Tunlametinib in Combination With Pucotenlimab and Hydroxychloroquine in NRAS Mutant Melanoma
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorSun Yat-sen University
About this trial
This study evaluates the combination of the autophagy inhibitor hydroxychloroquine (HCQ), the MEK inhibitor tunlametinib, and the anti-PD-1 antibody pucotenlimab in patients with locally advanced or metastatic melanoma. The primary objectives are to assess the objective response rate (ORR) and progression-free survival (PFS). Secondary objectives include evaluating adverse events (type, severity, and incidence), duration of response (DOR), disease control rate (DCR), and overall survival (OS), as well as exploring the molecular mechanisms by which autophagy modulation enhances immunogenicity in mutant melanoma. Further exploratory analyses will examine the mechanisms by which autophagy inhibition enhances tumor sensitivity to PD-1 blockade, thereby establishing experimental and theoretical grounds for refining future clinical approaches.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Age ≥ 18 years of age, both genders.
Subjects with unresectable or metastatic melanoma (Stage III/IV) confirmed by histology or cytology
The mutated NRAS genes were confirmed by sequencing.
Prior systemic antineoplastic therapy is allowed. All acute toxic effects of prior antitumor therapy must have resolved to grade 1 or lower before the start of the study drug, with the exception of alopecia (grade 1 or 2 permitted), neurotoxicity (grade 1 or 2 permitted), or bone marrow parameters (grade 1, 2, or 3 permitted).
Disqualifiers
Subjects who have previously received anti-PD-1 antibody, anti-PD-L1/PD-L2 antibody therapy, and/or VEGFR TKI therapy.
Subjects currently receiving systemic anti-tumor therapy.
Subjects who have participated in or are currently participating in other drug/therapy clinical trials within 4 weeks prior to enrollment (calculated from the date of the last dose of the previous trial).
Subjects who have undergone major surgery within 4 weeks prior to enrollment, or have not recovered from surgical side effects, or have received live vaccination within 4 weeks prior to enrollment.
Trial design
Design model
Single group
Treatments tested in this trial
Tunlametinib
DrugTunlametinib (3 mg/tablet): The recommended dose is 12 mg (4 tablets) orally twice daily (approximately every 12 hours), with or without food. Capsules must not be chewed, dissolved, or opened. If a dose is missed, it may be taken up to 8 hours before the next scheduled dose; if the missed dose is discovered within 8 hours of the next dose, it should be skipped.
Pucotenlimab
DrugPD-1 antibody (pucotenlimab): Administered via intravenous infusion over at least 60 minutes, using an in-line filter (0.2-5 μm). The drug is diluted with normal saline prior to infusion. One treatment cycle is defined as 3 weeks (21 days).
Hydroxychloroquine (HC)
DrugHydroxychloroquine (0.1 g/tablet): Administered orally at 2 tablets (0.2 g) twice daily, to be taken with meals or milk. Each treatment course consists of 4 consecutive weeks of administration, i.e., 30 days per course.
Treatment groups
37 Participants
are divided into 1 treatment groupGroup A: Tunlametinib + Pucotenlimab + HydroxychloroquineExperimental treatment 3 interventions
Trial outcomes
Primary outcomes
1
Objective Response Rate (ORR)
Defined as the percentage of subjects achieving complete response (CR) or partial response (PR) as assessed by RECIST 1.1.
Time frame
up to 180 days2
Progression Free Survival (PFS)
Defined as the time from randomization to the date of first documentation of from date of randomization until the date of first documented progression or date of death from any cause, whichever came first.
Time frame
up to 180 daysSecondary outcomes
1
Disease Control Rate (DCR)
DCR was defined as the proportion of CR+PR+SD subjects to total subjects
Time frame
up to 180 days2
Duration of Response (DoR)
DoR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death.
Time frame
up to 180 days3
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
The safety profile will be characterized by reporting the number and percentage of participants (with 95% Clopper-Pearson confidence intervals) for the following endpoints: overall TEAEs, Grade ≥3 TEAEs, serious adverse events (SAEs), treatment-related AEs, AEs leading to permanent drug discontinuation, and AEs leading to dose modification. All AEs will be graded per CTCAE v4.0, and causality will be determined by the investigator.
Time frame
30 days (average of 3 months).Other outcomes
1
Integrated mechanistic biomarkers of autophagy-mediated neoepitope presentation and T-cell-dependent sensitization to PD-1 blockade.
To investigate the mechanisms by which induced autophagy enhances immunogenicity and sensitises melanoma to PD-1-targeted therapy, we will conduct a correlative biomarker analysis using serial blood and available tumor samples. A panel of predefined markers related to autophagic activity, antigen presentation, and T-cell effector function will be assessed by standard laboratory techniques. Changes in these biomarker levels from baseline will be correlated with clinical outcomes (response, progression-free survival) and summarized using descriptive statistics (mean, standard deviation, median, range) and non-parametric correlation tests as appropriate. Detailed assay protocols and specific biomarker identities are not disclosed to preserve confidential information.
Time frame
up to 720 daysSponsors and contacts
Click on the lead sponsor to view all of their trials.
Source ClinicalTrials.gov