Patient case: 60-year-old male with melanoma; genetic feature: NTRK1 rearrangement

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

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

Detailed description: Part 1. Open-label, sequential PLX7486 TsOH single-agent dose escalation in approximately 60 patients with solid tumors.
  Part 2c. Based upon safety and clinical activity observations, an extension cohort is planned at the RP2D of single-agent PLX7486 TsOH in approximately 30 patients with:
  1. Advanced, non-resectable tumors of any histology with their growth driven by CSF-1R activity or 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) 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 who have received prior treatment, if there is a known therapy that results in increased survival for that particular disease OR
  2. Unresectable, locally advanced or refractory TGCT (including metastatic disease)

Eligibility: 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 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 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. 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.
  -  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%
  -  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 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.
  -  ≥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

Relevance to patient case: not relevant