Copanlisib in Treating Patients With Persistent or Recurrent Endometrial Cancer
Condition: Endometrial Endometrioid Adenocarcinoma; Endometrial Mixed Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Metastatic Endometrioid Adenocarcinoma; Recurrent Uterine Corpus Cancer
MeSH terms: Carcinoma; Adenocarcinoma; Cystadenocarcinoma, Serous; Carcinoma, Endometrioid; Recurrence
Intervention: Copanlisib; Laboratory Biomarker Analysis
Intervention description: Given IV; Correlative studies
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well copanlisib works in treating patients with endometrial
      cancer that has not decreased or disappeared, and the cancer may still be in the body despite
      treatment (persistent) or has come back (recurrent). Copanlisib may stop the growth of tumor
      cells by blocking some of the enzymes needed for cell growth.
    

Eligibility criteria:

        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