PRIMARY OBJECTIVES:
I. To determine the safety, toxicity profile, dose limiting toxicity (DLT), maximum tolerated
dose (MTD) and recommended phase 2 dose (RP2D) of copanlisib hydrochloride (copanlisib) in
combination with eribulin mesylate (eribulin) in metastatic triple negative breast cancer
(TNBC). (Phase I) II. To compare progression free survival (PFS) between eribulin and
eribulin plus copanlisib arms in patients with metastatic TNBC treated with prior taxane and
anthracycline. (Phase II)
SECONDARY OBJECTIVES:
I. To determine the objective response rate (ORR) and clinical benefit rate (CBR) of the
combination. (Phase I) II. To observe and record anti-tumor activity. (Phase I) III. To
compare the ORR, CBR (complete response [CR]+partial response [PR]+stable disease [SD] >= 24
weeks) and safety of eribulin and eribulin plus copanlisib arms. (Phase II) IV. To compare
the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors
harboring mutations in PIK3CA/ PTEN or with loss of PTEN expression by immunohistochemistry
(IHC) on baseline tumor biopsy. (Phase II) V. To compare the ORR, CBR, PFS of eribulin and
eribulin plus copanlisib arms in patients with tumors lacking PIK3CA/ PTEN pathway
alterations. (Phase II) VI. To compare the ORR, CBR, PFS of eribulin and eribulin plus
copanlisib arms in patients with tumors harboring loss of PTEN expression by IHC in
pre-treatment metastatic site (in patients with available tissue from metastatic site).
(Phase II) VII. To compare PTEN IHC results between paired archival primary tumor vs.
baseline tumor biopsies. (Phase II) VIII. To assess targeted inhibition by copanlisib and
eribulin by measuring treatment induced changes in phosphorylated (phospho)-AKT (T308),
phospho-AKT (S473), phospho-histone H3, and inhibition of apoptosis (cleaved caspase 3)
between post-treatment tumor (C2D1-2) versus baseline. (Phase II) IX. To compare the ORR,
CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors harboring
mutations in PIK3CA/PTEN by circulating tumor-derived deoxyribonucleic acid (ctDNA) at
baseline, and potential changes over time. (Phase II)
EXPLORATORY OBJECTIVES:
I. To compare PTEN IHC results between paired baseline tumor biopsy versus at time of disease
progression.
II. Assess baseline (pre-treatment) tumor tissue mutation or gene expression profiles to
correlate treatment response.
III. Assess intrinsic and adaptive resistance mechanisms by analyzing pre and post treatment
biopsies for gene expression and proteomic changes.
IV. Determine circulating tumor DNA (ctDNA) mutation profiles at baseline and changes in
mutation profile and variant allele frequencies (VAFs) on cycle 2 day 1 (C2D1) and at disease
progression compared to baseline to correlate with treatment response.
V. Assess circulating biomarkers predictive of treatment response. VI. Assess plasma and
serum proteomics and metabolomics predictive of treatment response.
OUTLINE: This is a phase I dose-escalation study of copanlisib and eribulin followed by a
phase II study. Patients are randomized to 1 of 2 groups.
GROUP I: Patients receive eribulin intravenously (IV) over 2-5 minutes on days 1 and 8.
Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
GROUP II: Patients receive copanlisib IV over 60 minutes and eribulin IV over 2-5 minutes on
days 1 and 8 or days 1 and 15. Cycles repeat every 21 or 28 days in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 3 years.
Inclusion Criteria:
- Patients must have metastatic or unresectable carcinoma of the breast that is estrogen
receptor (ER) negative (less than 10%), progesterone receptor (PR) negative (less than
10%), and HER2 negative/unamplified
- Patients must have had prior treatment with an anthracycline and taxane, unless
contraindicated
- Patients must have progressed on at least one and not more than five prior
chemotherapy regimens, including in the neoadjuvant, adjuvant, and metastatic settings
- All patients must agree to provide archival tumor material (most recent archival tumor
tissue immediately prior to enrollment is strongly preferred) for research and must
agree to undergo research tumor biopsy before treatment if presence of easily
accessible lesions (judged by the treating physician). For patients with bone only
disease, or patients without easily accessible lesions for the baseline research
biopsy, availability of archival tumor material (2 x 4-5 micron section unstained
slides, plus 15-20 x 10 micron section unstained slides or a tumor rich block) from
previous breast cancer diagnosis or treatment is required for PTEN and PIK3CA analysis
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 8.0 g/dL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (=< 3 x
institutional ULN for patients with Gilbert syndrome)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) /
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
institutional ULN
- Lipase =< 1.5 x ULN
- Creatinine < 1.5 mg/dL AND glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2
- Partial thromboplastin time (PTT) =< 1.5 x ULN
- International normalized ratio (INR) =< 1.5 x ULN
- Patients with history of known type I or type II diabetes must have a fasting glucose
level of < 120 mg/dL on at least 2 separate occasions or glycosylated hemoglobin
measurement (HbA1c) < 8.5% at screening within 14 days prior to registration
- Patients who are therapeutically treated with an agent such as warfarin or heparin
will be allowed to participate provided that their medication dose and INR/PTT is
stable
- Prophylactic antiemetics may be administered according to standard practice. The
routine use of standard antiemetics, including 5-HT3 blockers, such as granisetron,
ondansetron, or an equivalent agent, is allowed as needed, as long as corrected QT
(QTc) interval on baseline electrocardiogram (ECG) < 480 msec. The use of
corticosteroids as antiemetics prior to copanlisib administration will not be allowed
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
provided they are on a stable regimen of anti-retroviral therapy (ART) with no
medications otherwise prohibited by this protocol (e.g. drug-drug interactions)
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression. For
patients with history of treated brain metastases, brain scans will be performed
within 6 weeks of study enrollment. During study enrollment in the phase 2 portion of
the study, brain MRI will be performed every 12 weeks or sooner if
clinically-indicated in all patients with history of known brain metastases
- For phase 1 portion of the study only: patients with new or progressive brain
metastases (active brain metastases) or leptomeningeal disease are eligible if the
treating physician determines that immediate CNS specific treatment is not required
and is unlikely to be required during the first cycle of therapy. This is not allowed
for phase 2 portion of the study
- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better. Patients with history
of known congestive heart failure (left ventricular ejection fraction [LVEF] < 50%)
must have documented LVEF >= 50% within 12 months of study enrollment
- Known mutation status for PIK3CA and PTEN from archival tumor tissue analysis
- The effects of copanlisib on the developing human fetus are unknown. For this reason
and because maternal toxicity, developmental toxicity and teratogenic effects have
been observed in nonclinical studies and PI3K inhibitors as well as other therapeutic
agents used in this trial are known to be teratogenic, women of child-bearing
potential must agree to use adequate contraception (hormonal or barrier method of
birth control; abstinence) prior to study entry and for the duration of study
participation, and for 1 month after the last dose of study medication. Should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, she should inform her treating physician immediately. Men treated or
enrolled on this protocol must also agree to use adequate contraception prior to the
study, for the duration of study participation, and 3.5 months after completion of
study treatment
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 3 weeks
- Patients who have had prior treatment with nitrosoureas or mitomycin C
- Patients who have had prior treatment with eribulin
- Patients who have had prior treatment with PI3K/mTOR/AKT pathway inhibitor
- Clinically significant ECG abnormality, including prolonged corrected QT (QTc)
interval > 480 msec or history of risk factors for Torsades de Pointes (TdP) (i.e.
congestive heart failure, hypokalemia, hypomagnesemia, bradyarrhythmias, family
history of long QT syndrome)
- Patients with pre-existing neuropathy of grade 2 or higher
- Myeloid growth factors within 14 days prior to treatment start
- Platelet transfusion within 7 days prior to treatment start
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia
- Patients who are receiving any other investigational agents
- Immunosuppressive therapy is not allowed while on study
- Known tumor AKT mutation from archival tumor tissue analysis
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to copanlisib, PI3K inhibitors, or other agents used in study
- 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
- 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/magnetic resonance imaging (CT/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.
Short-term (up to 7 days) systemic corticosteroids above 15 mg prednisolone or
equivalent will be allowed for the management of acute conditions (e.g., treatment
non-infectious pneumonitis). The use of corticosteroids as antiemetics prior to
copanlisib administration will not be allowed
- Patients with uncontrolled intercurrent illness
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Patients with non-healing wound, ulcer, or bone fracture
- Patients with active, clinically serious infections > grade 2 (Common Terminology
Criteria for Adverse Events Version 5.0 [CTCAEv5.0]) (viral, bacterial or fungal
infection)
- History of known Pneumocystis jiroveci pneumonia (PJP) infection
- Patients with 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
- Concurrent diagnosis of pheochromocytoma due to risk of hypertension with copanlisib
- Uncontrolled hypertension (defined as blood pressure >= 150/90 mm/Hg) despite optimal
medical management (per investigator's opinion)
- Proteinuria as estimated by urine protein/creatinine ratio > 3.5 g/g on random urine
sample or grade >= 3 as assessed by 24-hour urine protein collection
- Patients with history of or current autoimmune disease
- Patients with congenital QT prolongation
- The patient has a personal history of any of the following conditions: syncope of
cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but
not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
cardiac arrest
- Pregnant women are excluded from this study because copanlisib is a PI3K inhibitor
agent and eribulin is an anti-tubulin 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 and
eribulin, breastfeeding should be discontinued if the mother is treated with
copanlisib and/or eribulin. These potential risks may also apply to other agents used
in this study