Clinical trial NCT04237805: A Phase I/II Clinical Study of SAF-189s in Non-small Cell Lung Cancer (NSCLC) Patients
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Cancer
Advanced Solid Tumor
Lung Cancer, Nonsmall Cell
Keywords: ALK-rearranged
ALK-positive
ROS1-rearranged
ROS1-positive
Lead sponsor: Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.
Sponsor class: INDUSTRY
First posted: 2020-01-23
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed 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；

Eligibility criteria: 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 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； 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.

Primary outcomes:
measure: DLT
timeFrame: 24 days after the first dose in the dose escalation phase
measure: ORR
timeFrame: until 6 months' treatment of the last patients in each cohort
Secondary outcomes:
measure: TEAE
timeFrame: through study completion, an average of 3 year
measure: PFS
timeFrame: 3 years
measure: CBR
timeFrame: 3 years
measure: DOR
timeFrame: 3 years
measure: OS
timeFrame: 4 years
measure: Cmax
timeFrame: 1 years
measure: CNS responses
timeFrame: 4 years
Other outcomes:
Locations:
city: Bengbu
country: China
facility: he First Affiliated Hospital of Bengbu Medical College
state: Anhui
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Chest Hospital,Capital Medical University
state: Beijing
city: Guangzhou
country: China
facility: Guangdong Province People's General Hospital
state: Guangdong
city: Guangzhou
country: China
facility: Nanfang Hospital, Southern Medical University
state: Guangdong
city: Shenzhen
country: China
facility: Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center
state: Guangdong
city: Baoding
country: China
facility: Affiliated Hospital of Hebei University
state: Hebei
city: Shijiazhuang
country: China
facility: The Fourth Hospital of Hebei Medical University
state: Hebei
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Zhengzhou
country: China
facility: Zhengzhou Central Hospital
state: Henan
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Henan University of Science and Technology
state: Henan
city: Wuhan
country: China
facility: Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Union Hospital of Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Hubei Cancer Hospital
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University
state: Hunan
city: Yongzhou
country: China
facility: The Central Hospital of Yongzhou
state: Hunan
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Xuzhou
country: China
facility: General Hospital of Xuzhou Mining Group
state: Jiangsu
city: Nanchang
country: China
facility: The second Affiliated Hospital of Nanchang University
state: Jiangxi
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Jilin
country: China
facility: Jilin Cancer Hospital
state: Jilin
city: Yanji
country: China
facility: Yanbian University Affiliated Hospital
state: Jilin
city: Shenyang
country: China
facility: The first affiliated hospital of China medical university
state: Liaoning
city: Jinan
country: China
facility: Jinan Central Hospital
state: Shandong
city: Jinan
country: China
facility: No. 960 Hospital of the Joint Service Support Force of Chinese People's Liberation Army
state: Shandong
city: Jinan
country: China
facility: Shandong Provincial Qianfoshan Hospital
state: Shandong
city: Linyi
country: China
facility: Linyi Cancer Hospital
state: Shandong
city: Shanghai
country: China
facility: Shanghai Chest Hospital,Shanghai Jiaotong University
state: Shanghai
city: Jieyang
country: China
facility: Jieyang Peoples Hospital
state: Shanxi
city: Chengdu
country: China
facility: West China Hospital，Sichuan University
state: Sichuan
city: Neijiang
country: China
facility: The second peoples hospital of Neijiang
state: Sichuan
city: Tianjin
country: China
facility: Tianjin Medical University General Hospital
state: Tianjin
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Hospital
state: Tianjin
city: Tianjin
country: China
facility: Tianjin Peoples Hospital
state: Tianjin
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Medical School of Zhejiang University
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Provincial People's Hospital
state: Zhejiang
city: Hangzhou
country: China
facility: SIR RUN RUN SHAW HOSPITAL Zhejiang University School of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Hangzhou
country: China
facility: Shulan (Hangzhou) Hospital
state: Zhengjiang
Study officials:
affiliation: Guangdong Province People's General Hospital
name: Yilong Wu, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Xia ZJ, Ji YC, Sun DQ, Peng X, Gao YL, Fang YF, Zhao XD, Wang WB, Ding J, Geng MY, Ai J. SAF-189s, a potent new-generation ROS1 inhibitor, is active against crizotinib-resistant ROS1 mutant-driven tumors. Acta Pharmacol Sin. 2021 Jun;42(6):998-1004. doi: 10.1038/s41401-020-00513-3. Epub 2020 Sep 11.