A Phase II Window of Opportunity Trial of PRMT5 Inhibitor, GSK3326595, in Early Stage Breast Cancer (OTT-19-06)

A Phase II Randomized Window of Opportunity Trial Evaluating Clinical and Biological Effects of PRMT5 Inhibitor, GSK3326595, in Early Stage Breast Cancer

This is a Phase II Randomized Window of Opportunity Trial Evaluating Clinical and Biological effects of PRMT5 inhibitor, GSK3326595, in Early Stage Breast Cancer

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: GSK3326595

Detailed Description

This is a phase II, randomized, open label, multi-center, parallel design, window of opportunity trial in up to 60 patients with early stage Hormone Receptor (HR) positive breast cancer evaluating GSK3326595. In a 2:1 randomization, patients will receive GSK3326595:no treatment for 15 +/- 3 days prior to breast surgery. There is no placebo in this trial.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • St. Joseph's Health Care London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Female patients with newly diagnosed histologically confirmed primary invasive breast cancer currently not undergoing any treatment while awaiting surgery
2. Operable breast cancer as assessed by treating surgical oncologist
3. Tumor ≥ 1.0 cm by palpation or imaging
4. ER or PR positive (≥1%) breast adenocarcinoma
5. Her2 negative as per ASCO 2018 guidelines 61
6. Invasive ductal or lobular carcinoma, invasive carcinoma Not Otherwise Specified (NOS)
7. ECOG PS 0-2 (Appendix A)
8. Post-menopausal and not of child bearing potential as defined as: by having 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40mlU/ml and estradiol < 20 pg/mL or have had documented surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks prior.
9. Able to provide written informed consent for the study.
10. Able to swallow and retain orally administered medication.

Exclusion Criteria:

1. Locally Advanced or metastatic breast cancer
2. Prior therapy with chemotherapy or planned neoadjuvant chemotherapy
3. Prior hormonal therapy including tamoxifen, aromatase inhibitors
4. Pre-dominant histology other than invasive ductal or lobular carcinoma
5. Concomitant other invasive malignancy.
6. Hgb < 100 g/L, Platelets < 100 x 10^9 per liter, Absolute Neutrophil Count < 1.5 x 10^9/L
7. Bilirubin ≥ 1.5 times Upper Limit Normal (ULN)
8. ALT ≥ 2.5 times ULN
9. Albumin < 25 g/L
10. INR/PTT > 1.5 times ULN
11. Creatinine clearance calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation of less than 50 mL/min/1.73m2.

12. Cardiac abnormalities as evidenced by any of the following:

    1. Baseline QTcF interval ≥ 480 msec
    2. Clinically significant conduction abnormalities or arrhythmias
    3. Presence of cardiac pacemaker or defibrillator with a paced ventricular rhythm limiting ECG analysis.
    4. History or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association (NYHA).
    5. History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months.
    6. Clinically significant cardiomegaly, ventricular hypertrophy, or cardiomyopathy.
13. Any serious known immediate or delayed hypersensitivity reaction(s) to GSK3326595, or idiosyncrasy to drugs chemically related to the investigational drugs.
14. Current use of a prohibited medication or planned use of any forbidden medications during treatment with GSK3326595, which include chemotherapy, immunotherapy, biologic therapy, investigational therapy, or hormonal therapy (other than corticosteroids) while on treatment in this study. GSK3326595 should not be co-administered with potent inhibitors of either BCRP or Pgp such inhibitors include cyclosporine, tacrolimus, and ketoconazole
15. Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption, such as malabsorption syndrome, chronic gastrointestinal disease, or major resection of the stomach and/or bowels that could preclude adequate absorption of the study medication.
16. Severe, uncontrolled systemic disease (respiratory, cardiac, renal, hepatic, bleeding)
17. Currently active liver or biliary disease
18. History of active HIV, Hepatitis B or C infection.
19. Any other criteria which, in the investigator's opinion, renders the patient ineligible to be on study.
20. Subjects with signs/symptoms suggestive of COVID-19 or known COVID-19 positive contacts in the past 14 days would be tested as per local Public Health and/or Institutional Guidelines. If patients are COVID-19 positive at the time of screening, they would be excluded from the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm; Participants randomized to treatment with GSK3326595 will be requested to take 15 +/- 3 days of the medication at the dose of 200 mg orally daily (2 capsules of 100 mg) prior to their breast cancer surgery or repeat biopsy. GSK3326595 is a first-in-class small molecule PRMT5 inhibitor in form of an oral capsule.	Drug: GSK3326595; GSK3326595 is a first-in-class small molecule PRMT5 inhibitor in form of an oral capsule.; Other Names: PRMT5 inhibitor
No Intervention: No Intervention Arm; Participants will receive no treatment for 15 +/- 3 days prior to breast surgery. There is no placebo in this trial.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete cell cycle arrest (CCCA)	The primary outcome is the proportion of patients who achieve a Complete Cell Cycle Arrest (CCCA), defined as a reduction in the proportion of Ki67 positively staining cells to ≤ 2.7%.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of complete cell cycle arrest (CCCA) in patients with wild-type TP53	The secondary outcome is to assess whether PRMT5 inhibition preferentially results in CCCA in patients with wild-type TP53.	2 years
Assess whether PRMT5 inhibition results in reduced expression of ER-α signaling compared to patients with no treatment based on gene expression analysis.	A secondary outcome is to assess whether PRMT5 inhibition results in reduced expression of ER-α signaling.	2 years
Assess whether PRMT5 inhibition results in changes in breast-cancer stem cell signature particularly FOXP1 compared to patients with no treatment based on gene expression analysis	A secondary outcome is to assess whether PRMT5 inhibition results in changes in breast-cancer stem cell signature particularly FOXP1.	2 years
Perform molecular analysis to identify immunomodulatory effects of GSK3326595 determined by abundance of different immune cells in tumor (CD4, CD8, NK cells, macrophages, etc) in the tumors treated with GSK3326595 alone versus the untreated tumours.	A secondary outcome is to identify the immunomodulatory effects of GSK3326595, by performing exploratory analyses.	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of alternative splicing of Murine Double Minute 4 (MDM4)	A tertiary outcome is to assess if PRMT5 inhibition results in alternative splicing of MDM4.	2 years
% of response in participants with high Programmed Cell Death 4 (PDCD4) expression and Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) loss	A tertiary outcome is to assess whether PRMT5 inhibition results in preferential response in patients with high PDCD4 expression and CDKN2A loss.	2 years
% of response in participants with defects in homologous recombination DNA repair	A tertiary outcome is to assess whether PRMT5 inhibition results in preferential response in patients with defects in homologous recombination DNA repair.	2 years
% of response in participants with defects in Cyclin D (CCND)/ Cyclin-dependent kinases (CDK) pathway	A tertiary outcome is to assess whether PRMT5 inhibition results in preferential response in patients with defects in CCND/CDK pathway.	2 years
% of response in patients with defects in phosphatidylinositol-3-kinase (PI3K)/Serine-threonine protein kinase 1 (AKT) pathway	A tertiary outcome is to assess whether PRMT5 inhibition results in preferential response in patients with defects in PI3K/AKT pathway.	2 years

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: GlaxoSmithKline; Hamilton Health Sciences Corporation; London Regional Cancer Program, Canada; Ontario Institute for Cancer Research
• Investigators: Principal Investigator: John F. Hilton, MD, The Ottawa Hospital Cancer Centre

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2021
• Primary Completion (Actual): August 15, 2022
• Study Completion (Actual): August 15, 2022

Study Registration Dates

• First Submitted: July 28, 2020
• First Submitted That Met QC Criteria: December 18, 2020
• First Posted (Actual): December 21, 2020

Study Record Updates

• Last Update Posted (Actual): October 25, 2022
• Last Update Submitted That Met QC Criteria: October 24, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Early Stage Breast Cancer; Window of Opportunity; PRMT5 inhibitor; GSK3326595; Hormone Receptor (HR) positive breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; GSK-3326595
• Other Study ID Numbers: OTT-19-06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Researchers may contact Dr. John Hilton for specific requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No