Olaparib for PAH: a Multicenter Clinical Trial

NCT03782818 | Terminated Phase 1 DMC

• 1 other identifier: CER-21724
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Pulmonary Arterial Hypertension

Keywords

Pulmonary Arterial Hypertension; PAH; poly (ADP-ribose) polymerases inhibition; PARP-1 inhibition; DNA damage; Multicenter study; Olaparib; Safety and efficacy

Outcome Measures

Primary Outcomes (1)

• Occurrence of treatment-emergent AEs at week 24

  Description of treatment-emergent AEs leading to premature discontinuation of the study treatment.

  Week 24

Secondary Outcomes (4)

• 6-min walk test (6MWT)

  At baseline and visits 1, 3, 4, 5 and 6.

• WHO functional class

  At baseline and visits 1, 3, 4, 5, 6 and 7.

• NT-proBNP levels

  At baseline and visits 1, 3, 4, 5 and 6.

• Health related Quality of Life (HRQoL)

  Visit 1 and visit 6

Study Arms (1)

Olaparib

EXPERIMENTAL

After a 4-week pre-treatment phase to ensure that patients are on stable doses of PAH medication, patients will be given progressive doses of olaparib up to 300 mg BID for 24 weeks.

Drug: Olaparib

Interventions

Olaparib DRUG

Olaparib up to 300 mg BID for 24 weeks

Also known as: Lynparza

Olaparib

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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);
• 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).

You may not qualify if:

• Medical conditions
• Other types of pulmonary hypertension \[130\], including pulmonary related to left heart diseases (group 2), lung diseases (group 3) or chronic thromboembolic disease (group 4);
• Significant restrictive (total lung capacity \<60% predicted) or obstructive (FEV1/FVC\<60% after a bronchodilator) lung disease;
• Systolic blood pressure \<90 mmHg;
• Acute RV failure within the last 3 months;
• Received any investigational drug within 30 days;
• Cardiopulmonary rehabilitation program planned or started ≤12 weeks prior to Day 1;
• Presence of ≥3 risk factors for heart failure with preserved ejection fraction, including: - BMI \>30 kg/m2, - Diabetes mellitus, - Hypertension, - Coronary artery disease;
• Other organ dysfunction other than RV failure including Childs-Pugh class B-C liver cirrhosis;
• Recent cancer (\<1yr)
• Recent bacterial infection (\<30 days);
• History of hypertensive crisis;
• 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, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \>500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
• Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.

Sponsors & Collaborators

• Laval University: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• AstraZeneca: collaborator

Study Sites (3)

University of Alberta Hospital

Edmonton, Alberta, T6G 2B7, Canada

Location

UHN-Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

Location

IUCPQ-UL

Québec, Quebec, G1V4G5, Canada

Location

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

olaparib

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Steeve Provencher, MD, MSc

  IUCPQ-UL

  PRINCIPAL INVESTIGATOR

• Sébastien Bonnet, PhD

  IUCPQ-UL

  PRINCIPAL INVESTIGATOR

• Pascale Blais-Lecours, PhD

  IUCPQ-UL

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: The design is open-label. A 4-week pre-treatment phase will allow ensuring that patients are on stable doses of medication. Patients will be given progressive doses of olaparib up to 300mg BID for 24 weeks.

Study Record Dates

• First Submitted: December 17, 2018
• First Posted: December 20, 2018
• Study Start: November 20, 2019
• Primary Completion: October 31, 2024
• Study Completion: October 31, 2024
• Last Updated: February 12, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3)