WTX-124 + Pembrolizumab for Solid Tumors

Recruiting at 12 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Werewolf Therapeutics, Inc.

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Active malignancy, Pneumonitis, Autoimmune, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment involving WTX-124 (an IL-2 INDUKINE molecule), both alone and in combination with pembrolizumab (KEYTRUDA), for advanced or metastatic solid tumors. The researchers aim to determine the optimal dose and assess the effectiveness of these treatments. Individuals with hard-to-treat cancers, such as kidney cancer (RCC), skin melanoma, or certain skin and lung cancers, who have tried other treatments, might be suitable candidates. Those with these types of cancer, where previous treatments have failed or ceased to work, may consider this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on immunosuppressive therapy or receiving chronic steroid treatment. Also, you must not have taken any investigational agents or anticancer therapy within a certain period before starting the study.

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

Research has shown that WTX-124, when used alone, is generally well-tolerated by people with advanced or spreading solid tumors. Studies indicate that it can be safely delivered to the tumor area, usually without causing severe side effects for most patients.

Specific data on the combination of WTX-124 with pembrolizumab (a type of immune therapy) is limited. However, pembrolizumab has FDA approval for other uses and is known to be safe for many people, although it can sometimes cause immune-related side effects.

As the trial is in its early stages, ensuring safety remains a top priority, and researchers will closely monitor participants for any negative effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about WTX-124 and pembrolizumab because they offer new hope for treating various advanced or metastatic cancers like renal cell carcinoma (RCC), cutaneous malignant melanoma, and cutaneous squamous cell carcinoma (cSCC). Unlike traditional treatments that often target cancer cells directly, WTX-124 works by enhancing the body's immune response, making it a novel approach. When combined with pembrolizumab, an already established immunotherapy that blocks a specific pathway used by cancer cells to evade the immune system, this combination could enhance anti-tumor activity. This dual approach of boosting immune response while blocking cancer cell evasion is what makes these treatments potentially game-changing.

What evidence suggests that this trial's treatments could be effective for advanced or metastatic solid tumors?

Research has shown that WTX-124, a new drug that activates only under certain conditions, holds potential for treating solid tumors. Studies have found it safe and effective for patients whose tumors have returned or are resistant to other treatments. This trial includes arms where participants receive WTX-124 as monotherapy, enhancing the immune system's ability to fight cancer cells.

Other participants in this trial will receive WTX-124 combined with pembrolizumab, a well-known cancer medication. Pembrolizumab alone has successfully treated various cancers, such as melanoma and lung cancer. Together, these treatments could offer a strong option for people with advanced or spreading tumors. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

Adults over 18 with certain advanced solid tumors, able to undergo biopsies, and have at least one measurable tumor lesion. They must be relatively healthy (ECOG status of 0 or 1), not have had recent major surgery or other cancer treatments, no active infections like hepatitis B/C or HIV, and agree to effective birth control.

Inclusion Criteria

My organs and bone marrow are functioning well.

I am fully active or can carry out light work.

Additional criteria may apply

Exclusion Criteria

I need steroids for my brain cancer symptoms.

History of hypersensitivity to any of the study drug components

I do not have an ongoing serious infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Part 1 of the study involves dose escalation of WTX-124, both as monotherapy and in combination with pembrolizumab

8-12 weeks

Dose Expansion

Part 2 involves dose expansion with six arms, administering WTX-124 as monotherapy and in combination with pembrolizumab

16-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• WTX-124

Trial Overview The trial is testing WTX-124 alone and combined with Pembrolizumab in patients with advanced solid tumors. It's a Phase I study which means it's the first time humans are being tested for safety and dosage levels.

How Is the Trial Designed?

Group I: WTX-124 monotherapy dose escalation Experimental Treatment 1 Intervention

WTX-124 monotherapy dose escalation

Group II: WTX-124 in combination with pembro dose escalation Experimental Treatment 2 Interventions

WTX-124 in combination with pembrolizumab (pembro) dose escalation

Group III: Arm F: WTX-124 in combination with pembro dose expansion. Advanced/metastatic PD-L1-positive NSCL Experimental Treatment 2 Interventions

Arm F: WTX-124 in combination with pembrolizumab dose expansion. Patients with advanced or metastatic PD-L1-positive NSCLC lines.

Group IV: Arm E: WTX-124 with pembro dose expansion. Advanced or metastatic cutaneous melanoma. Experimental Treatment 2 Interventions

Arm E: WTX-124 in combination with pembrolizumab dose expansion. Patients with advanced or metastatic cutaneous melanoma.

Group V: Arm D: WTX-124 in combination with pembro dose expansion. Advanced or metastatic RCC. Experimental Treatment 2 Interventions

Arm D: WTX-124 in combination with pembrolizumab dose expansion. Patients with advanced or metastatic RCC.

Group VI: Arm C: WTX-124 monotherapy dose expansion. Patients with advanced or metastatic cSCC. Experimental Treatment 1 Intervention

Arm C: WTX-124 monotherapy dose expansion. Patients with advanced or metastatic cSCC.

Group VII: Arm B: WTX-124 monotherapy dose expansion. Advanced or metastatic cutaneous malignant melanoma. Experimental Treatment 1 Intervention

Arm B: WTX-124 monotherapy dose expansion. Patients with advanced or metastatic cutaneous malignant melanoma.

Group VIII: Arm A: WTX-124 monotherapy dose expansion. Patients with advanced or metastatic RCC. Experimental Treatment 1 Intervention

Arm A: WTX-124 monotherapy dose expansion. Patients with advanced or metastatic RCC.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Werewolf Therapeutics, Inc.

Lead Sponsor

Trials

2

Recruited

180+

Merck Sharp & Dohme LLC

Industry 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

Published Research Related to This Trial

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

The first-in-human study of MK-4830, a novel IgG4 monoclonal antibody targeting the ILT4 receptor, showed it was well tolerated with no dose-limiting toxicities among 84 patients with advanced solid tumors.

In combination with pembrolizumab, MK-4830 demonstrated promising antitumor activity, with 11 out of 34 patients achieving objective responses, including some who had previously progressed on other therapies, suggesting enhanced effectiveness in certain tumor microenvironments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors. Siu, LL., Wang, D., Hilton, J., et al.[2023]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

Pembrolizumab (Keytruda) is an approved treatment for metastatic or locally advanced esophageal and gastroesophageal junction cancer, indicating its efficacy in targeting these specific cancer types.

It is used in combination with platinum- and fluoropyrimidine-based chemotherapy, suggesting a synergistic approach to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. Aschenbrenner, DS.[2023]

Nivolumab and pembrolizumab are FDA-approved monoclonal antibodies that target PD-1, helping to enhance T cell activity against cancer by blocking the PD-1/PD-L1 interaction, which allows cancer cells to escape immune detection.

Both drugs have shown efficacy across multiple cancer types, including melanoma and non-small cell lung cancer, and are considered interchangeable options for treating these conditions, which may help manage the rising costs of cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. Prasad, V., Kaestner, V.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.2623

A phase 1/1b study of the IL-2 prodrug WTX-124 in patients ... WTX-124 administered as a monotherapy IV Q2W in the outpatient setting is well tolerated and clinically active in patients with relapsed/refractory solid ...

2. investors.werewolftx.com investors.werewolftx.com/node/8866/pdf

Werewolf Therapeutics Reports Second Quarter 2025 ... WTX-124: a systemically delivered, conditionally activated Interleukin-2 (IL-2) INDUKINE molecule being developed as monotherapy and in ...

3. onclive.com onclive.com/view/wtx-124-nets-fda-fast-track-designation-in-melanoma-following-immunotherapy

WTX-124 Nets FDA Fast Track Designation in Melanoma ... WTX-124, an IL-2 therapy, received fast track designation for advanced cutaneous melanoma treatment after standard immunotherapy. The phase 1/1b ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02085070

NCT02085070 | MK-3475 in Melanoma and NSCLC ... Overall, historical melanoma patient cohorts have reported a median survival of patients with brain metastases in the order of 2.5 - 4 months despite use of ...

5. sec.gov sec.gov/Archives/edgar/data/1785530/000178553025000006/a12312024ex991.htm

99.1 WTX-124: a systemically delivered, conditionally activated Interleukin-2 (IL-2) INDUKINE molecule being developed as monotherapy and in combination with ...

6. investors.werewolftx.com investors.werewolftx.com/news-releases/news-release-details/werewolf-therapeutics-presents-preliminary-monotherapy-data

Werewolf Therapeutics Presents Preliminary Monotherapy ... Safety data indicate WTX-124 is generally well-tolerated ... INDUKINE molecule, in patients with advanced or metastatic solid tumors.

7. jitc.bmj.com jitc.bmj.com/content/11/Suppl_1/A830

737 A phase 1/1b study of the tumor-activated IL-2 prodrug ... ... IL-2. The data demonstrate the potential of WTX-124 to safely deliver a fully potent, wild-type IL-2 to the TME in patients with solid tumors.

8. cancernetwork.com cancernetwork.com/view/fda-grants-ftd-to-wtx-124-in-advanced-pretreated-cutaneous-melanoma

FDA Grants FTD to WTX-124 in Advanced Pretreated ... Data from a phase 1/1b trial showed that WTX-124 achieved clinically meaningful activity in those with advanced melanoma following SOC ...

9. werewolftx.gcs-web.com werewolftx.gcs-web.com/news-releases/news-release-details/werewolf-therapeutics-provides-business-update-and-highlights-0

Werewolf Therapeutics Provides Business Update and ... WTX-124: a systemically delivered, conditionally activated IL-2 ... INDUKINE molecule being developed in advanced or metastatic solid tumors.