A Phase I, Two-part Study to Determine the Recommended Dose and Evaluate the Safety and Tolerability of a Novel Oral Arsenic Trioxide Formulation (ORH-2014) in Subjects with Advanced Hematological Disorders
You are being asked to take part in this study because you have a type of blood cancer. The goal of this clinical research study is to find the highest recommended dose of ORH-2014 that can be given to patients with advanced blood cancers. ORH-2014 is a form of arsenic trioxide that is given by mouth. The research is also being done to find out if the recommended dose of ORH-2014 can help to control certain types of blood cancers. This is the first study of ORH-2014 in humans. The safety and side effects of this drug will also be studied.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: OHR-2014
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Orsenix Holdings, BV
Primary Objectives The primary objective of Part 1 is: To identify the recommended dose of oral ORH-2014 in subjects with advanced hematological disorders. The primary objective of Part 2 (expansion phase) is: To evaluate the safety and tolerability of oral ORH-2014 in a population of subjects with advanced hematological disorders when administered at the recommended dose. Secondary Objectives The secondary objectives of the study are: To determine the plasma pharmacokinetic (PK) profiles of total arsenic measured using inductively coupled plasma mass spectrometry (ICP-MS) following oral administration of ORH-2014 To evaluate the effect of ORH-2014 on QT-interval corrected for heart rate using Fridericia¡¦s formula (QTcF) at each dose level during the dose escalation, and at the recommended dose To evaluate the effect of oral ORH-2014 on safety parameters including changes in clinical laboratory measures (clinical chemistry, hematology, coagulation, urinalysis), vital signs, the incidence and severity of adverse events (AEs), and the incidence of serious AEs (SAEs) To evaluate the efficacy of oral ORH-2014 in subjects with advanced hematological disorders as evaluated by International Working Group (IWG) response criteria for the respective diseases.
IRB Review and Approval Date: 12/19/2016
Recruitment Status: Open
Projected Accrual: Up to 50
1) Female and male subjects >/=18 years of age with one of the
following: a. Relapsed or refractory AML with NPM1 mutations and no
available therapies. b. Relapsed or refractory APL, with no available
therapies. Note: Prior exposure to arsenic trioxide is allowed; however,
subjects who have failed arsenic trioxide within the last 12 months are
not allowed. c. Relapsed or refractory MDS, International Prognostic
Scoring System intermediate or high-risk, with no available therapies.
d. Relapsed or refractory CMML, and other MDS/MPN overlap syndromes,
with no available therapies. e. Relapsed or refractory MCL with no
2) Female partners of male subjects and female subjects of childbearing potential must be willing to avoid pregnancy during the study and until 1 month after the last study drug administration. Males with female partners of childbearing potential and female subjects of childbearing potential must therefore be willing to use adequate contraception such as 2 barrier methods or 1 barrier method with spermicide and intrauterine device from 2 weeks before the trial until 1 month after the trial. The use of hormonal contraceptives should be avoided. For the purposes of this study, childbearing potential is defined as: "All female subjects unless they are post-menopausal for at least 2 years, surgically sterile, or sexually inactive".
3) Negative pregnancy test at the Screening visit for women of childbearing potential;
4) Able to comprehend and willing to sign an Informed Consent Form (ICF);
5) Not willing to undergo, not a candidate for, or not having a donor for immdiate (within 3 months from the Screening date) bone marrow transplantation.
1) Eastern Cooperative Oncology Group performance status of >/=3;
2) Absolute myeloblast count >/=20,000/mm^3;
3) Administration of any antineoplastic therapy within 5-half-lives of the antineoplastic therapy before first dose of ORH-2014, with the exception of hydroxyurea that should be discontinued 1 day prior to the first dose of ORH-2014;
4) Presence of any remaining toxicities due to previous chemotherapy that are Grade >1 in severity (exclusive of alopecia and myelosuppression);
5) Participation in other interventional clinical trials within at least 2 weeks of the first ORH-2014 dose;
6) Clinical evidence of active central nervous system leukemia;
7) Active and uncontrolled infection including, but not limited to, known infection with human immunodeficiency virus, active hepatitis B, or hepatitis C. Note: Subjects with an infection receiving treatment with antibiotics may be entered into the trial if they are afebrile and hemodynamically stable for 48 hours prior to trial entry;
8) Major surgery within 2 weeks prior to trial entry;
9) Serum potassium <3.5 mEq/L despite supplementation or >5.5 mEq/L; serum magnesium outside the institutional normal limit despite adequate management; serum calcium (corrected for albumin levels) outside the institutional normal limit despite adequate management;
10) Liver function tests above the following limits at Screening: total bilirubin >1.5 x upper limit of normal (ULN) unless related to Gilbert’s syndrome or hemolysis; AST and/or ALT >2.5 x ULN; for subjects with liver involvement, AST and/or ALT >5 x ULN;
11) Serum creatinine >1.5 x ULN and/or creatinine clearance or estimated glomerular filtration rate <30 mL/min at Screening (calculated according to the Cockcroft-Gault equation or Modification of DIet in Renal Disease Study equation, respectively);
12) Impaired cardiac function including any of the following: a. QTcF >460 msec at Screening. Note: QTcF will be derived from the mean of triplicate readings; b. Congenital long QT syndrome; c. Clinically significant resting bradycardia (<50 beats per minute) d. Right bundle branch block plus left anterior hemiblock (bifascicular block); e. Left bundle branch block; f. History of clinically significant ventricular fibrillation or torsades de pointes; g. Atrial fibrillation documented within 2 weeks prior to planned first dose of study drug; h. History of second or third degree heart block. Note: Subjects with implanted pacemakers may be eligible at the discretion of the Investigator. i. Any other history or presence of an abnormal ECG, which, in the Investigator’s opinion, is clinically significant and precludes enrollment of the subject in the clinical trial;
13) Myocardial infarction of unstable angina within 6 months prior to the planned start date of study drug;
14) New York Heart Association Class III or Class IV heart disease, uncontrolled hypertension, uncontrolled congestive heart failure, or other uncontrolled cardiac conditions;
15) Subjects with solid tumors, for whom the Investigator has clinical suspicion of active disease at the time of enrollment. Note: Subjects with adequately treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia are eligible for this study;
16) Significant impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug;
17) Concomitant treatment with drugs associated with prolongation of QT/QTcF interval or induction of torsades de pointes. Note: Subjects may receive antibiotics, antifungals, and/or antivirals that are used as standard of care to prevent or treat infections, or other drugs that are considered by the Investigator to be essential for the care of the subject.
18) Other significant disease that in the Investigator’s opinion would exclude the subject from participation in the study;
19) Legal incapacity or limited legal capacity;
20) Any acute or chronic condition that, in the opinion of the Investigator, would limit the subject’s ability to complete and/or participate in the study.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
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