Estrogen Receptor PositivePhase 1NCT03128619
Copanlisib, Letrozole, and Palbociclib in Treating Patients With Hormone Receptor Positive HER2 Negative Stage I-IV Breast Cancer
A Phase 1 study testing Biopsy of Breast, Copanlisib and Laboratory Biomarker Analysis in people with Estrogen Receptor Positive and HER2/Neu Negative, run by Jonsson Comprehensive Cancer Center at 1 site in United States.
Trial summary
This phase I/II trial studies side effects and best dose of copanlisib when given together with letrozole and palbociclib and to see how well they work in treating hormone receptor positive HER2 negative stage I-IV breast cancer. Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- Estrogen Receptor Positive, HER2/Neu Negative, Invasive Breast Carcinoma
- What is being tested?
- Biopsy of Breast, Copanlisib and Laboratory Biomarker Analysis
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- 2 Aug 2017to 31 Mar 2022
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Post-menopausal (if female) defined as: 1) prior bilateral oophorectomy, 2) age 60 or over, or 3) < 60 years and amenorrheic for at least 12 months with follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range per institutional parameters); use of luteinizing hormone-releasing hormone (LHRH) agonists to induce chemical ovarian ablation will not be allowed for this study
- Tumor is hormone receptor (HR)+ (estrogen receptor and/or progesterone receptor positive with at least 10% expression of either receptor by local immunohistochemical staining) and HER2 negative based on local assessment
- FOR PHASE Ib PORTION OF THE STUDY:
- Locally advanced/non-operable or metastatic breast cancer that has not been previously treated in the metastatic setting with systemic therapy (i.e. first line treatment)
- Measurable disease per RECIST 1.1
- FOR PHASE II PORTION OF THE STUDY:
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- Clinical stage I (breast tumor >= 1.0 cm in diameter), stage II or stage III breast cancer (according to the American Joint Committee on Cancer [AJCC] Staging Manual, 7th Edition, 2010); multifocal disease is allowed if confined to 1 breast, as long as one tumor is at least 1 cm and meets all of the other inclusion criteria
- Breast cancer suitable for mandatory baseline core biopsy
- No prior systemic therapy or radiotherapy for currently-diagnosed invasive or noninvasive breast cancer
- FOR ALL PHASES (Ib AND II):
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- Platelets > 100 x 10^9/L
- Hemoglobin >= 8 g/dL (phase Ib) or >= 10 g/dL (for phase II portion)
- For phase Ib portion only: patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator; however, initial study drug treatment must not begin earlier than the day of the erythrocyte transfusion
- Bilirubin =< 1.5 times the upper limit of normal (ULN)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 times ULN
- Subjects with Gilbert's syndrome, confirmed by genotyping or Invader UGTIA1 molecular assay prior to study entry, must have total bilirubin < 3.0 times ULN
- Serum creatinine =< 1.5 times ULN
- Lipase =< 1.5 x ULN
- International normalized ratio (INR) and partial thromboplastin time (PTT) < 1.5 x ULN
- Left ventricular ejection fraction (LVEF) >= 50%
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Who cannot join
- FOR PHASE Ib ONLY:
- Early stage (curable) breast cancer
- FOR PHASE II ONLY:
- Metastatic breast cancer (local spread to axillary or internal mammary lymph nodes is permitted)
- Prior systemic therapy for invasive or non-invasive (DCIS) breast cancer
- Prior radiotherapy to the ipsilateral chest wall or breast for any malignancy
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- Bilateral invasive breast cancer
- FOR ALL PHASES (Ib AND II): Inflammatory breast cancer
- FOR ALL PHASES (Ib AND II): Concurrent therapy with any other non-protocol anti-cancer therapy
- FOR ALL PHASES (Ib AND II): History of any other malignancy within the past 5 years, with the exception of non-melanoma skin cancer or carcinoma-in-situ of the cervix
- FOR ALL PHASES (Ib AND II): Concurrent diagnosis of pheochromocytoma
- FOR ALL PHASES (Ib AND II): Current therapy with raloxifene, tamoxifen, aromatase inhibitor, or other selective estrogen receptor modulator (SERM), either for osteoporosis or prevention of breast cancer; subjects must have discontinued therapies for at least 28 days prior to first baseline biopsy
- FOR ALL PHASES (Ib AND II): Concurrent treatment with postmenopausal hormone replacement therapy; prior treatment must be stopped for at least 28 days prior to first baseline biopsy
- FOR ALL PHASES (Ib AND II): Type I diabetes or patients on insulin therapy are not allowed; uncontrolled type II diabetes not allowed (glycosylated hemoglobin [HbA1c] > 7.5)
- FOR ALL PHASES (Ib AND II): Proteinuria of >= Common Terminology Criteria for Adverse Events (CTCAE) grade 3 as estimated by urine protein : creatinine ratio > 3.5 on a random urine sample
- FOR ALL PHASES (Ib AND II): Uncontrolled arterial hypertension despite optimal medical management
- FOR ALL PHASES (Ib AND II): Hepatitis B (HBV) or hepatitis C (HCV); all patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel
- FOR ALL PHASES (Ib AND II): Known history of human immunodeficiency virus (HIV) infection
- FOR ALL PHASES (Ib AND II): Uncontrolled infection; active, clinically serious infections (> CTCAE grade 2)
- FOR ALL PHASES (Ib AND II): History of significant cardiac disease:
- Congestive heart failure > New York Heart Association (NYHA) class 2
- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
- Myocardial infarction less than 6 months before start of test drug
- Anti-arrhythmic therapy (beta blockers or digoxin are permitted)
- FOR ALL PHASES (Ib AND II): Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication
- FOR ALL PHASES (Ib AND II): Participants receiving anticoagulation therapy are not allowed
- FOR ALL PHASES (Ib AND II): Patients with evidence or history of bleeding diathesis; any hemorrhage or bleeding event >= CTCAE grade 3 within 4 weeks of start of study medication
- FOR ALL PHASES (Ib AND II): Blood or platelet transfusion within 7 days prior to treatment start
- FOR ALL PHASES (Ib AND II): Non-healing wound or ulcer
- FOR ALL PHASES (Ib AND II): History of, or current autoimmune disease
- FOR ALL PHASES (Ib AND II): Major surgical procedure or significant traumatic injury (as judged by the investigator) within 28 days before start of study medication, open biopsy within 7 days before start of study medication
- FOR ALL PHASES (Ib AND II): Patients with seizure disorder requiring medication
- FOR ALL PHASES (Ib AND II): Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
- FOR ALL PHASES (Ib AND II): Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not allowed; patients may be using topical or inhaled corticosteroids; previous corticosteroid therapy must be stopped or reduced to the allowed dose at least 7 days prior to the first study drug administration; if a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose after the patient has signed the consent document
- FOR ALL PHASES (Ib AND II): History of having received an allogeneic bone marrow or organ transplant
- FOR ALL PHASES (Ib AND II): Chronic oxygen therapy
Trial locations and contacts
1 site in 1 country.
United States1 site
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, 90095
About this study
Official title: A Phase Ib Trial Evaluating the Safety of Copanlisib, Letrozole, and Palbociclib in Metastatic Breast Cancer and Phase II Trial Comparing the Molecular Effects of Neoadjuvant Copanlisib in Combination With Palbociclib and Letrozole, vs. Copanlisib With Letrozole, vs. Palbociclib With Letrozole for Patients With Hormone Receptor Positive, HER2 Normal Breast Cancer
This phase I/II trial studies side effects and best dose of copanlisib when given together with letrozole and palbociclib and to see how well they work in treating hormone receptor positive HER2 negative stage I-IV breast cancer. Copanlisib and palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs, such as letrozole, may lessen the amount of estrogen made by the body. Giving copanlisib, letrozole, and palbociclib may work better in treating patients with breast cancer.
Read the detailed description
PRIMARY OBJECTIVES:
- Assess the safety, tolerability and to estimate the maximum tolerated dose (MTD) in a metastatic setting of the following combination: copanlisib + palbociclib + letrozole. (Phase Ib) II. Compare the biological activity of letrozole in combination with palbociclib, letrozole in combination with palbociclib and copanlisib, and letrozole in combination with copanlisib by assessing the percentage change from the baseline value in Ki67 expression after 2 weeks of therapy in non-metastatic breast cancer. (Phase II)
SECONDARY OBJECTIVES:
- Evaluate the pathologic complete response (pCR) defined as absence of invasive cancer in the breast and sampled regional lymph nodes.
II. Evaluate the clinical objective response Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1.
III. Assess safety and tolerability. IV. Evaluate the pharmacokinetics of copanlisib when given in combination with letrozole, and palbociclib.
- Measure the gene expression and/or biomarker changes that may be correlated with or predict biological, clinical, and pathologic response.
OUTLINE: This is a dose-escalation study of copanlisib.
PHASE Ib: Patients with metastatic breast cancer receive copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15, palbociclib orally (PO) once daily (QD) on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
PHASE II: After determination of MTD, subsequent non-metastatic breast cancer patients are randomized to 1 of 3 arms:
ARM A: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression, or unacceptable toxicity.
ARM B: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15, palbociclib PO QD on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
ARM C: Patients receive palbociclib PO QD for days 1-14 of course 1 and letrozole PO continuously on days 1-14. Patients then undergo biopsy. Patients then receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28. Treatment with copanlisib and letrozole repeats every 28 days for up to 3.5 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 1 month.
- Conditions
- Estrogen Receptor Positive, HER2/Neu Negative, Invasive Breast Carcinoma, Multifocal Breast Carcinoma, Postmenopausal, Progesterone Receptor Positive
- Being tested
- Biopsy of Breast, Copanlisib, Laboratory Biomarker Analysis, Letrozole, Palbociclib
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biopsy of BreastProcedure or surgery
Also called Breast Biopsy
Undergo biopsy
CopanlisibDrug
Also called BAY 80-6946, PI3K Inhibitor BAY 80-6946
Given IV
Laboratory Biomarker AnalysisOther
Correlative studies
LetrozoleDrug
Also called CGS 20267, Femara
Given PO
PalbociclibDrug
Also called Ibrance, PD-0332991, PD-332991
Given PO
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| Arm A (copanlisib, letrozole) | Experimental | PHASE II: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression, or unacceptable toxicity. Receives: Drug: Copanlisib; Other: Laboratory Biomarker Analysis; Drug: Letrozole; Other: Pharmacological Study |
| Arm B (copanlisib, palbociclib, letrozole) | Experimental | PHASE II: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15, palbociclib PO QD on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Receives: Procedure: Biopsy of Breast; Drug: Copanlisib; Other: Laboratory Biomarker Analysis; Drug: Letrozole; Drug: Palbociclib; Other: Pharmacological Study |
| Arm C (copanlisib, palbociclib, letrozole) | Experimental | PHASE II: Patients receive palbociclib PO QD for days 1-14 of course 1 and letrozole PO continuously on days 1-14. Patients then undergo biopsy. Patients then receive copanlisib IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28. Treatment with copanlisib (MTD) and letrozole repeats every 28 days for up to 3.5 courses in the absence of disease progression or unacceptable toxicity. Receives: Procedure: Biopsy of Breast; Drug: Copanlisib; Other: Laboratory Biomarker Analysis; Drug: Letrozole; Drug: Palbociclib; Other: Pharmacological Study |
| Phase Ib (copanlisib, palbociclib, letrozole) | Experimental | PHASE Ib: Patients with metastatic breast cancer receive copanlisib IV over 1 hour on days 1, 8, and 15, palbociclib PO QD on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Receives: Drug: Copanlisib; Other: Laboratory Biomarker Analysis; Drug: Letrozole; Drug: Palbociclib; Other: Pharmacological Study |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Ki-67 expression defined as the percent of cells staining positive by validated central assay (Phase II)
Will be evaluated on the log Ki-67 ratio scale. Primary analysis of this variable will utilize a linear model with treatment, PR status as fixed effects. The comparison of treatment arms will be based on the least squares mean (LSM) estimates and standard errors derived from this model. For descriptive purposes, LSM estimates and associated confidence intervals (CIs) will be back transformed to the geometric mean percent change scale. A second post-baseline evaluation of Ki67 expression will be performed following the completion of 4 months of treatment. Analysis of change from baseline to com
Measured: Baseline to 2 weeks
Incidence of dose-limiting toxicities (DLT) evaluated according to National Cancer Institute (NCI) CTCAE version 4.0 to determine MTD (Phase Ib)
If >= 2 of 6 participants treated at a dose level experience DLTs, then the MTD will have been exceeded. Up to 3 additional patients may be entered at the lower dose level to obtain additional safety information (if only 3 participants were treated previously at that dose) to demonstrate that =< 1 of 6 patients experience DLT.
Measured: Up to 112 days
Secondary outcomes (10)
Clinical objective response rate (ORR) evaluated by RECIST 1.1 using caliper measurements
A responder is defined as any participant who exhibits a complete response (CR) or partial response (PR). The clinical response rate is estimated as the total number of CRs and PRs divided by the total number of participants randomized. Clinical ORR will be estimated and 95% exact CIs will be provided.
Measured: Up to 1 month after surgery
Gene expression and/or biomarker changes
To compare the percent change in Ki67 expression from baseline to 2 weeks in the Ki67-evaluable population (expansion phase only).The Ki67 Evaluable Population will include all patients with a valid baseline Ki67 measurement of at least 5% and a valid 2-week measurement of any magnitude. This population will be used for the analysis of all Ki67-derived endpoints. All ki67 evaluable population will be correlated with pCR and clinical objective response.
Measured: Up to 1 month after surgery
Incidence of adverse events (AEs) evaluated according to NCI CTCAE version 4.0
Overall exposure to study drug, the numbers of patients completing each cycle and the dose intensity will be summarized using descriptive statistics. The number of patients with any dose adjustment will be presented for entire treatment period as well as for each cycle. The number of patients with dose reductions, dose delays, or dose omissions will also be summarized, as will the reasons for dose adjustments. AEs and severe AEs will be reported using a CTCAE version 4.0 terminology and severity.
Measured: Up to 1 month after surgery
pCR rate defined as the percentage of randomized patients with a pCR
pCR is defined as the absence of invasive cancer in the breast and sampled regional lymph nodes. Pathology reports from definitive breast surgery will be collected.
Measured: Up to 1 month after surgery
The pharmacokinetic (PK) parameter - area under the plasma concentration-time curve (AUC) will be determined for copanlisib in arms A, B, and escalation dose levels.
PK sampling will be performed in all the participants to characterize the PK profile for copanlisib, its metabolite M-1 (and other metabolites) in combination with letrozole and palbociclib.
Measured: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
The pharmacokinetic (PK) parameter - Elimination half-life (t½) will be determined for copanlisib in arms A, B, and escalation dose levels.
PK sampling will be performed in all the participants to characterize the PK profile for copanlisib, its metabolite M-1 (and other metabolites) in combination with letrozole and palbociclib.
Measured: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
The pharmacokinetic (PK) parameter - Maximum plasma concentration (Cmax) will be determined for copanlisib in arms A, B, and escalation dose levels.
PK sampling will be performed in all the participants to characterize the PK profile for copanlisib, its metabolite M-1 (and other metabolites) in combination with letrozole and palbociclib.
Measured: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
The pharmacokinetic (PK) parameter - Minimum plasma concentration of BAY 80-694 will be determined for copanlisib in arms A, B, and escalation dose levels.
PK sampling will be performed in all the participants to characterize the PK profile for copanlisib, its metabolite M-1 (and other metabolites) in combination with letrozole and palbociclib.
Measured: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
The pharmacokinetic (PK) parameter - Time when Cmax occurs (Tmax) will be determined for copanlisib in arms A, B, and escalation dose levels.
PK sampling will be performed in all the participants to characterize the PK profile for copanlisib, its metabolite M-1 (and other metabolites) in combination with letrozole and palbociclib.
Measured: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
The pharmacokinetic (PK) parameter - Average plasma concentration at steady state (Cavg) will be determined for copanlisib in arms A, B, and escalation dose levels.
PK sampling will be performed in all the participants to characterize the PK profile for copanlisib, its metabolite M-1 (and other metabolites) in combination with letrozole and palbociclib.
Measured: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Apr 2017
- Study start2 Aug 2017
- Primary completion31 Mar 2022
- Study completion31 Mar 2022
Why it stopped: Insufficient accrual
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Estrogen Receptor PositiveStudies of the same condition, open and under way.
- More trials run by Jonsson Comprehensive Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jonsson Comprehensive Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- Bayer, Translational Research in Oncology
- Responsible party
- Sponsor
- Investigators
- Sara Hurvitz, Principal investigator, UCLA / Jonsson Comprehensive Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03128619
- Sponsor's protocol ID
- 16-001271
- Other IDs
- NCI-2017-00435
- Status last verified
- Apr 2021
- First submitted
- 4 Apr 2017
- Last updated
- 26 Sep 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 26 Sep 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase Ib Trial Evaluating the Safety of Copanlisib, Letrozole, and Palbociclib in Metastatic Breast Cancer and Phase II Trial Comparing the Molecular Effects of Neoadjuvant Copanlisib in Combination With Palbociclib and Letrozole, vs. Copanlisib With Letrozole, vs. Palbociclib With Letrozole for Patients With Hormone Receptor Positive, HER2 Normal Breast Cancer
- ClinicalTrials.gov ID
- NCT03128619
- Acronym / sponsor ID
- 16-001271
- Conditions
- Estrogen Receptor Positive, HER2/Neu Negative, Invasive Breast Carcinoma, Multifocal Breast Carcinoma, Postmenopausal, Progesterone Receptor Positive
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Insufficient accrual
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Jonsson Comprehensive Cancer CenterUniversity, hospital or other
- Collaborators
- Bayer, Translational Research in Oncology
- Study start
- 2 Aug 2017 (actual)
- Primary completion
- 31 Mar 2022 (actual)
- Study completion
- 31 Mar 2022 (actual)
- First posted
- 25 Apr 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase I/II trial studies side effects and best dose of copanlisib when given together with letrozole and palbociclib and to see how well they work in treating hormone receptor positive HER2 negative stage I-IV breast cancer. Copanlisib and palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs, such as letrozole, may lessen the amount of estrogen made by the body. Giving copanlisib, letrozole, and palbociclib may work better in treating patients with breast cancer.
Detailed description
PRIMARY OBJECTIVES:
- Assess the safety, tolerability and to estimate the maximum tolerated dose (MTD) in a metastatic setting of the following combination: copanlisib + palbociclib + letrozole. (Phase Ib) II. Compare the biological activity of letrozole in combination with palbociclib, letrozole in combination with palbociclib and copanlisib, and letrozole in combination with copanlisib by assessing the percentage change from the baseline value in Ki67 expression after 2 weeks of therapy in non-metastatic breast cancer. (Phase II)
SECONDARY OBJECTIVES:
- Evaluate the pathologic complete response (pCR) defined as absence of invasive cancer in the breast and sampled regional lymph nodes.
II. Evaluate the clinical objective response Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1.
III. Assess safety and tolerability. IV. Evaluate the pharmacokinetics of copanlisib when given in combination with letrozole, and palbociclib.
- Measure the gene expression and/or biomarker changes that may be correlated with or predict biological, clinical, and pathologic response.
OUTLINE: This is a dose-escalation study of copanlisib.
PHASE Ib: Patients with metastatic breast cancer receive copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15, palbociclib orally (PO) once daily (QD) on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
PHASE II: After determination of MTD, subsequent non-metastatic breast cancer patients are randomized to 1 of 3 arms:
ARM A: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression, or unacceptable toxicity.
ARM B: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15, palbociclib PO QD on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
ARM C: Patients receive palbociclib PO QD for days 1-14 of course 1 and letrozole PO continuously on days 1-14. Patients then undergo biopsy. Patients then receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28. Treatment with copanlisib and letrozole repeats every 28 days for up to 3.5 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 1 month.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Arm A (copanlisib, letrozole) | Experimental | Drug: Copanlisib, Other: Laboratory Biomarker Analysis, Drug: Letrozole, Other: Pharmacological StudyPHASE II: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression, or unacceptable toxicity. |
| Arm B (copanlisib, palbociclib, letrozole) | Experimental | Procedure: Biopsy of Breast, Drug: Copanlisib, Other: Laboratory Biomarker Analysis, Drug: Letrozole, Drug: Palbociclib, Other: Pharmacological StudyPHASE II: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15, palbociclib PO QD on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. |
| Arm C (copanlisib, palbociclib, letrozole) | Experimental | Procedure: Biopsy of Breast, Drug: Copanlisib, Other: Laboratory Biomarker Analysis, Drug: Letrozole, Drug: Palbociclib, Other: Pharmacological StudyPHASE II: Patients receive palbociclib PO QD for days 1-14 of course 1 and letrozole PO continuously on days 1-14. Patients then undergo biopsy. Patients then receive copanlisib IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28. Treatment with copanlisib (MTD) and letrozole repeats every 28 days for up to 3.5 courses in the absence of disease progression or unacceptable toxicity. |
| Phase Ib (copanlisib, palbociclib, letrozole) | Experimental | Drug: Copanlisib, Other: Laboratory Biomarker Analysis, Drug: Letrozole, Drug: Palbociclib, Other: Pharmacological StudyPHASE Ib: Patients with metastatic breast cancer receive copanlisib IV over 1 hour on days 1, 8, and 15, palbociclib PO QD on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. |
Who may qualify
- Ages
- 19 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Post-menopausal (if female) defined as: 1) prior bilateral oophorectomy, 2) age 60 or over, or 3) < 60 years and amenorrheic for at least 12 months with follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range per institutional parameters); use of luteinizing hormone-releasing hormone (LHRH) agonists to induce chemical ovarian ablation will not be allowed for this study
- Tumor is hormone receptor (HR)+ (estrogen receptor and/or progesterone receptor positive with at least 10% expression of either receptor by local immunohistochemical staining) and HER2 negative based on local assessment
- FOR PHASE Ib PORTION OF THE STUDY:
- Locally advanced/non-operable or metastatic breast cancer that has not been previously treated in the metastatic setting with systemic therapy (i.e. first line treatment)
- Measurable disease per RECIST 1.1
Key exclusion criteria (36 listed)
- FOR PHASE Ib ONLY:
- Early stage (curable) breast cancer
- FOR PHASE II ONLY:
- Metastatic breast cancer (local spread to axillary or internal mammary lymph nodes is permitted)
- Prior systemic therapy for invasive or non-invasive (DCIS) breast cancer
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Biopsy of BreastAlso: Breast BiopsyUndergo biopsy | Procedure or surgery | Arm B (copanlisib, palbociclib, letrozole), Arm C (copanlisib, palbociclib, letrozole) |
| CopanlisibAlso: BAY 80-6946, PI3K Inhibitor BAY 80-6946Given IV | Drug | Arm A (copanlisib, letrozole), Arm B (copanlisib, palbociclib, letrozole), Arm C (copanlisib, palbociclib, letrozole), Phase Ib (copanlisib, palbociclib, letrozole) |
| Laboratory Biomarker AnalysisCorrelative studies | Other | Arm A (copanlisib, letrozole), Arm B (copanlisib, palbociclib, letrozole), Arm C (copanlisib, palbociclib, letrozole), Phase Ib (copanlisib, palbociclib, letrozole) |
| LetrozoleAlso: CGS 20267, FemaraGiven PO | Drug | Arm A (copanlisib, letrozole), Arm B (copanlisib, palbociclib, letrozole), Arm C (copanlisib, palbociclib, letrozole), Phase Ib (copanlisib, palbociclib, letrozole) |
| PalbociclibAlso: Ibrance, PD-0332991, PD-332991Given PO | Drug | Arm B (copanlisib, palbociclib, letrozole), Arm C (copanlisib, palbociclib, letrozole), Phase Ib (copanlisib, palbociclib, letrozole) |
| Pharmacological StudyCorrelative studies | Other | Arm A (copanlisib, letrozole), Arm B (copanlisib, palbociclib, letrozole), Arm C (copanlisib, palbociclib, letrozole), Phase Ib (copanlisib, palbociclib, letrozole) |
Primary outcome
Change in Ki-67 expression defined as the percent of cells staining positive by validated central assay (Phase II)
Time frame: Baseline to 2 weeks
Will be evaluated on the log Ki-67 ratio scale. Primary analysis of this variable will utilize a linear model with treatment, PR status as fixed effects. The comparison of treatment arms will be based on the least squares mean (LSM) estimates and standard errors derived from this model. For descriptive purposes, LSM estimates and associated confidence intervals (CIs) will be back transformed to the geometric mean percent change scale. A second post-baseline evaluation of Ki67 expression will be performed following the completion of 4 months of treatment. Analysis of change from baseline to com
Incidence of dose-limiting toxicities (DLT) evaluated according to National Cancer Institute (NCI) CTCAE version 4.0 to determine MTD (Phase Ib)
Time frame: Up to 112 days
If >= 2 of 6 participants treated at a dose level experience DLTs, then the MTD will have been exceeded. Up to 3 additional patients may be entered at the lower dose level to obtain additional safety information (if only 3 participants were treated previously at that dose) to demonstrate that =< 1 of 6 patients experience DLT.
10 secondary outcomes
Clinical objective response rate (ORR) evaluated by RECIST 1.1 using caliper measurements
Time frame: Up to 1 month after surgery
Gene expression and/or biomarker changes
Time frame: Up to 1 month after surgery
Incidence of adverse events (AEs) evaluated according to NCI CTCAE version 4.0
Time frame: Up to 1 month after surgery
pCR rate defined as the percentage of randomized patients with a pCR
Time frame: Up to 1 month after surgery
The pharmacokinetic (PK) parameter - area under the plasma concentration-time curve (AUC) will be determined for copanlisib in arms A, B, and escalation dose levels.
Time frame: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
The pharmacokinetic (PK) parameter - Elimination half-life (t½) will be determined for copanlisib in arms A, B, and escalation dose levels.
Time frame: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
The pharmacokinetic (PK) parameter - Maximum plasma concentration (Cmax) will be determined for copanlisib in arms A, B, and escalation dose levels.
Time frame: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
The pharmacokinetic (PK) parameter - Minimum plasma concentration of BAY 80-694 will be determined for copanlisib in arms A, B, and escalation dose levels.
Time frame: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
The pharmacokinetic (PK) parameter - Time when Cmax occurs (Tmax) will be determined for copanlisib in arms A, B, and escalation dose levels.
Time frame: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
The pharmacokinetic (PK) parameter - Average plasma concentration at steady state (Cavg) will be determined for copanlisib in arms A, B, and escalation dose levels.
Time frame: At pre-infusion, 10 minutes, 1, 2, 3, and 5 hours after start of infusion on days 1 and 8, course 1 (Ib); at pre-infusion and 1 hour after start of infusion on day 1, course 1 and pre-infusion, 5-15 minutes, 1, and 1-1.5 hours on day 8, course 2 (II)
Results and safety
The study was stopped early (reason given: Insufficient accrual). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Sep 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sara Hurvitz principal investigator
UCLA / Jonsson Comprehensive Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Biopsy of Breast, Copanlisib and Laboratory Biomarker Analysis in people with Estrogen Receptor Positive and HER2/Neu Negative, run by Jonsson Comprehensive Cancer Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 36 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Insufficient accrual). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Ki-67 expression defined as the percent of cells staining positive by validated central assay (Phase II) (time frame: Baseline to 2 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Sep 2022.