Clinical Trials /

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

NCT04283097

Description:

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.

Related Conditions:
  • Adult T-Cell Leukemia/Lymphoma
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Indolent Non-Hodgkin Lymphoma
  • Mantle Cell Lymphoma
  • Multiple Myeloma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: KPG-818-HEM-101
  • NCT ID: NCT04283097

Conditions

  • Hematological Malignancies

Interventions

DrugSynonymsArms
KPG-818KPG-818 capsulesKPG-818

Purpose

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 5 planned dose levels (cohorts) will be 2, 5, 10, 20, and 30 mg. The
      dose of KPG-818 for the first cohort will be 2 mg/day. The highest dose level which may be
      tested is 30 mg KPG-818. Dose escalation will follow a 3+3 design. Dose-limiting toxicity
      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.
    

Trial Arms

NameTypeDescriptionInterventions
KPG-818ExperimentalKPG-818 dose escalation
  • KPG-818

Eligibility Criteria

        Inclusion Criteria:

        Participants are eligible to be included in the study only if all the following criteria
        apply.

          1. ≥ 18 years of age at the time of signing the informed consent form (ICF).

          2. Willing and able to provide written ICF.

          3. Willing and able to adhere to the study visit schedule and other protocol
             requirements.

          4. Hematooncological or pathological diagnosis of MM, MCL, FL, DLBCL, indolent lymphoma,
             ATL or CLL.

          5. Subjects who have relapsed from or are refractory to all therapies known to provide
             clinical benefit AND for whom no standard treatment is available.

          6. Have measurable or assessable disease.

             For Multiple Myeloma:

               -  M-protein quantities ≥ 0.5 g/dL by serum protein electrophoresis (SPEP) or

               -  M-protein quantities ≥ 200 mg/24-hour urine collection by urine protein
                  electrophoresis (UPEP) 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, FL, DLBCL, indolent lymphoma, ATL, or CLL:

             • 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.

          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 Participants are excluded from the study if any of the following
        criteria apply.

          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) ≤ 1.5 × 109/L.

               -  Hemoglobin ≤ 8 g/dL.

               -  Platelet count < 75 000/μL.

               -  Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L).

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥ 2.5 × upper
                  limit of normal (ULN) or ≥ 5.0 × ULN if liver tumor is present.

               -  Total bilirubin > 1.5 × ULN.

               -  Potassium not within normal limits.

               -  Estimated serum creatinine clearance of ≤ 60 mL/min or requiring dialysis.

          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, 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 dosing:

               -  Plasmapheresis

               -  Radiation therapy other than local therapy for MM associated bone lesions

               -  Use of any systemic myeloma/lymphoma/CLL drug therapy.

         12. Has been treated with an investigational agent (ie, 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
             dosing.

         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 (eg, 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 (eg, CT scan
                  premedication).

         16. Subject known to test positive for human immunodeficiency virus, chronic or active
             hepatitis B, or active hepatitis C.

         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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame:Up to 6 months of treatment
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:PK profile of KPG-818
Time Frame:Up to 28-day of treatment
Safety Issue:
Description: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.
Measure:Preliminary clinical activity
Time Frame:Up to 6 months of treatment
Safety Issue:
Description: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).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Kangpu Biopharmaceuticals, Ltd.

Last Updated

February 21, 2020