Liquid Biopsy-Informed Therapy for Breast Cancer

Recruiting at 11 trial locations

Overseen By Laura Pearce

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Canadian Cancer Trials Group

Must be taking: CDK4/6 inhibitors, Endocrine therapy

Must not be taking: Live vaccines, Anticoagulants

Disqualifiers: Other malignancies, Infections, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 8-12 weeks

484 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is being done to answer the following question: Can testing breast cancer for DNA abnormalities or "biomarkers" help predict which patients are most likely to be helped by certain treatments? The pre-study screening is being done to test a sample of blood (or tumour tissue) for biomarkers to see if patients can participate in the study

Will I have to stop taking my current medications?

The trial protocol does not clearly specify if you must stop taking your current medications. However, it mentions that certain medications are not permitted during the study, and there is a washout period (time without taking certain medications) required for some prior therapies. It's best to discuss your specific medications with the trial coordinators.

Is the treatment generally safe for humans?

Niraparib has been studied for safety in various cancers, including breast and prostate cancer, and is generally considered safe, with known side effects that are manageable. ^{1 2 3 4 5}

What makes the drug combination of Fulvestrant, Gemcitabine, Niraparib, and RP-6306 unique for breast cancer treatment?

This drug combination is unique because it uses a liquid biopsy to inform therapy, potentially allowing for more personalized treatment. Additionally, it combines Fulvestrant, a hormone therapy, with Niraparib, a PARP inhibitor, and other agents, which may offer a novel approach compared to standard treatments that typically do not use this combination. ^{1 2 6 7 8}

Research Team

David Cescon

Principal Investigator

University Health Network, Princess Margaret Hospital, Toronto ON Canada

Nathalie Levasseur

Principal Investigator

BCCA - Vancouver Cancer Centre

Stephen Chia

Principal Investigator

BCCA - Vancouver Cancer Centre

John Hilton

Principal Investigator

Ottawa Hospital Research Institute

Moira Rushton

Principal Investigator

Ottawa Hospital Research Institute

Eligibility Criteria

This trial is for adults with ER+/HER2- metastatic breast cancer that has worsened after CDK4/6 inhibitor therapy. Participants must have a life expectancy of at least 3 months, be able to receive treatment and follow-up at the center, and not have had certain treatments or conditions that could interfere with the study.

Inclusion Criteria

My side effects from previous treatments have mostly gone away.

It's been over 28 days since my last major surgery and my wounds have healed.

Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to both screening registration as well as enrollment to a specific substudy to document their willingness to participate.

Exclusion Criteria

You have a known condition that weakens your immune system.

I do not have any serious infections or illnesses that would interfere with the treatment.

I have not received a live vaccine within the last 30 days, except for non-live COVID-19 vaccines.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive investigational drugs/drug combinations based on biomarker testing

8-12 weeks

Monitoring

Participants are monitored for progression and molecular changes in CDK4/6i resistance

Until progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• CFI-400945
• CFI-402257
• Fulvestrant
• Gemcitabine
• Niraparib
• Observation
• RP-6306

Trial Overview The trial tests if liquid biopsies can predict which patients will benefit from specific treatments like RP-6306, Gemcitabine, Niraparib, Fulvestrant or just observation. It involves screening blood/tissue for biomarkers before starting any substudy treatment.

Participant Groups

Group I: Substudy D - RP-6306 + RP-3500 Experimental Treatment 2 Interventions

Group II: Substudy C - Niraparib + Fulvestrant Experimental Treatment 2 Interventions

Group III: Substudy B - RP-6306 + Gemcitabine Experimental Treatment 2 Interventions

RP-6306 80mg BID D1-3, D8-10 and D15-17. Gemcitibine D1 and D8

Group IV: Substudy A - Monitoring Experimental Treatment 1 Intervention

Monitoring substudy. Biomarker+ (6=23); Biomarker- (n=6-23).

Fulvestrant is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in United States as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Canada as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Japan as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Who Is Running the Clinical Trial?

Canadian Cancer Trials Group

Lead Sponsor

Trials

135

Recruited

70,300+

Findings from Research

Niraparib at a dose of 200 mg/day was determined to be the recommended phase 2 dose when combined with abiraterone acetate plus prednisone (AAP) for patients with metastatic castration-resistant prostate cancer (mCRPC), as it showed a tolerable safety profile with no new safety signals.

The combination of niraparib with apalutamide resulted in a higher incidence of dose-limiting toxicities, leading to the decision not to further evaluate this combination, highlighting the importance of monitoring drug interactions in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE). Saad, F., Chi, KN., Shore, ND., et al.[2021]

In the BELLE-2 phase III study, buparlisib combined with fulvestrant showed a trend towards improved overall survival (OS) compared to placebo plus fulvestrant in patients with advanced hormone receptor-positive breast cancer, although the results were not statistically significant.

Patients receiving buparlisib experienced significantly higher rates of grade III/IV adverse events, such as elevated liver enzymes and hyperglycemia, suggesting that while the treatment may offer some benefits, it also comes with notable safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buparlisib plus fulvestrant versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: Overall survival results from BELLE-2. Campone, M., Im, SA., Iwata, H., et al.[2019]

Niraparib, administered at doses of 200 mg and 300 mg daily, was found to be tolerable in Japanese patients with advanced solid tumors, with only one case of dose-limiting toxicity observed.

The study demonstrated a favorable pharmacokinetic profile for niraparib, with dose-proportional increases in drug levels and some patients showing a partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study. Yonemori, K., Shimizu, T., Kondo, S., et al.[2021]

In a phase III trial involving patients with advanced breast cancer and germline BRCA1/2 mutations, niraparib showed a median progression-free survival (PFS) of 4.1 months compared to 3.1 months for physician's choice chemotherapy, although the difference was not statistically significant (P = 0.86).

Despite the trial being halted due to issues with data assessment, niraparib demonstrated a 35% objective response rate, indicating its potential effectiveness in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study. Turner, NC., Balmaña, J., Poncet, C., et al.[2023]

Niraparib, a recently approved treatment for recurrent platinum-sensitive ovarian cancer, has demonstrated a high oral bioavailability of 72.7% in humans, indicating effective absorption when taken orally.

The study involved six patients who received a therapeutic dose of 300 mg of niraparib, followed by a small intravenous dose to measure its levels in the bloodstream, confirming its potential as a convenient oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. van Andel, L., Rosing, H., Zhang, Z., et al.[2019]

In a study involving 416 women with advanced breast cancer, the addition of the PI3K inhibitor buparlisib to paclitaxel did not improve progression-free survival (PFS) compared to placebo, leading to the trial's termination for futility.

Common side effects of buparlisib included diarrhea, alopecia, rash, nausea, and hyperglycemia, affecting over 40% of patients, indicating that while the drug was well-tolerated, it did not provide the expected therapeutic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4). Martín, M., Chan, A., Dirix, L., et al.[2020]

AZD5363, a pan-AKT inhibitor, shows promising efficacy in treating triple-negative metastatic breast cancer, especially in patients with specific genetic alterations, as indicated by a study involving 28 patient-derived xenografts (PDXs).

The study identified key biomarkers for sensitivity to AZD5363, such as mutations in PIK3CA/AKT1, and revealed mechanisms of resistance, including cyclin D1 overexpression, which could help tailor more effective treatments for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. Gris-Oliver, A., Palafox, M., Monserrat, L., et al.[2021]

Capivasertib, an oral AKT inhibitor, was well tolerated when combined with weekly paclitaxel in patients with advanced ER+/HER2- breast cancer, with a recommended dosing schedule of 400 mg twice daily for 4 days on and 3 days off.

However, the addition of capivasertib did not significantly improve progression-free survival compared to placebo, with median PFS of 10.9 months for capivasertib versus 8.4 months for placebo in the overall population, indicating it may not enhance treatment outcomes in this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population. Turner, NC., Alarcón, E., Armstrong, AC., et al.[2023]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE). [2021]

2. England pubmed.ncbi.nlm.nih.gov

Buparlisib plus fulvestrant versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: Overall survival results from BELLE-2. [2019]

3. England pubmed.ncbi.nlm.nih.gov

The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. [2019]

6. England pubmed.ncbi.nlm.nih.gov

A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4). [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. [2021]

8. England pubmed.ncbi.nlm.nih.gov

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population. [2023]