Trametinib and Ceritinib for the Treatment of Refractory, Unresectable Stage IIIC-IV Melanoma
This phase I trial studies how well trametinib and ceritinib work in treating participants with stage IIIC-IV melanoma that has not responded to treatment (refractory) and cannot be removed by surgery (unresectable). Trametinib and ceritinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Inclusion Criteria
- Diagnosis of advanced/unresectable melanoma (American Joint Committee on Cancer [AJCC] v.8 stage 3C/D/4)
- Measurable disease, defined as per RECIST 1.1 criteria
- Must have at least one tumor site accessible for a biopsy
- Documented disease refractory to at least one PD1/PD-L1 (+/- CTLA-4) inhibitor treatment, or intolerance to these drugs. And if BRAFV600-mutant melanoma, refractory disease to at least one BRAF and MEK inhibitor (defined as progression while on treatment), or intolerance to these drugs
- Last line of treatment prior to study enrollment must not have been BRAF/MEK inhibitor therapy
- Prior treatment-related toxicity resolved to =< grade 2 or baseline
- Prior radiation allowed
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for 90 days after completion of trametinib + ceritinib administration
- Hemoglobin (Hgb) >= 8 g/dL
- Absolute neutrophil count (ANC) > 1,000/uL
- Platelets > 70,000/uL
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x upper limit of normal (ULN); =< 5 x ULN, if liver metastasis
- Total bilirubin =< 1.5 x ULN (unless Gilbert’s syndrome or disease infiltration of the liver is present, who may be included if total bilirubin =< 3.0 x ULN or direct bilirubin =< 1.5 x ULN)
- Creatinine =< 1.5 x the upper limit of normal (ULN)
- Amylase and lipase =< 2 x ULN
- Fasting plasma glucose =< 200 mg/dL
- Potassium, magnesium, phosphate must be corrected to at least lower limit of laboratory normal prior to start of treatment
Exclusion Criteria
- Patients with known hypersensitivity to any of the excipients of trametinib, ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
- Patients with untreated or uncontrolled brain metastases or evidence of leptomeningeal disease. Patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible
- Previous malignancy is not an exclusion provided that the other malignancy is considered under control, patient is not on concomitant anti-cancer drug therapy, and target lesions from melanoma are clearly defined for response assessment
- Other severe, acute, or chronic medical conditions including uncontrolled diabetes mellitus or psychiatric conditions or laboratory abnormalities that, in the opinion of the investigator, may increase the risk associated with study participation or may interfere with the interpretation of study results
- Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as: * Unstable angina within 6 months prior to screening; * Myocardial infarction within 6 months prior to screening; * History of documented congestive heart failure (New York Heart Association functional classification III-IV); * Cardiac arrhythmias not controlled with medication; * Corrected QT (QTcF) > 470 ms at baseline
- Patient has history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention). (Note, this does NOT include immune-mediated pneumonitis)
- Impaired gastrointestinal (GI) function or GI disease that may alter absorption of study drugs or inability to swallow
- Receiving medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to start of treatment with study drugs and for the duration of participation: * Medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes * Strong inhibitors or strong inducers of CYP3A4/5, and medications with a low therapeutic index that are primarily metabolized by CYP3A4/5, and/or CYP2C9 * Therapeutic doses of warfarin sodium (coumadin) or any other coumadin-derived anti-coagulant. Anticoagulants not derived from warfarin are allowed (e.g., dabigatran, rivaroxaban, apixaban) * Unstable or increasing doses of corticosteroids in the 5 days before first dose of study treatment * Enzyme-inducing anticonvulsive agents
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03501368.
PRIMARY OBJECTIVE:
I. To identify the maximum tolerated dose (MTD) and the recommend phase 2 dose (RP2D) of this regimen, by assessing the number and frequency of treatment-related adverse events (AEs) as determined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 criteria.
SECONDARY OBJECTIVES:
I. To evaluate the anti-tumor activity of trametinib dimethyl sulfoxide (trametinib) + ceritinib as defined by the overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
II. To estimate the median progression free survival (PFS), defined as the time from first dose to the date of assessment of progression or death by any cause in the absence of progression.
III. To estimate the median overall survival (OS), defined as the time from first dose to the date of death by any cause.
TRANSLATIONAL OBJECTIVE:
I. To determine signaling pathways in tumor biopsies via single cell ribonucleic acid (RNA) sequencing (seq) and correlate with response to trametinib + ceritinib, and to identify the effect of trametinib + ceritinib on the mTOR and MAPK pathways as well as immune infiltration.
OUTLINE: This is a dose-escalation study.
Participants receive trametinib dimethyl sulfoxide orally (PO) once daily (QD) and ceritinib PO QD. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity.
After completion of study treatment, participants are followed up between 30-40 days, every 3 months for 1 year, and then every 6 months for up to 5 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationMoffitt Cancer Center
Principal InvestigatorZeynep Eroglu
- Primary IDMCC-19475
- Secondary IDsNCI-2018-01353
- ClinicalTrials.gov IDNCT03501368