Sacituzumab Govitecan + Enfortumab Vedotin for Bladder Cancer

Overseen By Bradley A McGregor, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Dana-Farber Cancer Institute

Must be taking: Checkpoint inhibitors, Platinum therapy

Must not be taking: Topoisomerase inhibitors, High-dose corticosteroids

Disqualifiers: Pregnancy, Active CNS metastases, Active cardiac disease, Uncontrolled diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 5

Duration: 21 days per cycle

106 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the best combination of three drugs—Sacituzumab Govitecan, Enfortumab Vedotin, and Pembrolizumab—to treat bladder cancer that has spread (metastatic urothelial carcinoma). The first phase will identify safe doses of the first two drugs together, while the second phase will assess their effectiveness when combined with Pembrolizumab. Individuals with bladder cancer unresponsive to previous treatments, such as chemotherapy or immunotherapy, might be suitable candidates for this trial. As a Phase 1/Phase 2 trial, the research focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have had chemotherapy, targeted therapy, or radiation therapy within 2 weeks before starting the trial, and you cannot be on high-dose corticosteroids or other investigational agents.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining Sacituzumab Govitecan and Enfortumab Vedotin holds promise for treating advanced bladder cancer. In earlier studies, 70% of patients experienced a response to this treatment. However, like all treatments, side effects can occur. Some patients reported manageable side effects, and researchers continue to determine the safest dosages.

Another study demonstrated potential benefits by adding Pembrolizumab to this combination. Pembrolizumab is already used for other conditions, so its safety profile is well-established. The studies aim to ensure that using these drugs together remains safe for patients.

These treatments are still under investigation, but early results are encouraging. Participants have tolerated the drugs well, with ongoing monitoring to ensure safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments Sacituzumab Govitecan and Enfortumab Vedotin for bladder cancer because they offer a fresh approach compared to traditional therapies. Unlike standard treatments like chemotherapy, which attack cancer cells broadly, these drugs are antibody-drug conjugates that specifically target cancer cells. Sacituzumab Govitecan links a powerful chemotherapy drug to an antibody that binds to the Trop-2 protein found on many cancer cells, while Enfortumab Vedotin targets the Nectin-4 protein, common in bladder cancer cells. This targeted approach helps deliver the treatment directly to cancer cells, potentially increasing effectiveness while reducing damage to healthy cells. The combination of these drugs, especially with Pembrolizumab, adds an immunotherapy angle, potentially enhancing the body's immune response against cancer.

What evidence suggests that this trial's treatments could be effective for metastatic urothelial carcinoma?

Research has shown that using Sacituzumab Govitecan and Enfortumab Vedotin together has potential in treating advanced bladder cancer. In earlier studies, 11% of patients experienced tumor shrinkage or halted growth. However, patients lived without disease progression for about 2.1 months, and the average survival time was 6 months. While these results indicate some benefit, the overall effectiveness remains limited. In this trial, some participants will receive the combination of Sacituzumab Govitecan and Enfortumab Vedotin, while others will receive this combination along with Pembrolizumab, a type of immunotherapy. Early findings suggest that adding Pembrolizumab might improve results, but further research is needed to confirm this. ^{1 6 7 8 9}

Who Is on the Research Team?

Bradley A McGregor, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with advanced urothelial carcinoma who've had platinum-based therapy and a checkpoint inhibitor treatment can join. They must have good organ function, no active infections or serious heart conditions, not be pregnant or breastfeeding, and agree to use contraception.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document.

I've had platinum-based treatment for cancer that came back or worsened within a year.

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. 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. 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.

Exclusion Criteria

Participants with psychiatric illness/social situations that would limit compliance with study requirements.

I have a serious heart condition.

Participants who are receiving any other investigational agents.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Enfortumab Vedotin and Sacituzumab Govitecan on Days 1 and 8 of a 21-day cycle, with dose escalation and de-escalation guided by the Bayesian optimal interval design

21 days per cycle

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Enfortumab Vedotin
• Sacituzumab Govitecan

Trial Overview The trial is testing the safe combination doses of two drugs: Sacituzumab Govitecan (SG) and Enfortumab Vedotin (EV), for treating metastatic urothelial carcinoma. It aims to find out how these drugs work together.

How Is the Trial Designed?

Group I: Sacituzumab Govitecan (SG) and Enfortumab vedotin-ejfv (EV) and Pembrolizumab Experimental Treatment 3 Interventions

Participants will be given a triplet regimen of Enfortumab Vedotin 1.25mg/kg, Sacituzumab Govitecan 7.5mg/kg (D1 and D8 every three weeks), and Pembrolizumab 200mg (D1 every 3 weeks) or 400 mg (D1 every 6 weeks) as a front-line therapy. Dose reductions of Enfortumab Vedotin to 1, 0.75 and 0.5 mg/kg will be permitted while Sacituzumab Govitecan can be dose reduced to 5 mg/kg. No dose reductions of Pembrolizumab are permitted. Following C1D1, drugs may be held independently per investigator discretion. A safety run-in will be conducted for the first 12 patients to evaluate the tolerability of the triplet regimen using Bayesian toxicity monitoring (BTOX). The first stage will enroll 6 patients, and if there are 2 or fewer DLTs, then next 6 patients will be enrolled. The study will be halted if there are 5 or more DLTs observed among the total of 12 evaluable patients.

Group II: Dose Expansion Sacituzumab Govitecan (SG) and Enfortumab vedotin-ejfv (EV) Experimental Treatment 2 Interventions

Participants will be given the study drugs Enfortumab Vedotin and then Sacituzumab Govitecan on Days 1 and 8 of each 21-day study cycle. Three dose levels of this drug combination will be studied with 3-18 patients per dose level depending on treatment-related dose limiting toxicities.

Group III: Dose Escalation Sacituzumab Govitecan (SG) and Enfortumab vedotin-ejfv (EV) Experimental Treatment 2 Interventions

Participants will be given the study drugs Enfortumab Vedotin and then Sacituzumab Govitecan on Days 1 and 8 of a 21-day study cycle. Dose escalation and de-escalation for the Sacituzumab Govitecan (SG) and Enfortumab vedotin-ejfv (EV) combination will be guided using the Bayesian optimal interval (BOIN) design with up to 4 dose level escalations.

Enfortumab Vedotin is already approved in United States, European Union for the following indications:

Approved in United States as Padcev for:

• Locally advanced or metastatic urothelial cancer

Approved in European Union as Padcev for:

• Locally advanced or metastatic urothelial cancer

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Gilead Sciences

Industry Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Published Research Related to This Trial

Enfortumab vedotin (Padcev) is the first FDA-approved treatment specifically for adults with locally advanced or metastatic urothelial cancer who have already undergone treatment with PD-1/PD-L1 inhibitors and platinum-based chemotherapy.

This approval marks a significant advancement in cancer therapy, providing a new option for patients who have limited treatment choices after previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves First Agent to Treat Locally Advanced, Metastatic Urothelial Cancer. Kahl, KL.[2023]

Enfortumab vedotin and sacituzumab govitecan are novel antibody-drug conjugates that improve treatment options for patients with advanced bladder cancer after they have received platinum-based therapy and immune checkpoint inhibitors, with enfortumab vedotin showing improved overall survival.

Sacituzumab govitecan has a 27% response rate in treating advanced bladder cancer, highlighting its potential effectiveness, but careful consideration of the safety profiles of both agents is essential for optimizing patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of enfortumab vedotin and sacituzumab govitecan in treatment of advanced bladder cancer. Hanna, KS., Larson, S., Nguyen, J., et al.[2022]

Sacituzumab govitecan (SG) is an effective treatment for locally advanced and metastatic urothelial cancer, showing a 27% objective response rate in the TROPHY-U-01 phase II trial.

While SG has common side effects like diarrhea and neutropenia, these can be managed with supportive care, and it has received accelerated approval for patients who have previously undergone platinum-based chemotherapy and PD-1 or PD-L1 inhibitor treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and emerging role of sacituzumab govitecan in the management of urothelial carcinoma. Mathew Thomas, V., Tripathi, N., Agarwal, N., et al.[2022]

In a phase I trial involving 23 patients with metastatic urothelial carcinoma, the combination of sacituzumab govitecan (SG) and enfortumab vedotin (EV) demonstrated a high objective response rate of 70%, with three patients achieving complete responses.

The study identified a safe dose for further testing, with 78% of patients experiencing grade ≥3 adverse events, indicating that while the treatment is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma. McGregor, BA., Sonpavde, GP., Kwak, L., et al.[2023]

In a phase II study involving 113 patients with metastatic urothelial carcinoma who had previously progressed on platinum-based chemotherapy and checkpoint inhibitors, sacituzumab govitecan (SG) demonstrated an objective response rate of 27%, indicating significant efficacy in this difficult-to-treat population.

SG was associated with a manageable safety profile, with the most common severe side effects being neutropenia (35%) and diarrhea (10%), leading to a 6% discontinuation rate due to treatment-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. Tagawa, ST., Balar, AV., Petrylak, DP., et al.[2022]

Enfortumab vedotin (PADCEV) received accelerated FDA approval for treating locally advanced or metastatic urothelial cancer in patients who have already undergone specific prior therapies, based on substantial evidence from a study involving 125 patients.

The treatment showed a confirmed objective response rate of 44%, with a median response duration of 7.6 months, although 73% of patients experienced grade 3-4 adverse reactions, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma. Chang, E., Weinstock, C., Zhang, L., et al.[2022]

Citations

1. esmoopen.com esmoopen.com/article/S2059-7029(25)01174-3/fulltext

Real-world clinical outcomes of sacituzumab govitecan ... In a large real-world cohort, SG after EV resulted in limited efficacy: ORR 11%, mPFS 2.1 months and mOS 6.0 months. Grade 3-4 neutropenia rates were 36%.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12173038/

Real-world clinical outcomes of sacituzumab govitecan ... Real-world clinical outcomes of sacituzumab govitecan after prior exposure to enfortumab vedotin in patients with metastatic urothelial ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1078143925003953

Efficacy of sacituzumab govitecan after enfortumab vedotin ... Real-world data are needed to better define SG outcomes, particularly following treatment with enfortumab vedotin (EV). In this analysis, we aim ...

4. urotoday.com urotoday.com/conference-highlights/esmo-2024/esmo-2024-bladder-cancer/154784-esmo-2024-updated-efficacy-profile-of-the-double-antibody-drug-conjugate-dad-phase-i-trial-sacituzumab-govitecan-plus-enfortumab-vedotin-in-second-line-in-metastatic-urothelial-carcinoma-muc.html

Sacituzumab Govitecan plus Enfortumab Vedotin in ≥ ... In this report, Dr. McGregor presented the safety and efficacy outcomes after 22 months of follow-up. Patients with metastatic urothelial ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04724018

NCT04724018 | Sacituzumab Govitecan Plus EV in ... Sacituzumab Govitecan has appeared promising in patients with bladder cancer that has spread and works by a different mechanism than Enfortumab Vedotin.

6. onclive.com onclive.com/view/sacituzumab-govitecan-plus-enfortumab-vedotin-shows-early-promise-in-metastatic-urothelial-carcinoma

Sacituzumab Govitecan Plus Enfortumab Vedotin Shows ... Sacituzumab govitecan and enfortumab vedotin combination showed a 70% overall response rate in metastatic urothelial cancer, with dose level 2 ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03547973

NCT03547973 | Study of Sacituzumab Govitecan in ... The objective of this study is to evaluate the efficacy and safety of sacituzumab govitecan-hziy monotherapy and with novel combinations in participants with ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11181835/

Efficacy of Antibody Drug Conjugates Alone and in ... This agent has received US FDA approval for previously treated patients with metastatic triple negative breast cancer as well as for patients ...

9. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)00009-7/fulltext

TROPHY-U-01, a phase II open-label study of sacituzumab ... Sacituzumab govitecan (SG) is a Trop-2-directed antibody–drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan.