The objective of this study is to evaluate the effect of veliparib on QTcF.
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to evaluate the effect of veliparib on
QTcF. Evaluation of this point will be done once 36 subjects have completed all
3 dosing periods.
Secondary outcome
Not applicable.
Background summary
Poly(ADP-ribose)-polymerase (PARP) 1 and 2 are nuclear enzymes that recognize
DNA damage and facilitate DNA repair. Inactive PARPs 1 and 2 bind to damaged
DNA, which leads to their auto-activation. The resulting activated PARP
enzymes then poly(ADP-ribosyl)ate many nuclear target proteins, including those
that facilitate DNA repair of both single-stranded or double-stranded DNA
breaks. Thus PARP inhibition will result in less efficient DNA repair
following a cytotoxic insult.
DNA damaging agents including cytotoxic chemotherapy and radiation therapy,
remain a mainstay of treatment for many subjects with cancer. Veliparib is a
potent oral PARP inhibitor that delays the repair of DNA damage induced by
chemotherapeutic agents, including alkylating agents, platinums, radiation, and
topoisomerase inhibitors.
The effects of veliparib on cardiac repolarization were studied in in vitro and
in vivo models. Collectively these nonclinical studies suggest potential risk
of clinical QT/QTc prolongation with veliparib when used at the maximally
tolerated dose for veliparib monotherapy in humans.
Study objective
The objective of this study is to evaluate the effect of veliparib on QTcF.
Study design
This is a Phase 1, single-dose, placebo-controlled, single-blind, randomized,
3-period, 6 sequence crossover study enrolling approximately 48 subjects (36
completing subjects) with solid tumors.
The study will evaluate the effect of veliparib on QTcF. After meeting the
selection criteria, 48 subjects will be assigned in equal numbers to six
sequence groups.
Depending on the Sequence Group assigned, a single dose of veliparib (200 mg or
400 mg) or placebo will be administered orally on Period 1 Day 1. On Day 1 of
the subsequent Periods, per the sequence group to which the subject is
assigned, the other drug will be administered orally. Periods 1, 2 and 3 will
each last for 3 to 7 days.
Intervention
Subjects who participate in the clinical trial will pay extra visits to the
hospital. The study is divided in three periods. Each period lasts 3 to 7 days
During these visits blood will be drawn for both standard and research
purposes. Before and after study drug dosing series af triplicate ECGs will be
performed.
Study burden and risks
The burden for the subject consists of extra visits to the site, extra blood
draws besides the routine lab draws, and extra ECGs.
In Study M12-020, subjects will receive two single doses of veliparib and one
dose of placebo over 9 to 21 days. Based upon preclinical and clinical data,
veliparib is unlikely to have anti-cancer activity when administered in this
manner. As durable responses have been observed with both veliparib as single
agent therapy (BID, Days 1 - 28 of 28-day cycle) and in predefined doses in
combination with cytotoxic therapy, subjects will have the option to
participate in an extension study upon completion of Study M12-020.
Gastrointestinal toxicities such as nausea and vomiting are the most common
toxicities with veliparib single-agent therapy and have occurred in some
subjects following a single dose. In addition, 2 cases of seizure have
occurred in the Phase 1 single agent study (CTEP 8282) at the highest dose
levels achieved to date (veliparib 400 and 500 mg BID). Confounding
circumstances were identified in both of these cases; however, based upon the
preclinical data, seizures are considered a potential risk of veliparib.
Anemia has been observed in clinical studies with continuously dosed single
agent PARP inhibitors, including veliparib. As administered in this study,
hematological effects are not anticipated.
Wegalaan 9
Hoofddorp 2132 JD
NL
Wegalaan 9
Hoofddorp 2132 JD
NL
Listed location countries
Age
Inclusion criteria
- Confirmed solid malignancy that is metastatic or unresectable for which standard curative measures or other therapy that may provide clinical benefit do not exist or are no longer effective.
- Subjects with brain metastases must have clinically controlled neurologic sysptoms.
- Subject is able to swallow and retain oral medications and does not have uncontrolled emesis.
- Subject has adequate bone marrow, renal and hepatic function per local laboratory reference ranges.
- Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics
Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or
study-specific procedures.
Exclusion criteria
- Subject has a screening or baseline (pre-dose on Day 1 of Period 1 at approximately 8 - 10 AM) corrected QT interval (QTc) interval by Fridericia's correction (QTcF) > 470 ms.
- Uncorrected serum potassium, serum magnesium, serum calcium or free thyroxine (FT4) and thyroid stimulating hormone (TSH) outside of normal reference ranges, or grade 2 hyponatremia or hypernatremia.
- Subject has severe ECG morphologic abnormalities that make QTc evaluation difficult.
- Subject has a history of cardiac conduction abnormalities including:
• PR interval > 220 ms or < 115 ms;
• evidence of second or third degree atrioventricular (AV) block;
• evidence of ventricular pre-excitation;
• intraventricular conduction delay with QRS duration > 136 ms;
• bradycardia as defined by sinus rate < 47 bpm.
- Subject has a significant history of cardiovascular disease including congenital long-QT syndrome, angina, myocardial ischemia or infarction, thrombotic or thromboembolic event in the last 6 months, myocarditis, angina on exertion, uncorrected hypocalcemia (<= 8.2 mg/dL), idiopathic cardiomyopathy, amyloid, tumor, sarcoid, scleroderma, syncope, epilepsy, hypertonic cardiomyopathy, or other clinically significant cardiac disease or baseline ECG abnormalities that could potentially confound subsequent analyses.
- Subject has received any anti-cancer therapies 21 days prior to the first dose of study drug, or has recovered to no better than a grade 2 or higher clinically significant adverse effect(s)/toxicity(s) of the previous therapy.
- Use of drugs with a known risk for QT prolongation and Torsades de Pointes within 7 days prior to the first study dose.
- Use of tobacco or nicotine-containing products within 12 hours prior to the first study dose.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-002028-18-NL |
| ClinicalTrials.gov | NCT02009631 |
| CCMO | NL46329.042.13 |