Taletrectinib Phase 2 Global Study in ROS1 Positive NSCLC

The main purpose of the study is to evaluate safety and efficacy of taletrectinib (also known as AB-106 or DS-6051b) monotherapy in the treatment of advanced NSCLC.

This is a global Phase 2, multicenter, single-arm, open label study of taletrectinib in patients of NSCLC harboring with ROS1 fusion gene.

About 224 patients will be enrolled and divided into 6 cohorts, depending on past history of ROS1 TKI treatment.

In the cohorts open to enrollment, taletrectinib will be administered either 400mg or 600mg once daily in 21-day cycles. In one cohort, this will be in combination with carboplatin and pemetrexed both administered by IV infusion in 21-day cycles for 4 cycles. Patients will continue with the treatment on taletrectinib until progression of disease as determined by the investigator.

The tumor response evaluation will be conducted on a regular basis until progression of disease. Long-term survival follow up will be conducted as well.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥18 years (or ≥20 years as required by local regulations).
2. Histologically or cytologically confirmed diagnosis of locally advanced (including inoperable Stage IIIA or IIIB NSCLC) or metastatic NSCLC or other solid tumors.
3. Evidence of ROS1 fusion by a validated assay.
4. Patients with central nervous system (CNS) involvement, including leptomeningeal carcinomatosis, must be stable, either asymptomatic or previously treated and controlled within 14 days of first dose.
5. The patient can be either ROS1 TKI treatment naïve or treated with prior ROS1 TKI(s).
6. The patient must have at least 1 measurable disease per RECIST 1.1 as assessed by the investigator.
7. Eastern Cooperative Oncology Group Performance Status: 0 or 1.
8. Patient with a life expectancy ≥12 weeks based on the judgement of investigator.
9. Patients with adequate organ function meeting the following criteria:

   1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤3.0 × upper limit of normal (ULN) (or ≤5.0 × ULN, for patients with concurrent liver metastases)
   2. Serum total bilirubin: ≤1.5 × ULN (≤3.0 × ULN for patients with Gilbert syndrome or if liver function abnormalities are due to underlying malignancy)
   3. Absolute neutrophil count: ≥1,500/μL
   4. Platelet count: ≥100,000/μL
   5. Hemoglobin: ≥9.0 g/dL
   6. Serum creatinine ≤1.5 × ULN
10. Patients must be able to practice required contraception during the study.

    1. For males (irrespective of surgical sterilization \[vasectomy\]): agree to use effective contraception methods during the study intervention period and for at least 90 days after the last dose of investigational drug or agree with complete abstinence.
    2. Females without menses for at least 1 year prior to screening or documented to be surgically sterilized. Women of childbearing potential (WOCBP) must agree to use two concurrent highly effective methods of contraception or agree with complete abstinence from sexual intercourse since the informed consent until 45 days after the last dose of investigational drug. The patient is willing and capable to give written informed consent.
11. The patient is willing and capable to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.
12. The patient is willing and capable to comply with study site's COVID-19 policies.

Exclusion Criteria

1. Treatment with small molecule anticancer therapy including other investigational agents or cytotoxic systemic anticancer therapy within 2 weeks (or 5 half-lives of the compound, whichever is shorter) prior to the first dose of taletrectinib; Treatment with immuno-oncology (IO) including immune checkpoint inhibitors within 4 weeks before the first dose of taletrectinib.
2. Major surgical procedure, open biopsy, or significant traumatic injury ≤4 weeks before the first dose of taletrectinib.

   • Placement of vascular access device is not considered major surgery. Other minor surgical procedures, such as catheter placement or minimally invasive biopsy, are allowed.
3. Radiotherapy within 14 days before study treatment. Stereotactic radiosurgery (SRS), stereotactic radiation therapy (SRT), and palliative radiation outside the chest and brain are allowed but must be completed 1 week before starting study treatment.
4. Have been diagnosed with another primary malignancy other than NSCLC except for adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.
5. Adverse events due to prior therapy are unresolved to ≤ CTCAE Grade 1 or has not returned to baseline, by the first dose of taletrectinib except for AEs not constituting a safety risk to the patient based on the judgment of investigators.
6. Patients with untreated spinal cord compression caused by tumor and/or cancerous meningitis.
7. History or evidence of interstitial fibrosis, interstitial lung disease or drug-induced pneumonitis.
8. Any gastrointestinal disorders that may affect absorption of oral medications.
9. Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV), hepatitis C virus (HCV), or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
10. Clinically significant cardiovascular diseases within 3 months prior to the first dose of taletrectinib: myocardial infarction, severe/unstable angina, coronary/peripheral endovascular treatment, heart failure or cerebrovascular disorder including transient ischemic attack.
11. Ongoing cardiac dysrhythmias of ≥ CTCAE Grade 2, uncontrolled atrial fibrillation of any grade, or QT interval corrected for heart rate by Fredericia's formula (QTcF) \>470 milliseconds, or symptomatic bradycardia \<45 beats per minute; patient has family or medical history of long QT syndrome.
12. Pregnancy or lactation/breastfeeding.
13. Use of food or drugs that are known potent cytochrome P450 3A4/5 (CYP3A4/5) inhibitors or inducers or P-glycoprotein inhibitors or inducers within 14 days prior to the first dose of study treatment and while on treatment.
14. Administration of agents with potential QT interval prolonging effect within 14 days prior to first dose of study treatment and while on treatment.
15. Patients with other severe medical or mental diseases in whom the risk is increased by the participation to the study or treatment with study treatment in the opinion of the investigator.