A Phase 1, Randomised, Double-Blind, placebo controlled, single and multiple ascending dose study to evaluate the safety, tolerability and pharmacokinetics of KZR-616 in healthy female subjects.
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72 participants
Jan 21, 2019
Interventional
Conditions
Summary
This project is testing the safety, tolerability, pharmacokinetics (PK, the amount of study drug in your blood) and pharmacodynamics (PD, how the study drug affects your body) of multiple subcutaneous (into/under the skin) injections or single intravenous (IV) infusions (into the vein) of a new formulation of a drug called KZR-616.
Eligibility
Inclusion Criteria33
- Female, normal healthy volunteer (NHV), age at screening 18 to 55 years, inclusive.
- In good general health, with no significant medical history and with no clinically significant
- abnormalities on physical examination at Screening or before administration of the initial
- dose of study drug.
- Body mass index (BMI) between 18 and 32 kg/m2 inclusive.
- Suitable injection sites on abdomen without confounding scars or lesions (for Part 1 subjects)
- or accessible venous access (for Part 2 subjects).
- Agrees to abstain from alcohol intake 48 hours before administration of study agent, during
- the inpatient period of the study and during the 24 hours prior to a study visit.
- Have the ability and willingness to attend the necessary visits to the study centre.
- Have provided written informed consent prior to entry into the study.
- If of childbearing potential, subject has a negative serum pregnancy test at Screening and a
- negative urine pregnancy test at Day -1 and agrees to employ adequate birth control measures
- for the duration of the study from Screening and for 90 days following the last dose of
- KZR-616 Lyophile.
- a. For the purposes of this trial, women of childbearing potential (WOCBP) are defined as
- all female subjects after puberty unless they are postmenopausal (defined by amenorrhea
- for at least 1 year with confirmatory follicle stimulating hormone [FSH] level in the
- postmenopausal range if subject is not on supplementary hormonal therapy; or if onhormonal replacement therapy, age over 55 and 2 years of amenorrhea) or are surgically
- sterile (i.e. tubal ligation, hysterectomy, bilateral salpingoophorectomy) with procedure
- performed at least 12 months prior to Screening with no evidence of pregnancy since the
- procedure.
- b. Adequate birth control is defined as the use of double-barrier contraception which is
- defined as use of a condom by the male partner and one other form of the following:
- i. Hormonal contraceptives: oral, implant, ring, patch, or depot/injectable method
- which has been used for at least 4 weeks before Screening in a stable manner
- ii. Intrauterine device (IUD)
- iii. Male partner with vasectomy with documented aspermia post procedure or
- documented congenital sterility
- c. Rhythm, withdrawal and periodic abstinence (e.g., calendar, ovulation) methods will not
- be considered adequate birth control for this study. Subject abstinence for the duration of
- the study and 90 days after the last dose of KZR-616 Lyophile is acceptable. Subjects
- with same sex partners are not required to be using contraception.
Exclusion Criteria35
- Positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg),
- hepatitis B core antibody (HBcAb) or hepatitis C antibodies (HCV) at Screening.
- Positive QuantiFERON-TB (QFT) assay (or indeterminate result from repeat assessment) at
- Screening.
- Active infection (diagnosed or suspected) or a history of recurrent infections (defined as 3 or
- more infections requiring antimicrobial intervention in the last 12 months prior to Day 1).
- Serious local infection or systemic infection within 3 months of Day 1 requiring injectable
- antimicrobial treatment.
- Any clinically significant acute illness within 30 days prior to Day 1.
- Any underlying physical or psychological medical condition that, in the opinion of the PI,
- would make it unlikely that the subject will complete the study.
- Surgery within the past 3 months prior to the first study drug administration determined by
- the PI to be clinically relevant.
- Evidence of any ongoing chronic medical condition (e.g., hypertension, asthma or diabetes).
- Use of any prescription or over-the counter (OTC) medication (with the exception of
- multivitamin, paracetamol and hormonal contraceptives) within 7 days of randomization
- unless PI and Sponsor agree that the specific use of a prior medication is unlikely to impact
- the state objectives of this trial.
- Receipt of any live vaccine within 1 month of randomization.
- Any clinically significant laboratory abnormality.
- Absolute neutrophil count <1500/µL or haemoglobin <11 g/dL.
- Any other clinical laboratory values >1.2 x upper limit of normal (ULN) as specified by the
- testing laboratory, unless deemed not clinically significant (NCS) by the PI.
- History or presence of alcoholism or drug abuse within the 2 years prior to the first study
- drug administration.
- Positive urine drug screen or alcohol breath test at Screening or Day -1.
- Donated or received blood products or experienced significant blood loss within 60 days prior
- to the first study drug administration.
- Donated or received plasma within 7 days prior to the first study drug administration.
- Received investigational product (IP) in another trial within 30 days prior to the first study
- drug administration.
- Previously received KZR-616.
- Pregnant or lactating.
- Failure to satisfy the PI of fitness to participate in the study for any other reason.
- Known or suspected hypersensitivity to a, a-trehalose dihydrate (trehalose).
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Interventions
KZR-616 is a selective inhibitor of the immunoproteasome. This Phase I study is designed to investigate a lyophilized formulation of KZR-616 administered either as multiple (weekly) subcutaneous doses into the abdomen (Part 1) over 2 (Cohorts 1b and 1c) or 4 weeks (Cohort 1a only) or as a single 30-minute intravenous infusion (Part 2). Part 1: Multiple Ascending Subcutaneous Dose Each cohort will participate in intrasubject dose escalation in which the initial SC dose (Dose 1) will be 30 mg and the second SC dose (Dose 2) will involve a higher dose. Subjects will be enrolled into sequential cohorts as described below. Cohort 1a Dose 1- 30mg, Dose 2- 45mg Dose 3 - 60mg, Dose 4 - 75mg 1b Dose 1 - 30mg, Dose 2 - 60mg, Dose 3 - N/A, Dose 4- N/A 1c Dose 1 - 30mg, Dose 2 - 75mg, Dose 3 - N/A, Dose 4- N/A In Cohort 1a, two sentinel subjects will receive the first 2 doses of study drug and one sentinel subject will receive the first 2 doses of placebo (under double-blinded conditions). In Cohort 1b and 1c, two sentinel subjects will receive the first dose of study drug and one sentinel subject will receive the first dose of placebo (under double blinded conditions) If dosing of the sentinels proceeds without clinically significant safety signals over 48 hours after dosing, the remaining subjects for each cohort will be dosed according to the randomisation schedule. Part 2: Single Ascending IV Dose KZR-616 will be administered as a 30 minute IV infusion in sequential cohorts as described below: Cohort Dose (mg) 2a 15 2b 30 2c 45 2d 60 In all cohorts, one sentinel subject will receive study drug and one sentinel subject will receive placebo (under double-blinded conditions) on Day 1. If dosing of the sentinels proceeds without clinically significant safety signals over 48 hours after dosing, the remaining subjects in the cohort will be dosed according to the randomisation schedule.
Locations(1)
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ACTRN12618002060224