SNPMiner Trials by Shray Alag
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SNPMiner Trials (Home Page)
Report for Mutation H1047L
Developed by Shray Alag, 2020.
SNP Clinical Trial Gene
There are 2 clinical trials
Clinical Trials
1 An Open Label, Phase II Trial of BKM120 in Cancers With PIK3CA Activating Mutations
In people whos cancers have a PIK3CA mutation, this trial will be evaluating the drug BKM120 as a possible treatment. BKM120 works by blocking the phosphatidylinositol-3-kinase (PI3K)pathway, thereby inhibiting tumor growth and survival. The purpose of this study is to learn if the study drug BKM120 can shrink or slow the growth of your tumor. The safety of BKM120 will also be studied. Your physical state, symptoms, change in the size of your tumor, and laboratory findings obtained while you are on study will help the research team decide if BKM120 is safe and effective in patients with advanced cancers.
NCT01501604 Conditions
- Lung Cancer
- Breast Cancer
- Colorectal Cancer
- Cholangiocarcinoma
- Solid Tumors
Interventions
- Drug: BKM120
MeSH:Cholangiocarcinoma
HPO:Cholangiocarcinoma
Inclusion Criteria: - At least 1 site of measurable disease - Life expectancy >/= 12 weeks - Adequate marrow and organ function - Diagnosis of lung cancer, breast cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer, esophageal cancer, or head and neck cancer - Pathologically documented, definitively diagnosed, advanced solid tuor that is refractory to standard treatment, for which no standard therapy is available, or the subject refuses standard therapy - Cancer must have at least one of the following PIK3CA mutations: E542K, E545K, H1047R, H1047L. --- E542K --- --- E545K --- --- H1047R --- --- H1047L ---
The PIK3CA mutation must be documented in a CLIA approved laboratory Exclusion Criteria: - Prior treatment with a P13K inhibitor - Known hypersensitivity to BKM120 or its excipients - Untreated brain metastases - Acute or chronic liver, renal disease or pancreatitis - Currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A - Diarrhea >/= CTCAE grade 2 - Any concurrent severe and/or uncontrolled medical condition - Active cardiac disease - History of cardiac dysfunction - Poorly controlled diabetes mellitus or steroid-induced diabetes mellitus - Significant symptomatic deterioration of lung function - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKDM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) - Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant - Pregnant or breast-feeding - Known diagnosis of HIV infection - History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix - Unable to swallow the medication in its prescribed form Inclusion Criteria: - At least 1 site of measurable disease - Life expectancy >/= 12 weeks - Adequate marrow and organ function - Diagnosis of lung cancer, breast cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer, esophageal cancer, or head and neck cancer - Pathologically documented, definitively diagnosed, advanced solid tuor that is refractory to standard treatment, for which no standard therapy is available, or the subject refuses standard therapy - Cancer must have at least one of the following PIK3CA mutations: E542K, E545K, H1047R, H1047L. --- P13K --- --- E542K --- --- E545K --- --- H1047R --- --- H1047L ---
Primary Outcomes
Description: Objective Response Rate (CR or PR) by RECIST 1.1 criteria
Measure: Response Rate Time: 2 yearsSecondary Outcomes
Description: Clinical Benefit Rate (CR, PR, or SD) by RECIST 1.1 criteria
Measure: Clinical Benefit Rate Time: 2 yearsDescription: Progression Free Survival (PFS)
Measure: Survival Time: 2 yearsDescription: Determine if the presence of specific co-existing mutations may influence clinical benefit from BKM120
Measure: Clinical Benefit Time: 2 years2 A Phase II Evaluation of Copanlisib (BAY 80-6946), a Selective Inhibitor of PI3KCA, in Patients With Persistent or Recurrent Endometrial Carcinoma Harboring PIK3CA Hotspot Mutations
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.
NCT02728258 Conditions
- Endometrial Endometrioid Adenocarcinoma
- Endometrial Mixed Cell Adenocarcinoma
- Endometrial Serous Adenocarcinoma
- Endometrial Undifferentiated Carcinoma
- Metastatic Endometrioid Adenocarcinoma
- Recurrent Uterine Corpus Carcinoma
Interventions
- Drug: Copanlisib
- Other: Laboratory Biomarker Analysis
MeSH:Carcinoma Adenocarcinoma Cystadenocarcinoma, Serous Carcinoma, Endometrioid
HPO:Carcinoma
Associations between mutation subtypes and clinical outcomes will be explored using standard statistical methods for categorical and time to event data.. 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 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 Endometrial Endometrioid Adenocarcinoma Endometrial Mixed Cell Adenocarcinoma Endometrial Serous Adenocarcinoma Endometrial Undifferentiated Carcinoma Metastatic Endometrioid Adenocarcinoma Recurrent Uterine Corpus Carcinoma Carcinoma Adenocarcinoma Cystadenocarcinoma, Serous Carcinoma, Endometrioid 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. --- R88Q --- --- N345K --- --- C420R --- --- E542K --- --- E545A --- --- E545D --- --- E545G --- --- E545K --- --- Q546E --- --- Q546K --- --- Q546L --- --- Q546R --- --- M1043I --- --- H1047L ---
Associations between mutation subtypes and clinical outcomes will be explored using standard statistical methods for categorical and time to event data.. 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 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 Endometrial Endometrioid Adenocarcinoma Endometrial Mixed Cell Adenocarcinoma Endometrial Serous Adenocarcinoma Endometrial Undifferentiated Carcinoma Metastatic Endometrioid Adenocarcinoma Recurrent Uterine Corpus Carcinoma Carcinoma Adenocarcinoma Cystadenocarcinoma, Serous Carcinoma, Endometrioid 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. --- R88Q --- --- N345K --- --- C420R --- --- E542K --- --- E545A --- --- E545D --- --- E545G --- --- E545K --- --- Q546E --- --- Q546K --- --- Q546L --- --- Q546R --- --- M1043I --- --- H1047L --- --- H1047R --- --- H1047Y --- --- G1049R --- --- R88Q --- --- N345K --- --- C420R --- --- E542K --- --- E545A --- --- E545D --- --- E545G --- --- E545K --- --- Q546E --- --- Q546K --- --- Q546L --- --- Q546R --- --- M1043I --- --- H1047L ---
Primary Outcomes
Description: Confirmed complete and partial tumor response by RECIST 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Measure: Frequency of Objective Response Defined by RECIST 1.1 Criteria Time: approximate study duration 1 year 9 monthsSecondary Outcomes
Description: Percentage of participants who are progression free at 6 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Measure: Percentage of Participants Alive and Progression-free at 6 Months Time: Up to 6 months from enrollmentDescription: The median progression-free survival time
Measure: Median Progression-Free Survival Using RECIST 1.1 Criteria Time: September 16,2016 to April 4,2019, approximate duration of 2 years, 7 monthsDescription: Median time of overall survival
Measure: Median Overall Survival Time: September 16,2016 to April 4,2019, approximate duration of 2 years, 7 monthsDescription: Maximum grade of physician assessed adverse events reported during treatment
Measure: The Frequency and Severity of CTCAE v4 Graded Adverse Events Time: Study Start: September 16, 2016, Primary Completion: June 30, 2018, approximate study duration 1 year 9 monthsOther Outcomes
Description: Associations between mutation subtypes and clinical outcomes will be explored using standard statistical methods for categorical and time to event data.
Measure: Mutation Subtypes and Clinical Outcomes Time: Up to 5 years