Ivonescimab for Skin Cancer

Overseen By Aung Naing, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Autoimmune disease, HIV, Hepatitis B/C, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 year

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests ivonescimab, a new treatment for advanced skin cancer that cannot be removed or has spread, specifically squamous cell carcinoma (cSCC). The goal is to determine if ivonescimab can manage the cancer and assess its safety and effects. Individuals who have not responded to other treatments, such as anti-PD-1 therapy, might be suitable candidates. Participants will receive ivonescimab through an IV every three weeks. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, there is a requirement for a 'washout period' (time without taking certain medications) from previous therapies before starting the study treatment.

Is there any evidence suggesting that ivonescimab is likely to be safe for humans?

Research has shown that ivonescimab, a new treatment, is generally safe based on tests in other studies. It has produced promising results in patients with advanced lung cancer when combined with chemotherapy. Most patients tolerated it well, experiencing no severe side effects.

Ivonescimab is unique because it targets two proteins simultaneously: PD-1 and VEGF. These proteins help cancer grow and evade the immune system. By targeting them, ivonescimab aims to enhance the body's ability to fight cancer.

Although ivonescimab is still under study and not approved everywhere, it has received approval for use in China. This indicates it has passed certain safety checks and is considered safe for use under specific conditions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for skin cancer?

Most treatments for skin cancer, like surgery, chemotherapy, and radiation, work by physically removing or destroying cancer cells. Ivonescimab is unique because it targets specific proteins involved in cancer cell growth, acting as a more precise treatment. Researchers are excited about ivonescimab because it may offer a targeted approach, potentially leading to fewer side effects and more effective results compared to traditional treatments. Plus, it's given intravenously every three weeks, which might offer a more convenient schedule for patients.

What evidence suggests that ivonescimab might be an effective treatment for advanced cSCC?

Research has shown that ivonescimab yields promising results for treating certain cancers. In studies with patients who have advanced or spreading non-small cell lung cancer (NSCLC), ivonescimab significantly reduced tumor growth. It also outperformed the current drug pembrolizumab in delaying cancer progression, allowing patients to live longer without their cancer worsening. This suggests that ivonescimab may control tumors by inhibiting blood vessel growth and boosting the immune system. While these results come from different cancer types, they offer hope that ivonescimab could also help treat advanced skin cancer. Participants in this trial will receive ivonescimab to evaluate its effectiveness for skin cancer. ^{1 4 6 7 8}

Who Is on the Research Team?

Aung Naing, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with advanced skin cancer (cSCC) that can't be removed or has spread, and who didn't respond to anti-PD-1 therapy. They should have a life expectancy of at least 3 months, manageable blood pressure on up to one medication, and agree to use contraception. People with certain medical conditions, previous severe reactions to PD-1 inhibitors, active infections requiring IV antibiotics, or uncontrolled illnesses are excluded.

Inclusion Criteria

I am fully active or can carry out light work.

My blood pressure is controlled with up to one medication.

Measurable disease per the RECIST v1.1

Exclusion Criteria

I had to stop or pause PD-1 inhibitor treatment due to side effects.

I have no recent serious medical events or conditions.

Pregnant or breastfeeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ivonescimab by vein over about 1-2 hours on Day 1 of each 21-day cycle

1 year

1 visit every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ivonescimab

Trial Overview The study tests ivonescimab's ability to control advanced cutaneous Squamous Cell Carcinoma (cSCC). It will assess the safety and effects of this drug in patients who haven't responded well to other treatments like anti-PD-1 therapy.

How Is the Trial Designed?

Group I: Ivonescimab Experimental Treatment 1 Intervention

Participants found to be eligible to take part in this study, you will receive ivonescimab by vein over about 1-2 hours on Day 1 of each 21-day cycle (1 time every 3 weeks).

Ivonescimab is already approved in China for the following indications:

Approved in China as Ivonescimab for:

• Locally advanced or metastatic non-squamous NSCLC

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Summit Therapeutics

Industry Sponsor

Trials

18

Recruited

4,500+

Published Research Related to This Trial

In a study involving 32 patients with metastatic melanoma, the combination of bevacizumab (Bev) and low-dose interferon alfa-2b (IFN-alpha2b) was well tolerated, with manageable side effects, including mild hypertension and proteinuria.

Bev alone led to prolonged disease stabilization in about 25% of patients, but adding IFN-alpha2b did not enhance the treatment's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon alfa-2b in metastatic malignant melanoma. Varker, KA., Biber, JE., Kefauver, C., et al.[2020]

In a study of 106 patients with metastatic melanoma, ramucirumab combined with dacarbazine showed a median progression-free survival (PFS) of 2.6 months, compared to 1.7 months for ramucirumab alone, suggesting that combination therapy may be more effective.

Both treatment options had a good safety profile, with limited severe side effects, indicating that ramucirumab is a tolerable option for patients with metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma. Carvajal, RD., Wong, MK., Thompson, JA., et al.[2023]

The combination of erlotinib, an epidermal growth factor receptor inhibitor, and bevacizumab, a vascular endothelial growth factor monoclonal antibody, significantly reduced tumor volume and metastasis in a mouse model of metastatic melanoma, outperforming the effects of either drug alone.

This combined treatment led to decreased cell proliferation, increased apoptosis, and reduced tumor angiogenesis, suggesting a promising new therapeutic strategy for advanced melanoma where current options are limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erlotinib and bevacizumab have synergistic activity against melanoma. Schicher, N., Paulitschke, V., Swoboda, A., et al.[2018]

Icrucumab, a monoclonal antibody targeting VEGFR-1, was safely administered to 26 patients with advanced solid tumors, showing no dose-limiting toxicities at doses up to 12 mg/kg, indicating a favorable safety profile.

The treatment resulted in stable disease in 23.1% of patients, with a median duration of 11.1 weeks, suggesting potential antitumor activity against various cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Icrucumab, a fully human monoclonal antibody against the vascular endothelial growth factor receptor-1, in the treatment of patients with advanced solid malignancies: a Phase 1 study. LoRusso, PM., Krishnamurthi, S., Youssoufian, H., et al.[2021]

A study analyzing 8213 reports of skin-related adverse drug reactions linked to immune checkpoint inhibitors found that 3.8% of these reports involved psoriasis or psoriasiform reactions, highlighting a significant safety concern.

Most patients (70.8%) who developed psoriasis had a pre-existing condition, indicating that those with a history of psoriasis may be at higher risk when treated with immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psoriasis and psoriasiform reactions secondary to immune checkpoint inhibitors. Cutroneo, P., Ingrasciotta, Y., Isgrò, V., et al.[2021]

In a study of 6892 patients treated with ixekizumab for up to 5 years, the incidence of skin cancer was low, with a rate of 0.3 cases per 100 patient-years, primarily consisting of non-melanoma skin cancers (NMSC).

The most common skin cancer events were basal cell carcinoma and squamous cell carcinoma, with only two cases of melanoma reported, indicating that ixekizumab has a favorable safety profile regarding skin cancer risk in psoriasis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrated Safety Analysis on Skin Cancers among Patients with Psoriasis Receiving Ixekizumab in Clinical Trials. Smith, SD., Stratigos, A., Augustin, M., et al.[2023]

The identification of driver mutations in tumors has led to the rise of personalized medicine in cancer treatment, allowing for targeted therapies like the BRAF inhibitor vemurafenib, which was approved for metastatic melanoma in 2012.

While targeted treatments are generally well-tolerated, they come with a new range of side effects that healthcare providers must understand and manage to ensure optimal patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects of systemic oncological therapies in dermatology. Zimmer, L., Vaubel, J., Livingstone, E., et al.[2012]

In a study analyzing over 91,000 adverse events from patients receiving immune checkpoint inhibitors, 10,933 cases of cutaneous immune-related adverse events (cirAEs) were identified, highlighting the prevalence and diversity of skin complications associated with immunotherapy.

The onset of cirAEs varies significantly by subtype, with some, like erythema multiforme and Stevens-Johnson syndrome, appearing around one month after treatment, while others, such as bullous pemphigoid and vitiligo, may take five to six months to develop.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous Toxicities Associated with Immune Checkpoint Inhibitors: An Observational, Pharmacovigilance Study. Le, TK., Brown, I., Goldberg, R., et al.[2023]

In a phase I study involving 40 patients with advanced cancers, the novel anti-VEGFR2 monoclonal antibody AK109 demonstrated a manageable safety profile, with no dose-limiting toxicities observed, although 38 patients experienced treatment-related adverse events, primarily proteinuria and hypertension.

AK109 showed promising preliminary antitumor efficacy, with a 10% objective response rate and a 62.5% disease control rate, leading to the selection of 12 mg/kg Q2W and 15 mg/kg Q3W as recommended phase II doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human, phase I study of AK109, an anti-VEGFR2 antibody in patients with advanced or metastatic solid tumors. Zheng, Y., Zhong, H., Zhao, F., et al.[2023]

Ivonescimab, a bispecific antibody targeting PD-1 and VEGF, demonstrated promising efficacy in treating advanced non-small cell lung cancer (NSCLC), with an overall response rate (ORR) of 39.8% and a disease control rate of 86.1% among 108 patients studied over a median follow-up of 10.4 months.

The treatment was generally well tolerated, with only 22.2% of patients experiencing grade 3 or higher treatment-related adverse events, and a very low rate of treatment discontinuation (0.9%) due to adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1b Study of Ivonescimab, a Programmed Cell Death Protein-1 and Vascular Endothelial Growth Factor Bispecific Antibody, as First- or Second-Line Therapy for Advanced or Metastatic Immunotherapy-Naive NSCLC. Wang, L., Luo, Y., Ren, S., et al.[2023]

The phase I study of the OX40 agonistic monoclonal antibody GSK3174998, alone or with pembrolizumab, was well tolerated among 138 patients with advanced solid tumors, with treatment-related adverse events occurring in 51% of patients in Part 1 and 64% in Part 2, but no maximum-tolerated dose was reached.

Despite demonstrating target engagement and some immune response changes in the tumor microenvironment, GSK3174998 showed limited clinical activity, with a disease control rate of only 9% in Part 1 and no significant improvement when combined with pembrolizumab, indicating it may not be viable for further development in advanced cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1). Postel-Vinay, S., Lam, VK., Ros, W., et al.[2023]

In a study of 68 patients with stage IV melanoma treated with anti-PD-1 antibodies, 22% experienced adverse cutaneous reactions, including mild rashes and severe cases resembling toxic epidermal necrolysis (TEN).

Gene expression profiling indicated that all skin reactions had a TEN-like pattern, suggesting that the PD-1/PD-L1 interaction is crucial for maintaining skin integrity during inflammation, highlighting the need for monitoring skin toxicity in patients undergoing this immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxic Cutaneous Adverse Drug Reactions during Anti-PD-1 Therapy. Goldinger, SM., Stieger, P., Meier, B., et al.[2022]

In a phase II clinical trial involving 83 patients with advanced non-small cell lung cancer (NSCLC), the bispecific antibody AK112 combined with chemotherapy showed promising efficacy, with objective response rates of 53.5% for untreated patients, 68.4% for those with EGFR mutations after TKI failure, and 40.0% for patients who had failed previous treatments.

The treatment was generally safe, with the most common serious side effects being decreased white blood cell count and neutropenia, indicating that AK112 could be a valuable new option for patients with advanced NSCLC, including those who have exhausted other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial. Zhao, Y., Chen, G., Chen, J., et al.[2023]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.9087

Phase II results of ivonescimab (AK112/ SMT112), a novel ... Ivonescimab, plus chemotherapy has shown promising anti-tumor activity in pts with advanced/metastatic NSCLC without AGA and can be administered safely.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06959550

NCT06959550 | Phase II Study of Anti-PD-1/VEGF ... The goal of this clinical research study is to learn if ivonescimab can help to control previously treated, metastatic colorectal cancer.

3. onclive.com onclive.com/view/the-novel-bispecific-antibody-ivonescimab-may-be-poised-to-change-the-soc-in-nsclc

The Novel Bispecific Antibody Ivonescimab May be Poised ... Jonathan Wesley Riess, MD, MS, details the potential for ivonescimab in NSCLC after improving PFS vs pembrolizumab in the HARMONi-2 trial.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12202206/

A novel bispecific antibody CVL006 superior to AK112 for ... Preclinical and clinical studies highlight the enhanced anticancer efficacy of combining anti-VEGF/VEGFR drugs with immune checkpoint inhibitors (ICIs).

5. akesobio.com akesobio.com/en/media/akeso-news/250426/

Akeso, Inc | Ivonescimab Receives NMPA Approval for First ... Ivonescimab has shown superior efficacy over pembrolizumab in the HARMONi-2 Phase III trial, becoming the first therapy to achieve this globally.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40114411/

Safety, Pharmacokinetics, and Pharmacodynamics ... Ivonescimab (AK112) is a first-in-class bispecific antibody that simultaneously targets programmed death-1 (PD-1) and vascular endothelial growth factor (VEGF) ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04047290

NCT04047290 | A Study of AK112, a PD-1/VEGF Bispecific ... This study is to characterize the safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD) and anti-tumor activity of AK112, ...

8. smmttx.com smmttx.com/ivonescimab-smt112/

Ivonescimab (SMT112) Ivonescimab is an investigational therapy not presently approved by any regulatory authority other than China's National Medical Products Administration (NMPA).