This is a Phase 1 study to evaluate the safety, pharmacokinetics(PK), and preliminary
clinical activity of KPG-818 as a single agent in adult subjects with selected hematological
malignancies, including multiple myeloma (MM), mantle cell lymphoma (MCL), follicular
lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), indolent lymphoma, adult T-cell
leukemia-lymphoma (ATL), or chronic lymphocytic leukemia (CLL). This study will assist in
identifying appropriate, well tolerated doses that can be administered in subsequent studies
in subjects with selected hematological malignancies.
This is a Phase 1, multicenter, open-label, multiple-ascending dose study to evaluate the
safety, PK, and preliminary clinical activity of KPG-818 as a single agent in adult subjects
with selected hematological malignancies. The study center(s) will be in the US.
After providing informed consent, subjects will be assessed for study eligibility at the
Screening visit (Days -28 to -1). Cohorts of 3 to 6 subjects per dose level will be given
escalating doses of KPG-818 during Days 1 to 21 of each 28-day cycle orally until progressive
disease (PD), unacceptable toxicity, the subject withdraws, or any other study withdrawal
criterion is met. The 4 planned dose escalation cohorts will be 5, 10, 20, and 30 mg followed
by dose expansion. The dose of KPG-818 for the first cohort will be 2 mg/day.
Dose escalation will use an accelerated titration design (ATD) where the first two dose
levels will include one subject each. Subsequent dose levels will use a 3+3 approach to
establish a MTD. The first subject will receive the initial escalation dose level 5 mg/day
and be dosed on Day 1 to 21 over a 28-day treatment cycle, and in the absence of a DLT or
Grade 2 or greater study drug-related AE and after review of the data from the first full
cycle by the Safety Review Committee (SRC), the next subject will receive 10 mg/day followed
by review of the data by the SRC. Once 20 mg/day is reached, the enrolment will revert to a
standard 3+3 escalation design.
If 1 or more Grade 2 or greater study drug-related AE is observed at dose levels 5 or 10
mg/day, two additional subjects will be enrolled at the same dose level, and dose escalation
reverts to a standard 3+3 escalation design. If 1 or more DLT is observed at dose levels of 5
or 10 mg/day, five additional subjects will be enrolled at the same dose level and dose
escalation reverts to a standard 3+3 escalation design (Table 3). Enrolment to 20 mg/day will
follow a standard 3+3 escalation design.
The highest dose level which may be tested is 30 mg KPG-818. Dose escalation will follow a
3+3 design and dose-limiting toxicity (DLT) will be assessed during the 28-day DLT evaluation
period. The Safety Monitoring Committee (SMC) will be responsible for dose escalation
decisions, including whether to modify the dose escalation based on the DLT observations or
determine RP2D. Escalation to the Maximal Tolerated Dose (MTD) is not appropriate if activity
plateaus at a lower dose.
Inclusion Criteria
Subjects must satisfy all of the following criteria at the Screening visit unless otherwise
stated:
1. ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Willing and able to provide written consent.
3. Willing and able to adhere to the study visit schedule and other protocol
requirements.
4. Hematocytological or pathological diagnosis of MM, MCL, DLBCL, ATL, indolent lymphoma,
such as FL and CLL/SLL, etc.
5. Subjects who have relapsed from or are refractory to ALL FDA approved therapies* known
to provide clinical benefit for the specific disease, unless the subject is not
eligible for the approved therapy.
*Definition of ALL FDA approved therapies are specified as below:
Prior treatments for MM subjects:
- Received at least 3 prior anti-myeloma regimens including at least 2 consecutive
cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid
and an anti-CD38 antibody (induction with or without a bone marrow transplant
with or without maintenance therapy is considered one regimen).
- Refractory disease defined as disease that is nonresponsive to therapy (failure
to achieve minimal response or development of progressive disease) or disease
progression within 60 days from the last dose of their last myeloma therapy.
Prior treatments for NHL subjects:
- ATL: at least 2 prior lines of therapy containing alkylator-based chemotherapy.
- MCL: at least 2 prior lines of therapy, including CD20 antibody and alkylator
chemotherapy, and a Bruton's tyrosine kinase (BTK) inhibitor.
- DLBCL: at least 2 prior lines of therapy, including prior CD20 antibody therapy,
and has received prior autologous bone marrow transplant (or is ineligible for
bone marrow transplant).
- FL: at least 2 prior lines of therapy, including CD20 antibody therapy and
alkylator chemotherapy.
- CLL/SLL: at least 2 prior lines of therapy for CLL/SLL and require treatment by
2018 iwCLL criteria.
- Other indolent NHL: Subjects must have been treated with all standard of care
therapies available to the subject which, in the assessment of the investigator,
may be beneficial to the subject.
6. Have measurable or assessable disease.
For MM:
- M-protein quantities ≥ 0.5 g/dL by serum protein electrophoresis (SPEP or SIFE)
or
- M-protein quantities ≥ 200 mg/24-hour urine collection by urine protein
electrophoresis (UPEP or UIFE) or
- Serum free light chain (FLC) levels > 100 mg/L involved light chain and an
abnormal kappa/lambda (κ/λ) ratio in subjects without detectable serum or urine
M-protein or
- For subjects with immunoglobulin (Ig) class A (IgA) myeloma whose disease can
only be reliably measured by quantitative Ig measurement, a serum IgA level ≥
0.50 g/dL.
For MCL, DLBCL, ATL, indolent lymphoma, such as FL and CLL/SLL, etc.:
• At least 1 bidimensionally measurable lesion larger than 1.5 cm in largest dimension
by computed tomography (CT), positron emission tomography CT (PET-CT), or magnetic
resonance imaging (MRI) scan.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. ECOG of 2 is
allowed during dose expansion.
8. Males and females of childbearing potential must agree to use at least two methods of
contraception, as detailed in Section 6.1.3, during the study treatment and continue
until 3 months after the completion of study treatment.
Exclusion Criteria
Subjects will be excluded from the study if they satisfy any of the following criteria at
the Screening visit unless otherwise stated:
1. Has any significant medical condition, laboratory abnormality, or psychiatric illness
that would prevent the subject from participating in the study.
2. Currently enrolled in another clinical study, except observational studies.
3. Has known active central nervous system metastases and/or lymphomatous meningitis.
4. Persisting toxicities related to prior anticancer treatment > Grade 1 according to NCI
CTCAE v5.0.
5. Major surgery or significant traumatic injury within 6 weeks prior to Screening or
planned major surgery during the study period.
6. Any of the following laboratory abnormalities:
- Absolute neutrophil count (ANC) < 1.0 × 109/L.
- Hemoglobin ≤ 7.5 g/dL (red blood cell [RBC] transfusion is allowed to meet
eligibility).
- Platelet count ≤ 75 000/μL (except in the case of bone marrow involvement when
platelet count must not be < 50 000/μL).
- Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L).
- AST and/or ALT ≥ 2.5 × ULN or ≥ 5.0 × ULN if liver tumor is present.
- Total bilirubin > 1.5 × ULN.
- Estimated serum creatinine clearance of ≤ 60 mL/min or requiring
dialysis；estimated serum creatinine clearance between 50-60 mL/min may be
enrolled for KPG-818 dose ≤ 10mg/day. For subjects with serum creatinine
clearance between 50-60 mL/min at screening, serum creatinine clearance levels
should be monitored during the study.
7. Subjects with gastrointestinal disease that may significantly alter the absorption of
the study drug.
8. Subjects with a prior history of malignancies, other than MM, lymphoma, or CLL/SLL,
unless the subject has been free of the disease for ≥ 5 years with the exception of
the following noninvasive malignancies:
- Basal cell carcinoma of the skin.
- Squamous cell carcinoma of the skin.
- Carcinoma in situ.
- Incidental histological findings of prostate cancer such as T1a or T1b using the
tumor/node/metastasis classification of malignant tumors or prostate cancer that
is curative.
9. Has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, or
pomalidomide.
10. Has known or suspected hypersensitivity to the excipients contained in the formulation
of investigational product (IP).
11. Has received any of the following within the last 14 days of initiating IP:
- Plasmapheresis
- Radiation therapy other than local therapy for MM associated bone lesions
- Use of any systemic myeloma/lymphoma/CLL/SLL drug therapy.
12. Has been treated with an investigational agent (i.e., an agent not commercially
available) within 28 days or 5 half-lives (whichever is longer) of initiating IP.
13. Prior treatment of any inhibitors of PD-1 or PD-L1 within 3 months prior to initiating
IP.
14. Has any one of the following:
- Clinically significant abnormal ECG finding, including QTcF interval elongation
(> 480 ms), at Screening.
- Congestive heart failure (New York Heart Association Class III or IV).
- Myocardial infarction within 12 months prior to initiating IP.
- Unstable or poorly controlled angina pectoris, including the Prinzmetal variant
of angina pectoris.
- Peripheral neuropathy ≥ Grade 2.
- Subject has taken a strong inhibitor or inducer of CYP3A4/5 including grapefruit,
St. John's Wort or related products within 2 weeks prior to dosing and during the
course of study.
15. Has current or prior use of immunosuppressive medication within 14 days prior
initiating IP. The following are exceptions to this criterion:
- Intranasal, inhaled, topical, or local steroid injections (e.g., intra-articular
injection)
- Systemic corticosteroids at physiologic doses that do not exceed 10 mg/day of
prednisone or equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication).
16. Subject known to test positive for human immunodeficiency virus, active hepatitis B,
or active hepatitis C.
Note: subjects who are hepatitis B core antibody (anti-HBc) positive and hepatitis B
surface antigen (HBsAg) negative are required to have a negative hepatitis B DNA PCR
result before randomization and must be willing to undergo the DNA PCR testing during
the study. Subjects who are HBsAg positive or hepatitis B DNA PCR positive will be
excluded.
Subjects who are hepatitis C virus antibody positive are required to have a negative
hepatitis C RNA PCR result. Subjects who are hepatitis C RNA PCR-positive will be
excluded.
17. Subjects with any active or uncontrolled infection.
18. Subject is unable or unwilling to undergo protocol required thromboembolism
prophylaxis.
19. Subject is a female who is pregnant, nursing, or breastfeeding.
