CLN-617 + Pembrolizumab for Solid Tumors

Recruiting at 5 trial locations

Overseen By Shane McLoughlin

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Cullinan Therapeutics Inc.

Must not be taking: Immunosuppressants, Anticoagulants

Disqualifiers: Active autoimmune disease, Uncontrolled hypertension, Active CNS metastases, others

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

Compensation: Varies

Number of Visits: Unknown

86 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and optimal dose of a new treatment called CLN-617 (an IL2/IL12 fusion protein), both alone and in combination with Pembrolizumab, for individuals with advanced solid tumors. The researchers seek to determine the appropriate dose and evaluate its effectiveness in various cancers, such as melanoma and head and neck cancers. Individuals with hard-to-treat, injectable tumors may be suitable for this trial, particularly if standard treatments are unavailable to them. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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, certain medications like systemic anticancer treatments, immunotherapy, and immunosuppressive medications must not be taken within a specific period before starting the trial. It's best to discuss your current medications with the trial team.

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

Research shows that CLN-617, combined with pembrolizumab, is under study for safety and effectiveness in individuals with advanced solid tumors. While detailed safety information on CLN-617 is still being collected, early studies suggest it delivers proteins that boost the immune system directly to tumors, aiming to reduce side effects elsewhere in the body.

Pembrolizumab has FDA approval for treating various cancers, indicating general safety. However, combining new treatments like CLN-617 with existing ones like pembrolizumab can produce unique effects. Ongoing studies aim to determine the safest dosages and monitor for any side effects. As this is a Phase 1 trial, the primary goal is to understand the treatment's safety, and it remains in the early stages. Participants receive close monitoring to manage any side effects promptly. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CLN-617 combined with pembrolizumab because it offers a potentially powerful new approach to treating advanced solid tumors, melanoma, and head and neck squamous cell carcinoma. Unlike existing treatments that mainly rely on surgery, radiation, or chemotherapy, CLN-617 introduces a unique mechanism by using a dual cytokine fusion protein aimed at enhancing the immune response against tumors. When combined with pembrolizumab, a widely-used immune checkpoint inhibitor, this combination could amplify the body's ability to attack cancer cells more effectively. This novel strategy might provide better outcomes for patients who do not respond well to existing therapies.

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

Research shows that CLN-617 is a promising new treatment for solid tumors. This special protein delivers two substances, IL-2 and IL-12, directly to the tumor, helping the immune system attack cancer cells. Early lab studies have demonstrated that this method can create strong responses against tumors. In this trial, some participants will receive CLN-617 alone, while others will receive it with Pembrolizumab.

Pembrolizumab is already known for its effectiveness against certain cancers like melanoma and head and neck cancers. Studies have shown that it can help patients live longer. Combining Pembrolizumab with CLN-617 in this trial aims to boost these effects by further encouraging the immune system to fight tumors. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

Adults (18+) with advanced solid tumors who have measurable lesions, appropriate for pembrolizumab treatment, and a life expectancy of at least 12 weeks. They must have normal organ function, resolved prior therapy toxicities to Grade 1 or stable Grade 2, except alopecia. Excludes those with uncontrolled diseases like heart issues or diabetes, active infections including HIV/Hepatitis B/C and COVID-19, recent immunosuppressive treatments or cancer therapies.

Inclusion Criteria

I am eligible for the dose expansion part of the trial.

I have an advanced cancer that cannot be cured and can be injected for treatment.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

A serious uncontrolled medical disorder that would impair the ability of the patient to receive protocol therapy or whose control may be jeopardized by the complications of this therapy. These criteria include, but are not limited to the following:

CD4+ T cell counts ≤ 350 cells/uL

Blood hepatitis B DNA or HCV RNA are detectable

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Patients with advanced solid tumors are treated with CLN-617 alone and in combination with pembrolizumab to determine the safety and optimal dose

24 months

Dose Optimization

Patients receive selected doses of CLN-617 in combination with pembrolizumab to optimize dosing

24 months

Dose Expansion

Patients with advanced melanoma or head and neck squamous cell carcinoma are treated with CLN-617 in combination with pembrolizumab to expand the study population

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• CLN-617
• Pembrolizumab

Trial Overview The trial is testing CLN-617 alone and combined with Pembrolizumab in patients with advanced solid tumors. It's an early-phase study that includes dose escalation to find the safest dose that works best before expanding to more patients.

How Is the Trial Designed?

Group I: CLN-617 Dose Optimization (Part B) Experimental Treatment 2 Interventions

Patients with Advanced Solid Tumors enrolled in dose optimization receiving selected doses of CLN-617 in combination with pembrolizumab

Group II: CLN-617 Dose Expansion (Part C) Experimental Treatment 2 Interventions

Patients with Advanced Melanoma or Head and Neck Squamous Cell Carcinoma (HNSCC) enrolled in dose expansion treated with CLN-617 in combination with pembrolizumab

Group III: CLN-617 Dose Escalation (Part A) Experimental Treatment 2 Interventions

Patients with Advanced Solid Tumors enrolled in dose escalation cohorts treated with CLN-617 alone and in combination with pembrolizumab

Who Is Running the Clinical Trial?

Cullinan Therapeutics Inc.

Lead Sponsor

Trials

9

Recruited

1,000+

Cullinan Oncology, LLC

Lead Sponsor

Trials

7

Recruited

990+

Cullinan Oncology Inc.

Lead Sponsor

Trials

6

Recruited

710+

Published Research Related to This Trial

Antibody-cytokine fusion proteins, specifically ch225-IL2 and ch14.18-IL2, showed complete inhibition of hepatic and pulmonary metastases in melanoma when tested in mice, outperforming traditional treatments that combined antibodies with recombinant IL-2.

The fusion proteins not only effectively targeted tumors but also significantly increased survival times of treated mice, more than doubling their lifespan compared to those receiving standard antibody and IL-2 treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eradication of human hepatic and pulmonary melanoma metastases in SCID mice by antibody-interleukin 2 fusion proteins. Becker, JC., Pancook, JD., Gillies, SD., et al.[2019]

A study on antibody-cytokine fusion proteins showed that using a tandem-diabody format for the IL12 fusion protein significantly improved tumor uptake and tumor-to-organ ratios in tumor-bearing mice compared to the IgG1 format.

The optimization of the linker connecting the IL12 to the antibody revealed that a specific 15-amino acid linker provided the best tumor targeting, allowing for longer retention at the tumor site and quicker clearance from the bloodstream and normal organs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel anti-cancer L19-interleukin-12 fusion protein with an optimized peptide linker efficiently localizes in vivo at the site of tumors. Ongaro, T., Matasci, M., Cazzamalli, S., et al.[2019]

The study developed a fusion protein combining IL-12 with an anti-Her2/neu antibody, allowing targeted delivery of IL-12 to tumors while minimizing systemic toxicity, which is a common issue with direct IL-12 administration.

In vitro and in vivo tests showed that this fusion protein retains the bioactivity of IL-12 and effectively promotes antitumor activity, suggesting it could be a safer and more effective treatment option for targeting tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single-chain IL-12 IgG3 antibody fusion protein retains antibody specificity and IL-12 bioactivity and demonstrates antitumor activity. Peng, LS., Penichet, ML., Morrison, SL.[2021]

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]

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]

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) 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, 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]

Antibody-cytokine fusion proteins, or immunocytokines, show promise in enhancing cancer treatment by delivering cytokines directly to tumors, potentially increasing their anticancer effects while minimizing side effects.

While some immunocytokines are in late-stage clinical trials, further research is needed to understand their mechanisms and optimize their use in combination with other therapies to improve efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-Cytokine Fusions: Versatile Products for the Modulation of Anticancer Immunity. Neri, D.[2020]

The novel fusion protein Sm3E-TNF effectively targets tumors expressing carcinoembryonic antigen (CEA), achieving a remarkable tumor-to-blood accumulation ratio of 56:1, indicating high selectivity for cancer cells.

Combining Sm3E-TNF with oxaliplatin resulted in prolonged tumor stabilization and complete eradication in 40% of treated mice, suggesting a promising therapeutic strategy for colorectal cancer, while the combination with 5-fluorouracil reduced effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Antibody-Tumor Necrosis Factor Fusion Protein that Synergizes with Oxaliplatin for Treatment of Colorectal Cancer. Bajic, D., Chester, K., Neri, D.[2021]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11292205/

CLN-617 Retains IL2 and IL12 in Injected Tumors to Drive ... This study reports the successful preclinical development of CLN-617, a fusion protein that co-delivers IL2 and IL12 in a single molecule directly to the tumor ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06035744

Study Details | NCT06035744 | CLN-617 Alone and in ... Inclusion Criteria: Aged ≥ 18 years. Patient should have previously received or had a contraindication to standard therapy that confers an overall survival ...

3. aacrjournals.org aacrjournals.org/cancerimmunolres/article-pdf/doi/10.1158/2326-6066.CIR-23-0636/3460300/cir-23-0636.pdf

CLN-617 retains IL-2 and IL-12 in injected tumors to drive ... Two such cytokines are IL-2 and IL-12, which can drive antitumor immunity in a synergistic fashion. IL-2 is a common gamma chain cytokine produced by CD4+ T.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38842347/

CLN-617 Retains IL2 and IL12 in Injected Tumors to Drive ... CLN-617 is a single-chain fusion protein ... CLN-617 is being evaluated in a clinical trial in patients with advanced solid tumors (NCT06035744).

5. clients.adaptivebiotech.com clients.adaptivebiotech.com/pub/mehta-2024-cir

CLN-617 retains IL-2 and IL-12 in injected tumors to drive ... Here, we describe CLN-617, a first-in-class therapeutic for intratumoral (IT) injection that co-delivers IL-2 and IL-12 on a single molecule in ...

6. jitc.bmj.com jitc.bmj.com/content/11/Suppl_1/A866

771 A phase 1 study to assess safety, efficacy ... In Part 3, we will explore an optimized dose of CLN-617 in combination with Pembrolizumab in patients with advanced melanoma and head and neck ...

7. withpower.com withpower.com/trial/phase-1-neoplasms-8-2023-362dc

CLN-617 + Pembrolizumab for Solid Tumors This Phase 1 medical study run by Cullinan Therapeutics Inc. is evaluating whether CLN-617 and Pembrolizumab will have tolerable side effects & efficacy for ...