Ensayos clínicos

Inclusion Criteria - Escalation and Expansion Phases:

Patients must have histologically confirmed solid tumors or hematologic malignancies. Eligible patients include the following:

• GIST patients must have a KIT or PDGFRA mutation and must have progressed on or had an intolerability to at least 1 line of systemic anticancer therapy:
  • Patients with a pre-existing resistance mutation to an approved line of therapy are eligible. For example, imatinib resistant mutations including KIT Exon 17 and PDGFRA D842V;
• SM patients must have a confirmed diagnosis (confirmed by a central independent pathologist) of advanced SM according to 2016 World Health Organization (WHO) criteria for SM (15) and must have documented KIT mutant disease. Patients with imatinib-sensitive KIT mutations must have progressed on or were intolerant to a tyrosine kinase inhibitor. Patients with advanced SM must present with at least 1 eligible C Finding (organ damage) as outlined in Table 3 of the 2013 International Working Group Myeloproliferative Neoplasms Research and Treatment (IWG MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria; please see below for MCL exception.
• Advanced SM includes:
  • Aggressive SM (ASM);
  • SM-AHN, wherein the AHN does not require immediate alternative therapy, such as acute myeloid leukemia. AHNs that are eligible include: low-grade myelodysplastic syndrome (MDS) with a high SM burden who require for treatment SM only, myeloproliferative neoplasms (MPNs), MDS/MPN, unclassifiable MDS, and HES/CEL;
  • MCL - Patients with histopathologically-confirmed MCL without a C-finding are eligible;
  • Symptomatic SSM By definition, SSM patients must have at least 2 B-findings, and clinically significant symptom burden (e.g., flushing, diarrhea, etc.) despite maximal treatment with approved agents to treat mediator symptoms, such as antihistamines and cromolyn sodium;
  • Patients with hematologic malignancies featuring clonal expansion of eosinophils driven by genomic alterations of KIT or PDGFR (e.g., HES or CEL) must have a diagnosis confirmed by a central independent pathologist and are eligible if they have progressed on or are intolerant of imatinib therapy. Patients with de novo imatinib resistant mutations, such as but not limited to KIT D816V or PDGFRA D842V, are eligible without prior imatinib therapy.
• Malignant glioma patients with genomic alterations potentially conferring sensitivity to DCC-2618 including, but not limited to, amplification and/or mutations of PDGFRA and/or KIT.
  • Patients must not require use of enzyme-inducing antiepileptic drugs;
  • Patients that require steroids must be on a stable dose for 2 weeks prior to the first dose of study drug.
• Other solid tumor patients that have alterations in genes encoding kinases that are targets of DCC-2618. This includes KIT, PDGFR (A or B), TIE2, CSF1R, and VEGFR2. Patients must have received approved treatments known to provide clinical benefit prior to study entry.
• Melanoma patients with genomic mutations and/or amplification potentially conferring sensitivity to DCC-2618 including mutations of KIT, PDGFR (A or B), TIE2, CSF1R, and VEGFR2 (KDR).
  • Patients must have a histologically documented diagnosis of melanoma;
  • Patients must have received approved treatments known to provide clinical benefit prior to study entry.
• Soft tissue sarcoma patients (including but not limited to: malignant peripheral nerve sheath tumors [MPNST], desmoplastic small round cell tumors [DSRCT], and dermatofibrosarcoma protuberans tumors[DFSP) with genomic mutations and/or amplification potentially conferring sensitivity to DCC-2618; this includes mutations of KIT, PDGFR (A or B), TIE2, CSF1R, and VEGFR2.
  • Patients must have histologically documented diagnosis of soft tissue sarcoma;
  • Patients must have received approved treatments known to provide clinical benefit prior to study entry. 
  • Other solid tumor patients (non-melanoma, non-STS; specifically, germ-cell, penile, and non-small cell lung carcinoma) that have mutations and/or amplification in genes encoding kinases that are targets of DCC-2618. This includes KIT, PDGFR (A or B), TIE2, CSF1R, and VEGFR2. Patients must have received approved treatments known to provide clinical benefit prior to study entry.
• If signs or symptoms suggest suspected CNS metastases, a brain MRI must be performed to confirm absence of CNS disease prior to receiving study drug.
• A renal impairment cohort will be formed, comprised of advanced GIST patients as well as other solid tumor patients with at least one prior therapy and with genomic alterations in KIT or PDGFRA/B and creatinine clearance between 20 and 50 mL/min, not requiring dialysis.
• Patients with known CNS metastases may participate provided that:
  • they are stable (i.e., without evidence of progression by magnetic resonance imaging [MRI]) for at least 4 weeks prior to the first dose study drug (patients with active disease may be eligible following discussion between the Investigator and the Sponsor);
  • all neurologic symptoms have been stable for 2 weeks prior to the first dose of study drug;
  • patients must not require use of enzyme-inducing antiepileptic drugs;
  • patients that require steroids must be on a stable dose for 2 weeks prior to the first dose of study drug.
• Patients with solid tumors (with the exception of glial tumors and tumors that are anatomically inaccessible) must have an archival tumor biopsy sample as long as no anticancer therapy was administered since the sample was collected; otherwise, a current biopsy is required. In the case of glial tumors and anatomically inaccessible tumors, the most recent archival tissue is required.
• Male or female patients ≥ 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2.
• Female patients of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test within 28 days prior to the start of study drug. For clinical sites in the UK and Germany, pregnancy testing must occur within 7 days prior to the start of study drug.
• Patients of reproductive potential must agree to follow the contraception requirements.
• The patient is capable of understanding and complying with the protocol and has signed the informed consent document. A signed informed consent form must be obtained before any study-specific procedures are performed. Standard procedures performed as part of the practice of medicine prior to consent (e.g., imaging, physical exam) can be used to determine eligibility if completed within 28 days prior to the initial dose of study drug.
• Patients with solid tumors must have at least 1 measurable lesion according to RECIST Version 1.1 (non-nodal lesions must be ≥ 1.0 cm in the long axis or ≥ double the slice thickness in the long axis; nodal lesions must be ≥ 1.5 cm in the short axis) or Response Assessment in Neuro-Oncology Criteria (RANO).
  • A non-brain lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion before study enrollment.
• Adequate organ function and bone marrow function as indicated by the following central laboratory screening assessments performed within 14 days prior to the first dose of study drug. Local laboratory values obtained after screening and prior to Cycle 1 Day 1 dosing that do not meet the criteria below must be discussed with the Sponsor:
  • Solid Tumor Patients:  Bone Marrow Function; Absolute neutrophil count (ANC) ≥ 1500/µL; Hemoglobin ≥ 9 g/dL; Platelet count ≥ 75,000/µL.
  • All Patients:  Hepatic Function: Serum direct bilirubin ≤ 1.5 times the upper limit of normal (ULN) (≤ 3 × ULN if this elevation is solely due to ASM/MCL);  Aspartate transaminase (AST)/alanine transaminase (ALT), ≤ 3 × ULN (≤ 5 × ULN in the presence of hepatic metastases or if this elevation is solely due to ASM/MCL).
  • Renal Function: Serum creatinine ≤ 2.0 × ULN or creatinine clearance ≥ 50 mL/min based either on urine collection or Cockcroft Gault estimation with the exception of the renal impairment cohort (creatinine clearance of 20 to 50 mL/min is required).
  • Coagulation Profile: Prothrombin time (PT) - international normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 × ULN.  Patients on a stable, maintenance regimen of anticoagulant therapy for at least 30 days prior to study drug administration may have PT/INR measurements > 1.5 × ULN if, in the opinion of the Investigator, the patient is suitable for the study. An adequate rationale must be provided to the Sponsor prior to enrollment.
• SM patients with one or more inadequate organ function laboratory value may be eligible if both the Investigator and Sponsor deem it to be disease-related and the abnormality qualifies as a C-Finding.
• Resolution of all toxicities from prior therapy to ≤ Grade 1 (or baseline) within 1 week prior to the first dose of study drug (excluding alopecia) and ≤ Grade 3 clinically asymptomatic lipase, amylase, and creatine phosphokinase laboratory abnormalities).

Exclusion Criteria:

• GIST patients with wild type or unknown KIT or PDGFRA status.
• Patients with SM or other hematologic malignancies will be excluded if the following apply:
  • SM patients with neutropenia accompanied by fever or infection, or thrombocytopenia associated with clinically significant bleeding.
    • Patients with an infection that is well controlled with antibiotics are eligible if there is an immediate need for treatment.
  • SM-AHN patients diagnosed with:
    • SM with MDS (SM-MDS) who require treatment;
    • Patients requiring immediate treatment for AHN.
  • Patients with leukemias, with the exception of MCL and CEL, that have progressed after imatinib.
  • Eosinophilic myeloproliferative neoplasm patients:
    • Lacking a mutation that is a known target of DCC-2618. This includes, but is not limited to, fusions/mutations of FGFR1, JAK2, and ABL.
• Prior or concurrent malignancy whose natural history or treatment have the potential to interfere with the safety or efficacy assessment of DCC-2618. Patients receiving adjuvant cancer treatment are not eligible if those medications are potentially active against GIST or excluded per protocol.
• Treatment with anticancer therapy, including investigational therapy, within 2 weeks prior to the administration of study drug, with the exception of hydroxyurea that is allowed to control white blood cell count. For prior therapies with a half-life longer than 3 days, the interval must be at least 28 days prior to the first administration of study drug.
• New York Heart Association class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure.
• Arterial thrombotic or embolic events such as cerebrovascular accident (including ischemic attacks) or hemoptysis within 6 months before start of study drug.
• Venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events (e.g., pulmonary embolism) within the 3 months before start of study drug. Patients with venous thrombotic events ≥ 3 months before start of study drug on stable anticoagulation therapy are eligible.
• Baseline prolongation of the rate-corrected QT interval based on repeated demonstration of QT interval corrected by Fridericia’s formula (QTcF) > 450 ms in males or > 470 ms in females or history of long QT syndrome.
• Left ventricular ejection fraction (LVEF) < 50% or below the institute lower limit of normal (whichever is higher).
• Major surgery within 4 weeks of the first dose of study drug; following major surgeries > 4 weeks prior to the first dose of study drug, all surgical wounds must be healed and free of infection or dehiscence.
• Any other clinically significant comorbidities, such as uncontrolled pulmonary disease, active infection, or any other condition, which in the judgment of the Investigator, could compromise compliance with the protocol, interfere with the interpretation ofstudy results, or predispose the patient to safety risks.
• Malabsorption syndrome or other illness that could affect oral absorption.
• Known human immunodeficiency virus or hepatitis C infection only if the patient is taking medications that are described in Section 5.8.2.2, active hepatitis B, or active hepatitis C infection.
• If female, the patient is pregnant or lactating.
• Known allergy or hypersensitivity to any component of the investigational drug product. Patients with history of Stevens-Johnson syndrome (SJS) on a prior TKI are excluded.