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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma, B Cell
• Intervention / Treatment: Drug: KA2237

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years at the screening visit.
2. Has given written consent to participate in the study.
3. 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.
4. 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]
5. Eastern Co-operative Oncology Group (ECOG) performance status of ≤ 2.
6. For men and women of child-bearing potential, willing to use adequate contraception

Exclusion Criteria:

1. Subject is a chronic alcoholic (intake > 35 units of alcohol (>5 bottles of wine weekly)) or drug abuser
2. 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
3. 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
4. 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
5. Has had an allogeneic stem cell transplant with current active graft-versus-host-disease.
6. Has known active central nervous system involvement of the malignancy.
7. Has active, serious infection requiring systemic therapy. Patients may receive prophylactic antibiotics and antiviral therapy at the discretion of the treating physician.
8. Has a positive test for human immunodeficiency virus (HIV) antibodies.
9. Has active hepatitis B or C. Patients with serologic evidence of prior exposure are eligible.

10. 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

11. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: KA2237; Open label treatment with KA2237	Drug: KA2237; PI3 Kinase p110β/δ inhibitor; Other Names: PI3 Kinase p110β/δ inhibitor

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Karus Therapeutics Limited

Publications and helpful links

General Publications

• Nastoupil LJ, Neelapu SS, Davis RE, Samaniego F, Fowler NH, Westin J, Lee HJ, Wang M, Hagemeister F, Cecil ARL, Dow J, Haque K, Silva FA, Whale A, Lensun L, Bone EA, McElwaine-Johnn H, Beer PA. Preclinical and phase I studies of KA2237, a selective and potent inhibitor of PI3K beta/delta in relapsed refractory B cell lymphoma. Leuk Lymphoma. 2021 Dec;62(14):3452-3462. doi: 10.1080/10428194.2021.1957874. Epub 2021 Aug 9.

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Actual): December 24, 2018
• Study Completion (Actual): December 24, 2018

Study Registration Dates

• First Submitted: January 29, 2016
• First Submitted That Met QC Criteria: February 5, 2016
• First Posted (Estimate): February 10, 2016

Study Record Updates

• Last Update Posted (Actual): February 6, 2019
• Last Update Submitted That Met QC Criteria: February 4, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell
• Other Study ID Numbers: KTP-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED