Phase I/II Study of SY-3505 in Patients With ALK-positive Advanced Non-small Cell Lung Cancer

A Phase I/II, Open-label, Multicenter Study of the Safety, Pharmacokinetics, and Antitumor Activity of SY-3505 Capsule in Patients With ALK-positive Advanced Non-small Cell Lung Cancer

This is a phase I/II, open-label and multi-center study of SY-3505, a third-generation ALK TKI, in patients with advanced ALK-positive non-small cell lung cancer (ALK-positive NSCLC).

Study Overview

• Status: Recruiting
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: SY-3505

Detailed Description

The study consists of two parts:

Part 1: Dose-escalation and dose-expansion in patients with advanced ALK-positive NSCLC, including 9 SY-3505 dose levels.

Dose-escalation study phase is designed to determine the dose-limiting toxicity (DLT) according to a 3+3 design and recommended phase II dose (RP2D) and to characterize the safety, tolerability, and pharmacokinetics (PK) profile of SY-3505. Other dose regimens may be explored based on the analysis of emerging PK and safety data. At this study phase, SY-3505 administered orally once daily (QD) in 28-day treatment cycles to adult patients with ALK-positive NSCLC. Dose-expansion study is designed to evaluate the antitumor activity (ORR, DCR and DoR) of SY-3505 at selected doses in ALK-positive NSCLC patients who have received at least 1 prior ALK TKI therapy.

Part 2: Phase 2 study to evaluate the efficacy of SY-3505.

This phase is designed to determine the antitumor activity (ORR, DCR, DoR, PFS and OS), safety, and PK of SY-3505 at RP2D in ALK-positive NSCLC patients who have received alectinib only or ≥2 prior ALK TKIs.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100021
      • Recruiting
      • Cancer Hospital, Chinese Academy of Medical Sciences
      • Contact: Yuankai Shi, MD; Phone Number: 86-10-87788293; Email: syuankai@cicams.ac.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, age ≥ 18 years at the time of screening.
2. Must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
3. Estimated Life expectancy ≥ 12 weeks.
4. Must have either at least one measurable lesion with no prior local treatment or measurable lesions with definite progression (Bone metastases alone were not accepted) after local treatment per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
5. Dose-escalation phase: patients must have histological or cytological confirmed ALK-positive advanced NSCLC. Dose-expansion phase: patients must have histological or cytological confirmed ALK-positive advanced NSCLC and progressed after at least one prior line of ALK TKI therapy. Phase II: patients must have histological or cytological confirmed ALK-positive advanced NSCLC and progressed after only alectinib or ≥2 prior ALK TKIs treatment. The pathological report requires either positivity for ALK gene expression determined by fluorescence in-situ hybridization (FISH) assay, immunohistochemistry (IHC), reverse transcription-polymerase chain reaction (RT-PCR), next-generation sequencing (NGS) or other identified methods from previous reports and provide tissue for ALK retest if possible or providing tissue for ALK test if no previous report is available.
6. Patients without brain metastasis or with asymptomatic brain metastases (no need for intervention or stable more than 4 weeks after treated).

7. Adequate organ function within 10 days prior to the study of treatment as defined in the below:

   Hepatic function

   Total serum bilirubin (TBIL) ≤ 1.5 times upper limit of normal (ULN); Aspartate transaminase (AST), alanine transaminase (ALT) and γ- glutamyltransferase (GGT) ≤ 2.5 times ULN if no demonstrable liver metastases, or otherwise ≤ 5 times ULN.

   Bone marrow function

   Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L; Platelets (PLT) count ≥ 100 x 10⁹/L; Hemoglobin (Hb) ≥ 90 g/L.

   Renal function

   Creatinine clearance ≥ 60 mL/min.

   Pancreatic function

   Serum total amylase ≤1.5 times ULN; Serum lipase ≤ 1.5 times ULN.

   Blood glucose

   Fasting Blood Glucose (FBG) ≤ 200 mg/dL (11.1 mmol/L).

   Serum lipid

   Serum cholesterol ≤ 500 mg/dL (12.92 mmol/L).

   Cardiac function

   Left ventricular ejection fraction (LVEF) ≥ 50%.

8. Any toxicity of previous antineoplastic treatments was restored to ≤ 1 (except hair loss).
9. Female patients with reproductive potential must have a negative serum pregnancy test, male and female patients of childbearing potential must be willing to completely abstain or agree to use an appropriate method of contraception during the entire study duration and for at least 3 months after the last dose of study medication.
10. Willingness and ability to give informed consent and follow protocol procedures, and comply with follow-up visit requirements.

Exclusion Criteria:

1. Any of the following within 6 months prior to starting trial treatment: Cerebrovascular accident/ stroke, myocardial infarction, severe/ unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), second- or third- degree atrioventricular (AV) block (unless paced) or any AV block with PR interval >220 msec, or any grade of uncontrolled atrial fibrillation.
2. ECG evaluated QT interval corrected (Fridericia) (QTcF) of > 450 msec in males or > 470 msec in females or congenital long QT syndrome.
3. Grade ≥ 3 peripheral neuropathy (CTCAE version 5.0).
4. Any active autoimmune diseases or history of autoimmune diseases that require long-term steroid or other immunosuppressants treatment.
5. Previous medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
6. Patients being treated with any anticoagulants, prone to bleeding, or have a coagulation disorder.
7. Active hepatitis (Hepatitis B: HBsAg-positive and HBV-DNA ≥ 2000 IU/ mL; Hepatitis B: HCV antibody-positive and HCV-RNA ≥ 1000 IU/ml), HIV antibody-positive; Active syphilis.
8. Patient underwent major surgery within 4 weeks prior to starting trial treatment.
9. Patients received radical radiotherapy within 4 weeks, palliative radiotherapy within 2 weeks, or radioactive agents (strontium, samarium, etc.) within 8 weeks prior to starting trial treatment.
10. Patients received systemic antitumor therapy, including chemotherapy, immunotherapy, biotherapy (cancer vaccine, cytokine or cancer growth control factor), or clearly indicated antitumor traditional Chinese medicine within 4 weeks (targeted therapy within 2 weeks) prior to starting trial treatment.
11. Patients treated with the following drugs and could not be discontinued at least 7 days prior to starting trial treatment and during the entire study duration: drugs known to be strong inducers or suppressors of CYP3A (for details, see prohibited combination drugs in this trial).
12. Patients with any active infection requiring systemic therapy within 4 weeks prior to starting trial treatment.
13. Comorbidities that may seriously endanger the patient's safety or affect the completion of the trial, such as severe diabetes, according to the judgment of investigator.
14. A clear previous history of neurological or psychiatric disorders, including dementia or diagnosed epilepsy for any reason.
15. With a history (within 5 years) or presence of other malignancies, excluding cured skin basal cell carcinoma and carcinoma in situ of the cervix.
16. Other situations that may increase the risks related to the study medication, interfere with the interpretation of the study results, affect compliance of the trial, etc. are determined by the investigator to be not suitable for the trial.
17. In phase II: previously received third-generation ALK TKIs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Phase I/II Study of SY-3505; SY-3505 will be given orally in ascending doses (escalation cohort), until the DLT or RP2D is reached. Up to 6 patients will then be enrolled in the expansion cohort at the recommended dose. In phase II, SY-3505 will be given at RP2D in advanced ALK-positive NSCLC patients.	Drug: SY-3505; The third-generation ALK TKI; Other Names: CT-3505

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Incidence rate of dose limiting toxicities (DLTs) during the first cycle of treatment	Maximum Tolerated Dose(s) (MTD(s)) and/or recommended phase 2 dose (RP2D(s)) in Cycle 1.	Dose-escalation Cycle 1 (each cycle is 28 days)
Phase I: Incidence of adverse events (AEs) and serious adverse events (SAEs)	Characterization of the safety and tolerability	Up to 24 months
Phase II: Overall Response Rate (ORR) as assessed by RECIST 1.1 criteria	Anti-tumor activity of SY-3505	Up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Overall Response Rate (ORR) as assessed by RECIST 1.1 criteria	Preliminary anti-tumor activity of SY-3505	Up to 24 months
Phase I & II: Disease control rate (DCR) as assessed by RECIST 1.1 criteria	Preliminary anti-tumor activity of SY-3505	Up to 24 months
Phase I & II: Duration of response (DOR)	Anti-tumor activity of SY-3505	Up to 24 months
Phase I & II: Progression-free survival (PFS)	Anti-tumor activity of SY-3505	Up to 24 months
Phase I & II: Overall survival (OS)	Anti-tumor activity of SY-3505	Up to 24 months
Phase I & II: Incidence of adverse events (AEs) and serious adverse events (SAEs)	Characterization of the safety and tolerability	Up to 24 months
Phase I & II: Pharmacokinetics (Cmax) for SY-3505	Defined as maximum observed plasma concentration	Protocol-defined time points during Cycles 1 and 2 of treatment (each cycle is 28 days)
Phase I & II: Pharmacokinetics (Tmax) for SY-3505	Defined as time to maximum plasma concentration	Protocol-defined time points during Cycles 1 and 2 of treatment (each cycle is 28 days)
Phase I & II: Pharmacokinetics (AUC0-t) for SY-3505	Defined as area under the single-dose plasma concentration-time curve from Hour 0 to the last quantifiable measurable plasma concentration	Protocol-defined time points during Cycles 1 and 2 of treatment (each cycle is 28 days)
Phase I & II: Pharmacokinetics (t½) for SY-3505	Defined as the apparent plasma terminal phase disposition half-life	Protocol-defined time points during Cycles 1 and 2 of treatment (each cycle is 28 days)
Phase I & II: Pharmacokinetics (Cl/F) for SY-3505	Defined as oral dose clearance	Protocol-defined time points during Cycles 1 and 2 of treatment (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: Shouyao Holdings (Beijing) Co. LTD

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 26, 2020
• Primary Completion (ANTICIPATED): April 26, 2024
• Study Completion (ANTICIPATED): August 26, 2024

Study Registration Dates

• First Submitted: February 9, 2022
• First Submitted That Met QC Criteria: February 17, 2022
• First Posted (ACTUAL): February 25, 2022

Study Record Updates

• Last Update Posted (ESTIMATE): February 14, 2023
• Last Update Submitted That Met QC Criteria: February 12, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: NSCLC; ALK; SY-3505
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: SY-3505-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No