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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. (see Contacts and Locations)
Verified May 2014 by Plexxikon
Sponsor:
Information provided by (Responsible Party):
Plexxikon
ClinicalTrials.gov Identifier:
NCT01804530
First received: March 1, 2013
Last updated: May 8, 2014
Last verified: May 2014

March 1, 2013
May 8, 2014
August 2013
December 2014   (final data collection date for primary outcome measure)
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: No ]
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.
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.
Complete list of historical versions of study NCT01804530 on ClinicalTrials.gov Archive Site
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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 paitent 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).
  • Tumor response [ Time Frame: Patients that have received ≥2 administrations of gemcitabine + nab-paclitaxel and 21 days of PLX7486 ] [ Designated as safety issue: No ]
  • Duration of remission (DOR) [ Time Frame: From documented initial response (PR or better) to disease progression/relapse, or death ] [ Designated as safety issue: No ]
  • Duration of complete remission (DOCR) [ Time Frame: From date of initial response to first documented disease relapse or death. ] [ Designated as safety issue: No ]
  • 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 ]
  • 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 ]
  • Overall response rate (ORR) [ Time Frame: Baseline to end of study, estimated to be ≤ 1 year. ] [ Designated as safety issue: No ]
  • 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.
 
Phase 1 Study of PLX7486 as Single Agent and With Gemcitabine Plus Nab-Paclitaxel in Patients With Advanced Solid Tumors
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

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.

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.

Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • 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
  • Drug: PLX7486-TsOH
    Part 1: single-agent dose escalation Part 2a: sequential dose escalation with fixed dose levels nab-paclitaxel + gemcitabine Part 2b: Recommended phase 2 dose with fixed dose levels nab-paclitaxel + gemcitabine Part 2c: Recommended phase 2 dose as single agent
    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 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 1
    Open-label, sequential PLX7486-TsOH single-agent dose escalation in approximately 50 patients with solid tumors.
    Intervention: Drug: PLX7486-TsOH
  • 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.
    Interventions:
    • Drug: PLX7486-TsOH
    • Drug: gemcitabine
    • Drug: nab-Paclitaxel
  • 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.
    Interventions:
    • Drug: PLX7486-TsOH
    • Drug: gemcitabine
    • Drug: nab-Paclitaxel
  • Experimental: Part 2c
    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.
    Intervention: Drug: PLX7486-TsOH
Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. doi: 10.1200/JCO.2011.36.5742. Epub 2011 Oct 3.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
118
Not Provided
December 2014   (final data collection date for primary outcome measure)

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.
Both
18 Years and older
No
Contact: David Karlin, MD 510-647-4100 dkarlin@plexxikon.com
Contact: Sandy Tong, MD 510-647-4100 stong@plexxikon.com
United States
 
NCT01804530
PLX119-01
No
Plexxikon
Plexxikon
Not Provided
Study Director: David Karlin, MD Plexxikon Inc.
Plexxikon
May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP