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Safety,Tolerability and MTD KA2507 (HDAC6 Inhibitor) in Patients With Solid Tumours (HDAC6i)

This study is currently recruiting participants.
Verified August 2017 by Karus Therapeutics Limited
Sponsor:
ClinicalTrials.gov Identifier:
NCT03008018
First Posted: January 2, 2017
Last Update Posted: August 21, 2017
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.
Information provided by (Responsible Party):
Karus Therapeutics Limited
  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.


Condition Intervention Phase
Solid Tumor, Adult Drug: KA2507 Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label Ascending Dose Study Evaluating the Safety/Tolerability, Pharmacokinetic and Pharmacodynamic Effects of KA2507 in Patients With Solid Tumours

Further study details as provided by Karus Therapeutics Limited:

Primary Outcome Measures:
  • The occurrence of dose limiting toxicity [ Time Frame: 28 days ]
    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:
  • Concentration of KA2507 in plasma over time (hours) post dosing [ Time Frame: 24 weeks ]
  • Concentration of KA2507 in urine over time (hours) post dosing [ Time Frame: 24 weeks ]
  • Blood concentration of histone acetylation during KA2507 treatment [ Time Frame: 24 weeks ]
  • Blood concentration of tubulin during KA2507 treatment [ Time Frame: 24 weeks ]
  • Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment [ Time Frame: 24 weeks ]
  • Clinical outcomes using the RECIST 1.1 criteria [ Time Frame: 24 weeks ]
  • Clinical outcomes using Immuno-RECIST criteria [ Time Frame: 24 weeks ]

Other Outcome Measures:
  • Concentration of PD-L1 expression in tumor tissue [ Time Frame: 24 weeks ]
  • Concentration of MHC-1 expression in tumor tissue [ Time Frame: 24 weeks ]

Estimated Enrollment: 30
Actual Study Start Date: August 7, 2017
Estimated Study Completion Date: March 2019
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
KA2507 (HDAC6 inhibitor)
This is a single arm dose escalating study. Patients will be treated with open label KA2507 (HDAC6 inhibitor) capsules.
Drug: KA2507
KA2507, an orally-active new chemical entity, is a potent and selective inhibitor of the HDAC6 enzyme, with potential clinical utility in the treatment of melanoma and other solid tumors. KA2507 has been shown to display potent in vitro activity in a range of cancer cell lines, including melanoma cell lines. KA2507 exerts potent in vivo efficacy in a syngeneic model of B16 melanoma. Here, the combination of the agent's direct tumor growth inhibition and metastasis suppression, coupled with its immunotherapeutic activity - demonstrated by decreased expression of STAT-3 and PD-L1 and increased expression of acetylated tubulin, gp100 and MHC Class I in tumors - have been observed.
Other Names:
  • HDAC6 Inhibitor
  • HDAC6i

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03008018


Contacts
Contact: Anapostolia Tsimberidou, MD PhD 1 (713) 792-4259; atsimber@mdanderson.org

Locations
United States, Texas
M D Anderson Recruiting
Houston, Texas, United States, 77030
Contact: Apostolia-Maria Tsimberidou, MD    713-792-4259    tsimber@mdanderson.org   
Principal Investigator: Apostolia-Maria Tsimberidou, MD         
Sponsors and Collaborators
Karus Therapeutics Limited
  More Information

Responsible Party: Karus Therapeutics Limited
ClinicalTrials.gov Identifier: NCT03008018     History of Changes
Other Study ID Numbers: KTP-003
First Submitted: December 21, 2016
First Posted: January 2, 2017
Last Update Posted: August 21, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No