Genomic Based Assignment of Therapy in Advanced Urothelial Carcinoma

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

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.

Study Overview

• Status: Completed
• Conditions: Urinary Bladder Neoplasms; Bladder Cancer; Urothelial Carcinoma
• Intervention / Treatment: Drug: 75 approved agents; Other: COXEN

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:
• 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), defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as more than or equal to 20 mm with conventional techniques or as less than or equal to 10 mm with spiral computed tomography (CT) scan.
  • Or, appearance of one new bone lesion
• Patients must have been previously treated 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.
• Age more than or equal to 18 years. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky more than or equal to 60%,).

• Patients must have normal organ and marrow function as defined below:

  • hemoglobin more than or equal to 9 g/dL
  • leukocytes more than or equal to 3,000/mcL
  • absolute neutrophil count more than or equal to 1,200/mcL
  • platelets more than or equal to 75,000/mcL
  • total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST)/Serum glutamic oxaloacetic transaminase (SGOT)/Alanine aminotransferase (ALT)/Serum glutamic pyruvic transaminase(SGPT) less than or equal to 2.5 X institutional upper limit of normal
  • creatinine 1.5 x the normal institutional limits

OR

--creatinine clearance more than or equal to 40 mL/min/1.73 m^2

• Because many of the therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy may be eligible if there are no pharmacokinetic interactions with the agents used on the study, stable on Chimeric antigen receptor T-cell (CART) therapy and cluster of differentiation 4 (CD4) is >200 and viral load is undetectable.
• Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

• The patient has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) within 3 weeks or biologic agents (e.g., cytokines or antibodies) within 4 weeks prior to study enrollment.
• Patients who are receiving any investigational agents.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with brain metastases that are stable after more than or equal to 1 year after primary surgery or radiation will not be excluded.
• The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) less than or equal to Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs(.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who are Hepatitis B or C positive.
• Pregnant women are excluded from this study because the agents used in the study have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated with these agents. These potential risks may also apply to other agents used in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment Regimen; Treatment regimen selected by CO eXpression ExtrapolatioN (COXEN) model

Drug: 75 approved agents; 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; Other: COXEN; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Enrolled and Underwent a Biopsy Who Went on to Receive Treatment Within 21 Days	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.	time to treatment assignment, approximately 3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	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.	Every 2 cycles until progression, approximately 4 months.
Proportion of Patients With an Objective Response	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.	End of treatment, approximately 4 months.
Overall Survival	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.	From date of treatment content until the date of death from any cause or date off study, whichever came first, assessed up to 10 months and 16 days.
Number of Participants Who Had Adverse Events ≥ Grade 1	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.	Date treatment consent signed to date off study, approx. 5 mos/ 6 dys for the 1st Grp; 10 mos/16 dys for the 2nd Grp; 8 mos/13 dys for the 3rd Grp; 5 mos/16 dys for the 4th Grp; and 27 dys for the 5th Grp.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	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.	Date treatment consent signed to date off study, approx. 5 mos/ 6 dys for the 1st Grp; 10 mos/16 dys for the 2nd Grp; 8 mos/13 dys for the 3rd Grp; 5 mos/16 dys for the 4th Grp; and 27 dys for the 5th Grp.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2017
• Primary Completion (Actual): October 23, 2019
• Study Completion (Actual): October 23, 2019

Study Registration Dates

• First Submitted: May 28, 2016
• First Submitted That Met QC Criteria: May 28, 2016
• First Posted (Estimate): June 2, 2016

Study Record Updates

• Last Update Posted (Actual): November 6, 2020
• Last Update Submitted That Met QC Criteria: October 14, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Bladder Cancer; COXEN; Molecular Profiles
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell
• Other Study ID Numbers: 160121; 16-C-0121

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No