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

Sponsor

Ottawa Hospital Research Institute (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04676516

Collaborator

Ontario Institute for Cancer Research (Other), GlaxoSmithKline (Industry), London Regional Cancer Program, Canada (Other), Hamilton Health Sciences Corporation (Other)

Enrollment

Arms

21.4

Anticipated Duration (Months)

Study Details

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

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Phase II, randomized, open label, multi-center, parallel design, window of opportunity trialPhase 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

Anticipated Study Start Date :

Mar 21, 2021

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 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 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.

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.

Outcome Measures

Primary Outcome Measures

Complete cell cycle arrest (CCCA) [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

Rate of complete cell cycle arrest (CCCA) in patients with wild-type TP53 [2 years]
The secondary outcome is to assess whether PRMT5 inhibition preferentially results in CCCA in patients with wild-type TP53.
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]
A secondary outcome is to assess whether PRMT5 inhibition results in reduced expression of ER-α signaling.
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]
A secondary outcome is to assess whether PRMT5 inhibition results in changes in breast-cancer stem cell signature particularly FOXP1.
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]
A secondary outcome is to identify the immunomodulatory effects of GSK3326595, by performing exploratory analyses.

Other Outcome Measures

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

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

Exclusion Criteria:

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.
History or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association (NYHA).
History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months.
Clinically significant cardiomegaly, ventricular hypertrophy, or cardiomyopathy.
Any serious known immediate or delayed hypersensitivity reaction(s) to GSK3326595, or idiosyncrasy to drugs chemically related to the investigational drugs.
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
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.
Severe, uncontrolled systemic disease (respiratory, cardiac, renal, hepatic, bleeding)
Currently active liver or biliary disease
History of active HIV, Hepatitis B or C infection.
Any other criteria which, in the investigator's opinion, renders the patient ineligible to be on study.
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.