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A Safety, Tolerability and PK Study of DCC-2618 in Patients With Advanced Malignancies

NCT02571036

Description:

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.

Related Conditions:
  • Aggressive Systemic Mastocytosis
  • Gastrointestinal Stromal Tumor
  • Malignant Germ Cell Tumor
  • Malignant Glioma
  • Mast Cell Leukemia
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Penile Carcinoma
  • Soft Tissue Sarcoma
  • Systemic Mastocytosis
  • Systemic Mastocytosis with an Associated Hematological Neoplasm (SM-AHN)
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Safety, Tolerability and PK Study of DCC-2618 in Patients With Advanced Malignancies
  • Official Title: A Multicenter Phase 1, Open-Label Study of DCC-2618 to Assess Safety, Tolerability, and Pharmacokinetics in Patients With Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: DCC-2618-01-001
  • NCT ID: NCT02571036

Conditions

  • Gastrointestinal Stromal Tumors
  • Advanced Systemic Mastocytosis
  • Advanced Cancers

Interventions

DrugSynonymsArms
DCC-2618ripretinibExpansion Cohort 1
DCC-2618ripretinibEscalation

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
EscalationExperimentalEscalation Phase: DCC-2618 tablets in escalating dose cohorts given orally BID (twice daily) every 12 hours or once daily (QD) for repeated 28-day cycles. Participants may continue to receive study drug until discontinuation criteria are met. [Closed for Enrollment]
  • DCC-2618
Expansion Cohort 1Experimental150 mg DCC-2618 given once daily in repeated 28-day cycles in patients with GIST who have received 3 prior therapies. [Closed for Enrollment]
  • DCC-2618
Expansion Cohort 2Experimental150 mg DCC-2618 given once daily in repeated 28-day cycles in patients with GIST who have received 4 prior therapies. [Closed for Enrollment]
  • DCC-2618
Expansion Cohort 3Experimental150 mg DCC-2618 given once daily in repeated 28-day cycles in patients with GIST who have received at least one prior therapy and no more than 2 prior therapies. [Closed for Enrollment]
  • DCC-2618
Expansion Cohort 4Experimental150 mg DCC-2618 given once daily in repeated 28-day cycles in patients with systemic mastocytosis and other hematologic malignancies.
  • DCC-2618
Expansion Cohort 5Experimental150 mg DCC-2618 given once daily in repeated 28-day cycles in patients with malignant gliomas.
  • DCC-2618
Expansion Cohort 6Experimental150 mg DCC-2618 given once daily in repeated 28-day cycles in patients with other solid tumors. [Closed for Enrollment]
  • DCC-2618
Expansion Cohort 7Experimental150 mg DCC-2618 given once daily in repeated 28-day cycles in patients with melanomas.
  • DCC-2618
Expansion Cohort 8Experimental150 mg DCC-2618 given once daily in repeated 28-day cycles in patients with soft tissue sarcomas.
  • DCC-2618
Expansion Cohort 9Experimental150 mg DCC-2618 given once daily in repeated 28-day cycles in patients with germ cell, penile cancer and non-small cell lung carcinoma (NSCLC).
  • DCC-2618
Expansion Cohort 10Experimental150 mg DCC-2618 given once daily in repeated 28-day cycles in patients with GIST and other solid tumors with renal impairment.
  • DCC-2618

Eligibility Criteria

        Inclusion Criteria (Escalation and Expansion Phases)

        Patients must meet the following criteria to be eligible to enroll in the study:

          1. Male or female patients ≥18 years of age.

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

               1. 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.

               2. SM patients must have a confirmed diagnosis of advanced SM according to 2016
                  World Health Organization (WHO) criteria for SM 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) per
                  2013 International Working Group-Myeloproliferative Neoplasms Research and
                  Treatment (IWG-MRT) & European Competence Network on Mastocytosis consensus
                  response criteria; please see below for MCL exception.

             Advanced SM includes:

             i. Aggressive SM (ASM)

             ii. SM with associated hematologic neoplasm (SM-AHN), wherein the AHN does not require
             immediate alternative therapy. AHNs that are eligible include: low grade
             myelodysplastic syndrome (MDS) with a high SM burden who require treatment for SM
             only, myeloproliferative neoplasms (MPN), MDS/MPN, unclassifiable MDS, and HES/CEL.

             iii. MCL

             • Patients with histopathologically-confirmed MCL without a C-finding are eligible.

             iv. Symptomatic SSM

             • 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.

             v. Patients with hematologic malignancies featuring clonal expansion of eosinophils
             driven by genomic alterations of KIT or PDGFRA (eg, HES or CEL) 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.

             Other solid tumor patients that have alterations in genes encoding kinases that are
             targets of DCC-2618. This includes:

               -  Melanoma

               -  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)

               -  Other solid tumor patients (non-melanoma, non-STS; specifically germ-cell,
                  penile, and non-small cell lung carcinoma)

               -  Renal impairment cohort

          3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2.

          4. Adequate organ function and bone marrow function.

        Exclusion Criteria (Escalation and Expansion Phases)

        Patients meeting any of the following criteria will be excluded from the study:

          1. GIST patients with wild type or unknown KIT or PDGFRA status.

          2. Patients with SM or other hematologic malignancies will be excluded if the following
             apply:

               1. 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.

               2. SM-AHN patients diagnosed with:

             i. SM with MDS who require treatment for MDS. ii. Patients requiring immediate
             treatment for AHN.

             c. Patients with leukemias, with the exception of MCL and CEL, that have progressed
             after imatinib.

             d. Eosinophilic myeloproliferative neoplasm patients: i. Lacking a mutation that is a
             known target of DCC-2618.

          3. 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.

          4. 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.

          5. Arterial thrombotic or embolic events such as cerebrovascular accident (including
             ischemic attacks) or hemoptysis within 6 months before start of study drug.

          6. 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.

          7. 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.

          8. Left ventricular ejection fraction (LVEF) <50% or below the lower limit of normal
             (whichever is higher).

          9. 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.

         10. Any other clinically significant comorbidities.

         11. Illnesses that could affect oral absorption.

         12. Known human immunodeficiency virus or active hepatitis C infection only if the patient
             is taking per protocol prohibited medications, active hepatitis B, or active hepatitis
             C infection.

         13. If female, the patient is pregnant or lactating.

         14. Known allergy or hypersensitivity to any component of the investigational drug
             product. Patients with history of Stevens-Johnson syndrome on a prior tyrosine kinase
             inhibitor (TKI) are excluded.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety/tolerability of oral DCC-2618: incidence of adverse events
Time Frame:Approximately 24 months
Safety Issue:
Description:Dose limiting toxicities, AEs, SAEs, discontinuation of drug due to toxicity, physical exams and ECOG PS, ophthalmologic examinations, changes from baseline in laboratory parameters, electrocardiograms, LVEF, and vital signs.

Secondary Outcome Measures

Measure:Determine the PK profile of oral DCC-2618
Time Frame:Predose and up to 24 hours postdose (Cycle = 28 Days)
Safety Issue:
Description:
Measure:Escalation Phase: Assess Antitumor Activity of DCC-2618 in patients with advanced malignancies
Time Frame:Approximately 24 months
Safety Issue:
Description:Objective response rate (ORR); Disease control rate (DCR)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Deciphera Pharmaceuticals LLC

Trial Keywords

  • 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)
  • soft tissue sarcoma (STS)
  • germ cell tumors
  • penile cancer
  • non-small cell lung carcinoma (NSCLC)
  • renal impairment
  • malignant gliomas

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