Phase 2 Multicenter Study on Efficacy and Safety of Taletrectinib in Advanced or Metastatic ROS1 Positive Non-Small Cell Lung Cancer

Trial ID: 2024-516604-41-00
Protocol: AB-106-G208
Sponsor: Anheart Therapeutics Inc.

Trial statistics

science

test molecules

location_city

research sites

public

countries

medical_information

disease

person_search

investigators

handshake

vendors

Diseases & Conditions

Non-small cell lung cancer recurrent

Objectives

The primary objective of this study is to evaluate the efficacy of **taletrectinib** by the objective response rate (ORR) in patients with advanced or metastatic **ROS1 positive non-small cell lung cancer (NSCLC)**. This is clinically relevant as ORR is a critical measure of how well a treatment can induce tumor shrinkage, providing an early indication of the drug's potential benefit in managing the disease.

Secondary objectives include evaluating the efficacy of taletrectinib through various metrics:

Duration of response (DOR)
Progression-free survival (PFS)
Time to treatment failure (TTF)
Time to response (TTR)
Efficacy endpoints (ORR, DOR, and PFS) as assessed by investigators
Intracranial efficacy of taletrectinib
Overall survival (OS)

These secondary objectives are important for providing a comprehensive understanding of the drug's impact on disease progression, treatment durability, and overall patient survival, which are crucial for determining the long-term benefits and potential of taletrectinib in treating ROS1 positive NSCLC and other solid tumors.

Participants

The clinical trial involves a total of **126 participants** diagnosed with **Non-small Cell Lung Cancer** (NSCLC), specifically those with advanced or metastatic ROS1-positive NSCLC. The study population includes both male and female subjects aged **18 years and older**, with a life expectancy of at least 12 weeks. Participants were selected based on their ability to comply with study requirements, including scheduled visits and treatment plans. The trial includes individuals with adequate organ function and those who have a confirmed diagnosis of locally advanced or metastatic NSCLC. Participants may have been previously treated with ROS1 tyrosine kinase inhibitors (TKIs) or chemotherapy, depending on their cohort assignment. The study population is diverse, encompassing individuals with varying treatment histories, including those who are TKI-naïve or have received prior TKI treatment. The trial also considers lifestyle factors such as the use of effective contraception methods for both males and females of childbearing potential. The inclusion of a vulnerable population is acknowledged, ensuring that all participants meet the necessary health and safety criteria for trial participation.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **taletrectinib** in patients with advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) and other solid tumors. This is a single-arm, open-label, multicenter Phase 2 study. The primary objective is to assess the objective response rate (ORR) in patients, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS) among others, as evaluated by an independent radiology review committee (IRC) according to RECIST 1.1 criteria.

The trial is expected to run from August 2022 to June 2027. Participants will be involved in the study for a maximum treatment period of 60 days, with a daily dose of up to 800 mg of taletrectinib administered orally in capsule form. The study includes several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as age, life expectancy, and adequate organ function, followed by regular follow-up visits to monitor treatment response and safety. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any adverse events.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study requires participants to have a histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC or other solid tumors, with evidence of ROS1 fusion. Adequate tumor tissue must be available for confirmatory testing. The trial is not low-intervention and is categorized as a Phase II trial, focusing on patients who are either treatment-naïve or have been previously treated with ROS1 tyrosine kinase inhibitors (TKIs).

Treatment

The clinical trial involves the administration of **Taletrectinib**, an experimental medication, to evaluate its efficacy and safety in patients with advanced or metastatic ROS1 positive non-small cell lung cancer (NSCLC) and other solid tumors. **Taletrectinib** is provided in the form of a **capsule** and is intended for **oral use**. The maximum daily dose is 800 mg, with a total maximum dose of 800 mg per day. The treatment period is set for a maximum of 60 days. The active substance, **taletrectinib**, is of chemical origin and is developed by AnHeart Therapeutics Inc. The pharmaceutical form of the medication is a capsule, and it is not a pediatric formulation.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial is designed as a single-arm, open-label, multicenter Phase 2 study, focusing on the objective response rate (ORR) as the primary measure of efficacy. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The trial does not involve any additional devices or orphan drug designations.

Efficacy

The efficacy of Taletrectinib in patients with advanced or metastatic ROS1 positive non-small cell lung cancer (NSCLC) and other solid tumors will be assessed primarily through the **Objective Response Rate (ORR)**. This primary endpoint will be evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by an independent radiology review committee (IRC) for Cohorts 1 and 2. Secondary efficacy endpoints include Duration of Response (DOR), Progression-Free Survival (PFS), Time to Treatment Failure (TTF), and Time to Response (TTR), all assessed by IRC using RECIST 1.1 for the same cohorts. Additionally, the study will evaluate ORR, DOR, and PFS as assessed by investigators, as well as confirmed intracranial ORR, intracranial DOR, intracranial PFS, and time to intracranial progression according to modified RECIST 1.1, also assessed by IRC. Overall Survival (OS) will be measured for Cohorts 1 and 2.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Age ≥18 years (or ≥20 years as required by local regulations)
Patients with adequate organ function meeting the following criteria: a) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤ 3.0 × upper limit of normal (ULN) (or ≤ 5.0 × ULN, for patients with concurrent liver metastases) b) Serum total bilirubin: ≤1.5×ULN (≤3.0×ULN for patients with Gilbert syndrome or if liver function abnormalities are due to underlying malignancy) c) Absolute neutrophil count: ≥1,500/μL d) Platelet count: ≥100,000/μL e) Hemoglobin: ≥9.0 g/dL f) Serum creatinine ≤1.5×ULN and estimated creatinine clearance (CLcr) ≥45 mL/min as calculated using the method standard for the institution (e.g., Cockcroft - Gault Equation)
Histologically or cytologically confirmed diagnosis of locally advanced (including inoperable Stage III NSCLC) or metastatic NSCLC (cohorts 1-3, 5, and 6) or other solid tumors including NSCLC patients ineligible for other cohorts (cohort 4).
Evidence of ROS1 fusion by a validated assay as performed in Clinical Laboratory Improvement Amendments (CLIA)-certified or locally equivalent diagnostic laboratories. The molecular assays (i.e., Reverse Transcription Polymerase Chain Reaction [RT-PCR], Next-generation Sequencing [NGS]) are highly recommended.
Sufficient tumor tissue is required for patients in Cohort 1 and for TKI-naïve patients in Cohort 5 and Cohort 6 to perform confirmatory ROS1 fusion testing at the designated central laboratories. For patients in Cohort 1 and for TKI-naïve patients in Cohort 5 and Cohort 6, an archival tumor tissue specimen should be available and collected prior to enrollment. If archival tumor tissue is unavailable, then a fresh biopsy must be performed. Tumor tissue for patients in other cohorts is highly recommended and tumor tissue obtained after progression on the most recent prior ROS1 TKI therapy in these cohorts is preferred. Cytology samples (e.g., pleural effusion cell pellets) may be acceptable for patients that received prior treatment with TKI(s) having ROS1 activity in Cohorts 2 to 6.
Patients with central nervous system (CNS) involvement, including leptomeningeal carcinomatosis, which is stable (either asymptomatic or previously treated and controlled), are allowed: • Seizure prophylaxis is permitted with non-enzyme inducing antiepileptic drugs (non-EIAEDs; refer to Table 6-5 for examples of prohibited EIAEDs). • Corticosteroid treatment at a stable or decreasing dose within 7 days prior to the first dose of taletrectinib. • Whole brain radiation (WBRT) must be completed at least 14 days and stereotactic radiotherapy, stereotactic radiosurgery, or gamma knife radiotherapy at least 7 days prior to enrollment; the patient must be clinically stable for 7 days according to investigator judgement prior to first dose of taletrectinib.
The patient is either ROS1 TKI treatment naïve, or treated with prior ROS1 TKI(s): • Cohort 1: Patients with locally advanced or metastatic ROS1-positive NSCLC. Systemic chemotherapy naïve or pretreated with 1 prior line of chemotherapy but never treated with any ROS1 TKI. • Cohort 2: Patients with locally advanced or metastatic ROS1-positive NSCLC. Prior treatment with 1 approved ROS1 TKI (crizotinib or entrectinib) and disease progression. The patient can be either chemotherapy naïve or has received 1 line of systemic chemotherapy for the locally advanced or metastatic ROS1-positive NSCLC. • Cohort 3: Patients with locally advanced or metastatic ROS1-positive NSCLC. Prior treatment with ≥2 TKIs with ROS1 activity and disease progression. The patient can be either chemotherapy naïve or has received 1 line of systemic chemotherapy for locally advanced or metastatic ROS1-positive NSCLC, patients with known ROS1 resistant mutations are preferred. • Cohort 4: Patients with other ROS1-positive solid tumors, or NSCLC patients ineligible for Cohorts 1-3. Prior treatment with ≤3 TKIs with ROS1 activity. The patient can be either chemotherapy naïve or has received ≤ 2 lines of systemic chemotherapy for locally advanced or metastatic solid tumors. • Cohort 5: Patients with locally advanced or metastatic ROS1-positive NSCLC. The patient can be either chemotherapy naïve or has received ≤2 lines of systemic chemotherapy for locally advanced or metastatic ROS1-positive SCLC. ROS1-TKI-naïve or pretreated with TKI(s) having ROS1 activity. • Cohort 6a: Patients with locally advanced or metastatic ROS1-positive NSCLC. Systemic chemotherapy naïve or pretreated with 1 prior line of chemotherapy but never treated with any ROS1 TKI. For Cohort 6a and 6b Inclusion criteria please see section 5.1 in Protocol
At least 1 measurable disease per RECIST 1.1 assessed by investigator.
Eastern Cooperative Oncology Group Performance Status: 0 or 1.
Patient with a life expectancy ≥12 weeks based on the judgment of investigator.
Males and/or females who meet any of the following criteria: a) 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. b) 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 2 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. Usage of hormonotherapy for contraception should be recorded as well.
For all females of childbearing potential, a negative pregnancy test must be obtained within 7 days before starting study treatment. Female patients of non-childbearing potential must meet at least 1 of the following criteria: • Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state. • Have undergone a documented hysterectomy and/or bilateral oophorectomy. • Have medically confirmed ovarian failure. All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential.
The patient is willing and capable to give written informed consent.
The patient is willing and capable to comply with the study scheduled visits, treatment plans, laboratory tests, and other procedures.
The patient is willing and capable to comply with study site’s COVID-19 policies.

cancel

Exclusion Criteria

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; or treatment with monoclonal antibodies including immune checkpoint inhibitors, within 4 weeks before the first dose of taletrectinib.
Major surgical procedure, open biopsy, or significant traumatic injury ≤4 weeks before the first dose of taletrectinib or anticipation of need for major surgical procedure during the study. • Placement of vascular access device is not considered major surgery. Other minor surgical procedures, such as catheter placement or minimally invasive biopsy, are allowed.
Radiation outside the chest and brain <7 days prior to C1D1.
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 initial diagnosis of the other malignancy. Note: This criterion does not apply to patients to be enrolled in Cohort 4.
Adverse events due to prior therapy are unresolved to ≤ CTCAE Grade 1 or have not returned to baseline, at the time of the first dose of taletrectinib except for AEs not constituting a safety risk to the patient based on the judgment of investigators.
Patients with untreated spinal cord compression caused by tumor and/or cancerous meningitis.
History or evidence of interstitial fibrosis, interstitial lung disease, or drug-induced pneumonitis (Excluding clinically insignificant or asymptomatic post-radiation pneumonitis).
Any gastrointestinal disorders that may affect absorption of oral medications.
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. Note that the following are permitted: • Patients treated for hepatitis C (HCV) or HIV with no detectable viral load; for at least 1 month prior to the first dose of taletrectinib. Note: caution with drug-drug interactions of concomitant anti-HIV agents and CYP3A substrates. • Patients with known hepatitis B (HBV) infections: - With past or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of hepatitis B surface antigen [HBsAg]); or - With inactive HBV carrier state (defined as HBsAg-positive, with normal ALT, and HBV DNA <2,000 IU/mL or <10,000 copies/mL). Note: Please consider that for patients in an inactive HBV carrier state or with a resolved HBV infection, there may be a risk of HBV reactivation and anti-HBV prophylaxis should be considered
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.
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.
Pregnancy or lactation/breastfeeding.
Use of food or drugs that are known strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors or inducers within 14 days prior to the first dose of study treatment and while on treatment (see Section 6.9.5 for details).
Administration of agents with potential QT interval prolonging effect within 14 days prior to first dose of study treatment and while on treatment (see Section 6.9.5 and 10.4 for details).
Patients with other severe medical or mental diseases in whom the risk is increased by the participation in the study or treatment with study treatment in the opinion of the Investigator.