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

Trial Summary

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.

What data supports the effectiveness of the drug combination Sacituzumab Govitecan and Enfortumab Vedotin for bladder cancer?

Both sacituzumab govitecan and enfortumab vedotin have shown effectiveness as individual treatments for advanced bladder cancer. Enfortumab vedotin has been approved by the FDA for treating advanced urothelial cancer, with a 44% response rate in a study, while sacituzumab govitecan has shown preliminary activity in similar conditions. ^{1 2 3 4 5}

Is the combination of Sacituzumab Govitecan and Enfortumab Vedotin safe for humans?

The combination of Sacituzumab Govitecan and Enfortumab Vedotin has been evaluated for safety in a phase I trial for metastatic urothelial carcinoma. Enfortumab Vedotin has known side effects, including high blood sugar, nerve damage, eye problems, skin reactions, and risks to unborn babies. These side effects were observed in patients with advanced bladder cancer, and 73% of patients experienced severe reactions. ^{1 2 3 4 6}

How is the drug combination of Sacituzumab Govitecan and Enfortumab Vedotin unique for treating bladder cancer?

The combination of Sacituzumab Govitecan and Enfortumab Vedotin is unique because it uses two different antibody-drug conjugates that target distinct proteins on cancer cells, potentially enhancing treatment effectiveness for advanced bladder cancer compared to using each drug alone. ^{1 2 3 4 5}

What is the purpose of this trial?

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

Research Team

Bradley A McGregor, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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

Findings from Research

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 (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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma. [2023]

4. England pubmed.ncbi.nlm.nih.gov

The role of enfortumab vedotin and sacituzumab govitecan in treatment of advanced bladder cancer. [2022]

5. United States 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. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Current and emerging role of sacituzumab govitecan in the management of urothelial carcinoma. [2022]