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 June 2016 by Plexxikon
Sponsor:
Information provided by (Responsible Party):
Plexxikon
ClinicalTrials.gov Identifier:
NCT01804530
First received: March 1, 2013
Last updated: June 7, 2016
Last verified: June 2016
  Purpose
The goal of this clinical study is to learn how PLX7486 TsOH, Gemcitabine, and nab-Paclitaxel work together to affect the growth of cancer cells in advanced solid tumors.

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
Tenosynovial Giant Cell Tumor
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: Parallel 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 as measured by adverse events and serious adverse events. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Area under the plasma concentration-time curve [AUC0-t, AUC0-inf] [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Area under the plasma concentration-time curve [AUC0-t, AUC0-inf] will be used to assess the pharmacokinetic profile of PLX7486.

  • Peak concentration (Cmax) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Peak concentration (Cmax) will be used to assess the pharmacokinetic profile of PLX7486.

  • Time to peak concentration (Tmax) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Time to peak concentration (Tmax) will be used to assess the pharmacokinetic profile of PLX7486.

  • Half life (t1/2) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Half life (t1/2) will be used to assess the pharmacokinetic profile of PLX7486.

  • Terminal elimination rate constant (Kel) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Terminal elimination rate constant (Kel) will be used to assess the pharmacokinetic profile of PLX7486.


Secondary Outcome Measures:
  • Clinical Benefit Response Rate [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Clinical Benefit Response Rate will be assessed by the primary measures of pain, analgesic consumption, and Karnofsky Performance Status and the secondary measure of weight.

  • Duration of response (DOR) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Duration of response is defined as the number of days from the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first.

  • Progression-Free Survival (PFS) [ Time Frame: 6 month ] [ Designated as safety issue: No ]
    Progression-free survival (PFS) is defined as the number of days from start of therapy to the date of documented disease progression/relapse, whichever occurs first.

  • Overall response rate (ORR) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Overall response rate (ORR) 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.


Estimated Enrollment: 160
Study Start Date: August 2013
Estimated Study Completion Date: August 2021
Estimated Primary Completion Date: February 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PLX7486-TsOH, Dose escalation
Part 1: Open-label, sequential PLX7486-TsOH single-agent dose escalation in approximately 50 patients with solid tumors.
Drug: PLX7486 TsOH
PLX7486 TsOH capsules, 50mg
Experimental: PLX7486-TsOH with nab-Paclitaxel and Gemcitabine
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. (Not recruiting)
Drug: PLX7486 TsOH
PLX7486 TsOH capsules, 50mg
Drug: Gemcitabine
Gemcitabine IV
Other Name: Gemzar
Drug: nab-Paclitaxel
nab-Paclitaxel IV
Other Name: Abraxane
Experimental: RP2D of PLX7486-TsOH with nab-Paclitaxel and Gemcitabine
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. (Not recruiting)
Drug: PLX7486 TsOH
PLX7486 TsOH capsules, 50mg
Drug: Gemcitabine
Gemcitabine IV
Other Name: Gemzar
Drug: nab-Paclitaxel
nab-Paclitaxel IV
Other Name: Abraxane
Experimental: PLX7486-TsOH, RP2D
Part 2c: Extension cohort of single agent PLX7486-TsOH at the RP2D in patients with advanced non-resectable tumors of any histology with activating Trk (NTRK) point or NTRK fusion mutations or with unresectable, locally advanced or refractory Tenosynovial giant cell tumor (TGCT), including metastatic disease, in approximately 30 patients.
Drug: PLX7486 TsOH
PLX7486 TsOH capsules, 50mg

Detailed Description:

Part 1 of this study is a sequential single-agent dose escalation of PLX7486-TsOH in patients with solid tumors.

Part 2a of this study is a sequential dose escalation of PLX7486-TsOH in combination with fixed doses of nab-Paclitaxel and Gemcitabine, This arm of the study is not recruiting patients.

Part 2b of this study is an extension cohort at the recommended phase 2 dose (RP2D) of PLX7486-TsOH in combination with fixed doses of nab-Paclitaxel and Gemcitabine in patients with untreated, advanced, non-resectable or metastatic pancreatic adenocarcinoma. This arm of the study is not recruiting patients.

Part 2c of this study is an extension cohort at the RP2D of PLX7486-TsOH in patients with advanced non-resectable tumors of any histology with activating Trk (NTRK) point or NTRK fusion mutations or with unresectable, locally advanced or refractory Tenosynovial giant cell tumor (TGCT), including metastatic disease.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Male or female ≥18 years old
  • Patients with histologically confirmed solid tumors who:

    • Part 1: have tumor progression following standard therapy, have treatment-refractory disease, or for whom there is no effective standard of therapy
    • 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
    • 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.
    • Part 2c:
    • Have advanced, non-resectable tumors of any histology with their growth driven by CSF-1R activity or 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) or underlying pathology or pathophysiology that suggests that NTRK signaling may be playing a significant role in disease (e.g., TrkC/NT3 overexpression in adenoid cystic carcinoma, TrkB/BDNF overexpression in non-small cell lung 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), OR
    • have unresectable, locally advanced or refractory TGCT (including metastatic disease)
  • Patients in Part 2b and 2c must have measurable disease by RECIST criteria v1.1
  • 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 (see Attachment 8) 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 (see Attachment 8) while on study drug and up to 3 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
  • 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.
  • Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements
  • Karnofsky performance status ≥70% (see Attachment 7)
  • Life expectancy ≥3 months
  • Adequate hematologic, hepatic, and renal function

Exclusion Criteria

  • 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
  • Chemotherapy within 28 days prior to C1D1
  • Biological therapy within 5 half-lives prior to C1D1
  • Radiation therapy within 28 days or 5 half-lives prior to C1D1, whichever is longer
  • Investigational drug use within 28 days or 5 half-lives, whichever is longer, prior to C1D1
  • Part 1 only: (a) Patients with active or a history of glucose intolerance or diabetes mellitus and (b) Hemoglobin A1c ≥7%
  • Part 2a and 2b only: Patients with a known hypersensitivity to nab-paclitaxel or gemcitabine
  • Part 2a, 2b, and 2c: Patients with uncontrolled diabetes or Hemoglobin A1c >8%. 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.
  • 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.
  • ≥Grade 2 sensory neuropathy at baseline
  • 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
  • Refractory nausea and vomiting, malabsorption, small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption
  • Mean QTcF ≥450 msec (for males) or ≥470 msec (for females) at Screening
  • 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
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: Terry Cho tcho@plexxikon.com

Locations
United States, Arizona
Plexxikon Investigative Site Recruiting
Scottsdale, Arizona, United States, 85004
United States, California
Plexxikon Investigative Site Recruiting
Santa Monica, California, United States, 90404
United States, Maryland
Plexxikon Investigative Site Recruiting
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Plexxikon Investigative Site Recruiting
Boston, Massachusetts, United States, 02114
United States, South Carolina
Plexxikon Investigative Site Recruiting
Charleston, South Carolina, United States, 29425
Sponsors and Collaborators
Plexxikon
  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: June 7, 2016
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
Tenosynovial giant cell tumor
TGCT

Additional relevant MeSH terms:
Neoplasms
Adenocarcinoma
Pancreatic Neoplasms
Giant Cell Tumors
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
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Paclitaxel
Gemcitabine
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents

ClinicalTrials.gov processed this record on July 21, 2016