150 mg.

Paclitaxel 100 mg/m^2 and Erlotinib 150 mg

All participants that received Paclitaxel 135mg/m\^2 and Doxorubicin 40mg/m\^2.

Paclitaxel 135mg/m^2 and Doxorubicin 40mg/m^2

All participants that received Sunitinib 50mg.

Sunitinib 50mg

All participants that received Vorinostat 500mg and Etoposide 100mg/m\^2 and 60mg/m\^2.

Vorinostat 500mg and Etoposide 100mg/m^2 and 60mg/m^2

3 participants were enrolled and signed consent to this study but never started treatment. Treatment was assigned on course initiation.

Participants Who Were Enrolled But Not Treated

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Andrea Apolo

All participants who were enrolled that signed consent and received Doxorubicin 75mg/m\^2, Paclitaxel 100 mg/m\^2 and Erlotinib 150 mg, Paclitaxel 135mg/m\^2 and Doxorubicin 40mg/m\^2, Sunitinib 50mg, Vorinostat 500mg and Etoposide 100mg/m\^2 and 60mg/m\^2.

Three participants were enrolled to this study but never started treatment. Treatment was assigned on course initiation.

All COXEN Participants Enrolled

This primary measure was to determine the feasibility of the COXEN algorithm. Data collected from participants receiving different treatments were combined and analyzed as a single group as pre-specified in the study protocol.

Percentage of Participants Who Enrolled and Underwent a Biopsy Who Went on to Receive Treatment Within 21 Days

All participants that received Doxorubicin 75mg/m\^2, Paclitaxel 100 mg/m\^2 and Erlotinib 150 mg, Paclitaxel 135mg/m\^2 and Doxorubicin 40mg/m\^2, Sunitinib 50mg, Vorinostat 500mg and Etoposide 100mg/m\^2 and 60mg/m\^2.

All COXEN Participants Receiving Treatment

Not all patients enrolled received a treatment from the treatment algorithm. Those that went on for treatment were evaluated for progression free survival within the 4-month times frame. Data collected from participants receiving different treatments were combined and analyzed as a single group as pre-specified in the study protocol.

Progression Free Survival

Complete Response

Partial Response

Not all patients enrolled received a treatment from the treatment algorithm. We included all patient who received treatment in this group. Data collected from participants receiving different treatments were combined and analyzed as a single group as pre-specified in the study protocol.

Proportion of Patients With an Objective Response

Data collected from participants receiving different treatments were combined and analyzed as a single group as pre-specified in the study protocol.

Overall Survival

Grade 2 Dysgeusia

Grade 3 Anemia

Grade 3 Fatigue

Grade 3 Febrile neutropenia

Grade 3 Gastrointestinal disorders - Other

Grade 3 Generalized muscle weakness

Grade 3 GI disorder-Other, hernia

Grade 3 Thromboembolic event

Grade 3 Hyponatremia

Grade 3 Hypophosphatemia

Grade 3 Infections & Infestations-Other, Bactremia

Grade 3 Platelet count decreased

Grade 3 Small intestinal obstruction

Grade 3 White blood cell count decreased

Grade 4 Neutrophil count decreased

Grade 4 Platelet count decreased

Grade 4 White blood cell count decreased

Grade 5 - Death NOS

Adverse Events were not monitored for those participants who were enrolled but not treated.

Number of Participants Who Had Adverse Events ≥ Grade 1

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Genomic Based Assignment of Therapy in Advanced Urothelial Carcinoma	NCT02788201	Urothelial Carc... Bladder Cancer Urinary Bladder...	75 approved age... COXEN	18 Years -	National Institutes of Health Clinical Center (CC)
Genomic Based Assignment of Therapy in Advanced Urothelial Carcinoma	NCT02788201	Urothelial Carc... Bladder Cancer Urinary Bladder...	75 approved age... COXEN	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for molecular profiles