A Phase I/II Clinical Study of SAF-189s in Non-small Cell Lung Cancer (NSCLC) Patients

Advanced Solid Tumor Clinical Trial

Official title:

A Phase I/II, Multi-center Clinical Study: Dose-finding Phase I Study of Foritinib Succinate in Advanced ALK-positive NSCLC Patients and Phase II Study of Foritinib Succinate in ALK or ROS1-positive NSCLC Patients

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04237805
• Other study ID #: SAF001
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 14, 2016
• Est. completion date: March 31, 2026

Study information

• Verified date: May 2021
• Source: Shanghai Fosun Pharmaceutical Development Co, Ltd.
• Contact: Jinji Yang, Doctor
• Phone: +86-020-83827812
• Email: yangjinji2003[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study comprises two phases: phase I dose escalation (including PK run-in period and treatment period) and phase II study.

Description:

This is a multicenter, single-arm, open-label dose-finding phase I/II study to determine the MTD and RP2D of oral foritinib succinate monotherapy in patients with advanced ALK-positive malignant solid tumor, and to evaluate the safety, tolerability, and PK characteristics of SAF-189s in patients with advanced ALK-positive NSCLC. Phase II clinical study was conducted to evaluate the efficacy, tumor activity, and safety of remitinib succinate in patients with ALK/ROS1 positive advanced non-small cell lung cancer, and to preliminary evaluate the population pharmacokinetic characteristics of remitinib succinate.

This study consisted of two phases: phase I (including PK induction and continuous administration) and phase II, Phase I dose escalation : the patients with advanced ALK-positive malignant solid tumor who have progressed on standard therapies; Phase I study: histologically or cytologically confirmed, locally advanced ALK-positive and/or metastatic stage IIIB/IV NSCLC who have progressed on standard therapy; Phase II Study Part I: Patients with histologically and/or cytologically confirmed ALK or ROS1 positive locally-advanced and/or metastatic stage IIIb ~IV NSCLC;Patients who had not previously received or had received only one ALK/ROS1 inhibitor for disease progression or intolerance, and who had no more than 3 previous treatment lines overall Phase II Study Part Ⅱ: cohort1：ROS1-positive locally advanced and/or metastatic stage IIIB~IV NSCLC patients diagnosed histologically and/or cytologically, with no prior systemic therapy or only one line of non-ROS1-inhibitor treatment cohort 2: patients with histologically and/or cytologically confirmed ROS1-positive locally advanced and/or metastatic stage IIIb ~IV NSCLC who had previously only received crizotinib as a ROS1 inhibitor for disease progression or intolerance and had no more than 3 overall previous treatment lines；

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 280
• Est. completion date: March 31, 2026
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1) Have a full understanding of this study and voluntarily sign an informed consent form (ICF) 2)Phase I dose escalation : the patients with advanced ALK-positive malignant solid tumor who have progressed on standard therapies; Phase I study: histologically or cytologically confirmed, locally advanced ALK-positive and/or metastatic stage IIIB/IV NSCLC who have progressed on standard therapy; Phase II Study Part I: Patients with histologically and/or cytologically confirmed ALK or ROS1 positive locally-advanced and/or metastatic stage IIIb ~IV NSCLC;Patients who had not previously received or had received only one ALK/ROS1 inhibitor for disease progression or intolerance, and who had no more than 3 previous treatment lines overall Phase II Study Part ?: cohort1:ROS1-positive locally advanced and/or metastatic stage IIIB~IV NSCLC patients diagnosed histologically and/or cytologically, with no prior systemic therapy or only one line of non-ROS1-inhibitor treatment cohort 2: patients with histologically and/or cytologically confirmed ROS1-positive locally advanced and/or metastatic stage IIIb ~IV NSCLC who had previously only received crizotinib as a ROS1 inhibitor for disease progression or intolerance and had no more than 3 overall previous treatment lines; 3) At least one measurable lesion per RECIST1.1; Note: a lesion previously treated by radiotherapy is not considered as a target lesion, unless confirmed progression is documented after radiotherapy.

4) ECOG performance score = 2; 5) Male or female patients = 18 and = 75 years old in Phase I ;Male or female patients = 18 in Phase II 6) Life expectancy = 12 weeks; 7) Patient with appropriate organ function as documented by:

1. Absolute neutrophil count (ANC) = 1.5 × 109/L;

2. Hemoglobin = 90 g/L;

3. Platelets (PLT) = 100 × 109/L

4. Serum total bilirubin = 1.5 × ULN (if the patient has Gilbert's syndrome, = 3 × ULN and direct bilirubin = 1.5 × ULN);

5. Aspartate aminotransferase (AST) and alanine transaminase (ALT) = 2.5 × ULN (= 5 × ULN for patient with liver metastases);

6. Creatinine clearance (CrCL) = 50 mL/min (calculated by Cockcroft-Gault equation)

7. Fasting blood glucose = 200 mg/dL (= 11.1 mmol/L) 8) Toxicities from any prior therapy, surgery, or radiotherapy must have resolved to Grade 0 or 1 per NCI-CTCAE (Version 4.03), exception of alopecia; 9)Within 21 days prior to enrolment, women of reproductive age had to confirm a negative serological pregnancy test and agree to use an effective contraceptive method for all study drug use and for 28 days after the last dose.For the purposes of this protocol, women of childbearing age are defined as sexually mature women who: 1) have not undergone hysterectomy or bilateral oophorectomy, or 2) have natural menopause that has not lasted continuously for 24 months (amenorrhea after cancer treatment does not exclude fertility) (i.e., have had menstruation at any time during the previous consecutive 24 months);

Exclusion Criteria:

1. Has had prior chemotherapy, anti-cancer treatment with biological drugs, or other investigational agents within 28 days or received TKI or targeted therapies within 14 days prior to enrollment;

2. Received radiotherapy within 21 days prior to the 1st dose or continuance of toxicities due to prior radiotherapy that do not recover to Grade 0 or 1;

3. Patients who received major surgery within 3 weeks before enrollment or have not adequately recovered from prior surgery;

4. Patients with central nervous system (CNS) metastases requiring

1. Clinical local intervention such as surgical excision, radiotherapy or other therapies

2. Phase I dose escalation: patients requiring systemic treatment with corticosteroids (>10 mg/day prednisone or equivalent) are not eligible for dose escalation study (not applicable to patients participating Phase I cohort expansion or Phase II).

5. Diabetics without stable control and with insulin therapy (patients with fasting blood glucose below 7mmol/L, who are receiving stable hypoglycemic drug regimen, and whose blood glucose control is stable as evaluated by specialist doctors are allowed to be enrolled); 6)Difficulty in swallowing or having an active digestive disorder or having undergone major gastrointestinal surgery may significantly affect the administration or absorption of SAF189s (e.g. ulcerative lesions, uncontrollable nausea, vomiting, diarrhoea, malabsorption syndrome, and enteroctomies) 7)Patients who are taking the following medicines:

1. Repaglinide (cytochrome [CYP]2C8) and drugs metabolized via CYP3A4 enzyme within 1 week before enrollment;

2. Medicines which are known to cause QT prolongation or torsade de pointes;

3. Coumarin anticoagulants within 1 week before enrollment (low molecular weight heparin is permitted);

4. Illegal drugs;

8) Has a history of acute pancreatitis within 1 year before enrollment, or past history of chronic pancreatitis; 9) Patients have positive laboratory test for anti-HCV, or are diagnosed with human immunodeficiency virus (HIV) infection, or who refuse to receive HIV screen test; 10) Patients have other malignant tumor history or with other malignant tumors simultaneously; 11) Impairment of cardiac function or clinically significant heart disease, including New York College of Cardiology (NYHA) grade = 3 congestive heart failure, arrhythmias, conduction abnormalities requiring treatment, cardiomyopathy, or uncontrolled hypertension; 12) Corrected QT interval using Fridericia formula > 450 msec for male patients and > 470 msec for female patients; 13) Patients have uncured interstitial lung disease history or non-infectious pneumonitis prior to enrollment, except for those induced by radiation therapy; 14)Any other clinically significant disease or condition (such as uncontrolled diabetes, active or uncontrolled infections, etc.) that the investigator believes could affect protocol adherence or affect the patient's ability to sign up for ICF; 15)Spinal cord metastases with potential risk or symptoms of spinal cord compression; 16)The second cohort received ROS1 inhibitors other than crizotinib; 17)The patient had uncontrollable amounts of pleural effusion, ascites, and pericardial effusion.

Related Conditions & MeSH terms

• Advanced Cancer
• Advanced Solid Tumor
• Carcinoma, Non-Small-Cell Lung
• Lung Cancer, Nonsmall Cell
• Lung Neoplasms

Intervention

Drug:
• SAF-189s
20mg,40mg,80mg,120mg,160mg,210mg,once daily

Locations

Country	Name	City	State
China	Affiliated Hospital of Hebei University	Baoding	Hebei
China	Beijing Cancer Hospital	Beijing	Beijing
China	Beijing Chest Hospital,Capital Medical University	Beijing	Beijing
China	Peking Union Medical College Hospital	Beijing	Beijing
China	he First Affiliated Hospital of Bengbu Medical College	Bengbu	Anhui
China	The First Hospital of Jilin University	Changchun	Jilin
China	Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University	Changsha	Hunan
China	West China Hospital,Sichuan University	Chengdu	Sichuan
China	Guangdong Province People's General Hospital	Guangzhou	Guangdong
China	Nanfang Hospital, Southern Medical University	Guangzhou	Guangdong
China	Shulan (Hangzhou) Hospital	Hangzhou	Zhengjiang
China	SIR RUN RUN SHAW HOSPITAL Zhejiang University School of Medicine	Hangzhou	Zhejiang
China	The First Affiliated Hospital, Medical School of Zhejiang University	Hangzhou	Zhejiang
China	Zhejiang Cancer Hospital	Hangzhou	Zhejiang
China	Zhejiang Provincial People's Hospital	Hangzhou	Zhejiang
China	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang
China	Jieyang Peoples Hospital	Jieyang	Shanxi
China	Jilin Cancer Hospital	Jilin	Jilin
China	Jinan Central Hospital	Jinan	Shandong
China	No. 960 Hospital of the Joint Service Support Force of Chinese People's Liberation Army	Jinan	Shandong
China	Shandong Provincial Qianfoshan Hospital	Jinan	Shandong
China	Linyi Cancer Hospital	Linyi	Shandong
China	The second Affiliated Hospital of Nanchang University	Nanchang	Jiangxi
China	Jiangsu Province Hospital	Nanjing	Jiangsu
China	The second peoples hospital of Neijiang	Neijiang	Sichuan
China	Shanghai Chest Hospital,Shanghai Jiaotong University	Shanghai	Shanghai
China	The first affiliated hospital of China medical university	Shenyang	Liaoning
China	Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center	Shenzhen	Guangdong
China	The Fourth Hospital of Hebei Medical University	Shijiazhuang	Hebei
China	Tianjin Medical University Cancer Hospital	Tianjin	Tianjin
China	Tianjin Medical University General Hospital	Tianjin	Tianjin
China	Tianjin Peoples Hospital	Tianjin	Tianjin
China	Hubei Cancer Hospital	Wuhan	Hubei
China	Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei
China	Union Hospital of Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei
China	General Hospital of Xuzhou Mining Group	Xuzhou	Jiangsu
China	Yanbian University Affiliated Hospital	Yanji	Jilin
China	The Central Hospital of Yongzhou	Yongzhou	Hunan
China	The First Affiliated Hospital of Henan University of Science and Technology	Zhengzhou	Henan
China	The First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan
China	Zhengzhou Central Hospital	Zhengzhou	Henan

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Fosun Pharmaceutical Development Co, Ltd.

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	DLT	Dose Limiting Toxicity incidence within 24 days after the first dose in the dose escalation phase	24 days after the first dose in the dose escalation phase
Primary	ORR	Objective response rate	until 6 months' treatment of the last patients in each cohort
Secondary	TEAE	TEAE incidence, types, grade of toxicity according to NCI-CTCAE (version 5.0); study-related TEAE, SAE, study-related SAE, = Grade 3 TEAE, = Grade 3 TESAE, and TEAE leading to permanent discontinuation.	through study completion, an average of 3 year
Secondary	PFS	Progression-free survival (PFS)	3 years
Secondary	CBR	clinical benefit rate (CBR)	3 years
Secondary	DOR	duration of response (DoR)	3 years
Secondary	OS	Overall survival (OS)	4 years
Secondary	Cmax	Maximum Plasma Concentration	1 years
Secondary	CNS responses	Central nervous system efficacy evaluation,(time to CNS progression,CNS TTP),(CNS objective response rate,CNS ORR),(duration of CNS response,CNS DOR)	4 years