Trial record 1 of 1 for:    plx7486
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Phase 1 Study of PLX7486 as Single Agent and With Gemcitabine Plus Nab-Paclitaxel in Patients With Advanced Solid Tumors

This study is currently recruiting participants.
Verified September 2013 by Plexxikon
Sponsor:
Information provided by (Responsible Party):
Plexxikon
ClinicalTrials.gov Identifier:
NCT01804530
First received: March 1, 2013
Last updated: September 9, 2013
Last verified: September 2013
  Purpose

PLX7486 is a novel small molecule, selective inhibitor of the receptor tyrosine kinases Fms and TrkA, TrkB, and TrkC. Fms and Trk receptor expression and activity have been implicated in the development of metastatic disease, as well as tumor-associated pain in a variety of tumor tyes. The goal for developing a dual inhibitor of Fms and Trk is to simultaneously block multiple autocrine and paracrine signaling pathways that promote tumor survival, invasion and metastases while mitigating cancer-related pain.

Part 1 of this study will evaluate safety, pharmacokinetics, and pharmacodynamics of PLX7486 first as a single agent in patients with advanced solid tumors. Then, after adequately profiling the toxicity of the single agent PLX7486-TsOH (i.e., tosylate salt of PLX7486), evaluation of the safety of triple drug combination PLX7486-TsOH + gemcitabine + nab-paclitaxel will be initiated in patients with solid tumors, with the primary objective of determining the efficacy of the triple drug combination first in patients with solid tumors (part 2a) and next in patients with advanced, non-resectable pancreatic adenocarcinoma (part 2b).


Condition Intervention Phase
Solid Tumors
Untreated Pancreatic Adenocarcinoma
Pancreatic Cancer Non-resectable
Metastatic Pancreatic Adenocarcinoma
Drug: PLX7486-TsOH
Drug: gemcitabine
Drug: nab-Paclitaxel
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX7486 as a Single Agent and in Combination With Gemcitabine and Nab-Paclitaxel in Patients With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Plexxikon:

Primary Outcome Measures:
  • Safety of PLX7486 as single agent and in combination with gemcitabine and nab-paclitaxel [ Time Frame: Measured from baseline and weekly for the duration of drug administration, estimated to be ≤1 year. ] [ Designated as safety issue: Yes ]
    Adverse events, physical examinations, vital signs, clinical laboratory tests (hematology, chemistry, and urinalysis), ECGs, ophthalmic examinations, will all be evaluated to determine dose-limiting toxicities, i.e., any adverse event that is temporally related to the study drug administration and is not due to the patient's underlying malignancy and for which there is no clear evidence for an alternative etiology.


Secondary Outcome Measures:
  • Patient weight [ Time Frame: measured at each clinic visit for the duration of treatment, estimated to be ≤ 1 year. ] [ Designated as safety issue: No ]

    Change in patient weight from baseline.

    Positive: a weight gain of ≥7% from baseline, sustained for ≥4 weeks. Negative: any other result.


  • Pain intensity [ Time Frame: Measured daily from baseline for the duration of treatment, estimated to be ≤ 1 year. ] [ Designated as safety issue: No ]

    Changes in pain reported using the Memorial Pain Assessment Card.

    Positive: improvement of ≥50% from baseline sustained for 4 weeks, assuming minimum pain score of ≥20.

    Negative: any worsening from baseline, sustained for 4 weeks. Stable: any other result.


  • Analgesic consumption [ Time Frame: Measured weekly from baseline for the duration of treatment, estimated to be ≤ 1 year. ] [ Designated as safety issue: No ]

    Changes in analgesic requirements will be recorded daily by the patient and measured weekly in morphine-equivalent milligrams.

    Positive: a decrease of ≥50% from baseline, sustained for ≥4 weeks, assuming a minimum analgesic consumption of ≥10.

    Negative: any worsening from baseline, sustained for 4 weeks. Stable: any other result.


  • Karnofsky Performance Status [ Time Frame: changes from baseline measured weekly for the duration of treatment, estimated to be ≤ 1 year. ] [ Designated as safety issue: No ]

    Changes in performance status from baseline, determined at each clinic visit.

    Positive: an improvement of ≥20 points from baseline, sustained for ≥4 weeks, for patients with performance status of 50, 60, or 70.

    Negative: any worsening of ≥20 points from baseline, sustained for ≥4 weeks. Stable: any other result.


  • pharmacokinetics of PLX7486 [ Time Frame: first 21-days of drug administration ] [ Designated as safety issue: No ]
    The pharmacokinetics of PLX7486 will be analyzed by measurement of area under the plasma concentration-time curve [AUC0-t, AUC0-inf], peak concentration (Cmax), time to peak concentration (Tmax), half-life (t1/2), and terminal elimination rate constant (Kel).


Other Outcome Measures:
  • Tumor response [ Time Frame: Patients that have received ≥2 administrations of gemcitabine + nab-paclitaxel and 21 days of PLX7486 ] [ Designated as safety issue: No ]
    Patients will be considered response evaluable if they have received ≥2 administrations of gemcitabine + nab-paclitaxel and 21 days of PLX7486 and have at least one post-baseline tumor assessment (except in cases of study discontinuation due to treatment-related toxicity or clinical progression).

  • Duration of remission (DOR) [ Time Frame: from documented initial response (PR or better) to disease progression/relapse, or death ] [ Designated as safety issue: No ]
    For each subject with a response to therapy, duration of remission will be calculated. The duration of remission is defined as the number of days from the date of the initial response (PR or better) to the date of the first documented disease progression/relapse or death, whichever occurs first.

  • Duration of complete remission (DOCR) [ Time Frame: From date of initial response to first documented disease relapse or death. ] [ Designated as safety issue: No ]
    For each subject with a complete remission, the duration of complete response will be calculated. Duration of complete remission is defined as the number of days from the date of initial CR response to the date of the first documented disease relapse or death, whichever occurs first.

  • Progression-Free Survival (PFS) [ Time Frame: number of days from start of therapy to the date of documented disease progression/relapse, or death ] [ Designated as safety issue: No ]
    For each subject with a response to therapy, progression-free survival will be calculated. Progression-Free Survival is defined as the number of days from start of therapy to the date of documented disease progression/relapse, or death, whichever occurs first.

  • Disease-Free Survival (DFS) [ Time Frame: From the date of the initial CR response to the date of documented disease relapse or death from any cause ] [ Designated as safety issue: No ]
    For subjects with a complete remission, the disease-free survival will be calculated from the date of the initial CR response to the date of documented disease relapse or death from any cause, whichever occurs first.

  • Overall response rate (ORR) [ Time Frame: baseline to end of study, estimated to be ≤ 1 year. ] [ Designated as safety issue: No ]
    The overall response rate will be estimated as the number of patients with a best response of CR or PR divided by the total number of patients who are evaluable for efficacy. This analysis will be performed separately for Parts 1, 2a, and 2b.


Estimated Enrollment: 118
Study Start Date: August 2013
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1
Open-label, sequential PLX7486-TsOH single-agent dose escalation in approximately 50 patients with solid tumors.
Drug: PLX7486-TsOH
Part 1: single-agent dose escalation Part 2a: sequential dose escalation with fixed dose levels nab-paclitaxel + gemcitabine Part 2b: RP2D dose with fixed dose levels nab-paclitaxel + gemcitabine
Other Names:
  • tosylate salt of PLX7486
  • selective inhibitor for receptor tyrosine kinase Fms
  • selective inhibitor for receptor tyrosine kinases TrkA,B,& C
Experimental: Part 2a
Open-label, sequential dose escalation of PLX7486-TsOH with fixed dose levels of nab-paclitaxel + gemcitabine in approximately 30 patients with solid tumors.
Drug: PLX7486-TsOH
Part 1: single-agent dose escalation Part 2a: sequential dose escalation with fixed dose levels nab-paclitaxel + gemcitabine Part 2b: RP2D dose with fixed dose levels nab-paclitaxel + gemcitabine
Other Names:
  • tosylate salt of PLX7486
  • selective inhibitor for receptor tyrosine kinase Fms
  • selective inhibitor for receptor tyrosine kinases TrkA,B,& C
Drug: gemcitabine

Part 2a and 2b: 100 mg/m2 IV over 30-60 minutes with nab-paclitaxel on days 1, 8, and 15 of each 28-day cycle within 30 minutes after the nab-paclitaxel infusion.

Gemcitabine prophylaxis medications per institutional standard practice.

Other Names:
  • nucleoside analog
  • marketed as Gemzar, Eli Lilly and Company
Drug: nab-Paclitaxel
Part 2a and 2b: 125 mg/m2 administered IV over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle.
Other Names:
  • Albumin-bound paclitaxel
  • Abraxane
  • paclitaxel bound to albumin nano-particles
Experimental: Part 2b
Extension cohort at the RP2D of PLX7486-TsOH in combination with fixed dose levels of nab-paclitaxel + gemcitabine in approximately 50 patients with untreated, advanced, non-resectable or metastatic pancreatic adenocarcinoma.
Drug: PLX7486-TsOH
Part 1: single-agent dose escalation Part 2a: sequential dose escalation with fixed dose levels nab-paclitaxel + gemcitabine Part 2b: RP2D dose with fixed dose levels nab-paclitaxel + gemcitabine
Other Names:
  • tosylate salt of PLX7486
  • selective inhibitor for receptor tyrosine kinase Fms
  • selective inhibitor for receptor tyrosine kinases TrkA,B,& C
Drug: gemcitabine

Part 2a and 2b: 100 mg/m2 IV over 30-60 minutes with nab-paclitaxel on days 1, 8, and 15 of each 28-day cycle within 30 minutes after the nab-paclitaxel infusion.

Gemcitabine prophylaxis medications per institutional standard practice.

Other Names:
  • nucleoside analog
  • marketed as Gemzar, Eli Lilly and Company
Drug: nab-Paclitaxel
Part 2a and 2b: 125 mg/m2 administered IV over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle.
Other Names:
  • Albumin-bound paclitaxel
  • Abraxane
  • paclitaxel bound to albumin nano-particles

Detailed Description:

Part 1 of the study is an open label, sequential PLX7486-TsOH single-agent dose escalation in patients with solid tumors. This part of the study will include approximately 50 solid tumor patients from 3-6 treatment sites. The starting dose will be 30 mg. Each treatment cycle will be 21 days. Cohorts of 3 patients will be enrolled in a standard '3+3' design. In the absence of drug-related Grade 2 toxicity, the dose escalation will occur in 100% increments. The dose escalation will be reduced in increments of approximately 50% or less if there is either a dose-limiting toxicity (DLT) or at least 2 patients in one cohort experience ≥ Grade 2 toxicities that are considered possibly or probably related to PLX7486. In part 1, the secondary objective is efficacy, as measured by overall response rate, clinical benefit response rate, duration of response, and progression-free survival. Exploratory endpoints will include changes in pain severity scores and analgesic consumption and investigation of peripheral blood biomarkers and archival tumor tissue.

Part 2a of the study is also an open-label, sequential dose escalation of PLX7486-TsOH with fixed dose levels of nab-paclitaxel + gemcitabine in patients with solid tumors. Approximately 30 solid tumor patients will be enrolled using the standard '3+3' design.

Part 2b extension cohort is planned at the recommended phase 2 dose (RP2D) of PLX7486-TsOH in combination with fixed dose levels of nab-paclitaxel + gemcitabine in 28-day treatment cycles. Approximately 50 patients with previously untreated pancreatic adenocarcinoma will be enrolled to ensure 38 patients (28 patients with metastatic disease and 10 patients with locally advanced disease)will be evaluable for response.

In parts 2a and 2b, secondary endpoints include best overall response rate, duration of response, clinical benefit response rate, and pharmacokinetics. Exploratory endpoints for both parts 2a and 2b will include changes in pain severity scores and analgesic consumption, and investigation of biomarker data in peripheral blood and archival tumor tissue.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female ≥18 years old
  2. Patients with solid tumors who:

    1. Part 1: have tumor progression following standard therapy, have treatment-refractory disease, or for whom there is no effective standard of therapy
    2. Part 2a: have received ≤2 prior chemotherapy regimens for the treatment of their primary malignancy and for whom nab-paclitaxel and gemcitabine would be considered a reasonable chemotherapy option
    3. Part 2b: have previously untreated locally advanced, non-resectable or metastatic pancreatic adenocarcinoma, are not candidates for FOLFIRINOX treatment(i.e., leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin.) Patients who received prior neoadjuvant or adjuvant therapy with recurrent disease ≥6 months following completion of the regimen are also eligible
  3. Patients in Part 2b must have measurable disease by Response Evaluation Criteria for Solid Tumors (i.e., RECIST) criteria v1.1
  4. Women of child-bearing potential must have a negative pregnancy test within 7 days of 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. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. 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.
  5. All associated toxicity from previous or concurrent cancer therapy must be resolved (to ≤ Grade 1 or Baseline) prior to study treatment administration.
  6. 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.
  7. Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements
  8. Karnofsky performance score ≥ 70%
  9. Life expectancy ≥3 months.
  10. Adequate hematologic, hepatic, and renal function.

Exclusion Criteria:

  1. 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.
  2. Chemotherapy within 28 days prior to C1D1
  3. Biological therapy within 5 half-lives prior to C1D1
  4. Radiation therapy within 14 days prior to C1D1
  5. Investigational drug use within 28 days or 5 half-lives, whichever is longer, prior to C1D1
  6. Part 1 only: (a) patients with active or a history of glucose intolerance or diabetes mellitus and (b) Hemoglobin A1c >= 7%
  7. Part 2a and 2b only: (a) patients with known hypersensitivity to or nab-paclitaxel or gemcitabine and (b) Hemoglobin A1c >= 8%
  8. Part 2a and 2b: uncontrolled diabetes. Patients with glucose intolerance or diabetes whose blood glucose levels are consistently well-controlled with the use of oral hypoglycemic agents and/or insulin are permitted.
  9. Part 2b only: received radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic pancreatic adenocarcinoma. Prior treatment with 5-Fluorouracil or gemcitabine administered as a radiation sensitizer in the adjuvant setting is allowed, provided at least 6 months have elapsed since last dose and no lingering toxicities.

    Patients having received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting are not eligible for this study

  10. ≥ Grade 2 sensory neuropathy at baseline
  11. Uncontrolled intercurrent illness (i.e., active infection) or concurrent condition that, in the opinion of the Investigator, would interfere with the study endpoints or the patient's ability to participate
  12. Refractory nausea and vomiting, malabsorption, small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption
  13. Mean corrected QT interval (QTcF) ≥450 msec (for males) or ≥470 msec (for females) at Screening
  14. The presence of a medical or psychiatric condition that, in the opinion of the Principal Investigator, makes the patient inappropriate for inclusion in this study
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01804530

Contacts
Contact: David Karlin, MD 510-647-4100 dkarlin@plexxikon.com
Contact: Sandy Tong, MD 510-647-4100 stong@plexxikon.com

Locations
United States, Arizona
Translational Genomics Research Institute (TGen) Recruiting
Phoenix, Arizona, United States, 85004
Principal Investigator: Daniel Von Hoff, MD         
United States, California
University of California, Los Angeles Medical Center (UCLA) Recruiting
Santa Monica, California, United States, 90404
Principal Investigator: Zev Wainberg, MD         
United States, South Carolina
Medical Universtiy of South Carolina (MUSC) Recruiting
Charleston, South Carolina, United States, 29425
Principal Investigator: Carolyn Britten, MD         
Sponsors and Collaborators
Plexxikon
Investigators
Study Director: David Karlin, MD Plexxikon Inc.
  More Information

Publications:
Responsible Party: Plexxikon
ClinicalTrials.gov Identifier: NCT01804530     History of Changes
Other Study ID Numbers: PLX119-01
Study First Received: March 1, 2013
Last Updated: September 9, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Plexxikon:
pancreatic adenocarcinoma
solid tumors
non-resectable pancreatic cancer
metastatic pancreatic cancer

Additional relevant MeSH terms:
Adenocarcinoma
Pancreatic Neoplasms
Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Paclitaxel
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on April 17, 2014