A Safety, Tolerability and PK Study of DCC-2618 in Patients With Advanced Malignancies
This is a Phase 1, open-label, first-in-human (FIH) dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of DCC-2618, administered orally (PO), in adult patients with advanced malignancies. The study consists of 2 parts, a dose-escalation phase and an expansion phase.
A Multicenter Phase 1, Open-Label Study of DCC-2618 to Assess Safety, Tolerability, and Pharmacokinetics in Patients With Advanced Malignancies
Gastrointestinal Stromal Tumors Aggressive Systemic Mastocytosis Advanced Cancers Gastrointestinal stromal tumors (GIST) systemic mastocytosis (SM) PDGFR-alpha KIT mast cell leukemia (MCL) mast cell disease (MCD) DCC-2618 melanoma aggressive systemic mastocytosis (ASM) Aggression Mastocytosis Mastocytosis, Systemic Escalation
You can join if…
Open to people ages 18 years and up
(Escalation and Expansion Phases)
Patients must meet the following criteria to be eligible to enroll in the study:
- Patients must have histologically confirmed solid tumors or hematologic malignancies.
Eligible patients include the following:
a) GIST patients must have a KIT and PDGFRA mutation and must have progressed on or had an intolerability to at least 1 line of systemic anticancer therapy: i. 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.
b) 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 and must have documented KIT mutant disease. SM patients must also have a normal karyotype.
Advanced SM includes: 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 treatment for SM only, myeloproliferative neoplasms (MPNs), MDS/MPN, and HES/CEL], and MCL i.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 (Appendix 10.5);please see below for MCL exception) (#iii).
ii. Patients with imatinib-sensitive KIT mutations must have progressed on or were intolerant to a tryosine kinase inhibitor.
iii. Patients with histopathologically-confirmed MCL without a C-finding are eligible.
iv. Patients with symptomatic SSM are eligible. By definition, SSM patients must have at least 2 B-findings, and clinically significant symptom burden (eg, flushing,diarrhea, etc.) despite maximal treatment with approved agents to treat mediator symptoms, such as antihistamines and cromolyn sodium. Patients must have a normal karyotype.
- Patients with hematologic malignancies featuring clonal expansion of eosinophils driven by genomic alterations of KIT or PDGFR (eg, 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.
c) 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. ii. Patients that require steroids must be on a stable dose for 2 weeks prior to the first dose of study drug.
d) 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.
e) If signs or symptoms suggest CNS metastases, a brain MRI must be performed to confirm absence of CNS disease within 1 week prior to receiving study drug.
- Patients with known CNS metastases may participate provided that:
- they are stable (ie, 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, 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 outlined in Section 6.8.11.
- 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 (eg, 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) 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).
ii. Renal Function: Serum creatinine ≤2.0 × ULN or creatinine clearance ≥50 mL/min based either on urine collection or Cockcroft Gault estimation.
iii. Coagulation Profile: Prothrombin time (PT) - international normalized ratio(INR)/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.
c) 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 (see Appendix 10.5).
- . 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).
You CAN'T join if...
(Escalation and Expansion Phases)
Patients meeting any of the following criteria will be excluded from the study:
- 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 wild type KIT mutational status.
- 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 for MDS. ii. Patients requiring immediate treatment for AHN. d) Patients with leukemias, with the exception of MCL and CEL, that have progressed after imatinib.
e) Eosinophilic myeloproliferative neoplasm patients: i. 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.
- Has a known additional malignancy that is progressing or required active treatment within 3 years of the first dose of study treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or other in situ cancers.
- 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 and 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 (eg,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 interval corrected (QTc) syndrome.
- LVEF <50% or below the 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 of study results, or predispose the patient to safety risks.
- . Malabsorption syndrome or other illness that could affect oral absorption.
- . Known human immunodeficiency virus or active hepatitis C infection only if the patient is taking medications that are described in Section 220.127.116.11, 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.
- UCSF (glial malignancies only) accepting new patients
San Francisco California United States
- Stanford Hematology Center (mastocytosis) accepting new patients
Palo Alto California United States
- Stanford Sarcoma Center (GIST) accepting new patients
Palo Alto California United States
- accepting new patients
- Start Date
- Completion Date
- Deciphera Pharmaceuticals LLC
- Phase 1
- Study Type
- Last Updated
- June 11, 2018
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