Clinical Trials /

Study of a New Drug Combination, Copanlisib and Fulvestrant, in Postmenopausal Women With Advanced Breast Cancer

NCT03803761

Description:

This phase I/II trial studies the side effects and how well copanlisib works when given together with fulvestrant in treating postmenopausal patients with estrogen receptor positive (ER+) and epidermal growth factor receptor 2 negative (HER2-) breast cancer that has spread to other places in the body and progressing after prior treatment. HER2 and ER are two types of proteins called receptors that can affect the growth of breast cancer cells. Additionally, investigators hope to learn from this study if tumor genetic information is important for predicting whether this type of breast cancer will respond to fulvestrant and copanlisib. Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving copanlisib and fulvestrant may work better in treating patients with ER+ and HER2- breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Copanlisib and Fulvestrant in Treating Postmenopausal Patients With ER+ and HER2- Metastatic Breast Cancer Progressing After Aromatase and CDK 4/6 Inhibitors Treatment
  • Official Title: A Phase 2 Study of Copanlisib (BAY 80-6946) in Combination With Fulvestrant in Women With Metastatic Breast Cancer Progressing After Aromatase Inhibitor Plus CDK 4/6 Inhibitor

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-00048
  • SECONDARY ID: NCI-2019-00048
  • SECONDARY ID: NCI10195
  • SECONDARY ID: 10195
  • SECONDARY ID: 10195
  • SECONDARY ID: UM1CA186704
  • NCT ID: NCT03803761

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • Breast Carcinoma Metastatic in the Brain
  • Estrogen Receptor Positive
  • HER2/Neu Negative
  • Metastatic Breast Carcinoma
  • Postmenopausal
  • Prognostic Stage IV Breast Cancer AJCC v8

Interventions

DrugSynonymsArms
CopanlisibBAY 80-6946, PI3K Inhibitor BAY 80-6946Treatment (copanlisib, fulvestrant)
FulvestrantFaslodex, Faslodex(ICI 182,780), ICI 182,780, ICI 182780, ZD9238Treatment (copanlisib, fulvestrant)

Purpose

This phase I/II trial studies the side effects and how well copanlisib works when given together with fulvestrant in treating postmenopausal patients with estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer that has spread to other places in the body and progressing after aromatase and CDK 4/6 inhibitors treatment. Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving copanlisib and fulvestrant may work better in treating patients with ER+ and HER2- breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Establish safety of the combination of copanlisib and fulvestrant (FC). II. Evaluate the
      response rate (RR) of the combination of copanlisib and fulvestrant in patients with
      estrogen-receptor positive (ER+)/human epidermal growth factor receptor 2 (HER2) negative
      metastatic breast cancer that has previously progressed on aromatase inhibitor (AI)/cyclin
      dependent kinase (CDK) 4/6 inhibitor therapy.

      SECONDARY OBJECTIVES:

      I. Estimate progression-free survival (PFS) in patients treated with copanlisib and
      fulvestrant.

      II. Estimate the RR in subjects with PTEN loss by immunohistochemistry (IHC) analysis
      performed retrospectively.

      III. Evaluate toxicity in patients treated with FC in Phase II.

      EXPLORATORY OBJECTIVES:

      I. Evaluate copanlisib pharmacokinetics (PK) when given in combination with fulvestrant.

      II. Explore association between intrinsic subtype and response to FC therapy. III. Assess
      baseline levels and treatment-induced proteomic changes and correlate with response to FC.

      IV. Evaluate circulating tumor deoxyribonucleic acid (DNA) (ctDNA) mutations at baseline and
      over time for response predictors at baseline, clonal evolution associated with treatment,
      and resistance mechanisms at disease progression.

      V. Evaluate circulating markers of metabolism before and after PI3K inhibitor therapy which
      may predict treatment response and resistance mechanisms.

      OUTLINE:

      Patients receive copanlisib intravenously (IV) over 1 hour on days 1, 8, and 15 and
      fulvestrant intramuscularly (IM) over 1-2 minutes on days 1 and 15 of cycle 1 and on day 1
      beginning cycle 2. Cycles repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (copanlisib, fulvestrant)ExperimentalPatients receive copanlisib IV over 1 hour on days 1, 8, and 15 and fulvestrant IM over 1-2 minutes on days 1 and 15 of cycle 1 and on day 1 beginning cycle 2. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Copanlisib
  • Fulvestrant

Eligibility Criteria

        Inclusion Criteria:

          -  Postmenopausal women with estrogen receptor positive (ER+), human epidermal growth
             factor receptor 2 (HER2) negative metastatic breast cancer (MBC) who have progressed
             on combination therapy with an aromatase inhibitor and cyclin-dependent kinase 4/6
             (CDK 4/6) inhibitor

               -  Note: Postmenopausal females are considered of childbearing potential unless they
                  are surgically or permanently sterile (have undergone a hysterectomy, bilateral
                  tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal
                  for at least 12 consecutive months. A high follicle stimulating hormone (FSH)
                  level in the postmenopausal range may be used to confirm a post-menopausal state
                  in women not using hormonal contraception or hormonal replacement therapy.
                  Documentation of postmenopausal status must be provided

          -  Measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1
             (RECIST1.1)

          -  Patients must have had tumor sequencing for evaluation of actionable PIK3CA or PTEN
             mutations performed in a Clinical Laboratory Improvement Act (CLIA) certified, College
             of American Pathologist (CAP) tested and bioinformatics-validated testing lab PRIOR to
             enrollment in this current protocol. The testing may have been done at any time prior
             to enrollment. For patients who have not yet had tumor genomic assessment, after
             consultation with the principal investigator (PI), tumor specimens will be sent to the
             University of North Carolina (UNC) Hospitals Clinical Molecular Genetics Laboratory
             for assessment of the Solid Tumor Mutation Panel. In this case, results of genetic
             testing by the UNC lab must be available prior to the first on study disease
             assessment (i.e., prior to day 1 of cycle 4). In this case, the study will cover the
             cost of the Solid Tumor Panel

          -  Female subjects who are not of childbearing potential

               -  Note: Because no dosing or adverse event data are currently available on the use
                  of copanlisib in combination with fulvestrant in patients <18 years of age, and
                  only postmenopausal women with ER+/HER2 negative MBC are eligible or appropriate
                  for treatment with fulvestrant, children and pregnant or pre-menopausal women are
                  excluded from this study

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 70%)

          -  No prior treatment history with fulvestrant or a PI3K inhibitor

          -  Subject has not received more than 2 prior lines of chemotherapy in the metastatic
             setting

          -  Subject must have washout period from prior systemic anti-cancer therapy of at least
             21 days (or 5 half-lives of the systemic anti-cancer therapy, whichever is shorter)
             before the start of study treatment

          -  Subject must have washout period from prior radiation therapy of at least 2 weeks
             before the start of study treatment

          -  Subjects with a history of brain metastases are allowed if they are not on steroid
             therapy and there is no evidence of intracranial disease progression symptomatically
             or by imaging within 28 days prior to study registration

          -  Hemoglobin >= 9.0 g/dL (collected no more than 7 days before starting treatment)

          -  Leukocytes >= 3,000/mcL (collected no more than 7 days before starting treatment)

          -  Absolute neutrophil count >= 1,500/mcL (collected no more than 7 days before starting
             treatment)

          -  Platelets >= 100,000/mcL (collected no more than 7 days before starting treatment)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (collected no more than 7 days
             before starting treatment) (< 3 x ULN for patients with Gilbert syndrome, patients
             with cholestasis due to compressive adenopathies of the hepatic hilum or documented
             liver involvement)

          -  Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional upper limit of normal (ULN) OR =< 5 x institutional ULN if
             liver metastases present (collected no more than 7 days before starting treatment)

          -  Creatinine within institutional normal limits OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above the institutional normal
             (collected no more than 7 days before starting treatment)

          -  Fasting blood glucose < 120 mg/dL (collected no more than 7 days before starting
             treatment)

          -  Lipase =< 1.5 x ULN (collected no more than 7 days before starting treatment)

          -  International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x
             ULN (collected no more than 7 days before starting treatment)

          -  Left ventricular ejection fraction (LVEF) >= 50%

          -  Subject must agree to provide archival tumor material for research and/or agree to
             undergo a tumor biopsy for research if the tumor is accessible for biopsy prior to
             study treatment

          -  Ability to understand and the willingness to comply with study procedures and to sign
             a written informed consent document

        Exclusion Criteria:

          -  Previous assignment to treatment during this study. Patients permanently withdrawn
             from study participation will not be allowed to re-enter the study

          -  Concomitant participation in another clinical study with investigational medicinal
             product

          -  Subjects 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

          -  Immunosuppressive therapy is not allowed while on study

          -  Subjects who are receiving any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to copanlisib, fulvestrant, or PI3K inhibitors

          -  Subjects with moderate or severe hepatic impairment (ie, Child-Pugh B or C)

          -  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 (CT)/magnetic resonance imaging (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

          -  Uncontrolled intercurrent illness, including but not limited to, psychiatric
             illness/social situations that would limit compliance with study requirements

          -  Major surgical procedure or significant traumatic injury (as judged by the
             investigator) within 28 days prior to start of treatment, or not recovered from major
             side effects, or open biopsy within 7 days before start of study treatment

          -  Patients with non-healing wound, ulcer, or bone fracture

          -  Patients with active, clinically serious infections > grade 2 (Common Terminology
             Criteria for Adverse Events [CTCAE] version [v]5.0)

          -  Patients with uncontrolled type I or II diabetes mellitus; uncontrolled diabetes is
             defined as fasting blood glucose > 120 mg/dL

          -  Proteinuria of >= CTCAE grade 3 as assessed by a 24 hour (h) protein quantification or
             estimated by urine protein: creatinine ratio > 3.5 on a random urine sample

          -  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

          -  Congestive heart failure > New York Heart Association (NYHA) class 2

               -  Note: Class III NYHA Heart failure classification: Patients with cardiac disease
                  resulting in marked limitation of physical activity. They are comfortable at
                  rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or
                  anginal pain

               -  Note: Class IV NYHA Heart failure classification: Patients with cardiac disease
                  resulting in the inability to carry on any physical activity without discomfort.
                  Symptoms of heart failure or the anginal syndrome may be present even at rest. If
                  any physical activity is undertaken, discomfort is increased.

        Other cardiovascular-related abnormalities or therapy that prohibit study participation
        are:

          -  Myocardial infarction less than 6 months before start of study medications

          -  Unstable angina (angina symptoms at rest), new onset angina (begun within the last 3
             months)

          -  Uncontrolled arterial hypertension despite optimal medical management

          -  Anti-arrhythmic therapy (exceptions: beta blockers or digoxin are permitted)

               -  Pregnant or lactating (Pregnant women or women who are breastfeeding are excluded
                  from this study because copanlisib is a PI3K inhibitor agent with the potential
                  for teratogenic or abortifacient effects; there is no safety data in pregnancy;
                  because there is an unknown but potential risk for adverse events in nursing
                  infants secondary to treatment of the mother with copanlisib, breastfeeding
                  should be discontinued if the mother is treated with copanlisib and/or
                  fulvestrant; fulvestrant may also cause fetal harm and based on animal studies,
                  may impair fertility in females of reproductive potential)

               -  Hepatitis B virus (HBV) or hepatitis C virus (HCV). All patients must be screened
                  for HBV and HCV up to 28 days prior to study drug start using the routine
                  hepatitis virus lab panel; patients positive for hepatitis B virus surface
                  antigen (HBsAg) and/or hepatitis B virus core antibody (HBcAb) will be eligible
                  if they are negative for deoxyribonucleic acid (DNA), these patients should
                  receive prophylactic antiviral therapy; patients positive for anti-HCV antibody
                  will be eligible if they are negative for HCV ribonucleic acid (RNA)

               -  Human immunodeficiency virus (HIV)-positive patients on combination
                  antiretroviral agents that are strong CYP3A4 inhibitors or inducers and who are
                  unwilling or unable to change to antiretroviral therapies without such
                  interactions are ineligible because of the potential for pharmacokinetic
                  interactions with copanlisib

               -  Cytomegalovirus (CMV) polymerase chain reaction (PCR) positive at baseline

               -  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])

          -  Localized prostate cancer

               -  Subjects with seizure disorder requiring medication

               -  Subjects with evidence or history of bleeding diathesis; any hemorrhage or
                  bleeding event >= CTCAE grade 3 within 4 weeks prior to the start of study
                  medication

               -  Blood or platelet transfusion less than 7 days before start of study treatment or
                  myeloid growth factors within 14 days prior to treatment

               -  History of concurrent condition of interstitial lung disease of any severity
                  and/or severely impaired lung function (as judged by the investigator)

               -  History of, or current autoimmune disease

               -  Concurrent diagnosis of pheochromocytoma
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (DLT)
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:Toxicities will be tabulated based on type and grade.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From start of treatment to time of progression or death, assessed up to 30 days post treatment
Safety Issue:
Description:PFS will be estimated using the Kaplan Meier method, with median and 95% confidence interval (CI) reported.
Measure:Response rate
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:Response rate will be reported for subjects with PTEN loss by immunohistochemistry (IHC) analysis performed retrospectively. This will be done across cohorts.
Measure:Incidence of adverse events
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:Toxicities will be tabulated based on type and grade. Any toxicity seen in more than 10% of patients will be reported, and all grade 3-4 toxicities will be reported.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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