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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04283097
Recruitment Status : Recruiting
First Posted : February 25, 2020
Last Update Posted : June 8, 2021
Sponsor:
Information provided by (Responsible Party):
Kangpu Biopharmaceuticals, Ltd.

Tracking Information
First Submitted Date  ICMJE February 21, 2020
First Posted Date  ICMJE February 25, 2020
Last Update Posted Date June 8, 2021
Actual Study Start Date  ICMJE May 15, 2020
Estimated Primary Completion Date December 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 21, 2020)
  • Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Up to 6 months of treatment ]
    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.
  • Recommended Phase 2 Dose (RP2D) [ Time Frame: Up to 28-day of treatment ]
    Maximum tolerated dose defined as the highest dose level at which 33% or less subjects experience DLT as defined by the protocol.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 21, 2020)
  • PK profile of KPG-818 [ Time Frame: Up to 28-day of treatment ]
    Cmax, time of the maximum observed plasma concentration (Tmax), AUC0-t, AUC from time zero extrapolated to infinity (AUC0-∞), AUC within a dosing interval (AUC0-τ), apparent total plasma clearance (CL/F), apparent total plasma clearance at steady-state (CLss/F), apparent volume of distribution (Vz/F), apparent volume of distribution at steady-state (Vss/F), and t1/2.
  • Preliminary clinical activity [ Time Frame: Up to 6 months of treatment ]
    Objective response rate (ORR), disease control rate (DCR), time to response, duration of response (DOR), progression-free survival (PFS), 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 3 (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 (ATL).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 21, 2020)
Biomarkers of KPG-818 [ Time Frame: Up to 6 months of treatment ]
Aiolos and Ikaros in peripheral blood mononuclear cell (PBMC)
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability and Pharmacokinetics Study of KPG-818 in Hematological Malignancies Subjects
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Dose escalation will based on a 3+3 design followed by dose expansion. Dose-limiting toxicity will be assessed during the 28-day DLT evaluation period. Subjects who exit the study for reasons other than DLT prior to completion of the 28-day evaluation period will be replaced to ensure an adequate safety assessment at each dose level.
Masking: None (Open Label)
Masking Description:
This is a open label phase 1 study.
Primary Purpose: Treatment
Condition  ICMJE Hematological Malignancies
Intervention  ICMJE Drug: KPG-818
KPG-818 represents a novel generation of small molecule modulators of the CRBN E3 ubiquitin ligase complex CRL4CRBN and potently induces the ubiquitination and degradation of Aiolos (IKZF3) and Ikaros (IKZF1), two members of the Ikaros family of zinc-finger transcription factors critical in B-cell development. In preclinical studies, KPG-818 demonstrated outstanding in vitro anti-inflammatory properties and broad spectrum of anti-proliferative activities as well as remarkable in vivo efficacy in animal models of multiple blood cancers.
Other Name: KPG-818 capsules
Study Arms  ICMJE Experimental: KPG-818
KPG-818 dose escalation
Intervention: Drug: KPG-818
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 27, 2020)
56
Original Estimated Enrollment  ICMJE
 (submitted: February 21, 2020)
40
Estimated Study Completion Date  ICMJE December 30, 2022
Estimated Primary Completion Date December 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kai Wei, MD +8618201496205 kai.wei@kangpugroup.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04283097
Other Study ID Numbers  ICMJE KPG-818-HEM-101
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Kangpu Biopharmaceuticals, Ltd.
Study Sponsor  ICMJE Kangpu Biopharmaceuticals, Ltd.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Kai Guo, MD Kangpu Biopharmacuticals
PRS Account Kangpu Biopharmaceuticals, Ltd.
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP