The Safety, Pharmacokinetic and Pharmacodynamic Effect of KA2237 (PI3 Kinase p110β/δ Inhibitor) In B Cell Lymphoma

Study Overview
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Brief Summary
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Multiple ascending dose study to evaluate safety/tolerability, pharmacokinetic and pharmacodynamics effects of KA2237 (PI3 Kinase p110β/δ Inhibitor) in patients with B Cell Lymphoma and determine the maximum tolerated dose (MTD) in Part I of the study. In Part II, patients with B cell lymphoma will be treated with KA2237 at the MTD to evaluate safety and efficacy in the patient population.

Official Title
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An Open Label Ascending Dose Study Evaluating the Safety/Tolerability, Pharmacokinetic and Pharmacodynamic Effects of KA2237 In Patients With B Cell Lymphoma

Conditions
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Lymphoma, B Cell

Intervention / Treatment
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* Drug: KA2237


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years at the screening visit. Has given written consent to participate in the study. Has B-cell lymphoma refractory to or intolerant of established therapy known to provide clinical benefit for their condition and having received rituximab as a single agent or in combination with other therapies. Disease status requirement: Measurable disease defined as the presence of ≥ 1 nodal lesion that measures ≥ 1.5 cm in a single dimension as assessed by X-ray Computed Tomography (CT) (Positron Emission Tomography (PET/CT), or magnetic resonance imaging [MRI] Eastern Co-operative Oncology Group (ECOG) performance status of ≤ 2. For men and women of child-bearing potential, willing to use adequate contraception Exclusion Criteria: Subject is a chronic alcoholic (intake > 35 units of alcohol (>5 bottles of wine weekly)) or drug abuser Subject has any medical or psychiatric condition that, in the opinion of the Investigator, may compromise the subject's ability to participate in this study Female subjects who are breastfeeding, pregnant, or plan to become pregnant during the study or within 3 months following the last dose of investigational product Subjects with a current or recent history, as determined by the Investigator, of severe, progressive, and/or uncontrolled renal disease (estimated glomerular filtration rate (eGFR) <30ml/min), hepatic (Alanine transaminase (ALT) 2.5 times upper limit of normal (>2.5xULN), bilirubin > 2x ULN), hematological (absolute neutrophil count (ANC) <1.0 x 109/L, platelet count <75x109/L or requires regular platelet transfusions to maintain a platelet count ≥ 75 x 109/L , hemoglobin <9g/dL), endocrine (glycated Haemoglobin (HbA1c)>7% or random glucose >200mg/dL), pulmonary (Forced Expiratory Volume in 1 second (FEV1) <70% of predicted value), cardiac (New York Heart Association (NYHA)) class III/IV, or neurological disease Has had an allogeneic stem cell transplant with current active graft-versus-host-disease. Has known active central nervous system involvement of the malignancy. Has active, serious infection requiring systemic therapy. Patients may receive prophylactic antibiotics and antiviral therapy at the discretion of the treating physician. Has a positive test for human immunodeficiency virus (HIV) antibodies. Has active hepatitis B or C. Patients with serologic evidence of prior exposure are eligible. Disease-related exclusions Had treatment with a short course of corticosteroids (> 10mg daily prednisone equivalents) for symptom relief within 1-week prior to screening. Has poorly controlled diabetes mellitus (HbA1c >7% or random glucose >200mg/dL) Known tuberculosis (TB) disease or latent TB infection Has chronic, active colitis Medication related exclusions Had alemtuzumab therapy within 12-weeks prior to screening. Has taken a medication that is a potent inhibitor or inducer of cytochrome P450 3A4 (CYP3A4) within 1-week prior to screening. The subject has previously participated in this study. The subject has participated or is currently participating in another study of an investigational medicine or medical device (radiotherapy, radio-immunotherapy, biological therapy, chemotherapy), within 4-weeks prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KA2237<br>Open label treatment with KA2237 | Drug: KA2237<br>* PI3 Kinase p110β/δ inhibitor<br>* Other names: PI3 Kinase p110β/δ inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence of dose limiting toxicity (DLT); | 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 Cancer Institute's Common Terminology Criteria for Adverse Events version 4.03 | Day 28 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration (mg/ml) of KA2237 in serum/plasma over time (hours) |  | 24 weeks | 
| Concentration (mg/ml) of KA2237 in urine over time (hours) |  | 24 weeks | 
| Concentration (ng/ml) of key cytokine and intracellular signalling markers in immune cell subsets |  | 24 weeks | 
| Frequency of KA2237 related adverse events and laboratory abnormalities |  | 24 weeks |