Navtemadlin +/− Immunotherapy for Skin Cancer
Recruiting in Palo Alto (17 mi)
+52 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Kartos Therapeutics, Inc.
Disqualifiers: Autoimmune disease, Immunosuppression, Organ transplant, others
No Placebo Group
Breakthrough Therapy
Trial Summary
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.
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.
12345Is 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.
678910What 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.
123411Eligibility 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.
+6 more
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.
+2 more
Trial 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
Participant Groups
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.
11Treatment groups
Experimental Treatment
Group I: Cohort 4Experimental Treatment1 Intervention
KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.
Group II: Cohort 3Experimental Treatment1 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 avelumabExperimental Treatment2 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 avelumabExperimental Treatment2 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 ExpansionExperimental Treatment2 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 5Experimental Treatment1 Intervention
KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle.
Group VII: Cohort 1, Arm 3Experimental Treatment1 Intervention
KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle.
Group VIII: Cohort 1, Arm 2bExperimental Treatment1 Intervention
KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 28-day cycle.
Group IX: Cohort 1, Arm 1bExperimental Treatment1 Intervention
KRT-232 will be administered orally, once daily (QD) on Days 1-5 in a 23-day cycle.
Group X: Cohort 1, Arm 1Experimental Treatment1 Intervention
KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 21-day cycle.
Group XI: Cohort 1 ExpansionExperimental Treatment1 Intervention
KRT-232 will be administered orally, once daily (QD) per Cohort 1 RP2D dose and schedule.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Miami Cancer InstituteMiami, FL
Inova Health Care ServicesFairfax, VA
UPMC Hillman Cancer CenterPittsburgh, PA
Norton HealthcareLouisville, KY
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Kartos Therapeutics, Inc.Lead Sponsor
References
Immune Checkpoint Inhibition in Marjolin Ulcer: A Case Series. [2022]Immunotherapy has revolutionized the treatment of advanced cutaneous squamous cell carcinoma. However, the role of immune checkpoint inhibitors for the treatment of Marjolin ulcer (MU), a rare cutaneous malignancy that arises from previously traumatized and chronically inflamed skin, is not well defined. Thus, efficacy and clinical response to immunotherapy in patients with MU requires further investigation. MU with squamous cell carcinoma, the most commonly associated malignancy, is highly aggressive with a greater risk for lymph node and distant metastasis compared with non-MU cutaneous squamous cell carcinoma. Often associated with nonhealing chronic wounds from burn scars, injuries, venous stasis ulcers, osteomyelitis, and radiotherapy, MU carries a poor prognosis. We conducted a retrospective study and describe a single institution experience of patients with MU treated with anti-programmed cell death protein 1 (PD-1) therapy at Massachusetts General Hospital between 2016 and 2020. Five subjects with this rare presentation met inclusion criteria and were treated with pembrolizumab (N=2) or cemiplimab (N=3). Four subjects received immunotherapy in the first-line setting. Notably, 1 patient had durable disease control for 1 year while on immunotherapy, with continued disease control after the cessation of anti-PD-1 therapy. Of the 4 patients that progressed on anti-PD-1 therapy, disease control at 5 months was achieved in 2 patients. Furthermore, 60% overall survival (3 patients) was observed in this limited cohort at 12 months after initiating anti-PD-1 therapy for MU. We describe the clinicopathologic features and clinical outcomes of our MU-SCC cohort.
Immunomodulators for Non-Melanoma Skin Cancers: Updated Perspectives. [2023]Non-melanoma skin cancers (NMSCs) are the most common cancers worldwide and may be associated with significant morbidity and mortality, especially in immunosuppressed populations. Successful management of NMSC must take primary, secondary and tertiary prevention strategies into consideration. In response to an improved understanding of the pathophysiology of NMSC and associated risk factors, multiple systemic and topical immunomodulatory drugs have been developed and integrated into clinical practice. Many of these drugs are efficacious in the prevention and treatment of precursor lesions (actinic keratoses; AKs), low-risk NMSC, and advanced disease. The identification of patients at high risk for the development of NMSC is critical in reducing disease morbidity. Understanding the various treatment options available and their comparative effectiveness is paramount for developing a personalized treatment regimen for such patients. This review article provides an updated overview of the various topical and systemic immunomodulatory drugs available for the prevention and treatment of NMSC, and the published data supporting their use in clinical practice.
Topical Calcipotriol Plus Imiquimod Immunotherapy for Nonkeratinocyte Skin Cancers. [2023]Nonkeratinocyte cutaneous malignancies, including breast cancer cutaneous metastasis and melanoma in situ, are often poor surgical candidates. Imiquimod (IMQ), a toll-like receptor 7 agonist that activates innate immunity in the skin, is used to treat these cutaneous malignancies. However, IMQ's modest effect on the activation of adaptive immunity limits its efficacy as a monotherapy. In this study, we demonstrate that topical TSLP cytokine inducers-calcipotriol and retinoic acid-synergize with IMQ to activate CD4+ T-cell immunity against nonkeratinocyte cutaneous malignancies. Topical calcipotriol plus IMQ treatment reduced breast tumor growth compared with calcipotriol or IMQ alone (P < 0.0001). Calcipotriol plus IMQ-mediated tumor suppression was associated with significant infiltration of CD4+ effector T cells in the tumor microenvironment. Notably, topical calcipotriol plus IMQ immunotherapy enabled immune checkpoint blockade therapy to effectively control immunologically cold breast tumors, which was associated with induction of CD4+ T-cell immunity. Topical treatment with calcipotriol plus IMQ and retinoic acid plus IMQ also blocked subcutaneous melanoma growth. These findings highlight the synergistic effect of topical TSLP induction in combination with innate immune cell activation as an effective immunotherapy for malignancies affecting the skin.
Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma. [2023]Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development, consistent with our genomic analysis implicating MEK as a chemoprevention target. Although systemic MEKi suppresses the formation of cSCC in mice, systemic MEKi can cause severe adverse effects. Here, we report the development of a metabolically labile MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin before rapid metabolism in the systemic circulation. NFX-179 was identified on the basis of its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our ultraviolet-induced cSCC mouse model, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. We further confirmed the localized nature of these effects in an additional split-mouse randomized controlled study where suppression of cSCC was observed only in drug-treated areas. No toxicities were observed. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner, and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together, our data provide a compelling rationale for using topical MEK inhibition through the application of NFX-179 gel as an effective strategy for cSCC chemoprevention.
Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials. [2020]Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.
Topical pharmacotherapy for skin cancer: part I. Pharmacology. [2014]Topical pharmacotherapy represents an effective alternative treatment for superficial skin cancer, primarily actinic keratoses and basal cell carcinomas. We provide an in-depth analysis of the pharmacologic aspects of available topical drugs for the treatment of primary skin tumors. In particular, we evaluate the mechanisms of action, formulations and indications, side effects, and contraindications of 5-fluorouracil, imiquimod, diclofenac, ingenol mebutate, and retinoids. Moreover, the characteristics of some investigational molecules (ie, resiquimod, piroxicam, dobesilate, and betulinic acid) are presented.
Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies. [2018]The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies. We systematically review according to drug-targeting pathway the cutaneous AE profiles of these drugs, and offer insight when possible into whether pharmacologic target versus immunologic modulation primarily underlie presentation. We include discussion of tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib), blinatumomab, ibrutinib, idelalisib, anti-B cell antibodies (rituximab, ibritumomab, obinutuzumab, ofatumumab, tositumomab), immune checkpoint inhibitors (nivolumab, pembrolizumab), alemtuzumab, brentuximab, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib). We highlight skin reactions seen with antiliquid but not solid tumor agents, draw attention to serious cutaneous AEs that might require therapy modification or cessation, and offer management strategies to permit treatment tolerability. We emphasize the importance of early diagnosis and treatment to minimize disruptions to care, optimize prognosis and quality of life, and promptly address life-threatening skin or infectious events. This evolving partnership between oncologists and dermatologists in the iterative characterization and management of skin toxicities will contribute to a better understanding of these drugs' cutaneous targets and improved patient care.
Cutaneous side effects and types of dermatological reactions in metastatic melanoma patients treated by immunotherapies or targeted therapies: A retrospective single center study. [2023]Immunotherapy and target therapy have revolutionized treatment of stage III/IV melanoma. Both treatments show a favorable toxicity profile even if cutaneous adverse events (AEs) are frequent (30%-40% of cases). This is a retrospective single center cohort study that included patients with stage IV or inoperable stage III metastatic melanoma (AJCC 8th) who received BRAFi + MEKi therapy or immunotherapy with Checkpoint inhibitors. All cutaneous AEs were ascertained by a dermatologist based on clinical and histological findings. The primary outcome was to provide a detailed clinical dermatological classification of cutaneous adverse events and an evaluation of the incidence of skin toxicity in the two arms of therapy (immunotherapy and target therapy). A total of 286 patients with stages III-IV metastatic melanoma were included: 146 received immunotherapy and 140 target therapy. In the immunotherapy cohort, 63 (43.1%) cutaneous reactions were observed while 33 skin reactions (23.6%) were identified in patients treated with target therapy. All the skin toxicities observed were grade I, excepted four cases: an erythema multiforme-like eruption, a grade III psoriasis and two grade III maculopapular rashes. Immunotherapy in older age resulted statistically related to skin toxicities (p = 0.011), meanly in metastatic setting (p = 0.011). Cumulative incidence of skin toxicities was 65.63% in immunotherapy cohort (p = 0.001). Also multivariate logistic regression shows a significant association between skin adverse events and immunotherapy (odds ratio [OR] = 0.50; 95% confidence interval [CI]: 0.29-0.85, p: 0.01) and between cutaneous AEs and metastatic setting (OR = 1.97; 95% CI: 1.04-3.74, p: 0.04). We have also shown that as the age of initiation of therapy increases the probability of developing skin toxicity grows. However, stratifying by type of therapies the effect of age persists only in immunotherapy (OD: 1.04; CI: 1.01-1.06; p: 0.04) while for target therapy age does not affect the onset of skin toxicity (OD 1.01; CI 0.98-1.04; p = 0.42). No differences were shown between patients on target therapy and immunotherapy regarding gender. Patients were also evaluated regarding concomitant therapies and seems that Levotyroxine may be involved in AEs during immunotherapy treatment. More studies are needed to deepen this aspect, also considering the medical history and diverse drug associations. Cutaneous adverse events are characterized by heterogeneous manifestations, are more often seen in patients on immunotherapy and dermatologists can play a crucial role in multidisciplinary care.
Skin Manifestations of Targeted Antineoplastic Therapy. [2018]The management of oncology patients has changed significantly over recent years, with the development of new targeted anticancer therapies. Cutaneous adverse effects are among the most frequently observed toxicities with many targeted agents; their intensity can be dose-limiting or lead to the discontinuation of therapy. Tyrosine kinase inhibitors can cause maculopapular rash and hand-foot reaction, whereas papulopustular rash, paronychia, regulatory changes in hair, and dryness are caused by epidermal growth factor receptor inhibitors. SMO inhibitors, vismodegib and sonidegib, may result in muscle spasms and alopecia.
Dermatological adverse events associated with immune checkpoint inhibitor-based combinations of anticancer therapies: a systematic review. [2022]Aim: This paper presents the reported dermatological adverse events (AEs) associated with approved combinations of immunotherapy with drugs of the same class, or in combination with targeted therapy or chemotherapy. Materials & methods: PubMed was used as an electronic database, and a total of 29 articles were reviewed which reported dermatological AEs following combination therapies with nivolumab, ipilimumab, axitinib, pembrolizumab, lenvatinib, avelumab, atezolizumab, carboplatin, etoposide, paclitaxel, bevacizumab, pemetrexed, cisplatin and durvalumab. Results: The dermatological AEs reported were mutually inclusive and the highest incidence of specific AEs was seen in the following combinations: rash in the nivolumab/ipilimumab and lenvatinib/pembrolizumab combinations, pruritus in the atezolizumab/nab-paclitaxel combination, dry skin and palmar-plantar erythrodysesthesia in the axitinib/pembrolizumab combination, and alopecia and severe skin reactions in the pembrolizumab/carboplatin/paclitaxel combination. Conclusion: Knowledge of such side effects is of benefit when choosing an optimal treatment regimen and should be integrated into the monitoring and follow-up phases of treatment.
IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin. [2020]Establishment of a permissive pre-malignant niche in concert with mutant stem are key triggers to initiate skin carcinogenesis. An understudied area of research is finding upstream regulators of both these triggers. IL27, a pleiotropic cytokine with both pro- and anti-inflammatory properties, was found to be a key regulator of both. Two step skin carcinogenesis model and K15-KRASG12D mouse model were used to understand the role of IL27 in skin tumors. CD11b-/- mice and small-molecule of ETAR signaling (ZD4054) inhibitor were used in vivo to understand mechanistically how IL27 promotes skin carcinogenesis. Interestingly, using in vivo studies, IL27 promoted papilloma incidence primarily through IL27 signaling in bone-marrow derived cells. Mechanistically, IL27 initiated the establishment of the pre-malignant niche and expansion of mutated stem cells in K15-KRASG12D mouse model by driving the accumulation of Endothelin A receptor (ETAR)-positive CD11b cells in the skin-a novel category of pro-tumor inflammatory identified in this study. These findings are clinically relevant, as the number of IL27RA-positive cells in the stroma is highly related to tumor de-differentiation in patients with squamous cell carcinomas.