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Copanlisib in Treating Patients With Persistent or Recurrent Endometrial Cancer

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ClinicalTrials.gov Identifier: NCT02728258
Recruitment Status : Suspended (Scheduled Interim Monitoring)
First Posted : April 5, 2016
Last Update Posted : February 16, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Brief 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.

Condition or disease Intervention/treatment Phase
Endometrial Endometrioid Adenocarcinoma Endometrial Mixed Adenocarcinoma Endometrial Serous Adenocarcinoma Endometrial Undifferentiated Carcinoma Metastatic Endometrioid Adenocarcinoma PIK3CA Gene Mutation Recurrent Uterine Corpus Carcinoma Drug: Copanlisib Other: Laboratory Biomarker Analysis Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 16, 2016
Estimated Primary Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Copanlisib

Arm Intervention/treatment
Experimental: Treatment (copanlisib)
Patients receive copanlisib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Copanlisib
Given IV
Other Names:
  • BAY 80-6946
  • PI3K Inhibitor BAY 80-6946

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Frequency of objective response defined by RECIST 1.1 criteria [ Time Frame: Up to 5 years ]
    Confirmation of complete and partial responses in tumor evaluations at least 4 weeks apart is required. Exact 95% confidence limits, accounting for the interim analysis, will be provided.


Secondary Outcome Measures :
  1. Incidence of adverse events of copanlisib using CTCAE version 4.03 [ Time Frame: Up to 5 years ]
    Frequencies of maximum grade of adverse events by term or category will be reported. Grade 5 adverse events will be individually reported.

  2. Median PFS using RECIST 1.1 criteria [ Time Frame: Duration of time from study entry to time of progression or death, whichever occurs first, or date of last contact, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier product limit estimates.

  3. OS [ Time Frame: Duration of time from study entry to time of death or the date of last contact, assessed up to 5 years ]
    Will be estimated using Kaplan-Meier product limit estimates.

  4. PFS defined using RECIST 1.1 criteria [ Time Frame: Duration of time from study entry to time of progression or death, whichever occurs first, or date of last contact, assessed at 6 months ]
    Will be estimated using Kaplan-Meier product limit estimates.


Other Outcome Measures:
  1. Mutation subtypes and clinical outcomes [ Time Frame: Up to 5 years ]
    Associations between mutation subtypes and clinical outcomes will be explored using standard statistical methods for categorical and time to event data.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02728258


  Show 44 Study Locations
Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
Principal Investigator: Alessandro Santin NRG Oncology

Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT02728258     History of Changes
Other Study ID Numbers: NRG-GY008
NCI-2016-00325 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GY008
NRG-DT1419
NRG-GY008 ( Other Identifier: NRG Oncology )
NRG-GY008 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: April 5, 2016    Key Record Dates
Last Update Posted: February 16, 2018
Last Verified: February 2018

Additional relevant MeSH terms:
Carcinoma
Adenocarcinoma
Carcinoma, Endometrioid
Cystadenocarcinoma, Serous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endometrial Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Ovarian Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous