Clinical trial NCT04283097: Safety, Tolerability and Pharmacokinetics Study of KPG-818 in Hematological Malignancies Subjects
Official title: A Phase 1, Multicenter, Open-label, Multiple-ascending Dose Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of KPG-818 in Subjects With Hematological Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hematological Malignancies
Lead sponsor: Kangpu Biopharmaceuticals, Ltd.
Sponsor class: INDUSTRY
First posted: 2020-02-25
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Dose escalation will use a standard 3+3 approach to establish a maximum tolerated dose (MTD), and the initial escalation dose level will be 2mg/day. Subjects may be enrolled at dose levels 2, 3, 4, and 5 mg and/or intermediate dosing or alternative dosing schedule
Primary purpose: TREATMENT

Brief summary: This is a phase 1, multicenter, open-label, multiple-ascending dose study to evaluate the safety, pharmacokinetics and clinical activity of KPG-818 in subjects with hematological malignancies. Approximately 30 patients will be enrolled for dose escalation of 4 dose levels.

Indication: Hematological malignancies (multiple myeloma \[MM\], mantle cell lymphoma \[MCL\], diffuse large B-cell lymphoma \[DLBCL\], adult T-cell leukemia-lymphoma \[ATL\], and indolent non Hodgkin lymphomas such as follicular lymphoma \[FL\] and chronic lymphocytic leukemia \[CLL\]/small lymphocytic lymphoma \[SLL\]).

Detailed description: This will be a dose escalation study in subjects with selected hematological malignancies. KPG-818 will be used in combination with dexamethasone in subjects with MM, and as monotherapy for other selected hematological malignancies. Each dose of KPG-818 will be administered orally until the completion of treatment cycles, or progressive disease (PD), unacceptable toxicity, the subject withdraws, or any other study withdrawal criterion is met.

The highest dose level which may be tested is 5 mg KPG-818 and dose levels 2, 3, 4, and 5 mg and/or intermediate dosing or alternative dosing schedule may be explored. Each dose level (1-4) will be tested using the standard 3+3 design. DLT will be assessed during the DLT evaluation period (Cycle 1) and the treatment of study is divided into 6 cycles.

Eligibility criteria: Inclusion Criteria:

1. ≥ 18 years of age
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 MM, MCL, DLBCL, ATL, indolent lymphoma, such as FL and CLL/SLL.
6. Have measurable or assessable disease.
7. Meet the laboratory requirements:
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
9. Males and females of childbearing potential must agree to use at least two methods of contraception and continue until 3 months after the completion of study treatment.

Exclusion Criteria:

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.
5. Major surgery or significant traumatic injury within 6 weeks prior to Screening or planned major surgery during the study period.
6. Received live attenuated vaccine within 4 weeks of first dose.
7. Subjects with gastrointestinal disease that may significantly alter the absorption of the study drug.
8. Subjects with a plasma cell leukemia.
9. Subjects with prior history of malignancies, other than MM, lymphoma, or CLL/SLL, unless the subject has been free of the disease for ≥ 5 years.
10. Has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, or pomalidomide.
11. Has known or suspected hypersensitivity to the excipients contained in the formulation of investigational product (IP).
12. Has been treated with an investigational agent (i.e., an agent not commercially available) within 28 days 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 at Screening.
    * Congestive heart failure.
    * 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.
16. Subject known to test positive for human immunodeficiency virus, active hepatitis B, or active hepatitis C.
17. Subject is unable or unwilling to undergo protocol required thromboembolism prophylaxis.
18. Subject is a female who is pregnant, nursing, or breastfeeding.

Primary outcomes:
measure: Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: Up to 6 months of treatment
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: Up to 4 weeks of treatment
Secondary outcomes:
measure: PK profile of KPG-818: maximum observed plasma concentration (Cmax).
timeFrame: Up to 4 weeks of treatment
measure: PK profile of KPG-818: time of the maximum observed plasma concentration (Tmax)
timeFrame: Up to 4 weeks of treatment
measure: PK profile of KPG-818: area under the plasma concentration-time profile (AUC) from time zero to the last quantifiable concentration (AUC0-t).
timeFrame: Up to 4 weeks of treatment
measure: PK profile of KPG-818: AUC from time zero extrapolated to infinity (AUC0-∞).
timeFrame: Up to 4 weeks of treatment
measure: PK profile of KPG-818: AUC within a dosing interval (AUC0-τ).
timeFrame: Up to 4 weeks of treatment
measure: PK profile of KPG-818: apparent total plasma clearance (CL/F).
timeFrame: Up to 4 weeks of treatment
measure: PK profile of KPG-818: apparent total plasma clearance at steady-state (CLss/F).
timeFrame: Up to 4 weeks of treatment
measure: PK profile of KPG-818: apparent volume of distribution (Vz/F)
timeFrame: Up to 4 weeks of treatment
measure: PK profile of KPG-818: apparent volume of distribution at steady-state (Vss).
timeFrame: Up to 4 weeks of treatment
measure: PK profile of KPG-818: apparent plasma terminal elimination. half-life (t1/2)
timeFrame: Up to 4 weeks of treatment
measure: Assessment of clinical activity: objective response rate (ORR).
timeFrame: Up to 6 months of treatment
measure: Assessment of clinical activity: disease control rate (DCR).
timeFrame: Up to 6 months of treatment
measure: Assessment of clinical activity: time to response, duration of response.
timeFrame: Up to 6 months of treatment
measure: Assessment of clinical activity: progression-free survival.
timeFrame: Up to 6 months of treatment
measure: Assessment of clinical activity: event-free survival (EFS), and transplantation rate (TR).
timeFrame: Up to 6 months of treatment
Other outcomes:
measure: Biomarkers of KPG-818
timeFrame: Up to 6 months of treatment
Locations:
city: Sacramento
country: United States
facility: UC Davis Comprehensive Cancer Center
state: California
city: Plantation
country: United States
facility: BRCR Global - USA
state: Florida
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Detroit
country: United States
facility: Henry Ford Health System - Hemophilia and Thrombosis Treatment Center
state: Michigan
city: Morristown
country: United States
facility: Mohamad Medical Cherry
state: New Jersey
city: Durham
country: United States
facility: Duke University Health System - Duke Endoscopy - Duke Clinic 2H
state: North Carolina
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Pittsburgh
country: United States
facility: UPMC CancerCenter
state: Pennsylvania
city: Laredo
country: United States
facility: Laguna Clinical Research Associates
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Kangpu Biopharmacuticals
name: MD
role: STUDY_DIRECTOR
References: