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

Sponsor

Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04237805

Collaborator

(none)

280

Enrollment

Locations

Arm

112.5

Anticipated Duration (Months)

6.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Advanced Cancer Advanced Solid Tumor Lung Cancer, Nonsmall Cell	Drug: SAF-189s	Phase 1/Phase 2

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；

Study Design

Study Type:

Interventional

Anticipated Enrollment :

280 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 14, 2016

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Mar 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SAF-189s The phase I dose study will enrol patients with advanced malignant solid tumors that are ALK-positive, and the phase II study will be divided into two parts, Part I Some patients with ALK/ROS1 positive advanced non-small cell lung cancer were enrolled in the 210m,80mg,120mg and 160mg dose groups for safety evaluation.In the second part, two cohorts will be included and 110 ROS1 patients will be enrolled. Except for the PK induction period, all patients will receive oral administration of SAF189s once a day for a continuous period of 21 days.	Drug: SAF-189s 20mg，40mg，80mg，120mg，160mg，210mg，once daily Other Names: foritinib succinate

Arm

Intervention/Treatment

Experimental: SAF-189s

The phase I dose study will enrol patients with advanced malignant solid tumors that are ALK-positive, and the phase II study will be divided into two parts, Part I Some patients with ALK/ROS1 positive advanced non-small cell lung cancer were enrolled in the 210m,80mg,120mg and 160mg dose groups for safety evaluation.In the second part, two cohorts will be included and 110 ROS1 patients will be enrolled. Except for the PK induction period, all patients will receive oral administration of SAF189s once a day for a continuous period of 21 days.

Drug: SAF-189s

20mg，40mg，80mg，120mg，160mg，210mg，once daily

Other Names:

foritinib succinate

Outcome Measures

Primary Outcome Measures

DLT [24 days after the first dose in the dose escalation phase]
Dose Limiting Toxicity incidence within 24 days after the first dose in the dose escalation phase
ORR [until 6 months' treatment of the last patients in each cohort]
Objective response rate

Secondary Outcome Measures

TEAE [through study completion, an average of 3 year]
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.
PFS [3 years]
Progression-free survival (PFS)
CBR [3 years]
clinical benefit rate (CBR)
DOR [3 years]
duration of response (DoR)
OS [4 years]
Overall survival (OS)
Cmax [1 years]
Maximum Plasma Concentration
CNS responses [4 years]
Central nervous system efficacy evaluation，（time to CNS progression，CNS TTP），（CNS objective response rate，CNS ORR）,（duration of CNS response，CNS DOR）

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
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:

Absolute neutrophil count (ANC) ≥ 1.5 × 109/L;
Hemoglobin ≥ 90 g/L;
Platelets (PLT) ≥ 100 × 109/L
Serum total bilirubin ≤ 1.5 × ULN (if the patient has Gilbert's syndrome, ≤ 3 × ULN and direct bilirubin ≤ 1.5 × ULN);
Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for patient with liver metastases);
Creatinine clearance (CrCL) ≥ 50 mL/min (calculated by Cockcroft-Gault equation)
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:

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;
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;
Patients who received major surgery within 3 weeks before enrollment or have not adequately recovered from prior surgery;
Patients with central nervous system (CNS) metastases requiring
Clinical local intervention such as surgical excision, radiotherapy or other therapies
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).
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:
Repaglinide (cytochrome [CYP]2C8) and drugs metabolized via CYP3A4 enzyme within 1 week before enrollment;
Medicines which are known to cause QT prolongation or torsade de pointes;
Coumarin anticoagulants within 1 week before enrollment (low molecular weight heparin is permitted);
Illegal drugs;

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	he First Affiliated Hospital of Bengbu Medical College	Bengbu	Anhui	China	233004
2	Peking Union Medical College Hospital	Beijing	Beijing	China	100140
3	Beijing Cancer Hospital	Beijing	Beijing	China	100192
4	Beijing Chest Hospital,Capital Medical University	Beijing	Beijing	China	101149
5	Guangdong Province People's General Hospital	Guangzhou	Guangdong	China	510080
6	Nanfang Hospital, Southern Medical University	Guangzhou	Guangdong	China	510515
7	Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center	Shenzhen	Guangdong	China	518116
8	Affiliated Hospital of Hebei University	Baoding	Hebei	China	071000
9	The Fourth Hospital of Hebei Medical University	Shijiazhuang	Hebei	China	050000
10	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang	China	150081
11	The First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan	China	450014
12	Zhengzhou Central Hospital	Zhengzhou	Henan	China	450052
13	The First Affiliated Hospital of Henan University of Science and Technology	Zhengzhou	Henan	China	471003
14	Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei	China	430022
15	Union Hospital of Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei	China	430022
16	Hubei Cancer Hospital	Wuhan	Hubei	China	430079
17	Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University	Changsha	Hunan	China	410006
18	The Central Hospital of Yongzhou	Yongzhou	Hunan	China	425006
19	Jiangsu Province Hospital	Nanjing	Jiangsu	China	225001
20	General Hospital of Xuzhou Mining Group	Xuzhou	Jiangsu	China	221006
21	The second Affiliated Hospital of Nanchang University	Nanchang	Jiangxi	China	330006
22	The First Hospital of Jilin University	Changchun	Jilin	China	130031
23	Jilin Cancer Hospital	Jilin	Jilin	China	130021
24	Yanbian University Affiliated Hospital	Yanji	Jilin	China	133000
25	The first affiliated hospital of China medical university	Shenyang	Liaoning	China	110001
26	Jinan Central Hospital	Jinan	Shandong	China	250013
27	No. 960 Hospital of the Joint Service Support Force of Chinese People's Liberation Army	Jinan	Shandong	China	250031
28	Shandong Provincial Qianfoshan Hospital	Jinan	Shandong	China	250061
29	Linyi Cancer Hospital	Linyi	Shandong	China	276000
30	Shanghai Chest Hospital,Shanghai Jiaotong University	Shanghai	Shanghai	China	200030
31	Jieyang Peoples Hospital	Jieyang	Shanxi	China	522000
32	West China Hospital，Sichuan University	Chengdu	Sichuan	China	610041
33	The second peoples hospital of Neijiang	Neijiang	Sichuan	China	641100
34	Tianjin Medical University General Hospital	Tianjin	Tianjin	China	300052
35	Tianjin Medical University Cancer Hospital	Tianjin	Tianjin	China	300060
36	Tianjin Peoples Hospital	Tianjin	Tianjin	China	350000
37	The First Affiliated Hospital, Medical School of Zhejiang University	Hangzhou	Zhejiang	China	310009
38	Zhejiang Provincial People's Hospital	Hangzhou	Zhejiang	China	310014
39	SIR RUN RUN SHAW HOSPITAL Zhejiang University School of Medicine	Hangzhou	Zhejiang	China	310016
40	Zhejiang Cancer Hospital	Hangzhou	Zhejiang	China	310022
41	Shulan (Hangzhou) Hospital	Hangzhou	Zhengjiang	China	310000