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A Study of Selective HDAC6 Inhibition With KA2507 in Advanced Biliary Tract Cancer

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ClinicalTrials.gov Identifier: NCT04186156
Recruitment Status : Not yet recruiting
First Posted : December 4, 2019
Last Update Posted : February 20, 2020
Sponsor:
Collaborator:
University College, London
Information provided by (Responsible Party):
Karus Therapeutics Limited

Brief Summary:

To evaluate the safety, tolerability and preliminary evidence for efficacy of KA2507 (an orally active potent and selective HDAC6 inhibitor) in patients with advanced biliary tract cancer (BTC) previously treated with standard of care chemotherapy.

The specific aims of each part of the study are:

Part A : Phase Ib primary objective - to determine the recommended phase II dose (RP2D) of KA2507 for part B and evaluate its tolerability profile in advanced BTC.

Part B: Phase II primary objective - to assess the efficacy of KA2507 in patients with advanced BTC at the dose defined in part A.


Condition or disease Intervention/treatment Phase
Biliary Tract Cancer Drug: KA2507 Phase 1 Phase 2

Detailed Description:

To evaluate the safety, tolerability and preliminary evidence for efficacy of KA2507 (an orally active potent and selective HDAC6 inhibitor) in patients with advanced biliary tract cancer (BTC) previously treated with standard of care chemotherapy.

The specific aims of each part of the study are:

Part A : Phase Ib primary objective - to determine the recommended phase II dose (RP2D) of KA2507 for part B and evaluate its tolerability profile in advanced BTC.

Part B: Phase II primary objective - to assess the efficacy of KA2507 in patients with advanced BTC at the dose defined in part A.

ABC-11 is an open-label, multi-centre study of HDAC6 inhibition using KA2507 in patients with advanced biliary tract cancer previously treated with standard of care chemotherapy.

Part A design (phase Ib safety - dose finding)

This is a phase Ib dose finding study to determine the recommended Phase II dose (RP2D) for Part B.

Dose escalation of KA2507 in Part A will be based on a combination of treatment-related dose limiting toxicities (DLTs) at the end of cycle 1 and (plasma) KA2507 pharmacokinetics. This dose finding study will be conducted using the modified continual reassessment method (CRM)1-3, a model-based design that informs how the dosage of KA2507 should be adapted for the next patient cohort based on past trial data. The RP2D will be defined as the highest dose that has an estimated probability of a DLT closest to a target toxicity level of 30%. Patients will be dosed in cohorts of 2, with a maximum available sample size of 8 evaluable patients.

Part B design (phase II efficacy)

This is a single-arm single-stage phase II study designed using A'Hern's methodology.

Patients for part B are comprised of two groups: 1) the patients from Part A treated at the dose to be tested in Part B; and 2) an additional expansion cohort of patients registered to part B. A fixed daily dose of KA2507 will be administered to all patients based on the RP2D determined in Part A (anticipated to be one of either 800 mg bid, 1200 mg bid or 1600 mg daily bid).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study of Selective HDAC6 Inhibition With KA2507 in Advanced Biliary Tract Cancer Previously Treated With Standard of Care Chemotherapy (ABC-11)
Estimated Study Start Date : March 2020
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : October 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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




Primary Outcome Measures :
  1. Occurrence of Dose-limiting toxicity [ Time Frame: 6 - 8 months ]
    Occurrence of Dose-limiting toxicity. Dose limiting toxicities and KA2507 PK analysis (plasma +/- tumour) in order to determine recommended phase II dose.

  2. Proportion of patients alive and progression free at 4 months [ Time Frame: 26 months ]
    Proportion of patients alive and progression free at 4 months (objective disease progression as per RECIST 1.1)


Secondary Outcome Measures :
  1. Characterize the safety and tolerability profile of KA2507: Worst grade of adverse events (CTCAE v5.0) and Adverse events (CTCAE v5.0) [ Time Frame: 26 months ]
    Worst grade of adverse events (CTCAE v5.0) and Adverse events (CTCAE v5.0): first dose to within 30 days after last dose

  2. To determine the pharmacodynamic response to KA2507 [ Time Frame: 26 months ]
    Evidence of selective target engagement through measurement of an increase in acetylated tubulin in the absence of an increase in acetylated histone in peripheral blood (monocytes and T cells).

  3. Tumor response to KA2507 (response rates and duration of response) [ Time Frame: 26 months ]
    Best Objective overall Response Rate (ORR)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥18 years
  • Signed informed consent
  • Histological or cytological diagnosis of advanced (i.e. metastatic disease, or irresectable locally advanced, or recurrent) biliary tract cancer (to include intra or extra hepatic and gall bladder; ampullary cancer will not be included).
  • Patient must have disease amenable to biopsy at baseline and consent to pre-treatment biopsy
  • Clear evidence of disease progression following standard of care first line therapy with at least 1 measurable lesion using CT/MRI as defined by RECIST 1.1, OR clear evidence of disease progression based on the emergence of non-measurable disease (e.g. new cytologically confirmed ascites, pleural or pericardial effusion)
  • Previous treatment with any line of chemotherapy for advanced disease (e.g. currently gemcitabine/cisplatin) OR radiotherapy
  • ECOG performance status grade 0-1
  • Adequate biliary drainage, with no evidence of ongoing infection
  • Estimated life expectancy > 3 months
  • Patients intolerant of first-line standard of care chemotherapy will also be eligible provided there is evidence of disease progression

Exclusion Criteria:

  • Unresolved or unstable serious toxic side-effects of prior chemotherapy or radiotherapy, i.e. ≥ grade 2 per CTCAE (common terminology criteria for adverse events, v5.0) except fatigue, alopecia and infertility
  • Clinical evidence of cerebral metastases
  • History of previous malignancy that could interfere with response evaluation
  • Concurrent treatment with other investigational drugs within 4 weeks of initiating treatment
  • Inadequate renal, liver, or haematological function defined as any of:

    • eGFR < 45 ml/min/1.73 m2 using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula
    • ALT and/or AST > 5 x ULN
    • Neutropenia (absolute neutrophil count < 1.5 x 109/L)
    • Platelets <100 x 109/L
    • Haemoglobin ≤ 9 g/dL). NB the use of transfusion to achieve desired Hb is acceptable
    • Total bilirubin ≥ 1.5 x ULN (except for patients with known Gilbert's syndrome)
  • Known haemoglobinopathy due to HbS or HbC disease, α or β thalassemia, or Glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Concomitant use of dapsone
  • Untreated severe hypothyroidism
  • Significant heart disease defined as any of the following:

    • NYHA grade 3 or 4 symptomatic heart failure
    • Unstable angina or acute myocardial infarction within 3 months
    • cardiac ventricular arrhythmia within 3 months that is not controlled by drug therapy and/or by cardiac ablation
    • QTcF > 470 ms on screening ECG or history of Torsades de pointes
  • Any other concurrent severe and/or uncontrolled medical or surgical condition which, in the view of the investigator, could compromise the patient's participation in the study
  • Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
  • Active infection requiring antibiotics within two weeks prior to treatment
  • Males who are unable to or refuse to use barrier contraception during treatment and for 3 months after
  • Women who are pregnant, breast-feeding or either unable to or refuse to use effective means of contraception during treatment
  • Patients who are unable to swallow capsules and/or have a surgical or anatomical condition that precludes swallowing and absorbing oral medication on an ongoing basis
  • Any other condition that would, in the investigator's judgement, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures

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Responsible Party: Karus Therapeutics Limited
ClinicalTrials.gov Identifier: NCT04186156    
Other Study ID Numbers: ABC-11
First Posted: December 4, 2019    Key Record Dates
Last Update Posted: February 20, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Biliary Tract Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Biliary Tract Diseases
Digestive System Diseases