PRIMARY OBJECTIVES:
I. To determine the safety and recommended phase 2 dose (RP2D) of the combination of
copanlisib, trastuzumab and pertuzumab in patients with metastatic epidermal growth factor
receptor 2 (HER2)-positive breast cancer. (Phase Ib) II. To assess the benefit of adding
copanlisib to trastuzumab and pertuzumab in HER2-positive metastatic breast cancer patients
with PIK3CA mutations or PTEN mutation receiving maintenance therapy after induction
treatment, as measured by progression free survival (PFS). (Phase II)
SECONDARY OBJECTIVES:
I. To assess the benefit of adding copanlisib to trastuzumab and pertuzumab in HER2-positive
metastatic breast cancer patients with PIK3CA mutations or PTEN mutation receiving
maintenance therapy after induction treatment, as measured by overall survival (OS). (Phase
II) II. To evaluate the safety of copanlisib given at the RP2D in combination with
trastuzumab and pertuzumab. (Phase II)
EXPLORATORY OBJECTIVES:
I. To correlate PFS and OS of the patients who receive the triplet combination with:
Ia. The number of induction cycles. Ib. Hormone receptor status (estrogen receptor [ER] and
progesterone receptor [PR]).
Ic. PTEN loss by immunohistochemistry (IHC). Id. PIK3CA mutations or PTEN mutations. (Phase
Ib)
II. To assess PTEN IHC, Ki-67 IHC and cleaved caspase-3 IHC and to perform molecular
profiling assays on malignant and normal tissues, including, but not limited to, whole exome
sequencing (WES) and messenger ribonucleic acid (RNA) sequencing (RNAseq), in order to:
IIa. Identify potential predictive and prognostic biomarkers associated with treatment
outcomes (PFS and OS) with the addition of copanlisib to dual HER2-targeted treatment.
IIb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based
assessment platforms.
III. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
and future research; specimens will be annotated with key clinical data, including
presentation, diagnosis, staging, summary treatment, and if possible, outcome.
IV. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA
analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical
Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.
OUTLINE:
PHASE I: Patients receive copanlisib intravenously (IV) over 60 minutes on days 1 and 8.
Patients also receive trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60 minutes
on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable
toxicity.
PHASE II: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive copanlisib IV over 60 minutes on days 1 and 8. Patients also receive
trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60 minutes on day 1. Cycles
repeat every 21 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60
minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up within 30 days and at 3 months.
Inclusion Criteria:
- PHASE IB/SAFETY RUN-IN: Any prior number of lines of treatment in metastatic setting
is allowed, provided patients are eligible to receive induction chemotherapy with
taxane+ trastuzumab+pertuzumab
- PHASE II: Patients must have received only first line of induction chemotherapy
(taxane+ trastuzumab + pertuzumab) treatment in metastatic setting
- Prior to trastuzumab emtansine (T-DM1) exposure is allowed in phase 1b but not in
phase 2 study
- Presence of actionable mutation in either PIK3CA gene or PTEN gene on molecular
testing, in primary or metastatic tumor at Clinical Laboratory Improvement Act (CLIA)
certified laboratory. Results of molecular testing will be reviewed to confirm
eligibility by MD Anderson Precision Oncology Decision Support team and captured in
patient's record
- Patients must be within 8 weeks of completion of first-line induction chemotherapy
(i.e., 4-8 cycles of any taxane, trastuzumab and pertuzumab) without evidence of
progression. Patients may receive up to 2 doses of HER2 targeted treatment between end
of induction treatment and start of trial, while eligibility is being confirmed. In
addition, for phase-1 portion, patients on any period of maintenance on trastuzumab
and pertuzumab in the advanced setting are also eligible as long as DLT can be
determined
- Clinical stage IV as assessed by American Joint Committee on Cancer (AJCC) (8th
edition, anatomic staging) guidelines with known metastatic disease (Edge and Compton,
2010; Amin et al., 2017)
- HER2+ breast cancer patients with any ER/PR status as assessed by the American Society
of Clinical Oncology (ASCO)-College of American Pathologists (ASCO-CAP) guidelines
(Wolff et al., 2013; Wolff et al., 2018). HER2 testing of metastasis will be required
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 9 g/dL
- Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram or multigated
acquisition scan (MUGA)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) OR direct bilirubin
=< ULN for subjects with total bilirubin levels > 1.5 x ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN OR =< 5 x ULN for subjects with liver metastases
- Creatinine =< 1.5 x institutional ULN OR measured or calculated creatinine clearance
>= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (glomerular
filtration rate [GFR] can also be used in place of creatinine or creatinine clearance
[CrCl]). Creatinine clearance should be calculated per institutional standard
- International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless
patient is receiving anticoagulation as long as PT or partial thromboplastin time
(PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving
anticoagulation as long as PT or PTT is within therapeutic range of intended use of
anticoagulants
- Patients with treated brain metastases are eligible if follow-up brain imaging 30 days
after central nervous system (CNS)-directed therapy shows no evidence of progression
- Patients who are therapeutically treated with anticoagulation including warfarin will
be allowed to participate provided that their medication dose and INR/PTT is stable.
Due to interaction of copanlisib with warfarin, patients who are on warfarin should be
monitored closely while on this trial
- Women of child-bearing potential MUST have a negative serum or urine human chorionic
gonadotropin (HCG) test unless prior tubal ligation (>= 1 year before screening),
total hysterectomy or menopause (defined as 12 consecutive months of amenorrhea).
Patients should not become pregnant or breastfeed while on this study
- Patients and their partners, if sexually active and of childbearing potential, must
agree to the use of two highly effective forms of contraception in combination
throughout the period of taking study treatment and for 7 months after last dose of
study drug(s) to prevent pregnancy in the study patient or partner
- Hormone receptor positive (ER+ and / PR+) breast cancer patients will be allowed to
continue endocrine therapy as indicated while participating in this clinical trial
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Known active hepatitis B or hepatitis C infection. All patients must be screened for
hepatitis B virus (HBV) and hepatitis C virus (HCV) up to 28 days prior to study drug
start using the routine hepatitis virus lab panel. For patients with evidence of
chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on
non-CYP3A4-interactive suppressive therapy, if indicated. Patients with a history of
hepatitis C virus (HCV) infection must have been treated and cured. Patients positive
for anti-HCV antibody will be eligible if they are negative for HCV ribonucleic acid
(RNA)
- Human immunodeficiency virus (HIV)-positive patients, unless they have CD4 counts >
500 cells/mm^3 in the past 6 months and do not require CYP3A4-interactive
antiretroviral therapy
- Active infection requiring IV antibiotics or other uncontrolled intercurrent illness
requiring hospitalization
- Inability to comply with the study and follow-up procedures
- History of cerebrovascular accident (CVA), myocardial infarction, symptomatic
congestive heart failure, cardiac arrhythmia, or unstable angina within the previous 6
months before starting therapy
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the following exceptions: alopecia
(any grade is acceptable); neuropathy must have resolved to =< grade 2. Congestive
heart failure (CHF) due to prior anti-cancer therapy must have been =< grade 1 in
severity at the time of occurrence, and must have resolved completely
- Current uncontrolled hypertension (>= 150/90)
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer
- Has a known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Patients with uncontrolled type I or II diabetes mellitus (DM); uncontrolled DM is
defined as glycosylated hemoglobin (HbA1c) > 8.5% and a fasting blood glucose of > 120
mg/dL within 14 days prior to trial entry
- Immunosuppressive therapy is not allowed while on study
- Patients who are receiving any other investigational agents
- Patients with leptomeningeal disease or active untreated brain metastases
- Prior exposure to any PI3K, AKT or mTOR inhibitors. History of allergic reactions
attributed to compounds of similar chemical or biologic composition to copanlisib,
PI3K inhibitors, or HER2 inhibitors
- Copanlisib is primarily metabolized by CYP3A4. Therefore, the concomitant use of
strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin,
ritonavir, indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (e.g.
rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) are not permitted
from 14 days prior to enrollment until the end of the study. Other medications that
are prohibited while on copanlisib treatment:
- Herbal medications/preparations (except for vitamins)
- Anti-arrhythmic therapy other than beta blockers or digoxin
- Because the lists of these agents are constantly changing, it is important to
regularly consult a frequently-updated medical reference for a list of drugs to
avoid or minimize use of. 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
- Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or
equivalent is not permitted while on study. Previous corticosteroid therapy must be
stopped or reduced to the allowed dose at least 7 days prior to the computed
tomography (CT)/magnetic resonance imaging (MRI) screening. If a patient is on chronic
corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed
dose before the screening. Patients may be using topical or inhaled corticosteroids
- Patients with non-healing wound, ulcer, or bone fracture
- Pregnant women are excluded from this study because copanlisib is a PI3K inhibitor
agent with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with copanlisib, breastfeeding should be discontinued if the
mother is treated with copanlisib. These potential risks may also apply to other
agents used in this study
- Patients are eligible to receive standard of care therapy that would confer clinical
benefit to the patient
