WTX-124 + Pembrolizumab for Solid Tumors

Recruiting in Palo Alto (17 mi)

+7 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Werewolf Therapeutics, Inc.

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Active malignancy, Pneumonitis, Autoimmune, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a new medicine called WTX-124, alone and with pembrolizumab, in patients with severe forms of skin and kidney cancer. WTX-124 helps the immune system attack cancer cells, and pembrolizumab makes it easier for the immune system to see these cells.

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.

What data supports the effectiveness of the drug pembrolizumab for solid tumors?

Pembrolizumab has shown clinical activity in a variety of solid tumors and is approved for treating several types of cancer, including non-small cell lung cancer and melanoma. It works by helping the immune system recognize and attack cancer cells.

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What safety information is available for the treatment WTX-124 + Pembrolizumab?

Pembrolizumab (also known as Keytruda) has been associated with some side effects, including pneumonitis (lung inflammation) in 1%-5% of patients and rare cases of type 1 diabetes. Common side effects include fatigue, cough, nausea, and rash. While these side effects can occur, the benefits of pembrolizumab in treating certain cancers have been found to outweigh these risks.

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What makes the drug WTX-124 + Pembrolizumab unique for treating solid tumors?

The combination of WTX-124 and Pembrolizumab is unique because it combines a novel IL-2 INDUKINE molecule with a PD-1 inhibitor, Pembrolizumab, which enhances the immune system's ability to attack cancer cells by blocking the PD-1 pathway and potentially increasing the effectiveness of the immune response against solid tumors.

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Eligibility Criteria

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.

Trial Timeline

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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Honorhealth Scottsdale, AZ

NEXT Oncology San Antonio, TX

Roswell Park Comprehensive Cancer Care Buffalo, NY

HonorHealth Scottsdale, AZ

More Trial Locations

Who Is Running the Clinical Trial?

Werewolf Therapeutics, Inc. Lead Sponsor

Merck Sharp & Dohme LLC Industry Sponsor

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022] A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled.

2. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017] New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.

3. United States 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. [2023] In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.

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

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023] Pembrolizumab (Keytruda) has been approved to treat metastatic or locally advanced esophageal or gastroesophageal junction cancer. It is used in combination with platinum- and fluoropyrimidine-based chemotherapy.

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

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. [2022] Nivolumab (Opdivo, Bristol Meyer Squibb, New York, NY) and pembrolizumab (Keytruda, Merck, Kenilworth, NJ) are the first two US Food and Drug Administration (FDA)-approved monoclonal antibodies targeting programmed death-1 (PD-1). Nivolumab and pembrolizumab work by interfering with the interaction between PD-1 and programmed death ligand-1 (PD-L1), whose unimpeded interaction downregulates T cells allowing cancer cells to evade immune surveillance. These drugs have earned a series of FDA approvals for melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC), urothelial cancer, classical Hodgkin lymphoma, and renal cell cancer. In this review we will summarize the data for efficacy and toxicity for these two agents. We conclude that they represent two valuable but interchangeable alternatives to target their approved indications. We will discuss how this can help global payers seeking to contain the cost of cancer therapeutics that continues to spiral out of control.

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

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023] Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP).

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022] Pembrolizumab (Keytruda; Merck Sharp & Dohme) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAEs) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occurring in 0.2% of cases.

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021] On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. ©2017 AACR.

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022] On December 18, 2015, the FDA granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma based on results of two randomized, open-label, active-controlled clinical trials. In trial PN006, 834 patients with ipilimumab-naïve metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 or 3 weeks until disease progression or ipilimumab 3 mg/kg every 3 weeks for up to four doses. In trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg i.v. every 3 weeks or to investigator's choice of chemotherapy. In trial PN006, patients randomized to pembrolizumab demonstrated a statistically significant improvement in overall survival compared with ipilimumab [every-2-week arm: hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.47-0.83; P < 0.001; every-3-week arm: HR = 0.69; 95% CI, 0.52-0.90; P = 0.004]. In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (≥2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response-based endpoints using RECIST or immune-related RECIST. Clin Cancer Res; 23(19); 5661-5. ©2017 AACR.

10. United States 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. [2021] The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®, MK-3475) is a potent and highly selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances the functional activity of T cells to facilitate tumor regression and ultimately immune rejection. Pembrolizumab binds to human and cynomolgus monkey PD-1 with picomolar affinity and blocks the binding of human and cynomolgus monkey PD-1 to PD-L1 and PD-L2 with comparable potency. Pembrolizumab binds both the C'D and FG loops of PD-1. Pembrolizumab overcomes human and cynomolgus monkey PD-L1-mediated immune suppression in T-cell cultures by enhancing IL2 production following staphylococcal enterotoxin B stimulation of healthy donor and cancer patient cells, and IFNγ production in human primary tumor histoculture. Ex vivo and in vitro studies with human and primate T cells show that pembrolizumab enhances antigen-specific T-cell IFNγ and IL2 production. Pembrolizumab does not mediate FcR or complement-driven effector function against PD-1-expressing cells. Pembrolizumab displays dose-dependent clearance and half-life in cynomolgus monkey pharmacokinetic and toxicokinetic studies typical for human IgG4 antibodies. In nonhuman primate toxicology studies, no findings of toxicologic significance were observed. The preclinical data for pembrolizumab are consistent with the clinical anticancer activity and safety that has been demonstrated in human clinical trials.