A Liquid-biopsy Informed Platform Trial to Evaluate Treatment in CDK4/6-inhibitor Resistant ER+/HER2- Metastatic Breast Cancer

Plain English Summary

Liquid-biopsy Informed Platform Trial to Evaluate CDK4/6-inhibitor Resistant ER+/HER2- Metastatic Breast Cancer is a Phase 2 clinical trial sponsored by Canadian Cancer Trials Group studying Breast Cancer. This trial tests if analyzing DNA from a blood or tumor sample can help choose the best treatment for advanced ER+/HER2- breast cancer that has stopped responding to certain therapies. It is for patients with advanced ER+/HER2- metastatic breast cancer that has progressed after initial treatment with CDK4/6 inhibitors and endocrine therapy. Participation involves providing a blood or tumor sample for biomarker testing and then receiving one of the study treatments or being monitored. Alternatives may include other standard treatments for advanced breast cancer, palliative care, or clinical trials that do not involve biomarker selection. The trial aims to enroll 484 participants.

Official Summary

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

Who Can Participate

Here is what you need to know about eligibility for this trial. Patients must have ER+/HER2- metastatic breast cancer that has progressed on or within 8 weeks of their first line of CDK4/6 inhibitor plus endocrine therapy. Patients must be at least 18 years old, have a good performance status (ECOG 0 or 1), and a life expectancy of at least 3 months. Specific blood counts (hemoglobin, neutrophils, platelets) and organ function (liver, kidney) must be within certain limits. Patients who have received certain prior treatments, like specific types of chemotherapy or antibody-drug conjugates, may not be eligible. This trial is studying Breast Cancer, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcomes measure how well the selected treatments shrink tumors or stabilize the cancer, indicating if the biomarker approach helps patients achieve a better response. The specific primary outcome measures are: Evaluate whether biomarker selection improves outcomes as assessed by RECIST 1.1 for overall response rate (5 years); Evaluate whether biomarker selection improves outcomes as assessed by RECIST 1.1 for clinical benefit rate (5 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial addresses a critical need for effective treatments in patients with advanced breast cancer that has become resistant to CDK4/6 inhibitors, a common and important treatment class. Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Breast Cancer, where improved treatment options are needed.

Investor Insight

This trial targets a significant unmet need in a large patient population, with potential for biomarker-driven therapies to gain market share and improve treatment selection. Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor if your cancer is ER+/HER2- and if it has progressed after CDK4/6 inhibitor treatment. Discuss what biomarker testing involves and what the results might mean for your treatment options. Understand the schedule of study visits, potential side effects of the treatments being tested, and how your progress will be monitored. This trial is currently recruiting participants. The trial is being conducted at 10 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 484 participants

Interventions

• DRUG: RP-6306 — Dose and schedule will be assigned at enrolment
• DRUG: Gemcitabine — Dose and schedule will be assigned at enrolment
• OTHER: Observation — Monitoring arm
• DRUG: Niraparib — Dose and schedule will be assigned at enrolment
• DRUG: Fulvestrant — Dose and schedule will be assigned at enrolment

Primary Outcomes

• Evaluate whether biomarker selection improves outcomes as assessed by RECIST 1.1 for overall response rate (5 years)
• Evaluate whether biomarker selection improves outcomes as assessed by RECIST 1.1 for clinical benefit rate (5 years)

Secondary Outcomes

• Number and severity of adverse events (5 years)
• Progression-free survival (PFS) (5 years)
• Overall survival (5 years)

Full Eligibility Criteria

Inclusion Criteria:

* Patients must have histologically and/or cytologically confirmed, advanced / metastatic breast cancer, ER \>10% and not HER2 overexpressing/amplified as per ASCO/CAP criteria. Patients with locally advanced or inflammatory disease without distant metastases that is potentially resectable or treatable with curative intent are not eligible
* All patients must have a formalin fixed paraffin embedded tissue block (from primary or metastatic tumour) available and must have provided informed consent for the release of the block
* Patients must have had objective disease progression demonstrated on (defined as while taking or within 8 weeks of the last dose) first line CDK4/6i + ET for MBC. Patients who discontinued CDK4/6i + ET without disease progression more than 8 weeks prior to objective disease progression (toxicity, patient request) are not eligible. Patients must have received at least 24 weeks of first line CDK4/6i + ET therapy
* Presence of clinically and/or radiologically documented disease. All radiology studies must be performed within 21 days prior to enrollment (within 28 days if negative). All patients must have measurable disease as defined by RECIST 1.1.
* The criteria for defining measurable disease are as follows:

  * Chest x-ray ≥ 20 mm
  * CT scan (with slice thickness of 5 mm) ≥ 10 mm: longest diameter
  * Physical exam (using calipers) ≥ 10 mm
  * Lymph nodes by CT scan ≥ 15 mm: measured in short axis
* Patients must be ≥ 18 years of age
* Patients must have an ECOG performance status 0 or 1
* Patients must have a life expectancy ≥ 3 months.
* Hemoglobin ≥90 g/L\*
* Absolute neutrophils ≥ 1.5 x 10\^9/L (1500/µL)
* Platelets ≥ 100 x 109/L (100 x 10\^3/µL)
* Bilirubin ≤ 1.5 x ULN (upper limit of normal)\*\*
* AST \& ALT ≤ 2.5 x ULN
* ≤ 5.0 x ULN if patient has liver metastases
* Serum creatinine ≤ 1.5 x ULN, Creatinine clearance ≥50 mL/min
* All patients must have received at least 24 weeks of prior CDK4/6i in combination with first line ET for advanced or metastatic disease and have had disease progression on or within 8 weeks of the last dose of CDK4/6i. Patients who have progressed on, or within 12 months of completion of adjuvant therapy with an aromatase inhibitor who are treated with fulvestrant instead of an aromatase inhibitor combined with CDK4/6 inhibitor are only eligible for non fulvestrant containing substudies.

In addition, the following systemic therapies may have been given after CDK4/6i / ET prior to screening / enrollment to this study:

* For enrollment to "second line" substudies:

  \- An additional single agent non-fulvestrant/SERD endocrine therapy in the palliative setting is permitted provided patient remains eligible for and can access fulvestrant treatment. Patients who have received prior fulvestrant/SERD are not eligible for fulvestrant containing substudies. Contact CCTG in case of any other prior endocrine therapy other than an aromatase inhibitor or tamoxifen.
* For enrollment to "third line" substudies:

  * Non-SERD endocrine therapy and targeted agents (for example, PI3K/AKT/PTEN inhibitors unless excluded in substudy-specific eligibility criteria) alone or in combination.
  * Patients who have received a prior targeted agent may not be eligible for substudies that contain the same class of agent. Please refer to substudy-specific eligibility criteria.
  * Note: if a patient has not had fulvrestrant/SERD prior to enrollment to "third line: substudy, single agent fulvestrant/SERD must be given prior to enrollment (unless not possible for reasons such as fulvestrant/SERD not standard of care / not funded in province, patient cannot receive intramuscular injection; contact CCTG for other scenarios).
* Patients may also have received adjuvant/neoadjuvant systemic therapies; however cytotoxic chemotherapy or antibody drug conjugates (ADC) in the palliative setting are not permissible.
* Patients receiving LHRH agonists (for example premenopausal patients) may continue on the LHRH agonist, but may not start a LHRH agonist within 12 weeks prior to enrollment.
* Consult CCTG for other scenarios (for example where short course of other ET is given prior to CDKi + ET, patients who have received investigational drugs, vaccines or immunotherapies) as certain patients may be eligible.
* All reversible prior toxicity related to prior therapies must have recovered to grade ≤ 1 (consult CCTG in the case of irreversible toxicity) and have adequate washout as follows (screening may occur during the washout period): Longest of the following (for questions or any proposed variance, please discuss with CCTG prior to patient enrollment): Two weeks; 5 half-lives for investigational agents; standard cycle length of standard therapies
* Patients must not have received a transfusion (platelets or red blood cells) or colony stimulating factors ≤ 4 weeks prior to initiating treatment substudy therapy.
* Surgery: Prior surgery is permitted provided that a minimu

Trial Locations

• Arthur J.E. Child Comprehensive Cancer Centre, Calgary, Alberta, Canada
• BCCA - Kelowna, Kelowna, British Columbia, Canada
• BCCA - Vancouver, Vancouver, British Columbia, Canada
• QEII Health Sciences Centre, Halifax, Nova Scotia, Canada
• Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, Ontario, Canada
• Kingston Health Sciences Centre, Kingston, Ontario, Canada
• Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
• Odette Cancer Centre, Toronto, Ontario, Canada
• University Health Network, Toronto, Ontario, Canada
• The Jewish General Hospital, Montreal, Quebec, Canada

Frequently Asked Questions

Related Conditions

• Breast Cancer
• Metastatic Breast Cancer
• ER-positive Breast Cancer
• HER2-negative Breast Cancer
• Hormone Receptor-Positive Breast Cancer
• Endocrine Therapy Resistance
• CDK4/6 Inhibitor Resistance
• Advanced Breast Cancer
• Recurrent Breast Cancer
• Metastatic Cancer

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