Antibody-Drug Conjugate Therapy for Cancer

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Warfarin, UGT1A1 inhibitors, CYP3A4 inducers, others

Disqualifiers: Brain metastases, Cardiovascular conditions, Corneal disorders, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

Duration: Up to 3 years

500 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II ADC MATCH screening and multi-sub-study treatment trial is evaluating whether biomarker-directed treatment with one of three antibody-drug conjugates (ADCs) (sacituzumab govitecan, enfortumab vedotin, and trastuzumab deruxtecan) works in treating patients with solid tumor cancers that have high expression of the Trop-2, nectin-4, or HER2 proteins and that may have spread from where they first started (primary site) to nearby tissue, lymph nodes, or distant parts of the body (advanced) or to other places in the body (metastatic). Precision medicine is a form of medicine that uses information about a person's genes, proteins, and environment to prevent, diagnose, or treat disease in a way that is tailored to the patient. ADCs such as sacituzumab govitecan, enfortumab vedotin, and trastuzumab deruxtecan are monoclonal antibodies attached to biologically active drugs and are a form of targeted therapy. Sacituzumab govitecan is a monoclonal antibody, called sacituzumab, linked to a drug called govitecan. Sacituzumab attaches to a protein called Trop-2 on the surface of tumor cells and delivers govitecan to kill them. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of tumor cells. Enfortumab attaches to a protein called nectin-4 on tumor cells in a targeted way and delivers vedotin to kill them. Trastuzumab deruxtecan is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive tumor cells in a targeted way and delivers deruxtecan to kill them. Personalized treatment with sacituzumab govitecan, enfortumab vedotin, or trastuzumab deruxtecan may be an effective treatment option for patients with advanced or metastatic solid tumors that screen positive for high expression of Trop-2, nectin-4, or HER2, respectively.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a required 'washout period' (time without taking certain medications) from prior therapies before starting the study treatment. It's best to discuss your specific medications with the trial team to understand any necessary adjustments.

What data supports the effectiveness of the drug Enfortumab Vedotin, Sacituzumab Govitecan, and Trastuzumab Deruxtecan for cancer treatment?

Research shows that Sacituzumab Govitecan has been effective in treating various solid tumors, including breast and urothelial cancers, by targeting a protein called Trop-2, which is often found in these cancers. Additionally, a trial combining Sacituzumab Govitecan with Enfortumab Vedotin showed promise for treating metastatic urothelial carcinoma, suggesting potential effectiveness when used together. ^{1 2 3 4 5}

Is antibody-drug conjugate therapy generally safe for humans?

Antibody-drug conjugates like sacituzumab govitecan have shown acceptable safety in trials for various cancers, including breast and epithelial cancers. These treatments have been tested in multiple studies, showing they are generally well-tolerated by patients. ^{1 2 4 5 6}

How is the drug Enfortumab Vedotin, Sacituzumab Govitecan, Trastuzumab Deruxtecan unique for cancer treatment?

This drug is unique because it combines antibody-drug conjugates (ADCs) that target specific proteins on cancer cells, delivering powerful chemotherapy directly to the tumor. Sacituzumab Govitecan, for example, targets the Trop-2 protein, which is overexpressed in many cancers, and delivers SN-38, a potent chemotherapy agent, directly to the cancer cells, reducing side effects and increasing effectiveness. ^{1 2 3 5 7}

Research Team

Funda Meric-Bernstam

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Eligibility Criteria

This trial is for adults with advanced or metastatic solid tumors that have high levels of Trop-2, nectin-4, or HER2 proteins. Candidates must have progressed beyond standard treatments or be intolerant to them. They should not be dependent on transfusions and must have a good performance status (able to carry out daily activities). Key organ functions need to meet specific criteria, and they must consent to tumor biopsies.

Inclusion Criteria

My bilirubin levels are within the normal range, or I have Gilbert syndrome with levels not exceeding three times the normal limit.

My cancer can be measured by tests or scans.

My liver enzymes are within the normal range, or slightly elevated if I have liver cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

2 visits (in-person)

Treatment

Participants receive antibody-drug conjugates (ADCs) based on their tumor's protein expression. Treatment cycles repeat every 21 or 28 days depending on the cohort.

Up to 3 years

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 3 years

Every 3 months in years 1-2, every 6 months in year 3

Treatment Details

Interventions

• Enfortumab Vedotin
• Sacituzumab Govitecan
• Trastuzumab Deruxtecan

Trial Overview The study tests if personalized treatment with one of three antibody-drug conjugates (ADCs)—sacituzumab govitecan, enfortumab vedotin, trastuzumab deruxtecan—works against tumors expressing certain proteins. These ADCs are designed to deliver cancer-killing drugs directly to the tumor cells by attaching to specific proteins on their surface.

Participant Groups

Group I: Screening (record review, IHC assay) Experimental Treatment 2 Interventions

SCREENING STEP 1: Patients who have previously undergone SOC RNA testing have the results of their SOC RNA testing reviewed. Patients whose tumor expresses an appropriate TOI by RNA testing proceed to screening step 2. SCREENING STEP 2: Patients have TOI expression testing at the protein level by IHC assay performed on previously collected tissue. Patients with high Trop-2 protein expression are assigned to Cohort A. Patients with high nectin-4 protein expression are assigned to Cohort B. Patients with high HER2 protein expression are assigned to cohort C.

Group II: Cohort C (trastuzumab deruxtecan) Experimental Treatment 7 Interventions

Patients receive trastuzumab deruxtecan IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients also undergo ECHO or MUGA at screening and on study. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.

Group III: Cohort B (enfortumab vedotin) Experimental Treatment 5 Interventions

Patients receive enfortumab vedotin IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.

Group IV: Cohort A (sacituzumab govitecan) Experimental Treatment 5 Interventions

Patients receive sacituzumab govitecan IV over 1-3 hours on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI throughout the trial, undergo biopsy after enrollment to cohort but prior to treatment and again on study, and undergo collection of blood samples after enrollment to cohort but prior to treatment. Patients may optionally undergo biopsy at the time of progression and may optionally undergo collection of blood samples on study and at the time of progression.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Sacituzumab govitecan (SG) is an FDA-approved antibody-drug conjugate that has shown significant efficacy in treating metastatic triple-negative breast cancer, improving health-related quality of life and prolonging progression-free and overall survival in patients who have undergone multiple prior therapies.

Ongoing clinical trials are exploring the potential of SG for broader applications, including neoadjuvant and adjuvant therapies, combinations with immunotherapy, and treatment of various solid tumors, indicating its promise as a versatile cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of sacituzumab govitecan in solid tumors. Veeraballi, S., Khawar, Z., Aslam, HM., et al.[2023]

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]

Sacituzumab govitecan is an FDA-approved antibody-drug conjugate that effectively targets Trop-2, which is overexpressed in various solid tumors, including metastatic triple-negative breast cancer and urothelial carcinoma.

This drug combines an anti-Trop-2 antibody with the SN-38 payload, an active metabolite of irinotecan, showcasing a novel mechanism of action that enhances the delivery of potent anticancer agents directly to tumor cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trop-2 protein as a therapeutic target: A focused review on Trop-2-based antibody-drug conjugates and their predictive biomarkers. Vranic, S., Gatalica, Z.[2022]

Sacituzumab govitecan (SG) is a promising treatment for HR+/HER2- metastatic breast cancer (MBC), particularly for patients whose cancer has progressed despite other therapies, as it targets the Trop-2 protein which is highly expressed in these tumors.

The ongoing Phase III TROPiCS-02 study is evaluating the efficacy of SG compared to standard treatment options, aiming to address the significant clinical need for effective therapies in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TROPiCS-02: A Phase III study investigating sacituzumab govitecan in the treatment of HR+/HER2- metastatic breast cancer. Rugo, HS., Bardia, A., Tolaney, SM., et al.[2021]

Sacituzumab govitecan, an antibody-drug conjugate targeting Trop-2, showed promising therapeutic activity in a phase I trial with 25 patients suffering from various metastatic solid cancers, achieving partial responses in two patients and stable disease in 16 others.

The maximum tolerated dose was determined to be 12 mg/kg for the first cycle, with lower doses (8 and 10 mg/kg) being safer for extended treatment, leading to acceptable toxicity levels and disease control for up to 36 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors. Starodub, AN., Ocean, AJ., Shah, MA., et al.[2022]

Sacituzumab govitecan (SG) showed promising efficacy in treating advanced epithelial cancers, with partial response rates of 22.2% in endometrial cancer and 17.7% in small-cell lung cancer, indicating its potential as a treatment option.

The safety profile of SG was consistent with previous studies, with common treatment-related adverse events including neutropenia (57.8%) and nausea (62.6%), and a notable incidence of grade ≥3 neutropenia in patients with specific genetic variations (UGT1A1∗28 homozygotes).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Bardia, A., Messersmith, WA., Kio, EA., et al.[2021]

Sacituzumab govitecan, an antibody-drug conjugate that uses the active metabolite SN-38, shows promise in treating advanced cancers like triple-negative breast cancer, with a unique conjugation method that enhances drug delivery and minimizes side effects.

The drug has been granted Breakthrough Therapy status by the FDA and is currently under accelerated approval review, highlighting its potential efficacy and safety in patients with difficult-to-treat cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan. Goldenberg, DM., Sharkey, RM.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Role of sacituzumab govitecan in solid tumors. [2023]

2. 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]

3. Bosnia and Herzegovina pubmed.ncbi.nlm.nih.gov

Trop-2 protein as a therapeutic target: A focused review on Trop-2-based antibody-drug conjugates and their predictive biomarkers. [2022]

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

TROPiCS-02: A Phase III study investigating sacituzumab govitecan in the treatment of HR+/HER2- metastatic breast cancer. [2021]

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

First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors. [2022]

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

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. [2021]

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

Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan. [2020]