Navtemadlin +/− Immunotherapy for Skin Cancer

Not currently recruiting at 57 trial locations

Overseen By Emily Houlihan

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Kartos Therapeutics, Inc.

Disqualifiers: Autoimmune disease, Immunosuppression, Organ transplant, others

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

Compensation: Varies

Number of Visits: 1

Duration: 10 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new oral treatment called KRT-232 (Navtemadlin) for individuals with Merkel Cell Carcinoma (MCC), a type of skin cancer. The researchers aim to evaluate the effectiveness of KRT-232 alone and in combination with avelumab, particularly for those whose previous treatments failed or who have not yet tried certain treatments. The trial includes different groups to assess various drug combinations and schedules. Candidates may qualify if they have a confirmed MCC diagnosis and have tried at least one unsuccessful treatment or have not received specific other therapies. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that KRT-232, also known as navtemadlin, holds promise for treating patients with Merkel Cell Carcinoma (MCC) who haven't responded to other treatments. In studies, most patients tolerated it well, experiencing no severe side effects. Some trials have indicated that while side effects occurred, they were manageable.

When combined with avelumab, an immunotherapy drug, KRT-232 maintains a good safety profile, meaning the treatment did not cause serious side effects for most patients. Avelumab is already approved for some cancers, which adds confidence in its safety.

Overall, while side effects can occur with any treatment, evidence suggests that KRT-232, both alone and with avelumab, is generally safe for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about KRT-232 for skin cancer because it targets the MDM2 protein, which plays a crucial role in regulating the tumor suppressor protein p53. Unlike typical treatments that might focus on general chemotherapy, KRT-232 works by restoring the natural function of p53, potentially leading to more effective cancer cell death. Additionally, when combined with immunotherapy like avelumab, it might enhance the body's immune response against cancer cells, offering a double-pronged approach to treatment. This combination therapy could provide a more targeted and potent option compared to current skin cancer treatments.

What evidence suggests that this trial's treatments could be effective for Merkel Cell Carcinoma?

Studies have shown that KRT-232, also known as Navtemadlin, holds promise in treating skin cancers like Merkel Cell Carcinoma (MCC). Earlier research demonstrated that KRT-232 reduced tumor size in 73% of patients without certain mutations and in all patients with those mutations. It blocks a protein called MDM2, which can prevent cancer cells from dying. In this trial, some participants will receive KRT-232 alone, while others will receive it in combination with avelumab. Avelumab is known to provide lasting results in MCC. Early findings suggest that combining KRT-232 and avelumab offers a good response rate and manageable side effects, aiming to fight cancer cells more effectively by using two different methods. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for patients with Merkel Cell Carcinoma who have tried at least one anti-PD-1 or anti-PD-L1 therapy, except for one group that hasn't had these treatments. Participants must be in good physical condition (ECOG 0-1), have measurable cancer lesions, and proper organ function. Those with major organ transplants, certain autoimmune diseases, previous MDM2 antagonist therapies, untreated brain metastases, or significant heart rhythm issues cannot join.

Inclusion Criteria

I have tried at least one PD-1 or PD-L1 inhibitor for my metastatic MCC without success.

I can carry out all my usual activities without help.

My MCC is p53WT positive according to a certified test.

Exclusion Criteria

I don't have autoimmune diseases, need for immunosuppressants, had a stem cell transplant, or active hepatitis B or C.

My heart's electrical cycle is longer than normal.

I have brain metastases that have not been treated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive KRT-232 orally, once daily, with or without avelumab, in cycles of 21 to 28 days

10 weeks

Visits on Day 1 and 15 for avelumab administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• KRT-232

Trial Overview The study tests KRT-232 alone or combined with Avelumab in different groups of MCC patients based on their prior treatments. KRT-232 targets a protein called MDM2 to fight cancer cells. The goal is to see if this new approach works better for those who haven't responded well to existing immunotherapies.

How Is the Trial Designed?

Group I: Cohort 4 Experimental Treatment 1 Intervention

KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.

Group II: Cohort 3 Experimental Treatment 1 Intervention

KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.

Group III: Cohort 2, Arm 2 KRT-232 in combination with avelumab Experimental Treatment 2 Interventions

KRT-232 will be administered orally, once daily (QD) on Days 1-7, in combination with avelumab 800 mg IV on Day 1 and 15 in a 28-day cycle.

Group IV: Cohort 2, Arm 1 KRT-232 in combination with avelumab Experimental Treatment 2 Interventions

KRT-232 will be administered orally, once daily (QD) on Days 1-5, in combination with avelumab 800 mg IV on Day 1 and 15 in a 28-day cycle.

Group V: Cohort 2 Expansion Experimental Treatment 2 Interventions

KRT-232 will be administered orally, once daily (QD) per RP2D dose and schedule, in combination with avelumab 800 mg IV on Day 1 and 15 in a 28-day cycle.

Group VI: Cohort 1, Arm 5 Experimental Treatment 1 Intervention

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle.

Group VII: Cohort 1, Arm 3 Experimental Treatment 1 Intervention

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle.

Group VIII: Cohort 1, Arm 2b Experimental Treatment 1 Intervention

KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 28-day cycle.

Group IX: Cohort 1, Arm 1b Experimental Treatment 1 Intervention

KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 23-day cycle.

Group X: Cohort 1, Arm 1 Experimental Treatment 1 Intervention

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle.

Group XI: Cohort 1 Expansion Experimental Treatment 1 Intervention

KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.

Who Is Running the Clinical Trial?

Kartos Therapeutics, Inc.

Lead Sponsor

Trials

17

Recruited

2,100+

Published Research Related to This Trial

Topical treatments like 5-fluorouracil and imiquimod are effective alternatives for managing superficial skin cancers, such as actinic keratoses and basal cell carcinomas, by directly targeting the tumors.

The review highlights the importance of understanding the mechanisms of action, side effects, and contraindications of these topical therapies to optimize their use in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical pharmacotherapy for skin cancer: part I. Pharmacology. Micali, G., Lacarrubba, F., Nasca, MR., et al.[2014]

A review of 29 articles identified specific dermatological adverse events (AEs) associated with various immunotherapy combinations, highlighting that combinations like nivolumab/ipilimumab and lenvatinib/pembrolizumab had the highest incidence of rash.

Understanding these dermatological AEs, such as pruritus and alopecia, is crucial for optimizing treatment plans and improving patient monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dermatological adverse events associated with immune checkpoint inhibitor-based combinations of anticancer therapies: a systematic review. Salloum, A., Habre, M., Chebl, JA., et al.[2022]

Topical treatment with calcipotriol and imiquimod significantly reduced breast tumor growth and enhanced CD4+ T-cell immunity, demonstrating a synergistic effect that improves treatment outcomes for nonkeratinocyte cutaneous malignancies.

The combination of calcipotriol and imiquimod not only suppressed tumor growth but also enabled immune checkpoint blockade therapy to effectively target previously resistant breast tumors, indicating a promising new approach for immunotherapy in skin cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical Calcipotriol Plus Imiquimod Immunotherapy for Nonkeratinocyte Skin Cancers. Azin, M., Ngo, KH., Hojanazarova, J., et al.[2023]

Targeted anticancer therapies have led to significant changes in oncology patient management, but they often come with cutaneous adverse effects that can limit treatment effectiveness or lead to therapy discontinuation.

Specific side effects vary by drug class: tyrosine kinase inhibitors can cause rashes and hand-foot reactions, while epidermal growth factor receptor inhibitors may lead to papulopustular rashes and hair changes, highlighting the need for careful monitoring of skin reactions during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Skin Manifestations of Targeted Antineoplastic Therapy. Sanmartín, O.[2018]

IL27 is identified as a crucial regulator in the initiation of skin cancer by promoting a pre-malignant environment and the expansion of mutated stem cells, as demonstrated in a two-step skin carcinogenesis model and K15-KRASG12D mouse model.

The study reveals that IL27 enhances the incidence of skin tumors primarily through its signaling in bone-marrow derived CD11b cells, which accumulate in the skin and contribute to tumor development, highlighting a novel inflammatory pathway involved in skin carcinogenesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin. Dibra, D., Mitra, A., Newman, M., et al.[2020]

Non-melanoma skin cancers (NMSCs) are the most common cancers globally, particularly affecting immunosuppressed individuals, highlighting the need for effective prevention and treatment strategies.

The review discusses various systemic and topical immunomodulatory drugs that have been developed to prevent and treat NMSC, emphasizing the importance of identifying high-risk patients to tailor personalized treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulators for Non-Melanoma Skin Cancers: Updated Perspectives. Russomanno, K., Abdel Azim, S., Patel, VA.[2023]

The collaboration between dermatologists and oncologists has led to the establishment of supportive oncodermatology clinics, which focus on managing skin toxicities associated with targeted therapies for blood cancers.

A systematic review of various targeted therapies revealed distinct cutaneous adverse event profiles, emphasizing the need for early diagnosis and management to enhance treatment tolerability and patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies. Ransohoff, JD., Kwong, BY.[2018]

In a study of 286 patients with stage III-IV metastatic melanoma, immunotherapy was associated with a higher incidence of cutaneous adverse events (AEs) at 43.1%, compared to 23.6% in those receiving targeted therapy, indicating that immunotherapy may lead to more frequent skin reactions.

Older patients receiving immunotherapy were more likely to experience skin toxicities, with a significant correlation found between age and the likelihood of developing these AEs, suggesting that age may be an important factor to consider in treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous side effects and types of dermatological reactions in metastatic melanoma patients treated by immunotherapies or targeted therapies: A retrospective single center study. Gullo, G., Rubatto, M., Fava, P., et al.[2023]

In a retrospective study of 5 patients with Marjolin ulcer treated with anti-PD-1 therapy, one patient achieved durable disease control for 1 year, indicating potential efficacy of immunotherapy for this aggressive skin cancer.

The study found a 60% overall survival rate at 12 months among the patients treated with anti-PD-1 therapy, suggesting that immunotherapy may offer a promising treatment option for patients with Marjolin ulcer, despite the small sample size.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibition in Marjolin Ulcer: A Case Series. Shalhout, SZ., Kaufman, HL., Sullivan, RJ., et al.[2022]

NFX-179, a metabolically labile MEK inhibitor, effectively reduced the formation of cutaneous squamous cell carcinoma (cSCC) by an average of 60% in a mouse model when applied topically, demonstrating its potential as a chemopreventive treatment.

The topical application of NFX-179 showed no toxicities and selectively inhibited the MAPK pathway in the skin, suggesting a safer alternative to systemic MEK inhibitors for preventing cSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma. Sarin, KY., Kincaid, J., Sell, B., et al.[2023]

Recent advancements in melanoma treatment have significantly improved overall survival rates, highlighting the need for effective chemoprevention strategies to reduce the burden of metastatic disease.

The Melanoma Prevention Working Group is actively exploring and proposing new and repurposed drugs for melanoma prevention, assessing their mechanisms of action and clinical trial data to identify promising candidates for future phase 3 trials within the next 5 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials. Jeter, JM., Bowles, TL., Curiel-Lewandrowski, C., et al.[2020]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.9506

Navtemadlin (KRT-232) activity after failure of anti-PD-1/L1 ... A median survival of about 4 mo for pts with metastatic MCC who failed anti-PD-1/L1 therapy highlights an urgent need for novel therapies.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10010373/

The MDM2 Inhibitor Navtemadlin Arrests Mouse Melanoma ... These data suggest that Navtemadlin, when used as a monotherapy, can induce modest levels of apoptosis in B16-F10 melanoma cells because it induces both ...

3. news.vumc.org news.vumc.org/2020/04/23/study-explores-melanoma-drugs-effectiveness/

Study explores melanoma drug's effectiveness KRT-232 with trametinib was shown to reduce tumor size in 73% of patients without BRAF mutation. It reduced tumor size in 100% of patients with ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7367743/

Metastatic Melanoma Patient-derived Xenografts Respond ... Over 60 % of melanoma patients respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.10072

KRT-232, a first-in-class, murine double minute 2 inhibitor ... Results: At the time of this analysis, 11 pts were treated with KRT-232: 6 on the 240mg 7/21d, 3 on the 240mg 5/28d and 2 on the 180mg 5/28d ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36416118/

a global, phase III study of the MDM2 inhibitor navtemadlin ... The oral MDM2 inhibitor navtemadlin (KRT-232) restores p53 activity to drive apoptosis of wild-type TP53 tumor cells by inducing expression of ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS7063

An open-label, multicenter, phase 1b/2 study of ... An open-label, multicenter, phase 1b/2 study of navtemadlin (KRT-232) in patients with relapsed/refractory acute myeloid leukemia secondary to ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03107780

NCT03107780 | Testing the Ability of AMG 232 (KRT ... This phase I trial studies the side effects and best dose of navtemadlin in treating patients with glioblastoma (brain cancer) that is newly diagnosed or has ...