Zilovertamab Vedotin for Pediatric and Young Adult Cancers

Recruiting at 58 trial locations

Overseen By Toll Free Number

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: Corticosteroids, CYP3A4 inhibitors

Disqualifiers: Organ transplant, Cardiovascular disease, HIV, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: Up to approximately 60 months

90 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong CYP3A4 inhibitors or inducers, and ongoing corticosteroid therapy must be stable and below a certain dose. It's best to discuss your current medications with the trial team.

What safety data exists for Zilovertamab Vedotin (also known as VLS-101 or MK-2140) in humans?

There is no specific safety data available for Zilovertamab Vedotin, but similar treatments like brentuximab vedotin have shown that about half of the patients experienced significant side effects, including nerve damage and viral reactivation, which sometimes led to stopping or reducing the dose. ^{1 2 3 4 5}

What makes the drug Zilovertamab Vedotin unique for treating pediatric and young adult cancers?

Zilovertamab Vedotin is a novel drug that combines an antibody targeting cancer cells with a potent chemotherapy agent, allowing it to specifically attack and kill cancer cells while minimizing damage to healthy cells. This targeted approach is different from traditional chemotherapy, which can affect both cancerous and healthy cells. ^{6 7 8 9 10}

What is the purpose of this trial?

Substudy 01A is part of a platform study. The purpose of this study is to assess the efficacy and safety of zilovertamab vedotin in pediatric participants with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL)/Burkitt lymphoma, or neuroblastoma and in pediatric and young adult participants with Ewing sarcoma.

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for young people with certain blood cancers or solid tumors, like B-cell acute lymphoblastic leukemia, Burkitt lymphoma, diffuse large B-cell lymphoma, neuroblastoma, and Ewing sarcoma. Participants must have tried other treatments that didn't work (relapsed) or didn't respond to previous treatments (refractory).

Inclusion Criteria

I have been diagnosed with a specific type of blood cancer.

My cancer is either neuroblastoma or Ewing sarcoma.

Exclusion Criteria

I have had a solid organ transplant.

I have an active heart condition.

I have been diagnosed with a demyelinating form of Charcot-Marie-Tooth disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive escalating doses of zilovertamab vedotin via intravenous (IV) infusion on Day 1 of each 21-day cycle

Up to approximately 60 months

Every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Zilovertamab Vedotin

Trial Overview The study tests zilovertamab vedotin's effectiveness and safety in children and young adults. It's a targeted therapy aimed at treating specific types of cancer by delivering a toxin directly to the cancer cells.

Participant Groups

Group I: Zilovertamab vedotin Experimental Treatment 1 Intervention

Participants receive escalating doses of zilovertamab vedotin via intravenous (IV) infusion on Day 1 of each 21-day cycle (every 3 weeks).

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

Approved in European Union as Zilovertamab Vedotin for:

• Mantle-cell lymphoma

Approved in United States as Zilovertamab Vedotin for:

Who Is Running the Clinical Trial?

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a study of 39 patients treated with brentuximab vedotin (BV) at a French university hospital, over half (51.3%) experienced significant adverse drug reactions (ADRs), with 50% of these being severe.

The most common ADRs included peripheral sensory neuropathy and CMV reactivation, leading to drug discontinuation in 4 patients and dose reductions in 6, highlighting the need for better monitoring of BV's safety in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse reactions related to brentuximab vedotin use: A real-life retrospective study. Clarivet, B., Vincent, L., Vergely, L., et al.[2019]

The antibody-drug conjugate tisotumab vedotin (TV) has been shown to significantly increase the probability of objective response in patients with recurrent or metastatic cervical cancer as the maximum serum concentration (Cmax) increases, indicating its efficacy in treatment.

However, higher exposure levels of TV are also associated with an increased risk of treatment-related adverse events, particularly ocular side effects, suggesting a need for careful monitoring of dosage to balance efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-safety and exposure-efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors. Passey, C., Voellinger, J., Gibiansky, L., et al.[2023]

Brentuximab vedotin demonstrated a clinically meaningful response in 47% of pediatric patients with relapsed or refractory classical Hodgkin's lymphoma and 53% for systemic anaplastic large-cell lymphoma, indicating its efficacy in this challenging patient population.

The treatment had a manageable safety profile, with the most common adverse events being pyrexia and nausea, and 44% of patients experiencing at least one grade 3 or worse adverse event, suggesting that while side effects occurred, they were generally tolerable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brentuximab vedotin for paediatric relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma: a multicentre, open-label, phase 1/2 study. Locatelli, F., Mauz-Koerholz, C., Neville, K., et al.[2019]

In a study of 16 pediatric patients with Hodgkin lymphoma, brentuximab vedotin showed significant pharmacokinetic variability primarily influenced by the patients' weight, accounting for over 60% of the variability.

The drug's exposure levels (AUC and C max) were lower in children compared to adults, but the treatment was found to be safe and tolerable, with no development of anti-therapeutic antibodies during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, immunogenicity, and safety of weekly dosing of brentuximab vedotin in pediatric patients with Hodgkin lymphoma. Flerlage, JE., Metzger, ML., Wu, J., et al.[2019]

The study established a safe dose recommendation (SDR) of 130 mg/m2/day for vorinostat in children with relapsed or therapy-refractory malignancies, with a maximum tolerated dose (MTD) reaching up to 580 mg/m2/day.

Higher doses of vorinostat were associated with better treatment responses and prolonged disease control, while most treatment-related side effects were manageable and reversible, indicating a potential for effective use in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia. van Tilburg, CM., Milde, T., Witt, R., et al.[2020]

Zoledronic acid (ZOL) has shown potential anticancer activity across various cancer types, with evidence from clinical trials indicating survival benefits for patients with advanced cancers.

In early breast cancer patients, ZOL not only improves disease-free survival but also reduces the presence of tumor cells and decreases the size of residual invasive tumors, suggesting it may have significant clinical benefits beyond its role in preventing skeletal-related events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticancer evidence for zoledronic acid across the cancer continuum. Costa, L., Harper, P., Coleman, RE., et al.[2018]

Monepantel, a veterinary drug, was tested in a Phase I trial for its potential anticancer effects in adults with hard-to-treat solid tumors, showing some preliminary signs of efficacy by reducing mTOR pathway markers in blood cells.

While the drug was generally well-tolerated at the lowest dose of 5 mg/kg, gastrointestinal side effects were common, leading to concerns about its palatability and suggesting the need for reformulation to improve patient experience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A preliminary assessment of oral monepantel's tolerability and pharmacokinetics in individuals with treatment-refractory solid tumors. Mislang, A., Mollard, R., Tapia Rico, G., et al.[2021]

In a study of 120 women with locally advanced breast cancer, adding zoledronic acid (ZOL) to neoadjuvant chemotherapy did not improve overall clinical outcomes, such as time to recurrence or survival rates, compared to chemotherapy alone.

However, younger ER+/HER2- patients treated with ZOL experienced significantly worse time to recurrence and trends towards poorer survival outcomes, indicating that ZOL may not be safe for this specific group and highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcome of (neo)adjuvant zoledronic acid therapy in locally advanced breast cancer. Jallouk, AP., Paravastu, S., Weilbaecher, K., et al.[2022]

Zoledronic acid (ZOL) significantly inhibits the growth of non-small-cell lung cancer (NSCLC) cells in vitro and in vivo, demonstrating a dose-dependent effect that prolongs survival in treated mice.

ZOL induces cell-cycle arrest at the S/G2/M-phase without causing apoptosis, suggesting it may be a promising therapeutic strategy when combined with chemotherapy or radiotherapy for treating NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zoledronic acid is unable to induce apoptosis, but slows tumor growth and prolongs survival for non-small-cell lung cancers. Li, YY., Chang, JW., Chou, WC., et al.[2021]

In a study of 28,385 patients with solid tumors or multiple myeloma, treatment with zoledronic acid (ZOL) significantly reduced the incidence of skeletal complications, including a 24% reduction in fractures and a 45% reduction in spinal cord compression.

Patients who continued ZOL treatment for more than 180 days experienced better outcomes, including a 56% reduction in mortality risk, with the most significant benefits seen in those treated regularly for over 18 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the clinical benefit of long-term (beyond 2 years) treatment of skeletal-related events in advanced cancers with zoledronic acid. Henk, H., Teitelbaum, A., Kaura, S.[2018]

References

1. France pubmed.ncbi.nlm.nih.gov

Adverse reactions related to brentuximab vedotin use: A real-life retrospective study. [2019]

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

Exposure-safety and exposure-efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors. [2023]

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

Brentuximab vedotin for paediatric relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma: a multicentre, open-label, phase 1/2 study. [2019]

4. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, immunogenicity, and safety of weekly dosing of brentuximab vedotin in pediatric patients with Hodgkin lymphoma. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Anticancer evidence for zoledronic acid across the cancer continuum. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

A preliminary assessment of oral monepantel's tolerability and pharmacokinetics in individuals with treatment-refractory solid tumors. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Long-term outcome of (neo)adjuvant zoledronic acid therapy in locally advanced breast cancer. [2022]

9. Ireland pubmed.ncbi.nlm.nih.gov

Zoledronic acid is unable to induce apoptosis, but slows tumor growth and prolongs survival for non-small-cell lung cancers. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Evaluation of the clinical benefit of long-term (beyond 2 years) treatment of skeletal-related events in advanced cancers with zoledronic acid. [2018]