A Phase II Randomized Window of Opportunity Trial Evaluating Clinical and Biological Effects of PRMT5 Inhibitor, GSK3326595, in Early Stage Breast Cancer
Overview
- Phase
- Phase 2
- Intervention
- GSK3326595
- Conditions
- Breast Cancer
- Sponsor
- Ottawa Hospital Research Institute
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Complete cell cycle arrest (CCCA)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
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
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
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.
Intervention: GSK3326595
Outcomes
Primary Outcomes
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 Outcomes
- 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)