Navtemadlin +/− Immunotherapy for Skin Cancer

Recruiting at 52 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

115 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Navtemadlin +/− Immunotherapy for Skin Cancer?

The research highlights the effectiveness of immunotherapy in treating advanced skin cancers, such as squamous cell carcinoma, by activating the immune system to fight cancer cells. Additionally, immune checkpoint inhibitors, a type of immunotherapy, have shown promise in controlling aggressive skin cancers, suggesting potential benefits for similar treatments like Navtemadlin combined with immunotherapy. ^{1 2 3 4 5}

Is Navtemadlin +/− Immunotherapy for Skin Cancer safe for humans?

Immunotherapy treatments, including those with drugs like Avelumab (also known as Bavencio), can cause skin-related side effects in 30%-40% of patients, such as rashes and dry skin. These side effects are usually mild, but some can be more severe. It's important to monitor for these reactions and consult with healthcare providers for management. ^{6 7 8 9 10}

What makes the drug Navtemadlin unique for treating skin cancer?

Navtemadlin (KRT-232) is unique because it targets the MDM2 protein, which is involved in regulating the tumor suppressor protein p53, potentially offering a novel approach to treating skin cancer by reactivating p53's tumor-suppressing functions. This mechanism is different from other treatments that focus on immune modulation or direct inhibition of cancer cell growth pathways. ^{1 2 3 4 11}

What is the purpose of this trial?

This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with Merkel Cell Carcinoma (MCC) who have failed treatment with at least one anti-PD-1 or anti-PD-L1 immunotherapy or in combination with avelumab in MCC patients who are anti-PD-1 or anti-PD-L1 treatment naïve. Inhibition of MDM2 is a novel mechanism of action in MCC.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Immune Checkpoint Inhibition in Marjolin Ulcer: A Case Series. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Immunomodulators for Non-Melanoma Skin Cancers: Updated Perspectives. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Topical Calcipotriol Plus Imiquimod Immunotherapy for Nonkeratinocyte Skin Cancers. [2023]

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

Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma. [2023]

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

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials. [2020]

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

Topical pharmacotherapy for skin cancer: part I. Pharmacology. [2014]

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

Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies. [2018]

8. United States 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. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Skin Manifestations of Targeted Antineoplastic Therapy. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Dermatological adverse events associated with immune checkpoint inhibitor-based combinations of anticancer therapies: a systematic review. [2022]

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

IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin. [2020]