| Eligibility |
Inclusion Criteria:
- Dose escalation phase:
1. Age = 18 and = 70 years old, both men and women.
2. Tissue biopsy, bone marrow examination and / or hematological examination
confirmed relapsed refractory (Note 1) malignant lymphoma, chronic lymphoblastic
leukemia and multiple myeloma. (Note 2 and Note 3)
3. With measurable lesions . (Note 4)
4. Eastern Cooperative Oncology Group (ECOG) score=2.
5. The level of organ function must meet the following requirements:
Bone marrow:
1. Absolute neutrophil count (ANC) = 1000 /µL (if recent bone marrow biopsies or smears
prove tumor progression, this index can be < 1000/µL).
2. Hemoglobin (HGB) = 9g/dL.
3. Platelet count (PLT) = 1000000/µL (if recent bone marrow biopsies or smears prove
tumor progression, this index can be < 1000000/µL).
Liver function:
In patients with serum bilirubin = 1.5 ×upper limit of normal value (ULN) or Gilbert
syndrome, the total bilirubin is less than 3.0 × ULN and direct bilirubin is within the
normal range.
Serum creatinine < 1.5×ULN; Alanine aminotransferase (ALT), Aspartate aminotransferase
(AST)or Alkaline phosphatase (ALP) = 2.5 ×ULN.
When there is liver metastasis, ALT, AST or ALP = 5 × ULN.
6.Non-pregnant women and male and female subjects who did not consider fertility during and
after the trial, or who had preserved sperm or eggs in vitro before the trial, or
reconsidered fertility according to reproductive function 5 years after the end of the
trial.
7.After a comprehensive understanding, the subjects were willing to sign the informed
consent form.
Note 1: relapse or refractory is defined as follows:
Chronic Lymphoblastic Leukemia: subjects who are ineffective after at least 2 chemotherapy
regimens, and the subjects are not suitable or refuse to transplant. Relapse: the patient
reached Complete Response (CR) or Partial Response (PR), and Progressive Disease (PD) = 6
months later. Refractory: failed treatment (without CR or PR) or PD less than 6 months
after the last chemotherapy.
Malignant Lymphoma: refractory or relapse after at least 2 chemotherapy regimens.
Multiple Myeloma: relapse or refractory is defined as relapse or disease progression after
at least 2 chemotherapy regimens (refractory occurred during the last chemotherapy or
within 60 days after the last medication).
Note 2: Malignant Lymphoma includes B-cell non-Hodgkin's lymphoma, B-cell Hodgkin's
lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma and so on.
Note 3: If the subjects can provide test results to confirm the nature of the disease and
the researchers determine that the nature of the disease has not changed, there is no need
for reexamination.
Note 4: For subjects with malignant lymphoma, the lesions are measured by computed
tomography (CT) or magnetic resonance imaging (MRI) or positron emission tomography (PET) /
PET-CT. Bone marrow biopsy or smear may be performed in the evaluation of curative effect.
For subjects with multiple myeloma, it can be accepted that bone marrow biopsy or smear may
be performed during the evaluation of the curative effect.
For subjects with chronic lymphoblastic leukemia, it can be accepted that bone marrow
biopsy or smear may be performed during the evaluation of the curative effect.
- Dose expansion phase:
1. After a comprehensive understanding, the subjects were willing to sign the
informed consent form.
2. Age = 18 and = 70 years old, both men and women.
3. Tissue biopsy confirmed as relapse or refractory (Note 1) non-Hodgkin's lymphoma.
4. With measurable lesions .(Note 4)
5. Eastern Cooperative Oncology Group (ECOG) score=2.
6. The level of organ function must meet the following requirements:
Bone marrow:
1. Absolute neutrophil count (ANC) = 1000 /µL.
2. Hemoglobin (HGB) = 8g/dL.
3. Platelet count (PLT) = 1000000/µL (if recent bone marrow biopsies or smears prove
tumor progression, this index can be < 1000000/µL).
Liver function:
In patients with serum bilirubin = 1.5 ×upper limit of normal value (ULN) or Gilbert
syndrome, the total bilirubin is less than 3.0 × ULN and direct bilirubin is within the
normal range.
Serum creatinine < 1.5×ULN; Alanine aminotransferase (ALT), Aspartate aminotransferase
(AST) or Alkaline phosphatase (ALP) = 2.5 ×ULN.
When there is liver metastasis, ALT, AST or ALP = 5 × ULN.
7.Non-pregnant women and male and female subjects who did not consider fertility during and
after the trial, or who had preserved sperm or eggs in vitro before the trial, or
reconsidered fertility according to reproductive function 5 years after the end of the
trial.
Note 1: relapse or refractory is defined as refractory or relapse after at least 2
chemotherapy regimens.
Note 2: The lesions are measured by computed tomography (CT) or magnetic resonance imaging
(MRI) or positron emission tomography (PET) / PET-CT. Bone marrow biopsy or smear may be
performed in the evaluation of curative effect.
Exclusion Criteria:
- Dose escalation phase:
1. Severe allergies to research drugs or any of their excipients are known.
2. Because the research drugs may have genotoxicity, mutagenicity and
teratogenicity, the following subjects should be excluded: men and women who plan
to reproduce within 5 years without in vitro preservation of sperm or eggs before
the trial, unless follow-up studies confirm reproductive safety; pregnant or
lactating women.
3. The treatment of the subjects before the trial:
1. Bone marrow transplantation was performed within 3 months before enrolling
the group.
2. Received bone marrow inhibitory chemotherapy or biotherapy within 3 weeks
before enrolling the group.
3. Before enrolling the group, the subjects had been treated with any
persistent or intermittent small molecular targeted drugs (Phosphoinositide
3-kinase (PI3K) inhibitors or Mammalian Target of Rapamycin (mTOR)
inhibitors or Histone Deacetylase (HDAC) inhibitors). Subjects in the dose
increasing phase of this study will not be subject to the exclusion criteria
of this article if they participate in the expanded group phase screening.
4. Within 3 months before enrolling the group, subjects received radiotherapy
that affected the efficacy evaluation of this study, or local supportive
radiotherapy that affected the bone marrow function of the subjects.
5. Subjects received any hematopoietic colony stimulating factor therapy (such
as granulocyte colony stimulating factor (G-CSF), granulocyte macrophage
colony stimulating factor(GM-CSF)) within 2 weeks before enrolling the group
(Note 1).
6. Major surgery was performed within 14 days before enrolling the group, or
the side effects of the operation were not stable.
7. Subjects received glucocorticoid prednisone daily >10mg (or equivalent drug)
treatment within 7 days before enrollment. (Note 2)
4. After the previous treatment (chemotherapy or biotherapy), there was persistent
toxicity of grade 2 or above, which was not stable at the time of admission
(except hair loss).
5. The organ systems of the subjects were as follows:
1. Diabetes mellitus with poorly controlled blood sugar.
2. Severe lung disease (Common Terminology Criteria for Adverse Events Version
4.03(CTCAE V4.03), III-IV).
3. Active heart disease (Note 3) (New York Heart Association grade III and IV).
4. Has significant renal or liver dysfunction.
5. Poorly controlled active hepatitis B or C disease (Note 4).
6. Primary central nervous system lymphoma or metastasis of central nervous
system lymphoma.
7. A history of mental illness or emotional disorder is judged by a researcher
or psychiatrist (Note 5).
6. Occurrence of disease transformation (such as Richter syndrome, prolymphocytic
leukemia, etc.).
7. Combined use of drugs that cause prolonged QT interval or twisted ventricular
tachycardia.
8. Clinical severe infection with active > CTCAE V4.03 Grade 2; human
immunodeficiency virus (HIV) is known to be positive.
9. Persistent diarrhea (duration = 14 days).
10. There are other active malignant tumors that may interfere with this study.
11. Anything that significantly affects the parameters of pharmacokinetics.
12. Currently receiving moderate and potent cytochrome P450 (CYP) 3A4 isozyme
inhibitors or induction drugs (Note 6).
13. Are participating in other clinical trials.
14. Any condition that is unstable or may endanger the safety of subjects and their
compliance with the study.
15. The researchers believe that it is not suitable for subjects treated with this
regimen.
Note 1: subjects who began to receive erythropoietin or daipotene within 2 weeks before
entering the group can be enrolled in the group.
Note 2: if used to treat diseases other than lymphoma, such as rheumatoid arthritis,
rheumatic polymyalgia, adrenocortical dysfunction or asthma, subjects can receive a maximum
daily dose of 10mg with a stable dose of prednisone.
Note 3: includes any of the following: left ventricular ejection fraction (LVEF) found by
cardiac radionuclide scanning (Multigated Radionuclide Angiography (MUGA) ) or
echocardiography (ECHO) < 45% Fridericia corrected QT (between QTcF ) > 450ms (QTcF
formula); unstable angina pectoris; symptomatic pericarditis; abnormal recording of the
left ventricular wall in areas with persistent elevated myocardial enzymes or persistent
LVEF function measurements in the past 6 months of myocardial infarction. Has a history of
congestive heart failure (New York College of Cardiology Cardiac function Classification
III-IV), has a record of cardiomyopathy.
Note 4: a detailed assessment of the history and risk factors of hepatitis B / C must be
performed on all subjects during screening. In screening all subjects with positive medical
history, quantitative detection of hepatitis B virus deoxyribonucleic acid (DNA) and
hepatitis C virus (HCV) ribonucleic acid (RNA) was needed based on risk factors and
previous confirmation of hepatitis B/C virus infection. Hepatitis B/C virus replication
within the normal range can be included in this study.
Note 5: including medical records of depressive episodes, bipolar disorder (I or II),
obsessive-compulsive disorder, schizophrenia, suicidal attempts or suicidal ideation, or
thoughts of "causing harm to others immediately", anxiety level 3 or above, etc.
Note 6: allow a combination of inhibitors for weak CYP3A; a list of CYP3A4 inhibitors or
inducers is shown in Annex 2 of the study scheme.
- Dose expansion phase:
1. Severe allergies to research drugs or any of their excipients are known.
2. Because the research drugs may have genotoxicity, mutagenicity and
teratogenicity, the following subjects should be excluded: men and women who plan
to reproduce within 5 years without in vitro preservation of sperm or eggs before
the trial, unless follow-up studies confirm reproductive safety; pregnant or
lactating women.
3. The treatment of the subjects before the trial:
1. Before enrolling the group, the subjects had been treated with any
persistent or intermittent small molecular targeted drugs (Phosphoinositide
3-kinase (PI3K) inhibitors or Mammalian Target of Rapamycin (mTOR)
inhibitors or Histone Deacetylase (HDAC) inhibitors). Subjects in the dose
increasing phase of this study will not be subject to the exclusion criteria
of this article if they participate in the expanded group phase screening.
2. Subjects received any hematopoietic colony stimulating factor therapy (such
as granulocyte colony stimulating factor (G-CSF), granulocyte macrophage
colony stimulating factor(GM-CSF)) within 2 weeks before enrolling the group
(Note 1).
3. Major surgery was performed within 14 days before enrolling the group, or
the side effects of the operation were not stable.
4. Subjects received glucocorticoid prednisone daily >10mg (or equivalent drug)
treatment within 7 days before enrollment. (Note 2)
4. After the previous treatment (chemotherapy or biotherapy), there was persistent
toxicity of grade 2 or above, which was not stable at the time of admission
(except hair loss).
5. The organ systems of the subjects were as follows:
1. Diabetes mellitus with poorly controlled blood sugar.
2. Severe lung disease (Common Terminology Criteria for Adverse Events Version
4.03(CTCAE V4.03), III-IV).
3. Active heart disease (Note 3) (New York Heart Association grade III and IV).
4. Has significant renal or liver dysfunction.
5. Poorly controlled active hepatitis B or C disease (Note 4).
6. Primary central nervous system lymphoma or metastasis of central nervous
system lymphoma.
7. A history of mental illness or emotional disorder is judged by a researcher
or psychiatrist (Note 5).
6. Occurrence of disease transformation (such as Richter syndrome, prolymphocytic
leukemia, etc.).
7. Combined use of drugs that cause prolonged QT interval or twisted ventricular
tachycardia.
8. Clinical severe infection with active > CTCAE V4.03 Grade 2; human
immunodeficiency virus (HIV) is known to be positive.
9. Persistent diarrhea (duration =14 days).
10. There are other active malignant tumors that may interfere with this study.
11. Anything that significantly affects the parameters of pharmacokinetics.
12. Currently receiving moderate and potent cytochrome P450 (CYP) 3A4 isozyme
inhibitors or induction drugs (Note 6).
13. Are participating in other clinical trials.
14. Any condition that is unstable or may endanger the safety of subjects and their
compliance with the study.
15. The researchers believe that it is not suitable for subjects treated with this
regimen.
Note 1: subjects who began to receive erythropoietin or daipotene within 2 weeks before
entering the group can be enrolled in the group.
Note 2: if used to treat diseases other than lymphoma, such as rheumatoid arthritis,
rheumatic polymyalgia, adrenocortical dysfunction or asthma, subjects can receive a maximum
daily dose of 10mg with a stable dose of prednisone.
Note 3: includes any of the following: left ventricular ejection fraction (LVEF) found by
cardiac radionuclide scanning (Multigated Radionuclide Angiography (MUGA) ) or
echocardiography (ECHO) < 45% Fridericia corrected QT (between QTcF) > 450ms (QTcF
formula); unstable angina pectoris; symptomatic pericarditis; abnormal recording of the
left ventricular wall in areas with persistent elevated myocardial enzymes or persistent
LVEF function measurements in the past 6 months of myocardial infarction. Has a history of
congestive heart failure (New York College of Cardiology Cardiac function Classification
III-IV), has a record of cardiomyopathy.
Note 4: a detailed assessment of the history and risk factors of hepatitis B / C must be
performed on all subjects during screening. In screening all subjects with positive medical
history, quantitative detection of hepatitis B virus deoxyribonucleic acid (DNA) and
hepatitis C virus (HCV) ribonucleic acid (RNA) was needed based on risk factors and
previous confirmation of hepatitis B/C virus infection. Hepatitis B/C virus replication
within the normal range can be included in this study.
Note 5: including medical records of depressive episodes, bipolar disorder (I or II),
obsessive-compulsive disorder, schizophrenia, suicidal attempts or suicidal ideation, or
thoughts of "causing harm to others immediately", anxiety level 3 or above, etc.
Note 6: allow a combination of inhibitors for weak CYP3A; a list of CYP3A4 inhibitors or
inducers is shown in Annex 2 of the study scheme.
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