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

• ClinicalTrials.gov Identifier: NCT04676516
• Recruitment Status: Completed
• First Posted: December 21, 2020
• Last Update Posted: October 25, 2022
• Sponsor: Ottawa Hospital Research Institute
• Collaborators: Ontario Institute for Cancer Research; GlaxoSmithKline; London Regional Cancer Program, Canada; Hamilton Health Sciences Corporation
• Information provided by (Responsible Party): Ottawa Hospital Research Institute

Study Description

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

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: GSK3326595	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Phase II, randomized, open label, multi-center, parallel design, window of opportunity trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized Window of Opportunity Trial Evaluating Clinical and Biological Effects of PRMT5 Inhibitor, GSK3326595, in Early Stage Breast Cancer
• Actual Study Start Date: June 8, 2021
• Actual Primary Completion Date: August 15, 2022
• Actual Study Completion Date: August 15, 2022

Arms and Interventions

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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Complete cell cycle arrest (CCCA) [ Time Frame: 2 years ]
   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%.

Secondary Outcome Measures :

1. Rate of complete cell cycle arrest (CCCA) in patients with wild-type TP53 [ Time Frame: 2 years ]
   The secondary outcome is to assess whether PRMT5 inhibition preferentially results in CCCA in patients with wild-type TP53.
2. Assess whether PRMT5 inhibition results in reduced expression of ER-α signaling compared to patients with no treatment based on gene expression analysis. [ Time Frame: 2 years ]
   A secondary outcome is to assess whether PRMT5 inhibition results in reduced expression of ER-α signaling.
3. 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 [ Time Frame: 2 years ]
   A secondary outcome is to assess whether PRMT5 inhibition results in changes in breast-cancer stem cell signature particularly FOXP1.
4. 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. [ Time Frame: 2 years ]
   A secondary outcome is to identify the immunomodulatory effects of GSK3326595, by performing exploratory analyses.

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Female post-menopausal participants
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Canada, Ontario

St. Joseph's Health Care London

London, Ontario, Canada, N6A 4V2

Sponsors and Collaborators

Ottawa Hospital Research Institute

Ontario Institute for Cancer Research

GlaxoSmithKline

London Regional Cancer Program, Canada

Hamilton Health Sciences Corporation

Investigators

• Principal Investigator: John F. Hilton, MD; The Ottawa Hospital Cancer Centre

More Information

• Responsible Party: Ottawa Hospital Research Institute
• ClinicalTrials.gov Identifier: NCT04676516
• Other Study ID Numbers: OTT-19-06
• First Posted: December 21, 2020
• Last Update Posted: October 25, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Researchers may contact Dr. John Hilton for specific requests.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ottawa Hospital Research Institute:

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

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; GSK-3326595; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action