Dose Escalation and Expansion Study of WTX-124 as Monotherapy and in Combination With Pembrolizumab (Pembro) in Patients With Selected Advanced or Metastatic Solid Tumors

A Multicenter Phase I/Ib Dose Escalation and Expansion Study of WTX-124 as Monotherapy and in Combination With Pembrolizumab in Patients With Selected Advanced or Metastatic Solid Tumors

A first-in-human, Phase I, open-label, multicenter study of WTX-124 administered as monotherapy and in combination with pembrolizumab to patients with advanced or metastatic solid tumors.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced Solid Tumor; Metastatic Solid Tumor
• Intervention / Treatment: Drug: WTX-124; Drug: pembrolizumab

Detailed Description

This is a first-in-human, Phase I, open-label, multicenter study designed to evaluate the safety, tolerability and preliminary efficacy of WTX-124, a conditionally-activated IL-2 prodrug, when administered as monotherapy and in combination with pembrolizumab, for the treatment of patients with advanced solid tumors. Part 1 of the study is dose escalation of WTX-124, both as monotherapy and in combination with pembrolizumab. Part 2 is dose expansion and is comprised of six arms in which WTX-124 will be administered as monotherapy and in combination with pembrolizumab to patients with advanced or metastatic cutaneous malignant melanoma or advanced or metastatic renal cell carcinoma.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • HonorHealth
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Winship Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin and Bren Simon Comprehensive Cancer Center
  • Minnesota
    • Maple Grove, Minnesota, United States, 55369
      • Minnesota Oncology Hematology, P.A.
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States, 14203
      • Roswell Park Comprehensive Cancer Care
    • Hawthorne, New York, United States, 10532
      • Westchester Medical Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Cancer Institute Franz Clinic
  • Texas
    • Austin, Texas, United States, 78705-1165
      • Texas Oncology - Austin Midtown
    • Dallas, Texas, United States, 75390-8852
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77054
      • NEXT Oncology
    • San Antonio, Texas, United States, 78229
      • NEXT Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Each patient must meet all the following criteria to participate in the study:

1. Has histological or cytological documentation of a solid tumor indication for which a CPI (e.g. anti-PD-(L)1 is indicated for all parts of the clinical study;

2. Monotherapy Dose Escalation:

   Patients with relapsed/refractory locally advanced or metastatic solid tumors for which immunotherapy is approved, who have progressed on or are intolerant to standard therapy, including CPIs, or for whom no standard therapy with proven benefit exists.

   Combination Dose Escalation:

   Patients with relapsed/refractory locally advanced or metastatic solid tumors for which immunotherapy is approved, who have progressed on or are intolerant to standard therapy or for whom no standard therapy with proven benefit exists.

   Monotherapy Dose Expansion:

   • Arm A: Patients with relapsed advanced or metastatic RCC who have received no more than 4 prior lines of therapy in the advanced or metastatic setting
   • Arm B: Patients with relapsed advanced or metastatic cutaneous malignant melanoma who have received no more than 2 prior lines of therapy for BRAF V600 wild type and no more than 3 prior lines of therapy for BRAF V600 mutant melanoma.
   • Arm C: Patients with relapsed advanced or metastatic cSCC who have received no more than 2 prior lines of systemic therapy

   Combination Dose Expansion:

   1. Arm D: Patients with RCC who have received no more than 3 prior lines of therapy
   2. Arm E: Patients with cutaneous melanoma who may be naïve to all prior therapy for advanced or metastatic disease. For BRAF wild type melanoma, patients should have received no more than 2 prior lines of therapy. For BRAF V600 mutant disease, patients should have received no more than 3 prior lines of therapy.
   3. Arm F: Patients with PD-L1-positive NSCLC who have received no more than 3 prior lines;
3. ≥18 years of age;
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;
5. Has at least 1 measurable lesion per RECIST 1.1(lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions);
6. Agrees to undergo a pre-treatment and on-treatment biopsy of a primary or metastatic solid tumor lesion;
7. Has adequate organ and bone marrow function;
8. Willingness of men and women of reproductive potential to observe highly effective birth control for the duration of treatment and for 4 months following the last dose of study drug;
9. Additional criteria may apply

Exclusion Criteria:

1. Have a history of another active malignancy (a second cancer) within the previous 2 years except for localized cancers that are not related to the current cancer being treated, are considered cured, and, in the opinion of the Investigator, presents a low risk of recurrence. These exceptions include, but are not limited to, basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast;
2. Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease;
3. Have received prior IL-2-directed therapy;
4. Have had an allogeneic tissue/solid organ transplant;
5. Have known symptomatic brain metastases requiring steroids;
6. Have significant cardiovascular disease;
7. Have an active autoimmune disease that required systemic treatment in the past 2 years;
8. Diagnosis of immunodeficiency, is on immunosuppressive therapy, or is receiving chronic systemic or enteric steroid therapy
9. Major surgery (excluding placement of vascular access) within 2 weeks prior to the first dose of study drug;
10. Investigational agent or anticancer therapy within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;
11. Has received prior radiotherapy within 2 weeks of start of study treatment. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease;
12. Any unresolved toxicities from prior therapy greater than NCI CTCAE version 5.0 Grade 1 at the time of starting study drug with the exception of alopecia and Grade 2 prior platinum-therapy related neuropathy;
13. Received a live or live-attenuated vaccine within 30 days of the first dose of study drug; Note: Administration of killed vaccines or other formats are allowed.
14. Active, uncontrolled systemic bacterial, viral, or fungal infection;
15. HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease;
16. Active infection as determined by hepatitis B surface antigen and hepatitis B core antibody, or hepatitis B virus DNA by quantitative polymerase chain reaction (qPCR) testing;
17. Active infection as determined by hepatitis C virus (HCV) antibody or HCV RNA by qPCR testing;
18. Pregnant or lactating;
19. History of hypersensitivity to any of the study drug components;
20. Additional criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: WTX-124 monotherapy dose escalation	Drug: WTX-124; Investigation Product Monotherapy
Experimental: WTX-124 in combination with pembro dose escalation; WTX-124 in combination with pembrolizumab (pembro) dose escalation	Drug: WTX-124; Investigation Product Monotherapy; Drug: pembrolizumab; Investigation Product in combination with approved therapy; Other Names: KEYTRUDA®
Experimental: Arm A: WTX-124 monotherapy dose expansion. Patients with advanced or metastatic RCC.; Arm A: WTX-124 monotherapy dose expansion. Patients with advanced or metastatic RCC.	Drug: WTX-124; Investigation Product Monotherapy
Experimental: Arm B: WTX-124 monotherapy dose expansion. Advanced or metastatic cutaneous malignant melanoma.; Arm B: WTX-124 monotherapy dose expansion. Patients with advanced or metastatic cutaneous malignant melanoma.	Drug: WTX-124; Investigation Product Monotherapy
Experimental: Arm C: WTX-124 monotherapy dose expansion. Patients with advanced or metastatic cSCC.; Arm C: WTX-124 monotherapy dose expansion. Patients with advanced or metastatic cSCC.	Drug: WTX-124; Investigation Product Monotherapy
Experimental: Arm D: WTX-124 in combination with pembro dose expansion. Advanced or metastatic RCC.; Arm D: WTX-124 in combination with pembrolizumab dose expansion. Patients with advanced or metastatic RCC.	Drug: WTX-124; Investigation Product Monotherapy; Drug: pembrolizumab; Investigation Product in combination with approved therapy; Other Names: KEYTRUDA®
Experimental: Arm E: WTX-124 with pembro dose expansion. Advanced or metastatic cutaneous melanoma.; Arm E: WTX-124 in combination with pembrolizumab dose expansion. Patients with advanced or metastatic cutaneous melanoma.	Drug: WTX-124; Investigation Product Monotherapy; Drug: pembrolizumab; Investigation Product in combination with approved therapy; Other Names: KEYTRUDA®
Experimental: Arm F: WTX-124 in combination with pembro dose expansion. Advanced/metastatic PD-L1-positive NSCL; Arm F: WTX-124 in combination with pembrolizumab dose expansion. Patients with advanced or metastatic PD-L1-positive NSCLC lines.	Drug: WTX-124; Investigation Product Monotherapy; Drug: pembrolizumab; Investigation Product in combination with approved therapy; Other Names: KEYTRUDA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of Dose Limiting Toxicities (DLTs) in monotherapy and combination therapy	4 weeks
Incidence of treatment emergent adverse events in monotherapy and combination therapy	24 months
Incidence of changes in clinical laboratory abnormalities in monotherapy and combination therapy	24 months
Dose Expansion - Incidence of Dose Limiting Toxicities (DLTs) in monotherapy and combination therapy	4 weeks
Dose Expansion - Incidence of treatment emergent adverse events in monotherapy and combination therapy	24 months
Dose Expansion - Incidence of changes in clinical laboratory abnormalities in monotherapy and combination therapy	24 months
Dose Expansion - Investigator-assessed objective response rate (ORR) per RECIST 1.1 and iORR by iRECIST in monotherapy and combination therapy	24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	36 months
Duration of response	24 months
Investigator-assessed objective response rate (ORR) per RECIST 1.1 and iORR by iRECIST in monotherapy and combination therapy	24 months
Plasma concentrations of WTX-124 and free IL-2	24 months
Changes in circulating immune cell populations in response to monotherapy and combination therapy	24 months
Changes in soluble cytokines in response to monotherapy and combination therapy	24 months
Changes in tumor immune profile in response to monotherapy and combination therapy	24 months
Investigator-assessed objective response rate (ORR) per RECIST 1.1 and iORR by iRECIST in monotherapy and combination therapy (in advanced or metastatic renal cell carcinoma and advanced or metastatic cutaneous malignant melanoma)	24 months
Antidrug antibody (ADA) occurrence	24 months
Progression free survival	24 months
To investigate immunological biomarkers in peripheral blood and tumor that may correlate with the treatment outcome of WTX-124 as monotherapy or in combination with pembrolizumab	24 months
To assess tumor biopsies for potential biomarkers of target engagement and immune pathway activation	24 months

Collaborators and Investigators

• Sponsor: Werewolf Therapeutics, Inc.
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2022
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 31, 2026

Study Registration Dates

• First Submitted: July 14, 2022
• First Submitted That Met QC Criteria: July 26, 2022
• First Posted (Actual): July 29, 2022

Study Record Updates

• Last Update Posted (Actual): February 9, 2026
• Last Update Submitted That Met QC Criteria: February 5, 2026
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: mRCC; pembrolizumab; IL-2; Tumors; Renal Carcinoma; WTX-124; Cutaneous Malignant Melanoma; NSCLC (non-small cell lung cancer); Cutaneous SCC (cutaneous squamous cell carcinoma)
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplastic Processes; Lung Neoplasms; Skin Diseases; Urologic Neoplasms; Carcinoma; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Kidney Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Melanoma, Cutaneous Malignant; Neoplasms; Neoplasm Metastasis; Carcinoma, Renal Cell; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab
• Other Study ID Numbers: WTX-124x2101; MK-3475-D17 (Other Identifier: Merck Sharp & Dohme LLC); KEYNOTE-D17 (Other Identifier: Merck Sharp & Dohme LLC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No