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:

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 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.
    

Trial Arms

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

Eligibility Criteria

        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.
      
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:Recruiting
Lead Sponsor:Kangpu Biopharmaceuticals, Ltd.

Last Updated

June 8, 2021