Clinical Trials /

PLX9486 as a Single Agent and in Combination With PLX3397 or PLX9486 With Sunitinib in Patients With Advanced Solid Tumors

NCT02401815

Description:

The goal of this clinical research study is to learn how PLX9486 may affect cancer cells with certain mutations in the KIT gene, specifically in patients with types of advanced solid tumors including Gastrointestinal Stromal Tumor (GIST). PLX9486 is designed to block KIT gene mutations. These mutations can cause cancer and cancer cell growth. By blocking these mutations, the drug may kill the cancer cells with the mutation and/or stop the tumor from growing. By combining PLX9486 with PLX3397 and PLX9486 with Sunitinib, the investigators hope to block most gene mutations in KIT.

Related Conditions:
  • Gastrointestinal Stromal Tumor
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PLX9486 as a Single Agent and in Combination With PLX3397 or PLX9486 With Sunitinib in Patients With Advanced Solid Tumors
  • Official Title: A Phase 1b and 2a Study to Assess Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of PLX9486 as a Single Agent and in Combination With PLX3397 or Sunitinib (Sutent®) in Patients With Advanced Solid Tumors and Patients With Locally Advanced, Unresectable, or Metastatic Gastrointestinal Stromal Tumor (GIST) Who Have Been Previously Treated With Imatinib Mesylate/KIT-Directed Tyrosine Kinase Inhibitor (TKI) Therapy

Clinical Trial IDs

  • ORG STUDY ID: PLX121-01
  • NCT ID: NCT02401815

Conditions

  • Gastrointestinal Stromal Tumors

Interventions

DrugSynonymsArms
PLX9486Part 1
PLX3397Part 2b
SunitinibPart 2e

Purpose

The goal of this clinical research study is to learn how PLX9486 may affect cancer cells with certain mutations in the KIT gene, specifically in patients with types of advanced solid tumors including Gastrointestinal Stromal Tumor (GIST). PLX9486 is designed to block KIT gene mutations. These mutations can cause cancer and cancer cell growth. By blocking these mutations, the drug may kill the cancer cells with the mutation and/or stop the tumor from growing. By combining PLX9486 with PLX3397 and PLX9486 with Sunitinib, the investigators hope to block most gene mutations in KIT.

Trial Arms

NameTypeDescriptionInterventions
Part 1ExperimentalOpen-label, sequential cohort PLX9486 single-agent Dose Escalation in patients with solid tumors.
  • PLX9486
Part 2aExperimentalSingle-agent PLX9486 RP2D in patients with GIST who have failed or progressed on imatinib mesylate/KIT directed TKI therapy
  • PLX9486
Part 2bExperimentalOpen-label, sequential cohort PLX9486 combined with PLX3397 Dose Escalation in patients with advanced solid tumors (including GIST)
  • PLX9486
  • PLX3397
Part 2cExperimentalRP2D of the PLX9486/PLX3397 combination in patients with GIST who have failed or progressed on second-line or greater therapy.
  • PLX9486
  • PLX3397
Part 2dExperimentalSingle-agent PLX9486 RP2D in patients with advanced, unresectable, or metastatic solid tumors with KIT mutations who have failed or progressed on prior therapy.
  • PLX9486
Part 2eExperimentalOpen-label, sequential cohort PLX9486 combined with Sunitinib Dose Escalation in patients with solid tumors (including GIST).
  • PLX9486
  • Sunitinib
Part 2fExperimentalRP2D of the PLX9486/Sunitinib combination in patients who have advanced solid tumors (including GIST).
  • PLX9486
  • Sunitinib

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female ≥ 18 years old

          -  Part 1 and Part 2b: Patients with advanced solid tumors who have tumor progression
             following standard therapy, have treatment-refractory disease, or for whom there is no
             effective standard of therapy

          -  Part 2a and Part 2c: Histologically confirmed locally advanced, metastatic and/or
             unresectable GIST.

          -  Women of child-bearing potential must have a negative pregnancy test within 7 days
             prior to initiation of dosing and must agree to use an acceptable method of birth
             control from the time of the negative pregnancy test up to 3 months after the last
             dose of study drug, Fertile men must also agree to use an acceptable method of birth
             control while on study drug and up to 3 months after the last dose of study drug.

          -  All associated toxicity from previous or concurrent cancer therapy must be resolved
             (to ≤ Grade 1 or Baseline) prior to study treatment administration.

          -  Patients with stable, treated brain metastases are eligible for this trial.

          -  Willing and able to provide written informed consent prior to any study related
             procedures and to comply with all study requirements

          -  ECOG Performance Status 0-2

          -  Life expectancy ≥ 3 months

          -  Adequate hematologic, hepatic, and renal function

          -  Left ventricular ejection fraction (LVEF) >50% per echocardiogram or MUGA for patients
             on the sunitinib arms

        Exclusion Criteria:

          -  Use of any approved tyrosine kinase inhibitors or investigational agents within 2
             weeks or 6 half-lives of the agent, whichever is shorter, prior to receiving study
             drugs. Treatment-related adverse events must have resolved or reduced to Grade 1 prior
             to enrollment.

          -  Presence of symptomatic or uncontrolled brain or central nervous system metastases.
             Patients with stable, treated brain metastases are eligible for this trial. However,
             patients must not have required steroid treatment for their brain metastases within 30
             days of Screening.

          -  Known or suspected allergy to the investigational agent or any agent given in
             association with this trial

          -  Clinically significant cardiac arrhythmias including bradyarrhythmias and/or patients
             who require anti-arrhythmic therapy (excluding beta blockers or digoxin).

          -  Congenital long QT syndrome or patients taking concomitant medications known to
             prolong the QT interval

          -  History of clinically significant cardiac disease or congestive heart failure > New
             York Heart Association (NYHA) class 2. Patients must not have unstable angina (anginal
             symptoms at rest) or new-onset angina within the last 3 months or myocardial
             infarction within the past 6 months.

          -  Hypertension as defined by systolic blood pressure > 140 mmHg or diastolic blood
             pressure > 95 mmHg despite optimal medical management

          -  Arterial or venous thrombotic or embolic events such as cerebrovascular accident
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
             within the 6 months before start of study medication (except for adequately treated
             catheter-related venous thrombosis occurring more than 1 month before the start of
             study medication)

          -  Inability to take oral medication

          -  Refractory nausea and vomiting, malabsorption, or significant small bowel resection
             that, in the opinion of the Investigator, would preclude adequate absorption

          -  QTcF ≥ 450 msec (for males) or ≥ 470 msec (for females) at Screening

          -  Ongoing infection ≥ Grade 2

          -  Non-healing wound, ulcer, or bone fracture

          -  Known HIV-positive individuals on combination antiretroviral therapy

          -  Patients with known active hepatitis B or C, or chronic hepatitis B or C requiring
             treatment with antiviral therapy

          -  Interstitial lung disease with ongoing signs and symptoms at the time of informed
             consent

          -  Pregnant or lactating females

          -  Presence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol

          -  Strong CYP3A4 inhibitors or inducers within 14 days or 5 drug half-lives, whichever is
             longer, before start of study drug.

          -  Patients with > Grade 1 (high or low) serum potassium, magnesium, or calcium levels

          -  Other than the primary malignancy, active cancer (either concurrent or within the last
             3 years) that requires non-surgical therapy (e.g., chemotherapy or radiation therapy),
             with the exception of surgically treated basal or squamous cell carcinoma of the skin,
             melanoma in-situ, or carcinoma in-situ of the cervix

          -  Major surgery or significant traumatic injury within 14 days prior to Cycle 1 Day 1

          -  Chemotherapy within 14 days prior to Cycle 1 Day 1

          -  Biological therapy within 14 days prior to Cycle 1 Day 1

          -  Radiation therapy within 14 days prior to Cycle 1 Day 1

          -  Uncontrolled illness or concurrent condition that, in the opinion of the Investigator,
             would interfere with the study endpoints or the patient's ability to participate

          -  Known or demonstrated wild type KIT or PDGF-R, or known or demonstrated mutations of
             PDGF‑R, SDH, or NF‑1 causative for the observed malignancy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of PLX9486 as measured adverse events and serious adverse events
Time Frame:1 year
Safety Issue:
Description:Overall response rate (ORR) as defined by the proportion of patients who achieve a complete response (CR) or partial response (PR) by RECIST 1.1.

Secondary Outcome Measures

Measure:Duration of Response
Time Frame:1 year
Safety Issue:
Description:Duration of tumor response based on MRI and RECIST 1.1

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Plexxikon

Trial Keywords

  • Gastrointestinal Stromal Tumors
  • KIT
  • Biomarkers
  • PLX9486
  • PLX3397
  • Sunitinib

Last Updated

January 31, 2018