Breast Cancer
Conditions
Keywords
Breast Cancer
Brief summary
This research study is studying a drug called GDC-0084 as a possible treatment for HER2-Positive Breast Cancer. The drugs involved in this study are: * GDC-0084 * Trastuzumab (Herceptin®)
Detailed description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved GDC-0084 as a treatment for any disease. Trastuzumab is a targeted therapy approved by the FDA to be used alone or in combination with a chemotherapy drug to treat HER2-positive metastatic breast cancer. GDC-0084 has been shown to stop the activity of a protein called PI3-kinase. This action blocks a pathway in the body that cancer cells commonly use to grow and divide. Trastuzumab is called a "targeted therapy" because it works by attaching itself to specific receptors on the surface of breast cancer cells, known as HER2 receptors. When targeted therapies attach to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the immune system. This process allows trastuzumab to help slow or stop the growth of the breast cancer. In this research study, the investigators are looking to see how your cancer responds to the combination of GDC-0084 and Trastuzumab.
Interventions
DRUGTrastuzumab
Trastuzumab is called a "targeted therapy" because it works by attaching itself to specific receptors on the surface of breast cancer cells, known as HER2 receptors. When targeted therapies attach to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the immune system
DRUGGDC-0084
GDC-0084 has been shown to stop the activity of a protein called PI3-kinase. This action blocks a pathway in the body that cancer cells commonly use to grow and divide
Sponsors
Dana-Farber Cancer Institute
Kazia Therapeutics Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Cohort A: * At least one measurable CNS metastasis, defined as ≥ 10 mm in at least one dimension. * Unequivocal evidence of new and/or progressive brain metastases, and at least one of the following scenarios: * Treated with SRS or surgery with residual un-treated lesions remaining. Such participants are eligible for immediate enrollment on this study providing that at least one untreated lesion is measurable * Participants who have had prior WBRT and/or SRS and then whose lesions have subsequently progressed or who have new lesions are also eligible. In this case, lesions which have been treated with SRS may be considered as target lesions if there is unequivocal evidence, in the opinion of the treating physician, of progression following SRS. * Participants who have not previously been treated with cranial radiation (e.g., WBRT or SRS) are eligible to enter the study, but such participants must be asymptomatic from their CNS metastases and not requiring corticosteroids for symptom control. * Participants who present with systemic stable/absent or progressive disease are eligible to this trial, as long as they fulfill one of the above criteria. Cohort B: * New and/or progressive brain metastasis(es) with clinical indication for resection. * All Cohorts: * Pathologically confirmed HER2-positive MBC by local laboratory with the following requirements: HER2 overexpressed or amplified (immunohistochemistry of 3+ or HER2 gene amplification by in situ hybridization with a ratio of HER2-gene signals to centromere 17 signals ≥ 2.0 or average HER2 copy number ≥ 6.0 signals/cells). * Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. * Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan. * Stable or decreasing corticosteroid dose for at least 7 days prior to initiation of treatment. * Concurrent administration of other anti-cancer therapy during the course of this study is not allowed. Note that concurrent use of supportive care medications (e.g. anti-resorptive agents, pain medications) is allowed. * The participant is ≥18 years old. * Participants must have normal organ and marrow function as defined below: * Absolute neutrophil count ≥1,000/μl * Platelets ≥75,000/μl * Hemoglobin ≥9 g/dL * Total bilirubin ≤1.5mg/dL (upper limit of normal) except subject with documented Gilbert's syndrome (≤5 x ULN) or liver metastasis, who must have a baseline total bilirubin ≤3.0 mg/dL; * AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN OR ≤ 5.0 × institutional ULN for patients with documented liver metastases. * Serum creatinine ≤ 1.5 mg/dL (or glomerular filtration rate ≥ 30 ml/min as determined by the Cockcroft-Gault equation) * Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 8 days of initiating protocol therapy. * The effects of GDC-0084 on the developing human fetus are unknown and radiotherapy has known teratogenic effects so women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 7 months after completion of Trastuzumab administration per recommendations from the Trastuzumab package insert. * The subject is capable of understanding and complying with the protocol and has signed the informed consent document. * Participant must be able to swallow and retain oral medication.
Exclusion criteria
* Visceral crisis or impending visceral crisis at time of screening. * CNS complications for whom urgent neurosurgical intervention is indicated (e.g., resection, shunt placement). * Known leptomeningeal metastases \[Defined as positive CSF cytology and/or unequivocal radiological evidence of clinically significant leptomeningeal involvement. CSF sampling is not required in the absence of suggestive symptoms to exclude leptomeningeal involvement\]. * Patients with known contraindication to MRI (e.g., due to pacemaker, ferromagnetic implants, claustrophobia, extreme obesity, hypersensitivity, etc.). However, head CT with contrast may be used in place of MRI at baseline and throughout the trial if MRI is contraindicated and a participant's brain metastases are clearly measurable by head CT. * Chemotherapy or targeted therapy within 14 days prior to initiation of protocol therapy. No washout is required for trastuzumab. * Has received prior therapy with a PI3K or mTOR inhibitor. * No washout is required for endocrine therapy. If a patient has been on ovarian suppression for at least 28 days prior to initiation of study treatment, continuation of ovarian suppression is permitted on protocol. Starting a new endocrine therapy during protocol therapy is not permitted. * Current use or history of receiving a non-approved, investigational treatment within 14 days prior to initiation of protocol therapy. * Subjects with a history of hypersensitivity to compounds of similar biologic composition to GDC-0084 or any constituent of the product. * The subject has an uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association Class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus (DM), gastric or duodenal ulceration diagnosed within the previous 6 months, chronic liver or renal disease, or severe malnutrition. If a participant has controlled DM but is unable to monitor blood sugars at home, they will be excluded from the trial. * The subject is pregnant or breast-feeding. * No active, second potentially life-threatening cancer. * Has had major surgery within 21 days before initiation of protocol therapy. * Active infection requiring IV antibiotics at the time of protocol therapy initiation. * Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest. * Known intolerance to trastuzumab. * QT interval time of ≥ 470 msec. * Participants receiving any medications or substances that are strong inhibitors or strong inducers of CYP3A4 are ineligible. Should a participant be taking one of these agents and is able to discontinue the therapy or switch to a different agent, no washout will be required prior to starting study medication. Please see Appendix M for the list of medications. Corticosteroids, which are weak CYP3A4 inducers are allowed. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate in the CNS | Assessed every 2 cycles for the first 4 cycles, and then every 3 cycles thereafter, until CNS progression or initiation of new anticancer therapy, up to ~34 weeks. | Defined as the proportion of patients with partial or complete response in the CNS, per RANO-BM criteria (Complete response \[CR\]: disappearance of all CNS target lesions sustained for at least 4 weeks, no new lesions, no corticosteroids, stable or improved clinically; Partial response \[PR\]: At least 30% decrease in the sum of longest diameter of CNS target lesions, taking as reference the baseline sum, sustained for at least 4 weeks, no new lesions, stable to decreased corticosteroid dose, stable or improved clinically; Progressive disease \[PD\]: At least a 20% increase in the sum of longest diameter of CNS target lesions, taking as reference the smallest sum on study; Stable disease \[SD\]: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of long diameter of CNS target lesions while on study; Objective response = CR+PR) |
| Correlation Between Inhibition of p-4EBP1 in Resected Brain Tumor Tissue and Intracranial Response in the Corresponding Patient-derived Xenograft (PDX) Models of BCBM | 2 Years | to correlate on-treatment p4EBP1 levels in the resected brain tumor tissue collected from patients to intracranial response to GDC-0084/trastuzumab and survival in the PDX model generated from the same patient |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate in the CNS | Assessed every 2 cycles for the first 4 cycles, and then every 3 cycles thereafter, until CNS progression or initiation of new anticancer therapy, up to ~34 weeks | Defined as the proportion of participants with CNS response or stable disease in the CNS \>=18 or 24 weeks, per RANO-BM criteria (Complete response \[CR\]: disappearance of all CNS target lesions sustained for at least 4 weeks, no new lesions, no corticosteroids, stable or improved clinically; Partial response \[PR\]: At least 30% decrease in the sum of longest diameter of CNS target lesions, taking as reference the baseline sum, sustained for at least 4 weeks, no new lesions, stable to decreased corticosteroid dose, stable or improved clinically; Progressive disease \[PD\]: At least a 20% increase in the sum of longest diameter of CNS target lesions, taking as reference the smallest sum on study; Stable disease \[SD\]: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of long diameter of CNS target lesions while on study; Clinical benefit 18 weeks = CR+PR+SD\>=18 weeks; Clinical benefit 24 weeks = CR+PR+SD\>=24 weeks) |
| Clinical Benefit Rate in Extra-CNS | Assessed every 2 cycles for the first 4 cycles, and then every 3 cycles thereafter, until CNS progression or initiation of new anticancer therapy, up to ~34 weeks | Defined as the proportion of participants with non-CNS response or stable disease in non-CNS lesions \>=18 or 24 weeks, per RECIST 1.1 criteria (Complete response \[CR\]: Disappearance of all target lesions; Partial response \[PR\]: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum; Progressive disease \[PD\]: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study; Stable disease \[SD\]: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters on study; Clinical benefit 18 weeks = CR+PR+SD\>=18 weeks; Clinical benefit 24 weeks = CR+PR+SD\>=24 weeks) |
| Objective Response Rate in Extra-CNS | Assessed every 2 cycles for the first 4 cycles, and then every 3 cycles thereafter, until CNS progression or initiation of new anticancer therapy, up to ~34 weeks. | Defined as the proportion of patients with partial or complete response in non-CNS lesions, per RECIST 1.1 criteria (Complete response \[CR\]: Disappearance of all target lesions; Partial response \[PR\]: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum; Progressive disease \[PD\]: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study; Stable disease \[SD\]: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters on study; Objective response = CR+PR) |
| Duration of CNS Response | Assessed every 2 cycles for the first 4 cycles, and then every 3 cycles thereafter, until CNS progression or initiation of new anticancer therapy, up to ~34 weeks. | Defined as the time measurement criteria are met for CR or PR in the CNS (whichever is first recorded) until the first date that progressive disease is objectively documented |
| Bi-compartmental Progression-free Survival | Assessed every 2 cycles for the first 4 cycles, and then every 3 cycles thereafter, until CNS progression or initiation of new anticancer therapy, up to ~34 weeks. | Defined as the time from registration to the first occurrence of progression in the CNS (per RANO-BM criteria), the body (per RECIST 1.1 criteria), or death, whichever comes first. Patients free from progression in the CNS or body are censored at the date of last disease evaluation |
| Overall Survival | Assessed every 6 months until death of off-study, up to ~62 months | Defined as the time from registration to death from any cause. Patients still living are censored at the date last known alive |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJose P Leone, MD
Dana-Farber Cancer Institute
Participant flow
Recruitment details
Patients were enrolled at Dana-Farber Cancer Institute between 2/25/2019 and 3/21/2024
Pre-assignment details
The study planned to first enroll a safety run-in cohort of 6 patients at DL1 to evaluate for DLTs in the first cycle of therapy, to identify the RP2D. If DLT was observed in \>1/6 patients, a second safety run-in cohort of 6 patients would be enrolled at DL-1, and would follow the same evaluation. If DLT was observed in \>1/6 patients treated at DL-1, the study would close. If the RP2D was identified, the study would continue to the target phase II accrual. No patients were enrolled to Cohort B.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 42.2 years |
| Age, Customized Age category <50 years | 0 Participants |
| Age, Customized Age category >=50 years | 6 Participants |
| Eastern Cooperative Oncology Group Performance Status 0: Fully active; no restrictions on pre-disease performance | 0 Participants |
| Eastern Cooperative Oncology Group Performance Status 1: Restricted in physically strenuous activity but ambulatory; able to do light work | 3 Participants |
| Eastern Cooperative Oncology Group Performance Status 2: Ambulatory and capable of all self-care; unable to work; up and about >50% of waking hours | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 0 Participants |
| Stage at primary diagnosis I | 3 Participants |
| Stage at primary diagnosis II | 4 Participants |
| Stage at primary diagnosis III | 3 Participants |
| Stage at primary diagnosis IV - de novo metastatic | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 5 | 6 / 12 |
| other Total, other adverse events | 4 / 5 | 12 / 12 |
| serious Total, serious adverse events | 1 / 5 | 2 / 12 |
Outcome results
None listed