Clinical Trials /

Safety,Tolerability and MTD KA2507 (HDAC6 Inhibitor) in Patients With Solid Tumours

NCT03008018

Description:

The aim of the study is to evaluate the safety/tolerability, pharmacokinetic, and pharmaco-dynamic effects of KA2507 and establish the maximum tolerated dose (MTD). Patients with PD-L1 expressing solid tumors which have relapsed or are refractory to prior treatment will be eligible to participate in this study. Following completion of the multiple ascending dose study, the protocol may be amended to include expansion cohorts in patients with melanoma and/or other solid tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety,Tolerability and MTD KA2507 (HDAC6 Inhibitor) in Patients With Solid Tumours
  • Official Title: An Open Label Ascending Dose Study Evaluating the Safety/Tolerability, Pharmacokinetic and Pharmacodynamic Effects of KA2507 in Patients With Solid Tumours

Clinical Trial IDs

  • ORG STUDY ID: KTP-003
  • NCT ID: NCT03008018

Conditions

  • Solid Tumor, Adult

Interventions

DrugSynonymsArms
KA2507HDAC6 Inhibitor, HDAC6iKA2507 (HDAC6 inhibitor)

Purpose

The aim of the study is to evaluate the safety/tolerability, pharmacokinetic, and pharmaco-dynamic effects of KA2507 and establish the maximum tolerated dose (MTD). Patients with PD-L1 expressing solid tumors which have relapsed or are refractory to prior treatment will be eligible to participate in this study. Following completion of the multiple ascending dose study, the protocol may be amended to include expansion cohorts in patients with melanoma and/or other solid tumors.

Detailed Description

      The aim of the study is to evaluate the safety/tolerability, pharmacokinetic, and
      pharmaco-dynamic effects of KA2507 and establish the maximum tolerated dose (MTD). Patients
      with PD-L1 expressing solid tumors which have relapsed or are refractory to prior treatment
      will be eligible to participate in this study.

      Following completion of the multiple ascending dose study, the protocol may be amended to
      include expansion cohorts in patients with melanoma and/or other solid tumors.

      This is a multiple ascending dosing (MAD) study of up to 5 treatment regimens cohorts based
      on using a 3+3 design (up to 30 patients overall). The principal objective is to establish
      the maximum tolerated dose, safety, tolerability and pharmacokinetic (PK) profile in blood
      and urine of this HDAC6 inhibitor in patients with solid tumors and to explore effects on
      pharmacodynamic markers of target engagement and response to treatment.

      Daily/twice daily doses will be given as open label monotherapy. A review of safety and PK
      data will be conducted once the last patient in each cohort reaches day 28 of treatment. The
      review will confirm the dose to be used for the subsequent cohort. Dose escalation will be
      continued until the MTD is reached. Upon completion of the dose escalation phase of the
      study, dose expansion phases will be planned.

      Patients responding to treatment may elect to remain on therapy until disease progression,
      death or the investigator decides to stop treatment.
    

Trial Arms

NameTypeDescriptionInterventions
KA2507 (HDAC6 inhibitor)OtherThis is a single arm dose escalating study. Patients will be treated with open label KA2507 (HDAC6 inhibitor) capsules.
  • KA2507

Eligibility Criteria

        Inclusion Criteria:

          1. Age ≥18 years at the screening visit.

          2. Patients with confirmed diagnosis of advanced malignancy, whose disease failed to
             respond to or progressed after standard therapy; they could not tolerate standard
             therapy; or such measures are not acceptable to the subject.

          3. Either known PD-L1 expression at the time of treatment (measured using any FDA
             approved test) or PD-L1 expression demonstrated using the Ventana SP142 assay in a
             biopsy taken prior to the start of treatment

          4. Measurable or evaluable disease according to RECIST v1.1.

          5. ECOG performance status of ≤ 2.

          6. Predicted life expectancy ≥12 weeks.

          7. For men and women of child-bearing potential, willing to use adequate contraception
             (i.e., latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire
             duration of the study.

        1. If female, must be either postmenopausal, sterilised or, if sexually active, effectively
        practicing an acceptable method of contraception (either oral, parenteral, or implantable
        hormonal contraceptives, intrauterine device or barrier and spermicide). Subjects must
        agree to use adequate contraception during the study and for at least 12 weeks (or longer
        as per local requirement) after the last dose of study treatment.

        2. Male subjects agree to ensure that they or their female partner(s) use adequate
        contraception during the study and for at least 12 weeks (or longer as per local
        requirement) after the subject receives their last dose of study treatment.

        Exclusion Criteria:

          1. Patients are not able to provide written informed consent to study participation

          2. Patients who have been treated with most recent radiotherapy, hormonal therapy,
             immunotherapy, chemotherapy or investigational drugs within ≤21 days or 5 half-lives
             (whichever is shorter) from enrolment (screening), and/or who have any unresolved NCI
             Common Terminology Criteria of Adverse Events (CTCAE) v4.03 > Grade 1
             treatment-related side effect (with the exception of alopecia).

          3. Patient has anemia due to HbS or HbC disease, alpha or beta thalassaemia

          4. Patient has Glucose-6-phosphate deficiency

          5. Patient has untreated severe hypothyroidism

          6. Patient has laboratory estimations indicating organ system dysfunction:

               1. Absolute neutrophil count (ANC) <1.5 X 109/L

               2. Platelets <100 X 109/L

               3. Hemoglobin <9g/dL

               4. Total bilirubin >1.5 mg/dL

               5. ALT and AST >3.0 times the ULN if no liver involvement or >5 times the ULN with
                  liver involvement.

               6. Creatinine >1.5 x ULN, or measured creatinine clearance <60 mL/min, OR 24-hour
                  measured urine creatinine clearance <60 mL/min OR calculated creatinine clearance
                  <60mL/min estimated using the Cockcroft-Gault equation:

                    -  Cockcroft-Gault equation: creatinine clearance = (140 - age in years) x (wt
                       in kg)) x 1.23) / (serum creatinine in micromol/l) [For women multiply the
                       result of calculation by 0.85].

          7. Major surgery (excluding placement of vascular access) ≤21 days from beginning of the
             study drug or minor surgical procedures ≤7 days. No waiting is required following
             implantable port and catheter placement.

          8. Any of the following cardiac criteria:

               1. Congestive heart failure (CHF), grade III or IV per New York Heart Association
                  (NYHA) classification

               2. Symptomatic cardiomyopathy

               3. > Class II Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

               4. Unstable angina or new-onset angina

               5. QTcF interval >470 ms on screening ECG.

          9. Severe or uncontrolled systemic diseases including uncontrolled hypertension, active
             bleeding diatheses

         10. Any evidence of active infection including active Hepatitis B, Hepatitis C or human
             immunodeficiency virus

         11. Previously untreated brain metastases. Patients who have received radiation or surgery
             for brain metastases are eligible if therapy was completed at least 3 weeks previously
             and there is no evidence of central nervous system disease progression, mild
             neurologic symptoms, and no requirement for chronic corticosteroid therapy.

         12. Lactating, breastfeeding, or positive pregnancy test for female patients of
             child-bearing potential.

         13. The patient is unable to swallow capsules and/or has a surgical or anatomical
             condition that precludes swallowing and absorbing oral medication on an ongoing basis
             (for oral therapy only).

         14. Patients with prior stem cell transplantation or solid organ transplantation.

         15. The patient has concurrent severe and/or uncontrolled medical disease that could
             compromise participation in the study (i.e., uncontrolled diabetes, severe infection
             requiring active treatment, severe malnutrition, chronic severe liver or renal
             disease).

         16. History of other malignancies (except for adequately treated basal or squamous cell
             carcinoma or carcinoma in situ) within the last 3 years.

         17. Any other condition that would, in the investigator's judgment, contraindicate the
             patient's participation in the clinical study due to safety concerns or compliance
             with clinical study procedures.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The occurrence of dose limiting toxicity
Time Frame:28 days
Safety Issue:
Description:1. Any event with possible or probable relationship to study drug occurring up to day 28 from the start of treatment as assessed using the National Cancers Institutes Common Terminology Criteria for Adverse events version 4.03 therapy.

Secondary Outcome Measures

Measure:Concentration of KA2507 in plasma over time (hours) post dosing
Time Frame:24 weeks
Safety Issue:
Description:
Measure:Concentration of KA2507 in urine over time (hours) post dosing
Time Frame:24 weeks
Safety Issue:
Description:
Measure:Blood concentration of histone acetylation during KA2507 treatment
Time Frame:24 weeks
Safety Issue:
Description:
Measure:Blood concentration of tubulin during KA2507 treatment
Time Frame:24 weeks
Safety Issue:
Description:
Measure:Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
Time Frame:24 weeks
Safety Issue:
Description:
Measure:Clinical outcomes using the RECIST 1.1 criteria
Time Frame:24 weeks
Safety Issue:
Description:
Measure:Clinical outcomes using Immuno-RECIST criteria
Time Frame:24 weeks
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Karus Therapeutics Limited

Last Updated

August 16, 2017