PRIMARY OBJECTIVES:
I. To assess the activity of copanlisib (BAY 80-6946) in patients with persistent or
recurrent endometrial carcinoma harboring phosphatidylinositol-4,5-bisphosphate 3-kinase,
catalytic subunit alpha (PI3KCA) hotspot mutations with the frequency of objective response.
SECONDARY OBJECTIVES:
I. To estimate 6 month progression-free survival (PFS) and median PFS. II. To estimate the
distribution of the duration of overall survival (OS). III. To assess the safety profile of
copanlisib in endometrial cancer patients.
TERTIARY OBJECTIVES:
I. To systematically evaluate by sequencing the site (i.e., exome) and characteristics of
PIK3CA mutations in endometrial cancer patients and correlate such mutations to overall
response (OR), PFS, and OS in patients treated with copanlisib.
OUTLINE:
Patients receive copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.
Inclusion Criteria:
- Patients must have the psychological ability and general health that permits
completion of the study requirements and required follow-up
- Women of child-bearing potential (WOCBP) must agree to use adequate contraception when
sexually active; patients should continue contraception for 6 months after finishing
study drug
- Submission of tumor tissue is required for all patients; investigators should check
with their site pathology department regarding release of biospecimens before
approaching patients about participation in the trial
- Patients must have recurrent or persistent endometrial cancer (endometrioid
adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, mixed epithelial
carcinoma or adenocarcinoma not otherwise specified [NOS]); histologic confirmation of
the primary tumor is required
- All patients must have a somatic PIK3CA gene mutation (i.e., R88Q in exon 1, N345K in
exon 4, C420R in exon 7, E542K, E545X [E545A, E545D, E545G, and E545K], Q546X [Q546E,
Q546K, Q546L, and Q546R] in exon 9, and M1043I, H1047X [H1047L, H1047R, and H1047Y],
or G1049R in exon 20) in a representative primary or metastatic tumor sample confirmed
by the Roche COBAS PIK3CA Mutation Test at Q^2 Solutions
- All patients must have measurable disease as defined by Response Evaluation Criteria
in Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one lesion
that can be accurately measured in at least one dimension (longest diameter to be
recorded); each lesion must be >= 10 mm when measured by computed tomography (CT),
magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm
when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured
by CT or MRI
- Patients must have at least one "target lesion" to be used to assess response on this
protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be
designated as 'non-target" lesions unless progression is documented or a biopsy is
obtained to confirm persistence at least 90 days following completion of radiation
therapy
- Patients must have recovered from effects of recent surgery, radiotherapy, or
chemotherapy; at least 4 weeks must have elapsed since the patient underwent any major
surgery (e.g., major: laparotomy, laparoscopy); there is no delay required for minor
procedures (e.g., tumor fine-needle aspiration [FNA] or core biopsy, venous access
device placement)
- Patients may have received prior radiation therapy for treatment of endometrial
cancer; prior radiation therapy may have included pelvic radiation therapy, extended
field pelvic/para-aortic radiation therapy, intravaginal brachytherapy and/or
palliative radiation therapy; all radiation therapy must be completed at least 4 weeks
prior to registration
- Patients may have received prior hormonal therapy for treatment of endometrial
carcinoma; all hormonal therapy must be discontinued at least 4 weeks prior to
registration
- Patients may have received prior therapy (including chemotherapy, biologic/targeted
therapy and immunotherapy) for treatment of endometrial cancer; all therapy must be
discontinued at least 4 weeks prior to registration; any investigational agent must be
discontinued at least 30 days prior to registration
- Patients must have had at least one prior chemotherapeutic regimen for management of
endometrial carcinoma; initial treatment may include chemotherapy, chemotherapy and
radiation therapy, or consolidation/maintenance therapy; chemotherapy administered in
conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic
chemotherapy regimen
- Patients are allowed to receive, but not required to receive, up to a total of 3
lines of chemotherapy
- Appropriate stage for study entry based on the following diagnostic workup:
- History/physical examination within 28 days prior to registration
- Imaging of target lesion(s) within 28 days prior to registration
- Completion of pre-study protocol specific assessments as required
- Performance status (Eastern Cooperative Oncology Group [ECOG]/Karnofsky) of 0, 1 or 2
within 28 days prior to registration
- Absolute neutrophil count (ANC) >= 1,500/mcl
- Platelets >= 75,000/mcl
- Hemoglobin (Hgb) >= 8 g/dL
- Creatinine =< 1.5 x upper limit of normal (ULN)
- Bilirubin =< 1.5 x ULN (=< 3 x ULN for patients with Gilbert syndrome)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
- Left ventricular ejection fraction (LVEF) >= 50%
- Fasting cholesterol less than or equal to 300 mg/dl; fasting triglycerides less than
or equal to 300 mg/dl
- Prothrombin time (PT) such that international normalized ratio (INR) is less than or
equal to 1.5 x ULN (or an in range INR, usually between 2 and 3, if a patient is on a
stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) less than
or equal to 1.5 times the upper limit of normal
- The patient must provide study-specific informed consent prior to study entry and, for
patients treated in the United States (U.S.), authorization permitting release of
personal health information
- Diabetic patients (type I or II diabetes mellitus) must have baseline hemoglobin
(Hb)A1c levels NOT higher than 8.5% at study entry
- Patients with hypertension on medical management must have systolic blood pressure <
150 mmHG or diastolic pressure < 90 mmHG at study entry
- Note: ULN is institutional or laboratory upper limit of normal
- Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test
within 28 days of registration; the patient and her sexual partner(s) must agree to
use adequate contraception when sexually active for the duration of the study and for
6 months after finishing study drug; a woman is considered of childbearing potential
following menarche and until becoming post-menopausal unless permanently sterile;
permanent sterilization methods include hysterectomy, bilateral salpingectomy and
bilateral oophorectomy; a postmenopausal state is defined as no menses for 12 months
without an alternative medical cause; a high follicle stimulating hormone (FSH) level
in the postmenopausal range maybe used to confirm a post-menopausal state in women not
using hormonal contraception or hormonal replacement therapy
Exclusion Criteria:
- Patients who have had prior therapy with any phosphatidylinositol 3 kinase
(PI3K)/v-akt murine thymoma viral oncogene homolog 1 (AKT)/mammalian target of
rapamycin (mTor) pathway inhibitor
- Patients who have the following histologies: mucinous, squamous, sarcomas,
carcinosarcomas, clear cell
- Congestive heart failure > New York Heart Association (NYHA) class II
- Myocardial infarction or unstable angina less than 6 months before registration
- 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 registration
- Non-healing wound, ulcer or bone fracture
- Active, clinically serious infections > Common Terminology Criteria for Adverse Events
(CTCAE) grade 2
- History of, or current autoimmune disease
- Human immunodeficiency virus (HIV) infection
- 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; patients with active HBV or hepatitis C infection are not eligible for
enrollment; patients with serologic markers of HBV immunization due to known
vaccination (hepatitis B surface antigen [HBsAg] negative, anti-hepatitis B core [HBc]
negative and anti-hepatitis B surface [HBs] positive) will be eligible
- Previous or concurrent history of malignancies within 5 years prior to study treatment
except for curatively treated:
- Cervical carcinoma in situ
- Non-melanoma skin cancer
- Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and
T1 [tumor invades lamina propria])
- Patients with seizure disorder requiring medication
- Patients with evidence or history of bleeding diathesis; any hemorrhage or bleeding
event >= CTCAE grade 3 within 4 weeks prior to registration
- Proteinuria of CTCAE grade 3 or higher (estimated by urine protein: creatinine ratio
>= 3.5 on a random urine sample); patients who recently (i.e., at least 30 days prior
to registration) discontinued an anti-angiogenic therapy which caused proteinuria (ie,
grade 2 (> 2 to > 3 g of protein or 1-3.5 g/24 hours [h]) or grade 3 proteinuria (> 4
of protein or > 3.5 g/24 h) are not eligible for enrollment until proteinuria improves
to < 2 g of protein per 24 h
- History or concurrent condition of interstitial lung disease of any severity and/or
severely impaired lung function (as judged by the investigator)
- Concurrent diagnosis of pheochromocytoma
- Unresolved toxicity higher than CTCAE grade 1 attributed to any prior
therapy/procedure, excluding alopecia
- Known hypersensitivity to any of the test drugs, test drug classes, or excipients in
the formulation
- Strong CYP3A4 inhibitors and inducers; concomitant use of strong inhibitors of CYP3A4
(e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir
and saquinavir), and inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine,
phenobarbital, St. John's Wort) are not permitted within two weeks prior to start of
study treatment and for the duration of treatment with copanlisib
- Grapefruit and grapefruit juice (CYP3A4 inhibitor), Seville oranges and star fruit
consumption is not permitted during the study
- Anti-arrhythmic therapy other than beta blockers or digoxin
- 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
- Concomitant therapy with any anticancer agents, immunosuppressive agents, other
investigational anticancer therapies
- Concomitant radiotherapy
- Women who are breast feeding
