Olaparib for PAH: a Multicenter Clinical Trial (OPTION)

STATUS

Recruiting
End date

Nov 30, 2023
participants needed

20
sponsor

Laval University

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Updated on 9 June 2022

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body mass index

cancer

hypertension

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pulmonary disease

Summary

The main OBJECTIVE of this proposal is to extend our preclinical findings on the role of DNA damage and poly(ADP-ribose) polymerases (PARP) inhibition as a therapy for a devastating disease, pulmonary arterial hypertension (PAH), to early-phase clinical trials. We, and others, have published strong evidence that DNA damage accounts for disease progression in PAH and showed that PARP1 inhibition can reverse PAH in several animal models1. Interestingly, PARP1 inhibition is also cardioprotective. Olaparib, an orally available PARP1 inhibitor, can reverse cancer growth in animals and humans with a good safety profile, and is now approved for the treatment of ovarian cancer in Canada, Europe and the USA. The time is thus right to translate our findings in human PAH.

The primary objective of this Phase 1B study is to confirm the safety of using olaparib in PAH patients, and precise the sample size of a future Phase 2 trial. In addition to safety, efficacy signals will thus be assessed.

Description

Overall, 20 well-characterized PAH patients that have been stable for >4 months on standard PAH-therapies, as per guidelines will be recruited. The initial Health Canada approval will be obtained. Olaparib will be provided by AstraZeneca Canada, but AZ had no input into the trial design and will not be involved in the conduct of the trial, analysis, interpretation of the results or the final manuscript.

A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of PAH medication.

Given that PAH is a chronic disease and that patients may be at higher risk for drug-related adverse events (e.g. anemia), olaparib will be started at low-dose (100mg BID), then up-titrated weekly by 100mg BID up to 200mg BID (n=5, group 1) or 300mg BID (n=15, group 2) for a total treatment duration (including the up-titration phase) of 24 weeks. Using 100mg and 150mg tablets will allow minimizing the number of tablets taken (e.g. 2 x 150mg tablets BID) or adjusting the dose in case of drug-related adverse events (e.g. 250mg BID using 100mg and 150mg tablets).

Patients will be regularly followed to assess whether side effects are observed and whether olaparib can be up-titrated.

At baseline and week 24, a cardiac catheterization will assess changes in pulmonary hemodynamics and RV function.

An end-of-study visit is planned at week 28 week.

Details

Condition	Pulmonary Arterial Hypertension
Treatment	olaparib
Clinical Study Identifier	NCT03782818
Sponsor	Laval University
Last Modified on	9 June 2022

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Informed consent
	Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
	Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses
	Type of patient and disease characteristics
	PAH of idiopathic/ hereditary/drug or toxin-induced origin or associated with connective tissue diseases
	Mean PA pressure ≥25mmHg, PA wedge pressure ≤15mmHg, PVR >480 dyn.s.cm-5 and absence of acute vasoreactivity (we expect PARP1 inhibition will be most effective in patients with significant PA remodelling)
	WHO functional class II or III, which is the traditional inclusion criteria in all PAH RCT)
	Clinically stable with unchanged vasoactive therapy for ≥4 months; 5) two 6MWD of ≥150m and within ±15% of each other (the latter being used as baseline value)
	Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below
	Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
	Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
	Platelet count ≥ 100 x 109/L
	Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
	Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal
	Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test
	Estimated creatinine clearance =( [(140-age [years]) x weight (kg)] / [serum
	creatinine (mg/dL) x 72]) (x F); (where F=0.85 for females and F=1 for males)
	Patients must have a life expectancy ≥ 28 weeks
	Weight: Body mass index (BMI) within the range 18-40 kg/m2 (inclusive)
	Reproduction
	Postmenopausal or evidence of non-childbearing status for women of childbearing
	Postmenopausal is defined as
	potential: negative urine or serum pregnancy test within 28 days of study
	treatment and confirmed prior to treatment on day 1
	Amenorrheic for 1 year or more following cessation of exogenous hormonal
	treatments
	Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in
	the post menopausal range for women under 50
	surgical sterilisation (bilateral oophorectomy or hysterectomy)
	Male patients must use a condom during treatment and for 3 months after the last
	dose of olaparib when having sexual intercourse with a pregnant woman or with a
	woman of childbearing potential. Female partners of male patients should also use
	a highly effective form of contraception if they are of childbearing potential
Exclusion Criteria
	Medical conditions
	Systolic blood pressure <90 mmHg
	Acute RV failure within the last 3 months
	Received any investigational drug within 30 days
	Recent cancer (<1yr)
	Other types of pulmonary hypertension [130], including pulmonary related to left
	Recent bacterial infection (<30 days)
	heart diseases (group 2), lung diseases (group 3) or chronic thromboembolic
	History of hypertensive crisis
	disease (group 4)
	Significant restrictive (total lung capacity <60% predicted) or obstructive
	(FEV1/FVC<60% after a bronchodilator) lung disease
	Cardiopulmonary rehabilitation program planned or started ≤12 weeks prior to Day
	Presence of ≥3 risk factors for heart failure with preserved ejection fraction
	Prior/concomitant therapy
	including: - BMI >30 kg/m2, - Diabetes mellitus, - Hypertension, - Coronary
	Any previous treatment with PARP inhibitor, including Olaparib
	artery disease
	Other organ dysfunction other than RV failure including Childs-Pugh class B-C
	liver cirrhosis
	Prior/concurrent clinical study experience
	Stage ≥1 systemic hypertension, defined as a systolic blood pressure ≥140mmHg or
	a diastolic blood pressure ≥90mmHg, or requiring anti-hypertensive therapies
	Resting ECG indicating uncontrolled, potentially reversible cardiac conditions
	Other exclusions
	as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic
	arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte
	Breast feeding women
	disturbances, etc.), or patients with congenital long QT syndrome
	Lifestyle restrictions
	Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
	suggestive of MDS/AML
	Patients considered a poor medical risk due to a serious, uncontrolled medical
	disorder, non-malignant systemic disease or active, uncontrolled infection
	Examples include, but are not limited to, uncontrolled ventricular arrhythmia
	recent (within 3 months) myocardial infarction, uncontrolled major seizure
	disorder, unstable spinal cord compression, superior vena cava syndrome
	extensive interstitial bilateral lung disease on High Resolution Computed
	Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining
	informed consent
	Patients unable to swallow orally administered medication and patients with
	gastrointestinal disorders likely to interfere with absorption of the study
	medication
	Immunocompromised patients, e.g., patients who are known to be serologically
	positive for human immunodeficiency virus (HIV)
	Patients with known active hepatitis (i.e. Hepatitis B or C). Active hepatitis B
	virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result
	Patients with a past or resolved HBV infection (defined as the presence of
	hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive
	for hepatitis C virus (HCV) antibody are eligible only if polymerase chain
	reaction is negative for HCV RNA
	Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole
	telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or
	cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or
	moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem
	fluconazole, verapamil). The required washout period prior to starting olaparib
	is 2 weeks
	Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin
	rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort
	) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required
	washout period prior to starting olaparib is 5 weeks for enzalutamide or
	phenobarbital and 3 weeks for other agents
	Major surgery within 2 weeks of starting study treatment and patients must have
	recovered from any effects of any major surgery
	Previous allogenic bone marrow transplant or double umbilical cord blood
	transplantation (dUCBT)
	Whole blood transfusions in the last 120 days prior to entry to the study (packed
	red blood cells and platelet transfusions are acceptable, for timing refer to
	inclusion criteria no.7)
	Participation in another clinical study with an investigational product
	administered in the last 3 months
	Patients with a known hypersensitivity to olaparib or any of the excipients of
	the product
	Judgment by the investigator that the patient should not participate in the study
	if the patient is unlikely to comply with study procedures, restrictions and
	requirements
	Meals and dietary restrictions: It is prohibited to consume grapefruit juice
	while on olaparib therapy
	Activity: Women of childbearing potential and their partners, who are sexually
	active, must agree to the use of TWO highly effective forms of contraception in
	combination. This should be started from the signing of the informed consent and
	continue throughout the period of taking study treatment and for at least 1 month
	after last dose of study drug(s), or they must totally/truly abstain from any
	form of sexual intercourse
	Male patients must use a condom during treatment and for 3 months after the last dose of
	olaparib when having sexual intercourse with a pregnant woman or with a woman of
	childbearing potential. Female partners of male patients should also use a highly effective
	form of contraception if they are of childbearing potential. Male patients should not
	donate sperm throughout the period of taking olaparib and for 3 months following the last
	dose of olaparib
	For details of acceptable methods of contraception refer to Appendix B Acceptable Birth
	Control Methods

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Olaparib for PAH: a Multicenter Clinical Trial (OPTION)