Afatinib for Advanced Skin Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Must not be taking: Corticosteroids
Disqualifiers: Severe liver impairment, Pregnancy, others
No Placebo Group
Prior Safety Data
Approved in 4 Jurisdictions
Trial Summary
What is the purpose of this trial?The primary purpose of this study is to find out if Afatinib can help treat participants with advanced cSCC.
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, you must be at least 2 weeks from any prior systemic therapy before starting the study treatment.
Is Afatinib safe for humans?
Afatinib, also known as Gilotrif, has been used to treat advanced non-small cell lung cancer and has a predictable and manageable safety profile. Common side effects include diarrhea and skin issues, which are generally managed by adjusting the dose.
12345How is the drug Afatinib unique for treating advanced skin cancer?
Afatinib is unique because it targets the ERBB family of receptor tyrosine kinases, which are involved in cancer cell growth and survival, and it can be used in combination with other inhibitors like crizotinib to enhance its effectiveness, even in cases where other treatments have failed.
678910Eligibility Criteria
Adults with advanced cutaneous squamous cell carcinoma (cSCC) not suitable for surgery/radiation, who've had prior immunotherapy if eligible. Must have good organ function and performance status, a measurable lesion, and be at least 2 weeks post any major treatment or surgery. Those with treated brain metastases can join; however, those with severe liver issues, mixed cancer types, untreated HIV/HCV or pregnancy are excluded.Inclusion Criteria
I am a woman who can have children and have a negative pregnancy test, or I agree to use effective birth control.
I can have a biopsy before and during treatment.
I haven't had any major treatments or surgery for at least 2 weeks.
+8 more
Exclusion Criteria
I have HIV with undetectable viral load or cured hepatitis C.
My cancer is mainly invasive cutaneous squamous cell carcinoma.
I do not have severe liver cirrhosis.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive afatinib 40 mg once a day. Each cycle is 4 weeks. CT imaging and/or digital photography is done at baseline and every 8 weeks. Tumor biopsies are conducted at baseline, at 4 weeks, and at disease progression if feasible.
Up to 1 year
Baseline, every 8 weeks for imaging, biopsies at specified intervals
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessment of treatment-related adverse events up to 40 days after end of treatment.
40 days
Long-term follow-up
Participants are monitored for progression-free survival and overall survival.
Up to 5 years
Participant Groups
The trial is testing the effectiveness of Afatinib 40 MG in treating advanced cSCC. Participants will receive this medication to see if it improves their condition compared to previous treatments they may have received.
1Treatment groups
Experimental Treatment
Group I: Afatinib InterventionExperimental Treatment1 Intervention
Participants will receive afatinib 40 mg once a day. Each cycle is 4 weeks. They will have CT imaging (and/or digital photography) done at baseline and every 8 weeks while on treatment. Participants will have a baseline and on-treatment (at 4 weeks) tumor biopsy, and a biopsy at disease progression if feasible. Patients may remain on treatment as long as they are deriving clinical benefit, until disease progression or intolerable toxicity.
Afatinib is already approved in United States, European Union, Canada, Japan for the following indications:
🇺🇸 Approved in United States as Gilotrif for:
- Non-small cell lung cancer
🇪🇺 Approved in European Union as Giotrif for:
- Non-small cell lung cancer
🇨🇦 Approved in Canada as Gilotrif for:
- Non-small cell lung cancer
🇯🇵 Approved in Japan as Giotrif for:
- Non-small cell lung cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Moffitt Cancer CenterTampa, FL
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Who Is Running the Clinical Trial?
H. Lee Moffitt Cancer Center and Research InstituteLead Sponsor
Boehringer IngelheimIndustry Sponsor
References
Afatinib in advanced NSCLC: a profile of its use. [2020]Afatinib [Giotrif® (EU); Gilotrif® (USA)] is an orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases that provides an important first-line treatment option for advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations (i.e. EGFRactMUT+), and an additional treatment option for squamous NSCLC that has progressed following first-line platinum-based chemotherapy. Relative to gefitinib in the first-line treatment of EGFRactMUT+ advanced lung adenocarcinoma, afatinib prolonged progression-free survival (PFS) and time to treatment failure (TTF), but not overall survival (OS). Afatinib also prolonged PFS, but not OS, versus cisplatin-based chemotherapy in this setting; however, afatinib improved OS versus chemotherapy in the subgroup of patients with deletions in exon 19. As a second-line treatment for advanced squamous NSCLC, afatinib prolonged PFS and OS compared with erlotinib, regardless of EGFR mutation status. Afatinib had a predictable and manageable tolerability profile.
Minocycline prevents and repairs the skin disorder associated with afatinib, one of the epidermal growth factor receptor-tyrosine kinase inhibitors for non-small cell lung cancer. [2021]While epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) exert a breakthrough effect, the incidence of skin disorders as a side effect has significantly reduced patients' quality of life. This study aimed to develop a treatment for inflammatory ulcers as one of the side effects of afatinib (Giotrif®), a second-generation EGFR-TKI, and established a skin disorder mouse model to investigate the protective effect of minocycline.
Afatinib: a review of its use in the treatment of advanced non-small cell lung cancer. [2022]Afatinib (Gilotrif™, Giotrif(®)) is an orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases. Afatinib downregulates ErbB signalling by covalently binding to the kinase domains of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation; it also inhibits transphosphorylation of HER3. Afatinib is approved as monotherapy for the treatment of EGFR tyrosine kinase inhibitor (TKI)-naïve adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US. In two randomized, open-label, multinational phase III trials, progression-free survival was significantly prolonged with afatinib compared with pemetrexed plus cisplatin (LUX-Lung 3) or gemcitabine plus cisplatin (LUX-Lung 6) in treatment-naïve patients with advanced NSCLC with activating EGFR mutations. The objective response rate was significantly higher with afatinib than with pemetrexed plus cisplatin or gemcitabine plus cisplatin, and patient-reported outcomes for symptoms such as cough and dyspnoea and certain health-related quality of life measures significantly favoured afatinib versus pemetrexed plus cisplatin or gemcitabine plus cisplatin. Afatinib also showed efficacy in EGFR TKI-naïve patients with advanced lung adenocarcinoma and activating EGFR mutations who had received no more than one prior chemotherapy regimen for advanced disease, according to the results of the noncomparative, multinational, phase II LUX-Lung 2 trial. Oral afatinib had a manageable tolerability profile. EGFR-mediated adverse events (e.g. diarrhoea, rash/acne) were generally managed using dose reduction and delays. In conclusion, afatinib is a valuable new option for use in treatment-naïve or EGFR TKI-naïve patients with advanced lung adenocarcinoma and activating EGFR mutations.
Survival Outcomes of Nonsmall Cell Lung Cancer Patients Treated with Afatinib Who Are Affected by Early Adverse Events. [2022]Afatinib is a first-line treatment option for patients with an advanced nonsmall cell lung cancer (NSCLC) expressing an epidermal growth factor receptor (EGFR) activating mutation. This study aimed to evaluate the association between early adverse events induced by afatinib and overall survival (OS) and progression free survival (PFS) in patients with advanced NSCLC.
Afatinib: A Review in Advanced Non-Small Cell Lung Cancer. [2018]Afatinib (Giotrif®, Gilotrif®) is an orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases. In the first-line treatment of patients with advanced lung adenocarcinoma with activating epidermal growth factor receptor (EGFR) mutations, afatinib significantly prolonged progression-free survival (PFS) and time to treatment failure (TTF), but not overall survival (OS), compared with gefitinib (LUX-Lung 7 trial). In the overall population of patients receiving first-line treatment for advanced lung adenocarcinoma with activating EGFR mutations, afatinib significantly prolonged PFS, but not OS, compared with pemetrexed plus cisplatin (LUX-Lung 3 trial) or gemcitabine plus cisplatin (LUX-Lung 6 trial). However, in both LUX-Lung 3 and LUX-Lung 6, OS was significantly prolonged in the subgroup of patients with deletions in exon 19 receiving afatinib versus chemotherapy. In the second-line treatment of advanced squamous non-small cell lung cancer (NSCLC), afatinib significantly prolonged PFS and OS, compared with erlotinib, regardless of EGFR mutation status (LUX-Lung 8 trial). Afatinib had a predictable and manageable tolerability profile in patients with advanced NSCLC. In conclusion, afatinib is an important option for the first-line treatment of patients with advanced NSCLC and activating EGFR mutations, and provides an additional option for the treatment of patients with squamous NSCLC that has progressed following first-line platinum-based chemotherapy.
Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. [2021]The emergence of skin tumors in patients treated with sorafenib or with more recent BRAF inhibitors is an intriguing and potentially serious event. We carried out a clinical, pathologic, and molecular study of skin lesions occurring in patients receiving sorafenib.
Phase II study of apatinib combined with temozolomide in patients with advanced melanoma after failure of immunotherapy. [2023]Treatment for advanced melanoma after progression on immunotherapy is limited. This phase II trial (NCT03422445) was conducted to evaluate the efficacy and safety of apatinib plus temozolomide in patients with advanced melanoma after failure of immunotherapy. Patients with unresectable stage III or stage IV melanoma after progression on immunotherapy were treated with temozolomide 300 mg on days 1-5 and apatinib 500 mg daily every 28-day cycle until disease progression or intolerable toxicities. Besides immunotherapy, prior chemotherapy, targeted therapy, and clinical trials were allowed. The primary endpoint was progression-free survival. Secondary endpoints were objective response rate, disease control rate, overall survival, and safety. Of 29 patients, 28 (96.6%) had metastatic diseases, and the predominant subtypes were mucosal [12 (41.4%)] and acral melanoma [eight (27.6%)]. Five (17.2%) patients showed BRAF, CKIT, or NRAS mutation. Five achieved confirmed partial response, with an objective response rate of 17.2%. The disease control rate was 82.8%. The median progression-free survival was 5.0 months [95% confidence interval (CI): 4.7-5.3], and the median overall survival was 10.1 months (95% CI: 5.1-15.0). Grade 3-4 treatment-related adverse events included proteinuria [four (13.8%)], thrombocytopenia [two (6.9%)], hypertension [one (3.4%)], and hyperbilirubinemia [one (3.4%)]. No treatment-related death occurred. Apatinib plus temozolomide demonstrated promising efficacy and manageable safety profile in patients with advanced melanoma after progression on immunotherapy.
Metastatic melanoma: scientific rationale for sorafenib treatment and clinical results. [2018]In advanced metastatic melanoma (AJCC stage IV), the prognosis is still poor, and views differ on the appropriate systemic treatment for these patients. Therefore, new approaches in therapeutic regimens are mandatory. Sorafenib is an oral multikinase inhibitor that targets 2 classes of kinases which are known to be involved in both tumor proliferation and angiogenesis. These kinases include Raf kinases and the vascular endothelial growth factor (VEGF) receptor. Sorafenib has been evaluated as a single therapy agent as well as in combination with various chemotherapeutical drugs in a number of clinical trials. The vast majority of clinical data exists for patients with advanced renal cell cancer for which sorafenib has been approved by the FDA and EMEA. Very recently, sorafenib was approved for advanced hepatocellular cancers due to its overall survival improvement. Since B-raf gene mutations have been found in 69% of melanoma cell lines, sorafenib was brought into various phase I/II and phase III trials in metastatic melanoma. However, as a single-agent therapy, sorafenib seems to be of limited use. Also, the combination of sorafenib with the chemotherapeutic agents carboplatin and paclitaxel has failed to show superiority in progression-free and overall survival compared to the same chemoregimen plus an oral placebo in a phase III trial (PRISM study). More promising data were observed in large-sized phase II studies on dacarbazine (DTIC) plus sorafenib and temozolomide plus sorafenib. However, these data need to be confirmed in prospective randomized phase III trials. Till then, sorafenib remains an interesting but still experimental new agent for melanoma.
The Promise of Molecularly Targeted and Immunotherapy for Advanced Melanoma. [2018]Advanced melanoma, rarely diagnosed at the time of primary melanoma excision but most often occurring later via lymphatic or hematogenous dissemination, is the cause of death for approximately 10,000 people in the USA each year, with the rate of incidence and death increasing yearly. Its causes are multifactorial and depend in large part on solar ultraviolet damage to DNA as well as underlying genetic predisposition. Cutaneous melanoma is the most common, but other subsets of importance are mucosal and uveal primaries, with different biology and treatment considerations. Mutational oncogenic "drivers" may be targeted with chronically administered, oral kinase inhibitors, currently consisting of the mitogen-activated protein kinase (MAPK) inhibitor combinations of BRAF plus MEK-targeted drugs. These agents work quickly to relieve symptoms and induce remissions but generally have limited durations of disease control. Immunotherapies include the immune checkpoint inhibitors that block CTLA4 or PD-1-negative immune signaling as well as interleukin-2, a cytokine that stimulates T lymphocytes and natural killer cells. A combination of CTLA4 plus PD-1 blockade has the highest activity ever reported for metastatic melanoma, at the cost of high autoimmune-like toxicities. However, immunotherapies of this type may provide durable responses and even cure a subset of patients. Thus, these immunotherapeutic agents are recommended as first-line therapy for most patients with advanced melanoma. Patients with rapidly progressive, symptomatic melanoma whose tumor carries a BRAF mutation may benefit more from initial therapy with combined MAPK inhibitors.
Combining ERBB family and MET inhibitors is an effective therapeutic strategy in cutaneous malignant melanoma independent of BRAF/NRAS mutation status. [2021]Current treatment modalities for disseminated cutaneous malignant melanoma (CMM) improve survival; however, relapses are common. A number of receptor tyrosine kinases (RTKs) including EGFR and MET have been reported to be involved in CMM metastasis and in the development of resistance to therapy, targeting the mitogen-activated protein kinase (MAPK pathway). IHC analysis showed that patients with higher MET protein expression had a significantly shorter overall survival. In addition, silencing of MET caused an upregulation of EGFR and p-AKT, which was abrogated by concomitant silencing of MET and EGFR in CMM cells resistant to MAPK-targeting drugs. We therefore explored novel treatment strategies using clinically approved drugs afatinib (ERBB family inhibitor) and crizotinib (MET inhibitor), to simultaneously block MET and ERBB family RTKs. The effects of the combination were assessed in cell culture and spheroid models using established CMM and patient-derived short-term cell lines, and an in vivo xenograft mouse model. The combination had a synergistic effect, promoting cell death, concomitant with a potent downregulation of migratory and invasive capacity independent of their BRAF/NRAS mutational status. Furthermore, the combination attenuated tumor growth rate, as ascertained by the significant reduction of Ki67 expression and induced DNA damage in vivo. Importantly, this combination therapy had minimal therapy-related toxicity in mice. Lastly, the cell cycle G2 checkpoint kinase WEE1 and the RTK IGF1R, non-canonical targets, were altered upon exposure to the combination. Knockdown of WEE1 abrogated the combination-mediated effects on cell migration and proliferation in BRAF mutant BRAF inhibitor-sensitive cells, whereas WEE1 silencing alone inhibited cell migration in NRAS mutant cells. In summary, our results show that afatinib and crizotinib in combination is a promising alternative targeted therapy option for CMM patients, irrespective of BRAF/NRAS mutational status, as well as for cases where resistance has developed towards BRAF inhibitors.