Neoplasms

All Conditions

Rare Diseases

Carcinoma

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

All Drugs and Chemicals

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immunoconjugates

Immunologic Factors

Patients receive cabozantinib PO QD on days 1-28 and enfortumab vedotin IV on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib S-malate

Enfortumab Vedotin

Quality-of-Life Assessment

Questionnaire Administration

Mehmet Bilen, MD

Wilena A. Session

Mehmet A. Bilen, MD

Mehmet A Bilen, MD

This phase I/Ib trial seeks to find out the best dose, possible benefits and/or side effects of cabozantinib in combination with enfortumab vedotin in treating urothelial cancer that has spread to nearby tissues and lymph nodes (locally advanced) or other parts of the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to a toxic agent called vedotin. Enfortumab attaches to nectin-4 tumor cells in a targeted way and delivers vedotin to kill them. Cabozantinib in combination with enfortumab vedotin may be safe and effective in treating locally advanced or metastatic urothelial cancer.

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) of cabozantinib s-malate (cabozantinib) and enfortumab vedotin 1.25 mg/kg on days 1, 8 and 15 of a 28-day cycle based on safety and tolerability. (Phase I dose escalation) II. To evaluate the ongoing safety and tolerability of cabozantinib and enfortumab vedotin in a dose expansion cohort. (Phase Ib dose expansion)

SECONDARY OBJECTIVES:

I. Obtain preliminary evidence of anti-tumor activity of the combination of cabozantinib and enfortumab vedotin by assessing the objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.

II. Progression-free survival (PFS). III. Overall survival (OS). IV. Disease control rate by RECIST v1.1.

EXPLORATORY OBJECTIVES:

I. To assess the pharmacokinetic (PK) profile of cabozantinib during treatment with enfortumab vedotin.

II. To evaluate the effect of the combination on selected biomarkers in the tumor microenvironment, systemic circulation and gut microbiome and their relationship with efficacy of the combination.

III. To evaluate quality of life, frailty and sarcopenia before, during and at the time of treatment completion.

OUTLINE: This is dose-escalation study of cabozantinib.

Patients receive cabozantinib orally (PO) once daily (QD) on days 1-28 and enfortumab vedotin intravenously (IV) on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.

Cabozantinib in Combination With Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Cancer

A Phase I/Ib Open Label, Single-Arm Study of Cabozantinib in Combination With Enfortumab Vedotin (EV) in the Treatment of Locally Advanced or Metastatic Urothelial Cancer

Pharmacokinetic of cabozantinib during treatment with enfortumab vedotin will be analyzed

Tumor tissue from pre-enrollment biopsy and correlative peripheral blood samples collected at baseline, on days 1, 8 and 15 during cycle 1 and day 1 of cycle 2 will be assessed for molecular biomarkers not limited to Nectin-4, MET and PDL1. Stool samples will be collected at baseline, during Cycle 3 and at the Off-Treatment Visit to assess for changes in intestinal flora over the course of treatment.

Functional Assessment of Cancer Therapy - Bladder Cancer questionnaire will be filled out at baseline and every 8 weeks (+/- 7 days) during year 1 of treatment

Fried Frailty assessment will be obtained at baseline and every 8 weeks (+/- 7 days) during year 1 of treatment.

SliceOmatic v5.0 by TomoVision will be used to measure change in muscle/adipose tissue on imaging studies obtained.

Will be assessed by the Common Terminology Criteria for Adverse Events version 5.0.

Based on cross-sectional imaging. Categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. ORR will be summarized with the 2-sided 95% confidence interval (CI) using the Clopper-Pearson method in the full analysis set (FAS).

Kaplan-Meier methods will be used to estimate median survival time or time-specific survival rate with 95% confidence interval.

Defined as the percentage of patients who achieve complete response, partial response and stable disease as per RECIST v1.1. DCR will be summarized with the 2-sided 95% CI using the Clopper-Pearson method in the FAS.

Exelixis

National Cancer Institute (NCI)

Emory University

Principal Investigator

Antineoplastic Agents

Micronutrients

Hematinics

Vitamins

Pemetrexed

Avelumab

Folic Acid Antagonists

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Antineoplastic Agents, Immunological

Folinic Acid

Folate

Vitamin B9

Patients receive pemetrexed IV over 10 minutes on day 1. Starting cycle 2, patients also receive avelumab IV over 60 minutes. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Amishi Y Shah

This phase II trial studies how well pemetrexed and avelumab work in treating patients with MTAP-deficient urothelial cancer that has spread to other places in the body. Pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pemetrexed and avelumab may work better in treating patients with MTAP-deficient urothelial cancer.

PRIMARY OBJECTIVES:

I. To evaluate the response rate (RR) in patients with (methylthioadenosine phosphorylase) MTAP-deficient metastatic urothelial cancer treated sequentially with pemetrexed and avelumab.

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) and overall survival (OS) in patients with MTAP-deficient metastatic urothelial cancer treated sequentially with pemetrexed and avelumab.

II. To explore the effect of pemetrexed +/- avelumab on the immune system and tumor microenvironment including peripheral T-cells, tumor-infiltrating T-cells, macrophages, and myeloid-derived suppressor cells (MDSCs).

OUTLINE:

Patients receive pemetrexed intravenously (IV) over 10 minutes on day 1. Starting cycle 2, patients also receive avelumab IV over 60 minutes. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 120 days, and then every 3 months for 2 years.

Pemetrexed and Avelumab in Treating Patients With MTAP-Deficient Metastatic Urothelial Cancer

A Phase II Trial to Evaluate Combination Therapy With Pemetrexed and Avelumab in Previously Treated Patients With MTAP-Deficient Advanced Urothelial Cancer

Will be defined as the number of subjects with a best response of complete response or partial response at any protocol evaluation by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria divided by the total numbers of subjects receiving their first dose of trial therapy.

Will be presented using Kaplan-Meier estimates.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cabozantinib in Combination With Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Cancer	NCT04878029	Infiltrating Bl... Locally Advance... Metastatic Urot... Unresectable Ur...	Cabozantinib S-... Enfortumab Vedo... Quality-of-Life... Questionnaire A...	18 Years -	Emory University
Pemetrexed and Avelumab in Treating Patients With MTAP-Deficient Metastatic Urothelial Cancer	NCT03744793	Infiltrating Bl... Infiltrating Bl... Infiltrating Bl... Infiltrating Bl... Infiltrating Bl... Metastatic Urot... MTAP Negative	Avelumab Pemetrexed	18 Years -	M.D. Anderson Cancer Center
Cabozantinib in Combination With Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Cancer	NCT04878029	Infiltrating Bl... Locally Advance... Metastatic Urot... Unresectable Ur...	Cabozantinib S-... Enfortumab Vedo... Quality-of-Life... Questionnaire A...	18 Years -	Emory University

Spots Global Cancer Trial Database for infiltrating bladder urothelial carcinoma with squamous differentiation