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

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ClinicalTrials.gov Identifier: NCT02401815
Recruitment Status : Active, not recruiting
First Posted : March 30, 2015
Last Update Posted : November 15, 2018
Sponsor:
Information provided by (Responsible Party):
Plexxikon

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Gastrointestinal Stromal Tumors Drug: PLX9486 Drug: PLX3397 Drug: Sunitinib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : March 2015
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : March 2020


Arm Intervention/treatment
Experimental: Part 1
Open-label, sequential cohort PLX9486 single-agent Dose Escalation in patients with solid tumors.
Drug: PLX9486
PLX9486 tablets, 50mg

Experimental: Part 2b
Open-label, sequential cohort PLX9486 combined with PLX3397 Dose Escalation in patients with advanced solid tumors (including GIST)
Drug: PLX9486
PLX9486 tablets, 50mg

Drug: PLX3397
PLX3397 capsules, 200mg

Experimental: Part 2e
Open-label, sequential cohort PLX9486 combined with Sunitinib Dose Escalation in patients with solid tumors (including GIST).
Drug: PLX9486
PLX9486 tablets, 50mg

Drug: Sunitinib



Primary Outcome Measures :
  1. Part 1: Area under the curve (AUC) of PLX9486 [ Time Frame: 1 year ]
  2. Part 1: Maximum concentration (Cmax) of PLX9486 [ Time Frame: 1 year ]
  3. Part 1: Time to peak concentration (Tmax) of PLX9486 [ Time Frame: 1 year ]
  4. Part 1: Half life (T1/2) of PLX9486 [ Time Frame: 1 year ]
  5. Part 1: Number of Treatment Emergent Adverse Events (TEAEs) as assessed by CTAE v.4.0 [ Time Frame: 1 year ]
  6. Part 1: To identify the recommended Phase 2 dose (RP2D) of PLX9486 for further evaluation in dose extension [ Time Frame: 1 year ]
  7. Part 2b: Number of patients with treatment-related adverse events as assessed by CTCAE v4.0 (PLX9486 in combination of PLX3397) [ Time Frame: 1 year ]
  8. Part 2b: To determine the clinical benefit rate of PLX9486 and PLX3397 treatment at applicable RP2D in Part 2b [ Time Frame: 1 year ]
  9. Part 2b: To identify the recommended phase 2 dose (RP2D) of PLX9486 in combination with PLX3397 for further evaluation [ Time Frame: 1 year ]
  10. Part 2e: Number of patients with treatment-related adverse events as assessed by CTCAE v4.0 (PLX9486 in combination with sunitinib) [ Time Frame: 1 year ]
  11. Part 2e: To determine the clinical benefit rate of PLX9486 and sunitinib treatment at applicable RP2D in Part 2e [ Time Frame: 1 year ]
  12. Part 2e: To identify the recommended phase 2 dose (RP2D) of PLX9486 in combination with sunitinib for further evaluation [ Time Frame: 1 year ]

Secondary Outcome Measures :
  1. Part 1: To determine the overall response rate (ORR) of PLX9486 treatment [ Time Frame: 1 year ]
    Overall response rate is defined by the proportion of patients who achieve a complete response (CR) or partial response (PR) by RECIST 1.1.

  2. Part 1: To determine the duration of response rate of PLX9486 treatment [ Time Frame: 1 year ]
    Duration of tumor response based on MRI and RECIST 1.1.

  3. Part 1: To determine the progression-free survival of PLX9486 treatment [ Time Frame: 6 months ]
    Progressive free survival (PFS) as defined by the number of days from the first day of treatment (C1D1) to the date of the first documented disease progression or date of death, whichever occurs first.

  4. Part 2: Area under the curve (AUC) of PLX9486 in combination with PLX3397 or sunitinib. [ Time Frame: 1 year ]
  5. Part 2: Maximum concentration (Cmax) of PLX9486 in combination with PLX3397 or sunitinib. [ Time Frame: 1 year ]
  6. Part 2: Time to peak concentration (Tmax) of PLX9486) in combination with PLX3397 or sunitinib. [ Time Frame: 1 year ]
  7. Part 2: Half life (T1/2) of PLX9486 in combination with PLX3397 or sunitinib. [ Time Frame: 1 year ]
  8. Part 2: Number of participants with Treatment Emergent Adverse Events (TEAEs) as assessed by CTCAE v4.0 (PLX9486 in combination with PLX3397 or sunitinib) [ Time Frame: 1 year ]
  9. Part 2: To determine the overall response rate of PLX9486 treatment in combination with PLX3397 or sunitinib. [ Time Frame: 1 year ]
    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.

  10. Part 2: To determine the duration of response rate of PLX9486 treatment in combination with PLX3397 or sunitinib. [ Time Frame: 1 year ]
    Duration of tumor response based on MRI and RECIST 1.1.

  11. Part 2: To determine the progression-free survival of PLX9486 treatment in combination with PLX3397 or sunitinib. [ Time Frame: 6 months ]
    Progressive free survival (PFS) as defined by the number of days from the first day of treatment (C1D1) to the date of the first documented disease progression or date of death, whichever occurs first.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female ≥18 years old.
  • Part 1, Part 2b, Part 2d, and Part 2e: 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 2d: Patients with non GIST solid tumors with KIT mutations, who are TKI naïve or have been previously treated with KIT directed TKI therapy who are appropriate for KIT directed TKI therapy
  • Part 2a, Part 2c, and Part 2f (GIST patients): Histologically confirmed locally advanced, metastatic and/or unresectable GIST.
  • Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test at Screening (≤7 days prior to the first dose of Study drug) and must agree to use an effective form of contraception from the time of the negative pregnancy test up to 6 months after the last dose of study drug.
  • Fertile men must agree to use an effective method of birth control during the study and for up to 6 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.
  • 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 ECHO or MUGA for patients on the sunitinib arms (Parts 2e and f).

Exclusion Criteria:

  • Known or demonstrated wild type KIT or PDGF-R, or known or demonstrated mutations of PDGF R, SDH, or NF 1 that are causative for the observed malignancy.
  • For Part 1 (phase 1, single agent): Patients with a known or presumed pathogenic KIT exon 13 or 14 resistance mutation.
  • Parts 2a and 2d: Patients with known or presumed pathogenic KIT exon 13 or 14 resistance mutations. (However, such patients are permitted on the combination arms of Parts 2b, 2c, 2e, or 2f.)
  • 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 disease
  • Inability to take oral medication or significant nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption.
  • Ongoing infection of ≥ Grade 2 severity.
  • 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
  • Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis, inflammation, fibrosis, or cirrhosis of liver caused by viral, alcohol, or genetic reasons. Gilbert's disease is allowed if total bilirubin is ≤1.5 × ULN.
  • Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
  • Females who are pregnant or nursing.
  • Any psychological, familial, sociological, or geographical condition that could hamper compliance with the study protocol.
  • Strong CYP3A4 inhibitors or inducers within 14 days or 5 drug half-lives of the agent, whichever is longer, of study drug initiation or the need to continue these drugs during this study.
  • Major surgery or significant traumatic injury within 14 days of Cycle 1 Day 1.
  • History (within 2 years prior to first study drug administration) of another malignancy unless the malignancy was treated with curative intent and likelihood of relapse is small (<5% in 2 years in the judgment of the investigator).
  • Anti-cancer therapy within the period immediately before Cycle 1 Day 1

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02401815


Locations
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United States, Florida
Sylvester Comprehensive Cancer Center/ UMHC
Miami, Florida, United States, 33136
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Michigan
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States, 48109
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Ohio
OSU Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Plexxikon

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Responsible Party: Plexxikon
ClinicalTrials.gov Identifier: NCT02401815     History of Changes
Other Study ID Numbers: PLX121-01
First Posted: March 30, 2015    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: November 2018

Keywords provided by Plexxikon:
Gastrointestinal Stromal Tumors
KIT
Biomarkers
PLX9486
PLX3397
Sunitinib

Additional relevant MeSH terms:
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Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Sunitinib
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action