Clinical Trials /

Phase 1 Study of PLX7486 as Single Agent in Patients With Advanced Solid Tumors

NCT01804530

Description:

The objective of this study is to determine the safety, pharmacokinetics, maximum tolerated dose/recommended Phase 2 dose, and efficacy of PLX7486.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Phase 1 Study of PLX7486 as Single Agent and With <span class="go-doc-concept go-doc-intervention">Gemcitabine</span> Plus <span class="go-doc-concept go-doc-intervention">Nab-Paclitaxel</span> in Patients With Advanced Solid Tumors

Title

  • Brief Title: Phase 1 Study of PLX7486 as Single Agent and With Gemcitabine Plus Nab-Paclitaxel in Patients With Advanced Solid Tumors
  • 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
  • Clinical Trial IDs

    NCT ID: NCT01804530

    ORG ID: PLX119-01

    Trial Conditions

    Solid Tumors

    Untreated Pancreatic Adenocarcinoma

    Pancreatic Cancer Non-resectable

    Metastatic Pancreatic Adenocarcinoma

    Tumors of Any Histology With Activating Trk (NTRK) Point or NTRK Fusion Mutations

    Trial Interventions

    Drug Synonyms Arms
    PLX7486-TsOH tosylate salt of PLX7486, selective inhibitor for receptor tyrosine kinase Fms, selective inhibitor for receptor tyrosine kinases TrkA,B,& C Part 1, Part 2a, Part 2b, Part 2c
    gemcitabine nucleoside analog, marketed as Gemzar, Eli Lilly and Company Part 2a, Part 2b
    nab-Paclitaxel Albumin-bound paclitaxel, Abraxane, paclitaxel bound to albumin nano-particles Part 2a, Part 2b

    Trial Purpose

    PLX7486 is a novel small molecule, selective inhibitor of the receptor tyrosine kinases Fms
    and TrkA, TrkB, and TrkC.

    Part 1 of this study will evaluate safety, pharmacokinetics, and pharmacodynamics of PLX7486
    as a single agent in patients with advanced solid tumors.

    Part 2 of this study will evaluate the safety of the triple drug combination of PLX7486-TsOH
    + gemcitabine + nab-paclitaxel in patients with solid tumors, with the primary objective of
    first determining the efficacy of the triple drug combination in (Part 2a) patients with
    solid tumors; and then in (Part 2b) patients with advanced, non-resectable pancreatic
    adenocarcinoma.

    Part 2c of the study will assess the efficacy of single-agent PLX7486 in patients with
    advanced non-resectable tumors of any histology with activating Trk (NTRK) point or NTRK
    fusion mutations (e.g., mammary analogue secretory carcinoma, secretory breast cancer,
    papillary thyroid cancer, congenital fibrosarcoma, congenital mesoblastic nephroma, lung
    cancer, melanoma, and colon cancer), using best overall response (OR) rate, as well as
    safety.

    Detailed Description

    Part 1 of the study is an open-label, sequential PLX7486-TsOH single-agent dose escalation
    in patients with solid tumors.

    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.

    Part 2b is an open-label extension cohort at the recommended phase 2 dose of PLX7486-TsOH in
    combination with fixed dose levels of nab-paclitaxel + gemcitabine in 28-day treatment
    cycles in patients with advanced, non-resectable pancreatic adenocarcinoma.

    Part 2c is an open-label extension cohort of single agent PLX7486-TsOH at the recommended
    phase 2 dose in patients with advanced non-resectable tumors of any histology with
    activating Trk (NTRK) point or NTRK fusion mutations.

    Trial Arms

    Name Type Description Interventions
    Part 1 Experimental Open-label, sequential PLX7486-TsOH single-agent dose escalation in approximately 50 patients with solid tumors. PLX7486-TsOH
    Part 2a Experimental Open-label, sequential dose escalation of PLX7486-TsOH with fixed dose levels of nab-paclitaxel + gemcitabine in approximately 30 patients with solid tumors. PLX7486-TsOH, gemcitabine, nab-Paclitaxel
    Part 2b Experimental 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. PLX7486-TsOH, gemcitabine, nab-Paclitaxel
    Part 2c Experimental Extension cohort of single agent PLX7486-TsOH at the recommended phase 2 dose in patients with advanced non-resectable tumors of any histology with activating Trk (NTRK) point or NTRK fusion mutations in approximately 50 patients. PLX7486-TsOH

    Eligibility 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 that, in the opinion of the Principal
    Investigator, are not candidates for FOLFIRINOX treatment (i.e., bolus and
    infusional 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.

    4. Part 2c: have advanced, non-resectable tumors of any histology with activating
    Trk (NTRK) point or NTRK fusion mutations (e.g., mammary analogue secretory
    carcinoma, secretory breast cancer, papillary thyroid cancer, congenital
    fibrosarcoma, congenital mesoblastic nephroma, lung cancer, melanoma, and colon
    cancer) AND have received prior treatment, if there is a known therapy that
    results in increased survival for that particular disease (e.g., patients with
    melanoma should have received treatment with ipilimumab or BRAF inhibitors,
    patients with colon cancer should have received at least 2 prior lines of
    therapy with a fluoropyrimidine in combination with oxaliplatin and irinotecan,
    etc.).

    3. Patients in Part 2b must have measurable disease by RECIST criteria v1.1

    4. 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, 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 Status 70%

    9. Life expectancy 3 months.

    10. Adequate hematologic, hepatic, and renal function (absolute neutrophil count 1.5 X
    109/L, Hgb >9 g/dL, platelet count 100 X 109/L, AST/ALT 2.5 X ULN or <5 X ULN in
    the presence of liver metastases, creatinine 1.5 X ULN or calculated CrCl >60 mL/min
    using Cockcroft-Gault formula). Note: patients must not have received RBC
    transfusions (within 4 weeks), platelet transfusions (within 1 week) or growth
    factors (within 1 week).

    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 28 days prior to C1D1

    4. Radiation therapy within 28 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 a known hypersensitivity to nab-paclitaxel or
    gemcitabine and (b) Hemoglobin A1c >8%.

    8. Part 2a and 2b: Patients with 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: Patients who have received radiotherapy, surgery, chemotherapy or
    investigational therapy for the treatment of metastatic pancreatic adenocarcinoma.
    Prior treatment with 5-FU or gemcitabine administered as a radiation sensitizer in
    the adjuvant setting is allowed, provided at least 6 months have elapsed since
    completion of the last dose and no lingering toxicities are present. 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, or significant small bowel resection
    that, in the opinion of the Investigator, would preclude adequate absorption.

    13. QTcF 450 msec (for males) or 470 msec (for females) at Screening

    14. The presence of a medical or psychiatric condition that makes the patient
    inappropriate for inclusion in this study.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Safety of PLX7486 as single agent and in combination with gemcitabine and nab-paclitaxel

    Secondary Outcome Measures

    Patient weight

    Pain intensity

    Analgesic consumption

    Karnofsky Performance Status

    Pharmacokinetics of PLX7486

    Trial Keywords

    pancreatic adenocarcinoma

    solid tumors

    non-resectable pancreatic cancer

    metastatic pancreatic cancer

    activating NTRK point or fusion mutations