A Phase II Window of Opportunity Trial of PRMT5 Inhibitor, GSK3326595, in Early Stage Breast Cancer

NCT04676516 | Completed Phase 2 DMC

• 1 other identifier: OTT-19-06
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Breast Cancer

Keywords

Window of Opportunity; PRMT5 inhibitor; GSK3326595; Early Stage Breast Cancer; Hormone Receptor (HR) positive breast cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Rate of complete cell cycle arrest (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.

  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

  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.

  2 years

Other Outcomes (5)

• Rate of alternative splicing of Murine Double Minute 4 (MDM4)

  2 years

• % of response in participants with high Programmed Cell Death 4 (PDCD4) expression and Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) loss

  2 years

• % of response in participants with defects in homologous recombination DNA repair

  2 years

Study Arms (2)

Experimental Arm

EXPERIMENTAL

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

No Intervention Arm

NO INTERVENTION

Participants will receive no treatment for 15 +/- 3 days prior to breast surgery. There is no placebo in this trial.

Interventions

GSK3326595 DRUG

GSK3326595 is a first-in-class small molecule PRMT5 inhibitor in form of an oral capsule.

Also known as: PRMT5 inhibitor

Experimental Arm

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Female post-menopausal participants
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female patients with newly diagnosed histologically confirmed primary invasive breast cancer currently not undergoing any treatment while awaiting surgery
• Operable breast cancer as assessed by treating surgical oncologist
• Tumor ≥ 1.0 cm by palpation or imaging
• ER or PR positive (≥1%) breast adenocarcinoma
• Her2 negative as per ASCO 2018 guidelines 61
• Invasive ductal or lobular carcinoma, invasive carcinoma Not Otherwise Specified (NOS)
• ECOG PS 0-2 (Appendix A)
• 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.
• Able to provide written informed consent for the study.
• Able to swallow and retain orally administered medication.

You may not qualify if:

• Locally Advanced or metastatic breast cancer
• Prior therapy with chemotherapy or planned neoadjuvant chemotherapy
• Prior hormonal therapy including tamoxifen, aromatase inhibitors
• Pre-dominant histology other than invasive ductal or lobular carcinoma
• Concomitant other invasive malignancy.
• Hgb \< 100 g/L, Platelets \< 100 x 10\^9 per liter, Absolute Neutrophil Count \< 1.5 x 10\^9/L
• Bilirubin ≥ 1.5 times Upper Limit Normal (ULN)
• ALT ≥ 2.5 times ULN
• Albumin \< 25 g/L
• INR/PTT \> 1.5 times ULN
• Creatinine clearance calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation of less than 50 mL/min/1.73m2.
• Cardiac abnormalities as evidenced by any of the following:
• Baseline QTcF interval ≥ 480 msec
• Clinically significant conduction abnormalities or arrhythmias
• Presence of cardiac pacemaker or defibrillator with a paced ventricular rhythm limiting ECG analysis.

Sponsors & Collaborators

• Ottawa Hospital Research Institute: lead
• Ontario Institute for Cancer Research: collaborator
• GlaxoSmithKline: collaborator
• London Regional Cancer Program, Canada: collaborator
• Hamilton Health Sciences Corporation: collaborator

Study Sites (1)

St. Joseph's Health Care London

London, Ontario, N6A 4V2, Canada

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

GSK-3326595

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• John F. Hilton, MD

  The Ottawa Hospital Cancer Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase II, randomized, open label, multi-center, parallel design, window of opportunity trial

Study Record Dates

• First Submitted: July 28, 2020
• First Posted: December 21, 2020
• Study Start: June 8, 2021
• Primary Completion: August 15, 2022
• Study Completion: August 15, 2022
• Last Updated: October 25, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)