Olaparib for PAH: a Pilot Study

NCT03251872 | Terminated Early Phase 1

• 1 other identifier: CER-21658
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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 industry-sponsored clinical research on PARP1 inhibitor is currently entirely cancer-oriented. Nonetheless, AstraZeneca Canada accepted to support an early phase clinical trial through in-kind contribution, but the support from foundations and federal agencies is critical to catalyze early-stage development of PARP1 inhibitors for other indications, especially for orphan diseases. A CIHR Project Scheme grant will thus be submitted on September 15 2017, proposing a Phase 1, followed by a Phase 2 trial that will be conducted in recognized PAH programs throughout Canada. At this stage, however, we propose a pilot study to assess the feasibility of the proposed trials in the PAH population. The overall HYPOTHESIS is that PARP1 inhibition with olaparib is a safe and effective therapy for PAH. The primary objective of the study is to confirm feasibility, to support the safety of using olaparib in PAH patients, and precise the sample size of the coming Phase 1B trial. The feasibility of the comprehensive patient phenotyping that will be proposed within the phase 1B trial will thus be assessed, in addition to adverse events and efficacy signals. \*\*\*OPTION pilot trial was merged with the new OPTION multicenter trial (NCT03782818)\*\*\*

Conditions

Pulmonary Arterial Hypertension

Keywords

pulmonary arterial hypertension; PAH; poly (ADP-ribose) polymerases inhibition; PARP-1 inhibition; DNA damage; Early-phase clinical trial pilot study; Olaparib; Safety and efficacy

Outcome Measures

Primary Outcomes (1)

• Change in pulmonary vascular resistance (PVR) at week 16

  At baseline and week 16, a cardiac catheterization and MRI will assess changes in pulmonary hemodynamics and RV function

  16 weeks

Other Outcomes (6)

• Additional haemodynamic data by catheterization

  At baseline and week 16

• 6-min walk distance (6MWD)

  At baseline and week 16

• RV volumes and mass (cardiac MRI)

  At baseline and week 16

Study Arms (1)

Drug: Olaparib

EXPERIMENTAL

Olaparib up to 400 mg BID (100 to 400 mg) for 16 weeks

Drug: Olaparib

Interventions

Olaparib DRUG

Olaparib tablets

Also known as: Lynparza

Drug: 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:

• \) adults (18-75 yrs) with PAH of idiopathic/ hereditary/drug or toxin-induced origin or associated with connective tissue diseases; 2) 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); 3) WHO functional class II or III; 4) clinically stable with unchanged vasoactive therapy for ≥4 months; 5) two 6MWD of 150-550m and within ±15% of each other (the latter being used as baseline value); 6) a negative serum pregnancy test prior to receiving the first dose of study treatment and willing to use adequate contraception from enrolment through 3 months after the last dose of study treatment for patients of childbearing potential

You may not qualify if:

• \) other types of pulmonary hypertension; 2) significant restrictive (total lung capacity \<60% predicted) or obstructive (FEV1/FVC\<60% after a bronchodilator) lung disease; 3) systolic blood pressure \<90 mmHg; 4) acute RV failure within the last 3 months; 5) received any investigational drug within 30 days; 6) BMI \<18 or \>40 kg/m2; 7) cardiopulmonary rehabilitation program planned or started ≤12 weeks prior to Day 1; 8) presence of ≥3 risk factors for heart failure with preserved ejection fraction (BMI \>30 kg/m2, diabetes mellitus, hypertension or coronary artery disease); 9) organ dysfunction other than RV failure; 10) anticipated survival \<1 year due to concomitant disease

Sponsors & Collaborators

• Laval University: lead

Study Sites (1)

IUCPQ-UL

Québec, Quebec, G1V 4G5, Canada

Location

Related Publications (16)

• Chen PI, Cao A, Miyagawa K, Tojais NF, Hennigs JK, Li CG, Sweeney NM, Inglis AS, Wang L, Li D, Ye M, Feldman BJ, Rabinovitch M. Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension. JCI Insight. 2017 Jan 26;2(2):e90427. doi: 10.1172/jci.insight.90427.

  PMID: 28138562 BACKGROUND

• de Jesus Perez VA, Yuan K, Lyuksyutova MA, Dewey F, Orcholski ME, Shuffle EM, Mathur M, Yancy L Jr, Rojas V, Li CG, Cao A, Alastalo TP, Khazeni N, Cimprich KA, Butte AJ, Ashley E, Zamanian RT. Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014 May 15;189(10):1260-72. doi: 10.1164/rccm.201310-1749OC.

  PMID: 24702692 BACKGROUND

• Dedes KJ, Wetterskog D, Mendes-Pereira AM, Natrajan R, Lambros MB, Geyer FC, Vatcheva R, Savage K, Mackay A, Lord CJ, Ashworth A, Reis-Filho JS. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010 Oct 13;2(53):53ra75. doi: 10.1126/scitranslmed.3001538.

  PMID: 20944090 BACKGROUND

• Federici C, Drake KM, Rigelsky CM, McNelly LN, Meade SL, Comhair SA, Erzurum SC, Aldred MA. Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2015 Jul 15;192(2):219-28. doi: 10.1164/rccm.201411-2128OC.

  PMID: 25918951 BACKGROUND

• Happe CM, Szulcek R, Voelkel NF, Bogaard HJ. Reconciling paradigms of abnormal pulmonary blood flow and quasi-malignant cellular alterations in pulmonary arterial hypertension. Vascul Pharmacol. 2016 Aug;83:17-25. doi: 10.1016/j.vph.2016.01.004. Epub 2016 Jan 22.

  PMID: 26804008 BACKGROUND

• Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F, Wilkins MR, Badesch DB. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D42-50. doi: 10.1016/j.jacc.2013.10.032.

  PMID: 24355641 BACKGROUND

• Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012 Apr 12;366(15):1382-92. doi: 10.1056/NEJMoa1105535. Epub 2012 Mar 27.

  PMID: 22452356 BACKGROUND

• Li M, Vattulainen S, Aho J, Orcholski M, Rojas V, Yuan K, Helenius M, Taimen P, Myllykangas S, De Jesus Perez V, Koskenvuo JW, Alastalo TP. Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2014 Jun;50(6):1118-28. doi: 10.1165/rcmb.2013-0349OC.

  PMID: 24433082 BACKGROUND

• Meloche J, Le Guen M, Potus F, Vinck J, Ranchoux B, Johnson I, Antigny F, Tremblay E, Breuils-Bonnet S, Perros F, Provencher S, Bonnet S. miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol. 2015 Sep 15;309(6):C363-72. doi: 10.1152/ajpcell.00149.2015. Epub 2015 Jun 17.

  PMID: 26084306 BACKGROUND

• Meloche J, Pflieger A, Vaillancourt M, Paulin R, Potus F, Zervopoulos S, Graydon C, Courboulin A, Breuils-Bonnet S, Tremblay E, Couture C, Michelakis ED, Provencher S, Bonnet S. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014 Feb 18;129(7):786-97. doi: 10.1161/CIRCULATIONAHA.113.006167. Epub 2013 Nov 22.

  PMID: 24270264 BACKGROUND

• Moudry P, Watanabe K, Wolanin KM, Bartkova J, Wassing IE, Watanabe S, Strauss R, Troelsgaard Pedersen R, Oestergaard VH, Lisby M, Andujar-Sanchez M, Maya-Mendoza A, Esashi F, Lukas J, Bartek J. TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity. J Cell Biol. 2016 Feb 1;212(3):281-8. doi: 10.1083/jcb.201507042. Epub 2016 Jan 25.

  PMID: 26811421 BACKGROUND

• Park ES, Kang DH, Kang JC, Jang YC, Lee MJ, Chung HJ, Yi KY, Kim DE, Kim B, Shin HS. Cardioprotective effect of KR-33889, a novel PARP inhibitor, against oxidative stress-induced apoptosis in H9c2 cells and isolated rat hearts. Arch Pharm Res. 2017 May;40(5):640-654. doi: 10.1007/s12272-017-0912-3. Epub 2017 Apr 4.

  PMID: 28378219 BACKGROUND

• Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014 Jun 20;115(1):165-75. doi: 10.1161/CIRCRESAHA.113.301141.

  PMID: 24951765 BACKGROUND

• Ramsey BW, Nepom GT, Lonial S. Academic, Foundation, and Industry Collaboration in Finding New Therapies. N Engl J Med. 2017 May 4;376(18):1762-1769. doi: 10.1056/NEJMra1612575. No abstract available.

  PMID: 28467868 BACKGROUND

• Ranchoux B, Meloche J, Paulin R, Boucherat O, Provencher S, Bonnet S. DNA Damage and Pulmonary Hypertension. Int J Mol Sci. 2016 Jun 22;17(6):990. doi: 10.3390/ijms17060990.

  PMID: 27338373 BACKGROUND

• Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D34-41. doi: 10.1016/j.jacc.2013.10.029.

  PMID: 24355639 BACKGROUND

Related Links

• OPTION pilot trial merged to a new multicenter trial (OPTION multicenter - NTC03782818)

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, FAHA

  IUCPQ-UL

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early 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 400mg BID for 16 weeks.

Study Record Dates

• First Submitted: August 13, 2017
• First Posted: August 16, 2017
• Study Start: October 25, 2018
• Primary Completion: December 1, 2019
• Study Completion: December 1, 2019
• Last Updated: August 26, 2020

Record last verified: 2020-08

Locations

CA (1)