Urothelial Cancer, Metastatic Urothelial Carcinoma, Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter, Bladder Cancer
Conditions
Keywords
Urothelial cancer, Metastatic Urothelial Carcinoma, Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter, Bladder Cancer
Brief summary
Phase I of this research study will assess what doses of Sacituzumab Govitecan and Enfortumab Vedotin can be safely combined in the treatment of metastatic urothelial carcinoma (mUC). In Phase II of the study, patients in one of the two cohorts will receive Sacituzumab Govitecan, Enfortumab Vedotin, and Pembrolizumab to assess the efficacy of this drug combination. The names of the study drugs in these investigational combinations are: * Enfortumab Vedotin * Sacituzumab Govitecan * Pembrolizumab
Detailed description
Phase I of this study was a single-center, open-label, nonrandomized phase I trial testing the safety and efficacy as well as defining the appropriate dose for future studies of Sacituzumab Govitecan and Enfortumab for people with metastatic urothelial carcinoma (mUC) progressing on platinum-based chemotherapy and PD1/L1 inhibitors. The U.S. Food and Drug Administration (FDA) has approved Enfortumab Vedotin for the treatment of metastatic urothelial carcinoma (mUC) (bladder cancer). The FDA has not approved Sacituzumab Govitecan for metastatic urothelial carcinoma (mUC) (bladder cancer) but it has been approved for other uses. The FDA has approved Sacituzumab Govitecan to treat a type of breast cancer at this time. Sacituzumab Govitecan has appeared promising in patients with bladder cancer that has spread and works by a different mechanism than Enfortumab Vedotin. Therefore, the researchers believe that combining these 2 drugs may control the cancer better than each drug does on its own. This will be done through testing different combinations and checking for serious side effects; if there are no serious side effects a different dose combination will be explored. Once the best combination has been determined, the study will expand to a phase 2 trial looking how effective (how well the drug works)the combination in slowing down the growth of metastatic urothelial carcinoma (mUC) progressing on platinum-based chemotherapy and PD1/L1 inhibitors and in combination with PD1/PDL1 inhibitors in treatment naive disease. Phase II of this study is a multicenter phase 2 trial to to test the efficacy of Sacituzumab Govitecan in combination with Enfortumab Vedotin in patients with treatment refractory urothelial carcinoma (Cohort A). Phase II will also study the efficacy of the combination of Enfortumab Vedotin, Sacituzumab Govitecan, and Pembrolizumab in patients who have not yet received systemic therapy for metastatic carcinoma and are more than 6 months from completion of any immunotherapy in the perioperative setting (Cohort B). The research study procedures include screening for eligibility, study treatment, and safety follow-up visits, in addition to general health status follow-up after study treatment. Participants will receive study treatment for as long as they do not have serious side effects and their disease does not get worse. However, the duration may vary depending on how long the treatment works to control the cancer and how someone's body tolerates the side effects. Gilea, a pharmaceutical company, is supporting this research study by providing funding for the research study, tests required for research purposes only, and the study drug Sacituzumab Govitecan. It is expected that up to 24 people will take part in Phase I of this research study and up to 41 people will take part in each of the two Phase II cohorts.
Interventions
Intravenous infusion
DRUGEnfortumab vedotin-ejfv (EV)
Intravenous infusion
DRUGPembrolizumab
Intravenous infusion
Sponsors
Gilead Sciences
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Phase II Study Cohort A (dose expansion study to assess efficacy of Sacituzumab Govitecan (SG) and Enfortumab vedotin-ejfv (EV) combination) Inclusion Criteria: * Participants must have histologically documented confirmed predominant urothelial carcinoma (i.e. of the bladder, renal pelvis, ureter or urethra). Patients with squamous differentiation or mixed cell types are eligible if the urothelial component is more than 50%; small-cell carcinoma is not allowed. Patients with locally advanced unresectable disease are eligible. * Patient who are cisplatin eligible must have received prior treatment with platinum containing therapy defined as within the adjuvant/neoadjuvant setting with ≥ ypT2 disease at surgery or recurrent or progressive disease within 12 months or receiving treatment with platinum in locally advanced or metastatic setting. In addition, they must have received a checkpoint inhibitor (CPI) in locally advanced or metastatic urothelial cancer setting. Patients who received CPI therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease either during or within 12 months of therapy completion are eligible. A CPI is defined as a PD-1 or PD-L1 inhibitor. * Patients who are cisplatin-ineligible need only have progressed on or since one line of therapy defined as therapy given in the adjuvant/neoadjuvant setting within 12 months of progression or receiving therapy for locally advanced or metastatic disease * Patient must be progressing on or since most recent therapy * Age ≥18 years. Children are excluded from this study, but will be eligible for future pediatric trials. * ECOG performance status 0-1. * Participants must have adequate organ and marrow function as defined below: * Leukocytes ≥3,000/mcL * Absolute neutrophil count ≥1,500/mcL * Platelets ≥100,000/mcL * Total bilirubin ≤ institutional upper limit of normal (ULN) * AST(SGOT)/ALT(SGPT) ≤2.5x institutional ULN OR * ≤5x ULN with liver metastases and serum albumin \> 3 g/dL * Glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 (by Cockcroft Gault formula) * Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. * For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. * Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better. * Have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) as per response evaluation criteria in solid tumors version 1.1 (RECIST 1.1 criteria). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions * Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 6 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \>2 years * The effects of SG and EV on the developing human fetus are unknown. 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 and 6 months after last study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study and up to 6 months after last study drug dose, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of SG administration. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
Subjects meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Sacituzumab Govitecan (SG) and Enfortumab vedotin-ejfv (EV) in Combination | 21 days | The Maximum Tolerated Dose (MTD) in mg of Sacituzumab Govitecan (SG) and Enfortumab vedotin-ejfv (EV) in Combination is assessed. |
| Dose-limiting toxicity (DLT) of Sacituzumab Govitecan (SG) and Enfortumab Vedotin in combination | 21 days | Treatment-Related Adverse Events are assessed by CTCAE v5.0 when administering Sacituzumab Govitecan (SG) and Enfortumab Vedotin (EV) in combination. |
| Efficacy of Sacituzumab Govitecan (SG) and Enfortumab Vedotin in combination | 21 days | Study SG + EV combination to further refine the recommended dose and to assess the ORR (unconfirmed CR or PR) per RECIST Version 1.1 as determined by investigator for the combination of EV and SG in combination in patients with mUC progressing on platinum-based chemotherapy and PD1/L1 inhibitors. |
| Efficacy of Sacituzumab Govitecan (SG) and Enfortumab Vedotin and Pembrolizumab in combination | 21 days | Study SG + EV + Pembrolizumab in combination to assess the ORR (unconfirmed CR or PR) per RECIST Version 1.1 as determined by investigator for the combination therapy of Pembrolizumab in combination with EV and SG in treatment-naïve patients with mUC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin in combination overall survival (OS) Rate | 21 days | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 |
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin in combination expansion cohort progression-free survival. | 21 days | Assessed as progression-free survival per investigator assessment. |
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin in combination expansion cohort overall survival (OS) rate. | 21 days | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 |
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin in combination objective response rate (ORR) | 21 days | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 |
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin and Pembrolizumab in combination progression-free survival. | 21 days | Assessed as progression-free survival per investigator assessment. |
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin and Pembrolizumab in combination overall survival (OS) rate. | 21 days | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 |
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin and Pembrolizumab in combination safety assessment. | 21 days | Treatment-Related Adverse Events are assessed by CTCAE v5.0 when administering Sacituzumab Govitecan (SG) and Enfortumab Vedotin (EV) and Pembrolizumab in combination. |
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin in combination expansion cohort safety assessment. | 21 days | Treatment-Related Adverse Events are assessed by CTCAE v5.0 when administering Sacituzumab Govitecan (SG) and Enfortumab Vedotin (EV) in combination. |
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin in combination rate of complete responses (CR) | 21 days | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 |
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin in combination rate of partial responses (PR) | 21 days | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 |
| Sacituzumab Govitecan (SG) and Enfortumab Vedotin in combination rate of participants with progressive disease | 21 days | Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 |
Countries
United States
Contacts
Primary ContactBradley A McGregor, MD
Backup ContactMerdith Flynn
Outcome results
None listed