Open Actively Recruiting

A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Participants With Breast Cancer

About

Brief Summary

This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants with breast cancer. Cohort 1 will focus on participants with inoperable, locally advanced or metastatic, estrogen receptor (ER)-positive, HER2-negative breast cancer who had disease progression during or following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i; e.g., palbociclib, ribociclib, abemaciclib) in the first- or second-line setting. Cohort 2 will focus on inoperable, locally advanced or metastatic, ER-positive, HER2-positive breast cancer with prior disease progression on trastuzumab-and-taxane- and ado-trastuzumab emtansine-based therapies. The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, or modify the patient population. During Stage 1, participants in each cohort will be randomly assigned to treatment arms. Participants in the control or experimental arms who experience disease progression (as determined by the investigator according to RECIST v1.1) or unacceptable toxicity during Stage 1 will be given the option of receiving a different treatment combination during Stage 2, provided they meet eligibility criteria and a treatment arm is open for enrollment. No Stage 2 treatment is currently available.

Primary Purpose
Treatment
Study Type
Interventional
Phase
Phase I/II

Eligibility

Gender
Female
Healthy Volunteers
No
Minimum Age
18 Years
Maximum Age
N/A

Inclusion Criteria:

Inclusion Criteria for Cohort 1 (Stage 1 [and Stage 2, only where indicated]):

  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  • Documented estrogen receptor-positive (ER+) tumor
  • Patients for whom endocrine therapy is recommended and treatment with cytotoxic chemotherapy is not indicated at time of entry into the study, as per national or local treatment guidelines
  • Radiologic/objective evidence of recurrence or progression after the most recent systemic therapy for breast cancer
  • Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease (note: at least one line of therapy must have contained a CDK4/6i administered for a minimum of 8 weeks prior to disease progression.)
  • Postmenopausal status for women
  • Life expectancy ≥3 months
  • Availability of a representative tumor specimen that is suitable for evaluation of Ki67, and/or additional biomarkers via central testing
  • Prior fulvestrant therapy is allowed
  • Stages 1 and 2: Measurable disease (at least one target lesion) according to RECIST v1.1
  • Stages 1 and 2: Adequate hematologic and end-organ function
  • Stages 1 and 2: Stable anticoagulant regimen for patients receiving therapeutic anticoagulation

Inclusion Criteria for Cohort 2 (Stage 1 [and Stage 2, only where indicated]):

  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  • Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally advanced disease not amenable to curative resection
  • ER-positive, HER2-positive breast cancer
  • Previous progression to standard of care anti-HER2 therapies, of which one was a trastuzumab-and-taxane-based systemic therapy (including in the early setting if recurrence occurred within 6 months of finishing adjuvant therapy) and one was ado-trastuzumab emtansine
  • Postmenopausal status for women
  • Life expectancy ≥3 months
  • Availability of a representative tumor specimen that is suitable for evaluation of Ki67, and/or additional biomarkers via central testing
  • Up to one line of endocrine therapy in the advanced setting allowed, including fulvestrant if given more than 28 days prior to randomization, but excluding other SERDs
  • Stages 1 and 2: Measurable disease (at least one target lesion) according to RECIST v1.1
  • Stages 1 and 2: Baseline left ventricular ejection fraction (LVEF) ≥50% as measured by ECHO or MUGA scans
  • Stages 1 and 2: Adequate hematologic and end-organ function
  • Stages 1 and 2: Stable anticoagulant regimen for patients receiving therapeutic anticoagulation

Inclusion Criteria for Cohorts 1 and 2 (Stage 2):

  • Ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1, provided that a Stage 2 slot is available and patient meets eligibility criteria for Stage 2
  • Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 because of unacceptable toxicity to drugs or disease progression as determined by the investigator according to RECIST v1.1.

Exclusion Criteria:

General Exclusion Criteria for all Treatment Arms in Stage 1, Cohorts 1 and 2 (unless only

applicable to one cohort, as indicated):

  • Cohort 1 only: Known HER2-positive breast cancer
  • Cohort 1 only: Concurrent hormone replacement therapy
  • Cohort 1 only: Prior treatment with cytotoxic chemotherapy for metastatic breast cancer
  • Prior treatment with any of the protocol-specified study treatments
  • Treatment with investigational therapy within 28 days prior to initiation of study treatment
  • Systemic treatment for breast cancer within 2 weeks of Cycle 1, Day 1 or 5 half-lives of the drug prior to Cycle 1, Day 1
  • Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤1 or better, with the exception of alopecia of any grade and Grade ≤2 peripheral neuropathy
  • Eligible only for the control arm
  • Prior allogeneic stem cell or solid organ transplantation
  • Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study
  • History of malignancy other than breast cancer within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death
  • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
  • Uncontrolled tumor-related pain
  • Uncontrolled or symptomatic hypercalcemia
  • Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
  • History of leptomeningeal disease
  • Active tuberculosis
  • Severe infection within 4 weeks prior to initiation of study treatment
  • Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
  • History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
  • Active cardiac disease or history of cardiac dysfunction
  • Positive HIV test at screening or at any time prior to screening
  • Active Hepatitis B or Hepatitis C virus infection
  • Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery, including gastric resection, potentially affecting enteral absorption
  • Known allergy or hypersensitivity to any of the study drugs or any of their excipients
  • Cohort 2 only: Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy
  • Cohort 2 only: Current chronic daily treatment (continuous for >3 months) with corticosteroids (dose of 10 mg/day methylprednisolone equivalent), excluding inhaled steroids

Additional Exclusion Criteria for Giredestrant + Abemaciclib Arm (Cohort 1, Stage 1):

  • Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy
  • History of major surgical resection involving the stomach or small bowel, or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea
  • History of syncope of cardiovascular etiology, ventricular arrhythmia, or sudden cardiac arrest

Additional Exclusion Criteria for Giredestrant + Ipatasertib Arm (Cohort 1, Stage 1):

  • Prior treatment with an Akt inhibitor
  • Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
  • Grade ≥2 uncontrolled or untreated hypercholesterolemia or hypertriglyceremia
  • History of Type 1 or Type 2 diabetes mellitus requiring insulin
  • Congenital long QT syndrome or screening QTcF >480 milliseconds
  • History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion
  • Treatment with strong CYP3A4 inducers and inhibitors within 4 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug

Additional Exclusion Criteria for Giredestrant + Inavolisib Arm (Cohort 1, Stage 1):

  • Prior treatment with any PI3K, Akt, or mTOR inhibitor, or any agent whose mechanism of action is to inhibit the PI3K/Akt/mTOR pathway
  • Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes
  • Fasting glucose ≥126 mg/dL or ≥7.0 mmol/L and HbA1c ≥5.7%
  • Any concurrent ocular or intraocular condition that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition
  • Active inflammatory or infectious conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye
  • Symptomatic active lung disease, including pneumonitis
  • Inability to confirm biomarker eligibility based on valid results from either central testing of blood or local testing of blood or tumor tissue that documents one of the protocol-defined PIK3CA mutations

Additional Exclusion Criteria for Giredestrant + Ribociclib Arm (Cohort 1, Stage 1):

  • Currently receiving any of the following substances within 7 days before randomization: concomitant medications, herbal supplements, and/or fruits that are known as strong inhibitors or inducers of CYP3A4/5 or medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
  • Currently receiving or has received systemic corticosteroids ≤2 weeks prior to starting trial treatment
  • Impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments

Additional Exclusion Criteria for Giredestrant + Samuraciclib Arm (Cohort 1, Stage 1):

  • Prior treatment with mTOR inhibitor
  • Receipt of systemic corticosteroids (at a dose >10 mg prednisone/day or equivalent) within 14 days before the first dose of samuraciclib
  • Active bleeding diatheses
  • History of hemolytic anemia or marrow aplasia
  • Receipt of a live-virus vaccination within 28 days or less of planned treatment start

Additional Exclusion Criteria for Giredestrant + PH FDC SC + Abemaciclib Arm (Cohort 2,

Stage 1):

  • Interstitial lung disease or severe dyspnea
  • History of major surgical resection involving the stomach or small bowel, preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea, or a condition that may significantly alter the absorption of the oral trial treatments
  • History of syncope of cardiovascular etiology, ventricular arrhythmia, or sudden cardiac arrest

Additional Exclusion Criteria for Giredestrant + PH FDC SC + Palbociclib Arm (Cohort 2,

Stage 1):

  • Currently receiving any of the following substances within 7 days before randomization: Concomitant medications, herbal supplements, and/or fruits that are known as strong inhibitors or inducers of CYP3A4/5 or medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
  • History of major surgical resection involving the stomach or small bowel, preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea, or a condition that may significantly alter the absorption of the oral trial treatments
  • Interstitial lung disease or severe dyspnea

Join this Trial

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Study Stats
Protocol No.
20-002325
Category
Hematology-Oncology
Oncology
Contact
Monica Rocha
Location
  • UCLA Alhambra
  • UCLA Burbank
  • UCLA Laguna Hills
  • UCLA Parkside
  • UCLA San Luis Obispo
  • UCLA Santa Monica
  • UCLA Westlake Village
  • UCLA Westwood
For Providers
NCT No.
NCT04802759
For detailed technical eligibility, visit ClinicalTrials.gov.