Clinical Trials

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumor that harbors an NTRK1/2/3, ROS1, or ALK gene rearrangement that is predicted to translate into a fusion protein with a functional TrkA/B/C, ROS1, or ALK kinase domain, respectively, without a concomitant second oncodriver (e.g., EGFR, KRAS) as determined by Foundation Medicine, Inc. or by any nucleic acid-based diagnostic testing method performed at a local CLIAcertified or equivalently-accredited diagnostic laboratory.
  • Note: Patients diagnosed with anaplastic large cell lymphoma (ALCL) harboring a gene rearrangement of interest are no longer eligible. For the United States only: Other hematological malignancies (e.g., acute leukemia, myeloma, etc.) are also known to potentially harbor gene rearrangements of interest. Although these patients are not eligible for study enrollment, they may be eligible for treatment under a Single Patient Protocol. Please make all such requests directly to the Sponsor.
• For patients enrolled via local molecular testing, an archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Foundation Medicine, Inc. or to the alternative, approved central laboratory for that region.
• Measurable disease as assessed locally using RECIST v1.1.
  • Note: Patients with non-measurable disease (evaluable disease only) will be eligible for enrollment in the “non-evaluable for the primary endpoint” basket and will mainly contribute to assessment of safety, PK, and other secondary endpoints.
  • Note: The non-evaluable basket will be limited to patients with CNS primary tumor with either NTRK or ROS1 fusions.
• Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previously-treated and controlled, are allowed. The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme-inducing anti-epileptic drugs (non-EIAEDs). If patients were previously on EIAEDs and these have been discontinued, they must have been discontinued for at least 2 weeks prior to the start of entrectinib treatment. If patients require an anti-epileptic medication, a CYP3A4 non-EIAED can be used such as levetiracetam, valproic acid, gabapentin, topiramate, or lacosamide.  Patients requiring steroids must be at stable or decreasing doses for at least 2 weeks prior to the start of entrectinib treatment.
• Prior anticancer therapy is allowed (excluding approved or investigational Trk, ROS1, or ALK (non-NSCLC patients only) inhibitors in patients who have tumors that harbor those respective gene rearrangements).
  • Note: The ALK basket is closed to enrollment.
• At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy, respectively, at the time of the start of entrectinib treatment.
  • Note: For targeted therapies, there must be no signs of disease flare or accelerated disease progression after treatment discontinuation.
• At least 4 weeks must have elapsed since completion of antibody-directed therapy at the time of the start of entrectinib treatment.
• Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and minimum life expectancy of at least 4 weeks
• Adequate liver function as defined by the following criteria:
  • Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase (SGOT)) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase (SGPT)) ≤ 3.0 x upper limit of normal (ULN); ≤ 5.0 x ULN if liver metastases are present;
  • Total serum bilirubin ≤ 2.0 × ULN; patients with a known history of Gilbert’s syndrome and/or isolated elevations of indirect bilirubin are eligible.
• For women of childbearing potential:
  • Must have a negative serum pregnancy test during screening and must not be breastfeeding or intending to become pregnant during the study;
  • Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs as defined below: Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year prior to the treatment period and for 5 weeks after the final dose of entrectinib. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations;
  • Examples of contraceptive methods with a failure rate of > 1% per year include bilateral tubal ligation; male sterilization; hormonal and non-hormonal contraceptives that inhibit ovulation; hormone-releasing intrauterine devices, and copper intrauterine devices. In female patients, hormonal contraceptives must be supplemented with a barrier method. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient;
  • Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form;
  • A female patient may have a vasectomized partner as a method of highly effective contraception only when this is the only partner of the female patient of child-bearing potential. Progestogen-only oral hormonal contraception not having inhibition of ovulation as the primary mode of action, condoms, diaphragms, caps (with spermicide), or sponges (with spermicide) have a failure rate > 1% per year and must be used in combination with another method of contraception.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined below:
  • With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of > 1% per year during the treatment period and for for 3 months after the final dose of entrectinib. Men must refrain from donating sperm during this same period;
  • With a pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 5 weeks after the final dose of entrectinib to avoid exposing the embryo;
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form;
  • Ability to swallow entrectinib intact without chewing, crushing, or opening the capsules;
  • Willingness to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
  • Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to the start of entrectinib treatment.

Exclusion Criteria:

• Current participation in another therapeutic clinical trial.
• Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements.
  • Note: In cases where the patient was intolerant to prior Trk, ROS1, or ALK inhibitors, please discuss with the Sponsor. In addition, prior treatment with crizotinib is permitted ONLY in ALK- or ROS1- rearranged NSCLC patients presenting with radiographically-confirmed CNS-only progression. Other ALK or ROS1 inhibitors are prohibited in that scenario.
  • Note: The ALK-rearranged NSCLC basket for patients previously treated with crizotinib and presenting with CNS-only progression is closed for further enrollment.
• History of other previous cancer that would interfere with the determination of safety or efficacy of entrectinib with respect to the qualifying solid tumor malignancy.
  • Note: The non-evaluable basket will be limited to patients with CNS primary tumor with either NTRK or ROS1 fusions. Patients presenting with dual primary cancers may enroll in the “non-evaluable for the primary endpoint” basket if at least one of the cancers is a CNS primary and it harbor an NTRK1/2/3 or ROS1 gene rearrangement as per Inclusion Criterion 1.
• Familial or personal history of congenital bone disorders or bone metabolism alterations.
• Incomplete recovery from any surgery prior to the start of entrectinib treatment that would interfere with the determination of safety or efficacy of entrectinib.
• Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of entrectinib: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or uncontrolled arrhythmias requiring medication.
• History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction ≤ 50% observed during screening for the study
• History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 450 milliseconds from ECGs performed at least 24 hours apart).
• History of additional risk factors for torsades de pointes (e.g., family history of long QT syndrome).
• Peripheral sensory neuropathy Grade ≥ 2.
• Known active infections that would interfere with the assessment of safety or efficacy of entrectinib (bacterial, fungal, or viral), with the exceptions of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections, as noted below:
  • HIV positivity, only if patients meet any of the following criteria: Patients with a CD4+ T-cell count of < 350 cells/µL Patients with a detectable HIV viral load;
  • Patients with a history of an opportunistic infection within the past 12 months;
  • Patients who are on stable antiretroviral therapy for < 4 weeks.
  • Active HBV infection (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test), with the following exception:
  • Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) if they are negative for HBV DNA.
  • HCV antibody (HCV Ab) positivity, with the following exceptions:
  • Patients who are HCV Ab-positive but HCV RNA-negative due to prior treatment or natural resolution are eligible;
  • Patients with untreated HCV if the HCV is stable, the patient is not at risk for hepatic decompensation, and the intended treatment is not expected to exacerbate the HCV infection;
  • Patients on concurrent HCV treatment if they have HCV below the limit of quantification.
• Active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption.
• Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis.
  • Note: Radiation-induced lung disorders are not included in this exclusion criterion.
• 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.

Eligibility last updated 1/6/22. Questions regarding updates should be directed to the study team contact.