Safety, Tolerability and Pharmacokinetics Study of KPG-818 in Hematological Malignancies Subjects

Hematological Malignancies Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04283097
• Other study ID #: KPG-818-HEM-101
• Status: Recruiting
• Phase: Phase 1
• Start date: September 13, 2021
• Est. completion date: May 14, 2025

Study information

• Verified date: March 2024
• Source: Kangpu Biopharmaceuticals, Ltd.
• Contact: Yao Wang, MD
• Phone: +19738738678
• Email: yao.wang[@]kangpugroup.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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]).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: May 14, 2025
• Est. primary completion date: October 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hematologic Neoplasms
• Hematological Malignancies
• Neoplasms

Intervention

Drug:
• KPG-818
The 4 planned dose level (cohorts) of KPG-818 will be explored: 2, 3, 4 and 5mg. Each dose of KPG-818 will be administered orally with approximately 240 ml of water daily, and used as a single agent in subjects with selected hematological malignancies (or in combination with dexamethasone weekly for MM), according to specific dosing schedule in each treatment cycle until disease progression, unacceptable toxicity, the subject withdraws, or any other study withdrawal criterion is met. The treatment of study is divided into 6 cycles.

Locations

Country	Name	City	State
United States	Henry Ford Health System - Hemophilia and Thrombosis Treatment Center	Detroit	Michigan
United States	Duke University Health System - Duke Endoscopy - Duke Clinic 2H	Durham	North Carolina
United States	Laguna Clinical Research Associates	Laredo	Texas
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Mohamad Medical Cherry	Morristown	New Jersey
United States	UPMC CancerCenter	Pittsburgh	Pennsylvania
United States	BRCR Global - USA	Plantation	Florida
United States	Providence Portland Medical Center	Portland	Oregon
United States	UC Davis Comprehensive Cancer Center	Sacramento	California

Sponsors (1)

Lead Sponsor	Collaborator
Kangpu Biopharmaceuticals, Ltd.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biomarkers of KPG-818	Aiolos and Ikaros in peripheral blood mononuclear cell (PBMC)	Up to 6 months of treatment
Primary	Treatment-Emergent Adverse Events [Safety and Tolerability]	Number of Treatment-Emergent Adverse Events(TEAE), serious adverse events (SAEs), dose-limiting toxicities (DLTs), and changes from baseline in laboratory parameters, vital signs, and ECG.	Up to 6 months of treatment
Primary	Recommended Phase 2 Dose (RP2D)	Maximum tolerated dose defined as the highest dose level at which 33% or less subjects experience DLT as defined by the protocol.	Up to 4 weeks of treatment
Secondary	PK profile of KPG-818: maximum observed plasma concentration (Cmax).		Up to 4 weeks of treatment
Secondary	PK profile of KPG-818: time of the maximum observed plasma concentration (Tmax)		Up to 4 weeks of treatment
Secondary	PK profile of KPG-818: area under the plasma concentration-time profile (AUC) from time zero to the last quantifiable concentration (AUC0-t).		Up to 4 weeks of treatment
Secondary	PK profile of KPG-818: AUC from time zero extrapolated to infinity (AUC0-8).		Up to 4 weeks of treatment
Secondary	PK profile of KPG-818: AUC within a dosing interval (AUC0-t).		Up to 4 weeks of treatment
Secondary	PK profile of KPG-818: apparent total plasma clearance (CL/F).		Up to 4 weeks of treatment
Secondary	PK profile of KPG-818: apparent total plasma clearance at steady-state (CLss/F).		Up to 4 weeks of treatment
Secondary	PK profile of KPG-818: apparent volume of distribution (Vz/F)		Up to 4 weeks of treatment
Secondary	PK profile of KPG-818: apparent volume of distribution at steady-state (Vss).		Up to 4 weeks of treatment
Secondary	PK profile of KPG-818: apparent plasma terminal elimination. half-life (t1/2)		Up to 4 weeks of treatment
Secondary	Assessment of clinical activity: objective response rate (ORR).	Responses are evaluated based on International Myeloma Working Group (IMWG) Uniform Response Criteria (for MM), Lugano Classification (for lymphoma), International Workshop Group on CLL (iwCLL) Response Criteria, and according to the 'Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma' (for ATL).	Up to 6 months of treatment
Secondary	Assessment of clinical activity: disease control rate (DCR).	Responses are evaluated based on International Myeloma Working Group (IMWG) Uniform Response Criteria (for MM), Lugano Classification (for lymphoma), International Workshop Group on CLL (iwCLL) Response Criteria, and according to the 'Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma' (for ATL).	Up to 6 months of treatment
Secondary	Assessment of clinical activity: time to response, duration of response.	Responses are evaluated based on International Myeloma Working Group (IMWG) Uniform Response Criteria (for MM), Lugano Classification (for lymphoma), International Workshop Group on CLL (iwCLL) Response Criteria, and according to the 'Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma' (for ATL).	Up to 6 months of treatment
Secondary	Assessment of clinical activity: progression-free survival.	Responses are evaluated based on International Myeloma Working Group (IMWG) Uniform Response Criteria (for MM), Lugano Classification (for lymphoma), International Workshop Group on CLL (iwCLL) Response Criteria, and according to the 'Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma' (for ATL).	Up to 6 months of treatment
Secondary	Assessment of clinical activity: event-free survival (EFS), and transplantation rate (TR).	Responses are evaluated based on International Myeloma Working Group (IMWG) Uniform Response Criteria (for MM), Lugano Classification (for lymphoma), International Workshop Group on CLL (iwCLL) Response Criteria, and according to the 'Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma' (for ATL).	Up to 6 months of treatment