Entrectinib (previously known as RXDX-101) is an orally available inhibitor of the tyrosine
kinases TrkA, TrkB, TrkC, ROS1, and ALK. Molecular alterations to one or more of these
targets are present in several different tumor types, including non-small cell lung cancer
(NSCLC), colorectal cancer (CRC), prostate cancer, papillary thyroid cancer, pancreatic
cancer, and neuroblastoma. Patients with locally advanced or metastatic cancer with a
detectable molecular alteration in targets of interest may be eligible for enrollment.
Phase 1 will assess safety and tolerability of entrectinib via standard dose escalation
scheme and determine the recommended Phase 2 dose.
Phase 2 will assess treatment efficacy and safety of entrectinib.
Inclusion Criteria:
- Histologically or cytologically confirmed diagnosis of locally advanced or metastatic
solid tumors that have a TrkA, TrkB, TrkC, ROS1, or ALK molecular alteration.
- Measurable disease according to RECIST version 1.1.
- Prior cancer therapy is allowed, including crizotinib and investigational drugs. At
the time of treatment start, at least 2-4 weeks must have elapsed after prior
cytotoxic chemotherapy (at least 6 weeks for nitrosureas, mitomycin C and liposomal
doxorubicin). In the absence of toxicity, 7 days must have elapsed since completion
of prior non-cytotoxic cancer therapy.
- Prior radiotherapy is allowed if >14 days have elapsed since end of treatment,
provided that no more than 25% of bone marrow reserve has been irradiated.
- Patients with controlled asymptomatic central nervous system involvement are allowed
in absence of therapy with anticonvulsants.
- Patients who have received brain irradiation must have completed whole brain
radiotherapy and gamma knife at least 4 weeks prior to enrollment.
- Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.03 Grade less than or equal to 1.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2.
- Adult patients age 18 years or older.
- Life expectancy of at least 3 months.
Exclusion Criteria:
- Current participation in another therapeutic clinical trial.
- Known symptomatic brain metastases or leptomeningeal involvement as assessed by MRI
or contrast CT scan examination.
- History of previous cancer, except squamous cell or basal-cell carcinoma of the skin,
or any in situ carcinoma that has been completely resected, requiring therapy within
the previous 3 years.
- Incomplete recovery from any surgery prior to treatment.
- Any of the following in the past 6 months: myocardial infarction, unstable angina,
coronary/peripheral artery bypass graft, symptomatic congestive heart failure,
cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein
thrombosis.
- History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval >
450 milliseconds).
- History of additional risk factors for torsade de pointes (e.g., heart failure,
family history of long QT syndrome).
- Use of concomitant medications that increase or possibly increase the risk to prolong
the QTc interval and/or induce torsades de pointes ventricular arrhythmia.
- Known active infections (bacterial, fungal, viral including HIV positivity).
- Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact on drug absorption.
- Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase
inhibitor-induced pneumonitis.
- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or may interfere with the interpretation of study results and, in
the judgment of the Investigator, would make the patient inappropriate for entry into
this study or could compromise protocol objectives in the opinion of the Investigator
and/or the Sponsor.
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
