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. (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
  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.


Condition Intervention Phase
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
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: 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.


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.

  • 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).


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 ]
  • 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 ]

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: 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
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: 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 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: 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 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.
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

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.

  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 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.
  Contacts and Locations
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, see Learn About Clinical Studies.

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
Scottsdale, 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: May 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Plexxikon:
pancreatic adenocarcinoma
solid tumors
non-resectable pancreatic cancer
metastatic pancreatic cancer
activating NTRK point or fusion mutations

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

ClinicalTrials.gov processed this record on October 22, 2014