Phase Ib Clinical Study of Keynatinib
Phase Ib Clinical Study of Keynatinib
The purpose of this study is to evaluate the efficacy, safety, PK characteristics in subjects
 with relapsed/refractory B-cell lymphoma. Furthermore, the relationship between the exposure
 level of Keynatinib and its efficacy and safety, the penetration rate of keynatinib in the
 Blood-Brain Barrier (BBB) and its PK characteristics in cerebrospinal fluid in R/R-PCNSL
 patients, the relationship between the BTK receptor occupancy rate and the efficacy are also
 evaluated.
This tiral adopts a multi-center, single-arm, multi-cohort, and open-label design to evaluate
 the efficacy and safety of keynatinib in patients with relapsed/refractory B-cell lymphoma.

 There will be three cohorts in this trial, details as follows: Cohort 1: R/R-PCNSL subjects;
 Cohort 2: R/R-CLL/SLL subjects; Cohort 3: R/R-MCL subjects.

 10-25 subjects will be enrolled in the R/R-PCNSL, R/R-CLL/SLL, and R/R-MCL cohorts,
 respectively.
Inclusion Criteria:

 1. Unlimited gender, age ≥ 18 years (including critical value)-Cohort 1/2/3;

 2. Voluntarily participate in the study and sign the ICF, follow the trial treatment
 protocol and interview plan-Cohort 1/2/3;

 3. The subject's disease diagnosis meets all of the following conditions:

 Cohort 1:

 1. Primary central nervous system lymphoma (PCNSL) confirmed by pathology;

 2. For relapsed or refractory PCNSL, at least first line treatment must be given to
 Central Nervous System (CNS) lesions;

 3. Brain Magnatic resonance Imaging (MRI) or Computerized tomography (CT) shows
 solid lesions of PD;

 Cohort 2:

 1. CLL/SLL diagnosed according to IWCLL 2008 standards;

 2. Refractory or relapsed CLL/SLL that previously received at least first-line
 systemic treatment. First-line treatment is defined as at least 2 cycles of
 standard protocol or clinical trial research protocol completed based on current
 guidelines;

 3. Accord with at least one indication of CLL / SLL that requiring treatment;

 4. There is medical record confirming that it is invalid or Progression Disease
 occurs after response for the latest treatment;

 5. CT /MRI shows measurable lesions, which is defined as at least one lymph node
 with a maximum axis of more than 1.5 cm and with 2 measurable vertical dimension;

 6. It is allowed to include the patients with a stable condition involving the
 central nervous system;

 Cohort 3:

 1. Mantle cell lymphoma diagnosed by histopathology: including that t (11; 14) (q13;
 q32) positive by cytogenetic test and / or cyclin D1 highly expressed by
 immunohistochemistry;

 2. Who have been pretreated with > 1 but failed in ≤ 3 different chemotherapies and
 / or targeted drugs treatment.

 3. There is a medical record confirming that it is invalid or Progression Disease
 occurs after response for the latest treatment;

 4. CT / MRI shows measurable lesions, which is defined as the longest diameter (of
 ≥1 lymph node) > 1.5 cm, and 2 vertical diameters is clearly measurable;

 5. It is allowed to include the patients with a stable condition involving the
 central nervous system;

 4. When screening, the status score of Eastern Cooperative Oncology Group (ECOG) is 0 to
 2 points-Cohort 1/2/3;

 5. Estimated survival time ≥ 4 months-Cohort 1/2/3;

 6. Subjects have appropriate organ functions, the main organ functions meet the following
 criteria:

 1. Blood routine: Neutrophil absolute value ≥ 1.0(in cohort1, 0.75 in cohort
 2/3)×109 /L, platelet ≥ 75(in cohort1, 50 in cohort 2/3, 30×109/L are acceptable
 if CLL patients have bone marrow involvement, transfusion-dependent
 thrombocytopenia is excluded )×109 /L, hemoglobin ≥ 80 g/L(in cohort1). [No blood
 transfusion and hematopoietic stimulating factor are used within 21 days (7 days
 in cohort 2/3) before the first administration-Chort1];

 2. Blood biochemistry: Total bilirubin (TBIL) ≤ 2 × ULN (unless diagnosed as Gilbert
 syndrome), Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤
 2.5 × ULN; serum creatinine ≤ 2 × ULN or creatinine clearance rate ≥ 50 ml / min
 (calculated according to Cockcroft Gault formula)-Cohort 1/2/3;

 3. Coagulation function: International Standardized Ratio (INR) and Activated
 Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN-Cohort 1/2/3;

 7. Fertile female subjects must agree to use contraceptives with an annual failure rate
 of < 1% or maintain abstinence (avoid heterosexual intercourse) during the study and
 at least 90 days after the last administration of the study drug. Contraceptive
 methods with an annual failure rate of <1% includes bilateral tubal ligation, male
 sterilization, proper use of hormonal contraceptives that inhibit ovulation,
 hormone-releasing IUD (intrauterine devices), and copper-containing IUD. Male subjects
 must be sterilized by vasectomy or barrier contraception, and female partners should
 use the effective contraceptives as described above. In addition, male subjects are
 not allowed to donate sperm within 90 days after the last administration-Cohort 1/2/3.

 Exclusion Criteria:

 -  Cohort 1: R/R-PCNSL

 1. PCNSL is pathologically diagnosed as T-cell lymphoma;

 2. Have previously received any of the following treatments:

 1. Chemotherapy, targeted therapy, radiotherapy or antibody based anti-tumor
 therapy are used within 4 weeks before the first administration or within 5
 half-lives (whichever is shorter);

 2. Have previously received the treatment of B Cell Receptor (BCR) inhibitors
 (such as BTK, phosphoinositide kinase 3 kinase [PI3K] or SYK inhibitors) or
 BCL-2 inhibitors (such as ABT-199) or Chimeric Antigen Receptor T-Cell
 Immunotherapy (CAR-T) or a bispecific antibody drug;

 3. Have received Allogenetic Haematopoietic Stem Cell Transplantation
 (Allo-HSCT) or other organ transplants (except for those who have received
 ASCT more than six months);

 3. Take ≥ 8 mg dexamethasone or equivalent daily to control lymphoma symptoms;

 4. CNS external beam radiotherapy within 21 days before the first administration;

 5. The systemic immunosuppressants, including cyclosporine A, tacrolimus, sirolimus
 and other drugs, haven't stopped 28 days before the first use of the study drug,
 or > 5 mg/day of prednisone or its equivalent has been taken for long period;

 6. Have other malignant tumors within 3 years, except for the curable basal or
 squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of
 cervix or breast;

 7. Non-hematologic toxicity of the previous anti-tumor treatment has not recovered
 to ≤ grade 1 (except for hair loss);

 8. Have uncontrollable or severe cardiovascular disease, including:

 1. Congestive heart failure with New York Heart Association (NYHA) grade II or
 higher, unstable angina, myocardial infarction within 6 months before first
 study drug administration, or arrhythmia requiring treatment during
 screening, Left Ventricular Ejection Fraction (LVEF) <50% ;

 2. Primary cardiomyopathy (such as dilated cardiomyopathy, hypertrophic
 cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive
 cardiomyopathy, and atypical cardiomyopathy);

 3. Clinically significant QTc interval prolonged medical history, or the QTc
 interval of screening period > 470 ms in female, and > 450 ms in male;

 4. Uncontrollable high blood pressure (on the basis of improving life style,
 with 2 or more antihypertensive drugs (including diuretics) that will be
 reasonably tolerable and sufficient for more than one month being applied,
 the blood pressure has not reached to the standard yet, or the blood
 pressure could only be effectively controlled by taking 4 or more
 antihypertensive drugs);

 9. Have active bleeding within 2 months before screening or are taking
 anticoagulant/antiplatelet drugs, or the investigators believe that there is a
 clear bleeding tendency (such as esophageal varices with bleeding risk, or a
 locally active ulcer lesions);

 10. Have medical history of deep vein thrombosis or pulmonary embolism;

 11. Have medical history of stroke or intracranial hemorrhage within 6 months before
 taking the study drug, except for intracranial hemorrhage due to surgical
 sequelae;

 12. Have clinically significant gastrointestinal abnormalities, which might affect
 drug intake, transport or absorption (such as inability to swallow, chronic
 diarrhea, intestinal obstruction, etc.);

 13. Have serious or active infection requiring systematic anti infection treatment;

 14. At screening, patients with active uncontrolled infection [such as infection that
 requiring intravenous antibiotic therapy, human immunodeficiency virus (HIV),
 hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, etc.]; Note: If
 hepatitis B virus surface antigen (HBsAg) is positive, HBV-DNA < 1000 cop/ml, and
 ALT/AST ≤ 2.0 × ULN can be included. HCV infection is defined as HCV-Ab positive.

 15. Have past history of or current pulmonary fibrosis, interstitial pneumonia,
 pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe impairment of
 lung function, etc;

 16. Have undergone major surgery or have not recovered from the invasive operation
 within 4 weeks before taking the study drug for the first time and are not
 suitable for the clinical trial according to the judgment of the investigators;

 17. Who is participating in other clinical studies or have participated in other
 intervention clinical trials within 4 weeks before screening;

 18. Have history of alcohol or drug abuse;

 19. Pregnant or lactating women;

 20. Concomitant administration of drugs with moderate to severe inhibition or strong
 induction of cytochrome P450 CYP3A

 21. Subjects determined by the investigators to be unsuitable for other reasons;

 Cohort 2: R/R-CLL/SLL

 1. Have medical history of prolymphocytic leukemia, known medical history of Richter
 syndrome or currently suspected Richter transformation (patients with clinical
 suspicion need biopsy to exclude transformation)

 2. Have previously received any of the following treatments:

 1. Chemotherapy, targeted therapy, radiotherapy or antibody-based anti-tumor therapy
 within 4 weeks or 5 half-lives (whichever is shorter) before the first
 administration;

 2. Previous treatment with BTK, phosphoinositide kinase 3 kinase [PI3K] or SYK
 inhibitors or BCL-2 inhibitors (such as ABT-199) or chimeric antigen receptor T
 cell immunotherapy (CAR-T) or treatment with bispecific antibody drugs;

 3. Patients who received allogeneic hematopoietic stem cell transplantation
 (Allo-HSCT) or other organ transplantation within the past 6 months;

 4. Patients who received autologous hematopoietic stem cell transplantation within
 the past 6 months;

 3. Use of systemic corticosteroids within 7 days before the first administration of study
 drug, or continuous use of prednisone at or above 20 mg/day or equivalent;

 4. Other malignancies within 3 years, except for curable basal or squamous cell skin
 cancer, superficial bladder cancer, and carcinoma in situ of the uterine cervix or
 breast;

 5. Non-hematologic toxicity of the previous anti-tumor treatment has not recovered to ≤
 grade 1 (except for hair loss);

 6. Have uncontrollable or severe cardiovascular disease, including:

 1. Congestive heart failure with New York Heart Association (NYHA) grade II or
 higher, unstable angina, myocardial infarction within 6 months before first study
 drug administration, or arrhythmia requiring treatment during screening period,
 Left Ventricular Ejection Fraction (LVEF) <50%;

 2. Primary cardiomyopathy (such as dilated cardiomyopathy, hypertrophic
 cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive
 cardiomyopathy, and atypical cardiomyopathy);

 3. Clinically significant QTc interval prolonged medical history, or the QTc
 interval of screening period > 470 ms in female, and > 450 ms in male;

 4. Uncontrollable high blood pressure (on the basis of improving life style, with 2
 or more antihypertensive drugs (including diuretics) being applied that will be
 reasonably tolerable and sufficient for more than one month, the blood pressure
 has not reached to the standard yet, , or the blood pressure could only be
 effectively controlled by taking 4 or more antihypertensive drugs);

 7. Have active bleeding within 2 months before screening or is taking
 anticoagulant/antiplatelet drugs, or the investigators believe that there is a clear
 bleeding tendency (such as esophageal varices with bleeding risk, or a locally active
 ulcer lesions);

 8. Active and/or persistent autoimmune anemia and/or autoimmune thrombocytopenia
 requiring treatment (e.g., idiopathic thrombocytopenic purpura);

 9. Have medical history of deep vein thrombosis or pulmonary embolism;

 10. Have medical history of stroke or intracranial hemorrhage within 6 months before
 taking study drug;

 11. Have clinically significant gastrointestinal abnormalities, which might affect drug
 intake, transport or absorption (such as inability to swallow, chronic diarrhea,
 intestinal obstruction, etc.);

 12. Have active infection requiring systemic anti-infective treatment;

 13. At screening, patients with active uncontrolled infection [such as intravenous
 infection that requiring antibiotic therapy, human immunodeficiency virus (HIV),
 hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, etc.]; Note: If
 hepatitis B virus surface antigen (HBsAg) is positive, HBV-DNA < 1000 cop/ml, and
 ALT/AST ≤ 2.0 × ULN can be included. HCV infection is defined as HCV-Ab positive.

 14. Have past history of or current pulmonary fibrosis, interstitial pneumonia,
 pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe impairment of lung
 function, etc;

 15. Have history of alcohol or drug abuse;

 16. Have undergone major surgery or have not recovered from the invasive operation within
 4 weeks before taking the study drug for the first time and are not suitable for the
 clinical trial according to the judgment of the investigators;

 17. Whowill participating in other clinical studies or haveparticipated in other
 intervention clinical trials within 4 weeks before screening;

 18. Pregnant or lactating women;

 19. Concomitant administration of drugs with moderate to severe inhibition or strong
 induction of cytochrome P450 CYP3A;

 20. Subjects determined by the investigators to be unsuitable for other reasons;

 Cohort 3: R/R-MCL

 1. Havepreviously received any of the following treatments:

 1. Chemotherapy, targeted therapy, radiotherapy or antibody based anti-tumor therapy
 are used within the first 4 weeks or 5 half-lives (whichever is shorter) before
 the first administration;

 2. Have previously received the treatment of BTK, phosphoinositide kinase 3 kinase
 [PI3K] or SYK inhibitors) or BCL-2 inhibitors (such as ABT-199) or Chimeric
 Antigen Receptor T-Cell Immunotherapy (CAR-T) or received bispecific antibody
 drug;

 2. Use of systemic corticosteroids at or above 20 mg/day prednisone or equivalent within
 7 days before the first administration of study drug;

 3. Have other malignant tumors within 3 years, except for the curable basal or squamous
 cell skin cancer, superficial bladder cancer, carcinoma in situ of cervix or breast ;

 4. Non-hematologic toxicity of the previous anti-tumor treatment has not recovered to ≤
 grade 1 (except for hair loss);

 5. Have uncontrollable or severe cardiovascular disease, including:

 1. Congestive heart failure with New York Heart Association (NYHA) grade II or
 higher, unstable angina, myocardial infarction within 6 months before first study
 drug administration, or arrhythmia requiring treatment during screening period,
 Left Ventricular Ejection Fraction (LVEF) <50% ;

 2. Primary cardiomyopathy (such as dilated cardiomyopathy, hypertrophic
 cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive
 cardiomyopathy, and atypical cardiomyopathy);

 3. Clinically significant QTc interval prolonged medical history, or the QTc
 interval of screening period > 470 ms in female, and > 450 ms in male;

 4. Uncontrollable high blood pressure (on the basis of improving life style, with 2
 or more antihypertensive drugs (including diuretics) that will be reasonably
 tolerable and sufficient for more than one month being applied, the blood
 pressure has not reached to the standard yet, , or the blood pressure could only
 be effectively controlled by taking 4 or more antihypertensive drugs);

 6. Have medical history of deep vein thrombosis or pulmonary embolism;

 7. Have medical history of stroke or intracranial hemorrhage within 6 months before
 taking study drug;

 8. Have clinically significant gastrointestinal abnormalities, which might affect drug
 intake, transport or absorption (such as inability to swallow, chronic diarrhea,
 intestinal obstruction, etc.);

 9. Have serious or active infection requiring systematic anti infection treatment;

 10. At screening, patients with active uncontrolled infection [such as infection that
 requiring intravenous antibiotic therapy, human immunodeficiency virus (HIV),
 hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, etc.]; Note: If
 hepatitis B virus surface antigen (HBsAg) is positive, HBV-DNA < 1000 cop/ml, and
 ALT/AST≤ 2.0 × ULN can be included. HCV infection is defined as HCV-Ab positive.

 11. Have past history of or current pulmonary fibrosis, interstitial pneumonia,
 pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe impairment of lung
 function, etc;

 12. Have history of alcohol or drug abuse;

 13. Have undergone major surgery or have not recovered from the invasive operation within
 4 weeks before taking the study drug for the first time and is not suitable for the
 clinical trial according to the judgment of the investigators;

 14. Who is participating in other clinical studies or have participated in other
 intervention clinical trials within 4 weeks before screening;

 15. Pregnant or lactating women;

 16. Concomitant administration of drugs with moderate to severe inhibition or strong
 induction of cytochrome P450 CYP3A;

 17. Subjects determined by the investigators to be unsuitable for other reasons;