Clinical Trials /

Testing the Addition of Copanlisib to Usual Treatment (Fulvestrant and Abemaciclib) in Metastatic Breast Cancer - Dose-Finding Study

NCT03939897

Description:

This phase I/II trial studies the effects (good and bad) of adding copanlisib to the usual therapy of fulvestrant and abemaciclib in treating patients with hormone receptor positive and HER2 negative stage IV breast cancer. Some breast cancer cells have receptors for the hormones estrogen or progesterone. These cells are hormone receptor positive and they need estrogen or progesterone to grow. This can affect how the cancer is treated. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Abemaciclib and copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Adding copanlisib to the usual therapy of fulvestrant and abemaciclib may work better than giving fulvestrant and abemaciclib alone in treating patients with breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Fulvestrant and Abemaciclib With or Without Copanlisib in Treating Patients With Hormone Receptor Positive and HER2 Negative Stage IV Breast Cancer
  • Official Title: A Randomized Phase I/II Trial of Fulvestrant and Abemaciclib in Combination With Copanlisib (FAC) Versus Fulvestrant and Abemaciclib Alone (FA) for Endocrine-Resistant, Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer (FAC vs FA)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-02752
  • SECONDARY ID: NCI-2019-02752
  • SECONDARY ID: 10287
  • SECONDARY ID: 10287
  • SECONDARY ID: UM1CA186704
  • NCT ID: NCT03939897

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • ERBB2 Gene Amplification Negative
  • Estrogen Receptor Positive
  • HER2/Neu Negative
  • Hormone Receptor Positive Breast Carcinoma
  • Metastatic Breast Carcinoma
  • Progesterone Receptor Positive
  • Prognostic Stage IV Breast Cancer AJCC v8
  • Progressive Disease
  • Recurrent Breast Carcinoma

Interventions

DrugSynonymsArms
AbemaciclibLY-2835219, LY2835219, VerzenioArm I (FAC) (copanlisib, abemaciclib, fulvestrant)
CopanlisibBAY 80-6946, PI3K Inhibitor BAY 80-6946Arm I (FAC) (copanlisib, abemaciclib, fulvestrant)
Copanlisib Hydrochloride5-Pyrimidinecarboxamide, 2-Amino-N-(2,3-dihydro-7-methoxy-8-(3-(4-morpholinyl)propoxy)imidazo(1,2-C)quinazolin-5-yl)-, Hydrochloride (1:2), Aliqopa, BAY 80-6946 Dihydrochloride, BAY-80-6946 Dihydrochloride, Copanlisib DihydrochlorideArm I (FAC) (copanlisib, abemaciclib, fulvestrant)
FulvestrantFaslodex, Faslodex(ICI 182,780), ICI 182,780, ICI 182780, ZD9238Arm I (FAC) (copanlisib, abemaciclib, fulvestrant)

Purpose

This phase I/II trial studies the side effects and best dose of copanlisib and abemaciclib and how well they work together with fulvestrant in treating patients with hormone receptor positive and HER2 negative stage IV breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Abemaciclib and copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Adding copanlisib to the usual therapy of fulvestrant and abemaciclib may work better than giving fulvestrant and abemaciclib alone in treating patients with breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety profile of fulvestrant + abemaciclib + copanlisib hydrochloride
      (copanlisib) (FAC) and determine the recommended phase 2 dose (RP2D).

      II. To determine if FAC is superior to fulvestrant + abemaciclib (FA) using progression-free
      survival (PFS) as an endpoint.

      SECONDARY OBJECTIVES:

      I. To assess the objective response rate (ORR = partial response [PR] + complete response
      [CR]) and clinical benefit rate (CBR = PR + CR + stable disease [SD] >= 6 months) of FAC
      versus (vs.) FA.

      II. To compare the median PFS between FAC and FA arms in the following subgroups:

      IIa. Tumor PIK3CA/PTEN altered (PIK3CA mutation or PTEN mutation/PTEN loss). IIb. Tumor
      PIK3CA/PTEN not altered (wild-type PIK3CA and PTEN and without PTEN loss).

      IIc. Tumor phosphorylated (p)AKT levels (above or below the median). III. To assess whether
      triplet therapy with FAC inhibits AKT phosphorylation, reduces cyclin D1, and is more
      effective than FA in inhibiting Rb phosphorylation.

      EXPLORATORY OBJECTIVES:

      I. To assess whether the combination of abemaciclib and fulvestrant affect the copanlisib
      pharmacokinetics (PK).

      II. To assess the median PFS in the following molecularly defined subgroups treated with
      either FAC or FA:

      IIa. Tumor PIK3CA mutation vs. not. IIb. Tumor PTEN mutation/PTEN loss vs. not. IIc.
      Circulating tumor deoxyribonucleic acid (DNA) (ctDNA) PIK3CA mutation vs. not.

      IId. CtDNA PI3K/PTEN mutation vs. not. IIe. CtDNA ESR1 mutation vs. not. III. To assess
      baseline and treatment induced changes in various cancer associated pathways, including but
      not limited to PI3K, MAPK, ER, cyclins, CDKs and CDK inhibitors; and to correlate with
      treatment response and progression.

      IV. To correlate baseline and treatment induced changes in breast cancer intrinsic subtypes
      (PAM50), and PI3K messenger ribonucleic acid (mRNA) signature and expression of candidate
      genes with treatment response and benefit from adding copanlisib.

      V. To evaluate ctDNA mutations at baseline and over time for response predictors at baseline,
      and clonal evolution associated with treatment.

      VI. To correlate ctDNA mutation profiles with tumor sequencing, and correlate baseline ctDNA
      mutations, particularly in components of the PI3K pathway with treatment response, and
      correlate early changes in ctDNA variant allele frequencies (VAFs) with PFS, assess emergent
      resistant mutations at progression.

      VII. To assess resistance mechanisms to FA and FAC at baseline and at disease progression.

      VIII. To examine the molecular effects of FA and FAC on tumor and circulating markers.

      IX. To analyze tumor infiltrating lymphocytes at baseline, during treatment, and at disease
      progression.

      X. To assess whether copanlisib affects abemaciclib pharmacokinetics (PK).

      OUTLINE: This is a phase I, dose-escalation study of copanlisib hydrochloride and
      abemaciclib, followed by a phase II study.

      PHASE I: Patients receive copanlisib hydrochloride intravenously (IV) over 1 hour on days 1,
      8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib orally (PO) twice daily
      (BID) on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive
      fulvestrant intramuscularly (IM) on days 2 and 16 of cycle 1, and on day 1 of subsequent
      cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      PHASE II: Patients are randomized to 1 of 2 arms.

      ARM I (FAC): Patients receive copanlisib hydrochloride as in phase I. Patients also receive
      abemaciclib PO BID on days 1-28 and fulvestrant IM on days 1 and 15 of cycle 1 and day 1 of
      subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      ARM II (FA): Patients receive abemaciclib PO BID on days 1-28 and fulvestrant IM on days 1
      and 15 of cycle 1 and day 1 of subsequent cycles. Cycles 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 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (FAC) (copanlisib, abemaciclib, fulvestrant)ExperimentalPHASE I: Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive copanlisib hydrochloride as in phase I. Patients also receive abemaciclib PO BID on days 1-28 and fulvestrant IM on days 1 and 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Abemaciclib
  • Copanlisib
  • Copanlisib Hydrochloride
  • Fulvestrant
Arm II (FA) (abemaciclib, fulvestrant)Active ComparatorPHASE I: Patients receive copanlisib hydrochloride IV over 1 hour on days 1, 8, and 15 or days 1 and 15 (depending on dose level) and abemaciclib PO BID on days 2-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive fulvestrant IM on days 2 and 16 of cycle 1, and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive abemaciclib PO BID on days 1-28 and fulvestrant IM on days 1 and 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Abemaciclib
  • Fulvestrant

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed ER and/or PR positive,
             HER2 negative or non-amplified breast cancer that is stage IV, with measurable or
             non-measurable disease. ER/PR positivity is defined as at least 1% positive or an
             Allred score of at least 3. HER2 status is defined per the 2018 American Society of
             Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline

          -  All patients must agree to provide archival tumor material for research and must agree
             to undergo research tumor biopsy before treatment if presence of easily accessible
             lesions (judged by the treating physician). For patients with bone only disease, or
             patients without easily accessible lesions for the baseline research biopsy,
             availability of archival tumor material (2 x 4-5 micron section unstained slides, plus
             15-20 x 10 micron section unstained slides or a tumor rich block) from previous breast
             cancer diagnosis or treatment is required for central PTEN and PIK3CA analysis

          -  No more than 1 prior chemotherapy in the metastatic setting. There is no limit on
             prior lines of endocrine therapy. (For patients enrolling to the phase 1 portion of
             the study, prior fulvestrant, CDK4/6 inhibitor, and everolimus is allowed)

          -  For patients enrolling to the randomized phase 2 portion of this study, demonstrated
             resistance to prior endocrine therapy in the metastatic setting is required; this is
             defined as:

               -  Progressed on prior endocrine therapy in the metastatic setting or,

               -  Relapsed on adjuvant endocrine therapy or,

               -  Relapsed within 12 months of completing adjuvant endocrine therapy or,

               -  If received adjuvant CDK4/6 inhibitor, relapsed at least 2 years after completion
                  of adjuvant CDK4/6 inhibitor

          -  Washout from prior systemic anti-cancer therapy of at least 3 weeks from chemotherapy
             or 5 half-lives from oral endocrine therapy or targeted drugs, and treatment related
             adverse events recovered to grade 1 (except for alopecia) before the start of study
             treatment. Washout from prior radiation therapy of at least 2 weeks before the start
             of the study treatment

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

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

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

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

          -  Hemoglobin >= 8.0 g/dL (no more than 7 days before starting study treatment)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (=< 3 x institutional
             upper limit of normal for patients with Gilbert syndrome) (no more than 7 days before
             starting study treatment)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x institutional upper limit of normal (=< 5 x institutional upper limit of normal
             for patients with liver involvement) (no more than 7 days before starting study
             treatment)

          -  Glomerular filtration rate >= 30 mL/min according to the Modification of Diet in Renal
             Disease (MDRD) abbreviated formula (no more than 7 days before starting study
             treatment)

          -  Lipase =< 1.5 x upper limit of normal (ULN) (no more than 7 days before starting study
             treatment)

          -  International normalized rate (INR) and partial thromboplastin time (PTT) =< 1.5 x ULN
             (except those on anti-coagulation therapy) (no more than 7 days before starting study
             treatment)

          -  Hemoglobin (Hb)A1c =< 8.5% or fasting glucose =< 120 mg/dL on at least 2 occasions
             within 14 days prior to registration if diabetic (no more than 7 days before starting
             study treatment)

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

          -  Patients may be postmenopausal or premenopausal women on or planned to receive
             gonadotropin-releasing hormone (GnRH) agonist

          -  The effects of copanlisib on the developing human fetus are unknown. For this reason
             and because maternal toxicity, developmental toxicity and teratogenic effects have
             been observed in nonclinical studies and PI3K inhibitors as well as other therapeutic
             agents used in this trial are known to be teratogenic, women of child-bearing
             potential and men must agree to use adequate contraception (hormonal or barrier method
             of birth control; abstinence) prior to study entry, for the duration of study
             participation, and for 6 months after the last dose of copanlisib. Should a woman
             become pregnant or suspect she is pregnant while she or her partner is participating
             in this study, she should inform her treating physician immediately. Men treated or
             enrolled on this protocol must also agree to use adequate contraception prior to the
             study, for the duration of study participation, and 6 months after completion of
             copanlisib administration

          -  Ability to understand and willing to sign a written informed consent document (or
             legally authorized representative, if applicable)

          -  Patients with a history of treated brain metastases are allowed in the phase I portion
             of the trial provided there is no disease progression symptomatically and by imaging
             within 28 days prior to registration AND if the patient is off steroids

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

        Exclusion Criteria:

          -  For patients enrolling to the randomized phase 2 portion of the study, prior treatment
             with a CDK4/6 inhibitor or fulvestrant, or a PI3K inhibitor in the metastatic setting
             is not allowed

          -  Patients who have had chemotherapy within 3 weeks or radiotherapy within 2 weeks (6
             weeks for nitrosoureas or mitomycin C) prior to entering the study

          -  Patients who are receiving any other investigational agents

          -  Immunosuppressive therapy is not allowed while on study

          -  Receiving anti-arrhythmic therapy (beta blockers or digoxin are permitted)

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to copanlisib, PI3K inhibitors, or other agents used in study

          -  For the randomized phase 2 portion of the study, patients with brain metastasis or a
             history of brain metastasis are not eligible

               -  For the phase 1 portion of the study, patients with progressive brain metastases
                  should be excluded because of their poor prognosis and because they often develop
                  progressive neurologic dysfunction that would confound the evaluation of
                  neurologic and other adverse events (AEs)

          -  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

               -  It is important to regularly consult a frequently-updated medical reference for a
                  list of drugs to avoid or minimize use of. As part of the enrollment/informed
                  consent procedures, the patient will be counseled on the risk of interactions
                  with other agents, and what to do if new medications need to be prescribed or if
                  the patient is considering a new over-the-counter medicine or herbal product

          -  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)

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

          -  Uncontrolled intercurrent illness, including but not limited to, symptomatic
             congestive heart failure (> New York Heart Association [NYHA] class 2), unstable
             angina pectoris, new-onset angina, uncontrolled hypertension despite optimal medical
             management, seizure disorder requiring medication, or psychiatric illness/social
             situations that would limit compliance with study requirements

          -  Myocardial infarction < 6 months before start of treatment

          -  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

          -  The patient has a personal history of any of the following conditions: syncope of
             cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but
             not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
             cardiac arrest

          -  Proteinuria >= 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

          -  History of bleeding diathesis. Any hemorrhage or bleeding event >= grade 3 within 4
             weeks prior to the start of study medication

          -  History or concurrent condition of interstitial lung disease of any severity and/or
             severely impaired lung function

          -  History of having received an allogeneic bone marrow or organ transplant

          -  Patients with non-healing wound, ulcer, or bone fracture not due to breast cancer

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

          -  Patients with HbA1c > 8.5% at screening

          -  Concurrent diagnosis of pheochromocytoma

          -  Has undergone blood or platelet transfusion < 7 days prior to start of treatment

          -  Pregnant women are excluded from this study because copanlisib is a PI3K inhibitor
             agent with the potential for teratogenic or abortifacient effects. 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. These potential risks may also apply to other
             agents used in this study

          -  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 lab panel.
             Patients positive for hepatitis B surface antigen (HBsAg) and/or hepatitis B core
             antibody (HBcAb) will be eligible if they are negative for HBV DNA, these patients
             should receive prophylactic antiviral therapy. Patients positive for anti-HCV antibody
             will be eligible if they are negative for HCV RNA

          -  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, abemaciclib, and fulvestrant.
             Appropriate studies will be undertaken in patients receiving combination
             antiretroviral therapy when indicated

          -  Patients with history of, or current autoimmune disease are not eligible

          -  History of major surgical resection involving the stomach or small bowel, or
             preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition
             resulting in baseline grade 2 or higher diarrhea
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicity (DLT) (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:DLT will be determined based on the incidence, intensity and duration of adverse events (AEs) that are related to the drug combinations and occur within 28 days of drug administration. The severity of AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. AEs will be summarized by counts and percentages, overall as well as by dose levels and by patient characteristics.

Secondary Outcome Measures

Measure:Objective response rate (ORR) (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:Will be defined as the proportion of response-evaluable patients who achieve complete response (CR) or partial response (PR) and assessed by RECIST 1.1 criteria. Will be estimated with a 95% exact CI and difference between the two arms will be compared by Fisher's exact test. Raw and adjusted odds ratio (OR) will be derived with 95% CI from logistic regression without and with adjustment for patient characteristics.
Measure:Clinical benefit rate
Time Frame:Up to 5 years
Safety Issue:
Description:Will be defined as the proportion of response-evaluable patients who achieve CR or PR or stable disease for at least 6 months and assessed by RECIST 1.1 criteria. Will be estimated with a 95% exact CI and difference between the two arms will be compared by Fisher's exact test. Raw and adjusted OR will be derived with 95% CI from logistic regression without and with adjustment for patient characteristics
Measure:Overall survival
Time Frame:Time of randomization to time of death due to any cause or latest follow-up, whichever earlier, assessed up to 5 years
Safety Issue:
Description:Will be assessed by RECIST 1.1 criteria. Will be estimated by the KM product limit method and survival difference will be compared between the two arms by stratified log rank test. Hazard ratio with 95% CI will be estimated between the two arms from the stratified Cox proportional hazard model, without and with adjustment for patient characteristics.
Measure:Median PFS by PIK3CA/PTEN status
Time Frame:Baseline
Safety Issue:
Description:To investigate the predictive effect of PTEN/PIK3CA mutation, the treatment arms will be compared within the subset of patients with PIK3CA mutation or PTEN mutation, as well as in the subset of patients without these mutations, separately using the KM product limit method. Survival difference will be compared between the two arms by stratified log rank test. Hazard ratio with 95% CI will be estimated between the two arms from the stratified Cox proportional hazard model, without and with adjustment for patient characteristics. The interaction between the gene mutation and the treatment arm will be tested in a Cox proportional hazard model setting. If the interaction effect is not statistically significant, the prognostic effect of the PTEN/PIK3CA gene mutations for survival will be evaluated, PTEN/PIK3CA mutation will be associated with the survival endpoints by the KM method and Cox model among the control arm.
Measure:Median PFS by tumor phosphorylated (p)AKT levels
Time Frame:Baseline
Safety Issue:
Description:pAKT level at baseline will be associated with PFS by Cox proportional hazard model and by KM method in the binary scale dichotomized by median. Within each arm, the measurements at cycle 1, day 15 (C1D15) will be compared to the baseline by paired sample t-test or Wilcoxon signed rank test as appropriate. The percentage change at C1D15 from baseline will be calculated and compared between the FPC arm vs. FP arm by two sample t-test or Wilcoxon rank sum test as appropriate.
Measure:Change in tumor pAKT levels
Time Frame:Baseline up to C1D15
Safety Issue:
Description:Will be associated with PFS by Cox proportional hazard model and by KM method in the binary scale dichotomized by median. Within each arm, the measurements at C1D15 will be compared to the baseline by paired sample t-test or Wilcoxon signed rank test as appropriate. The percentage change at C1D15 from baseline will be calculated and compared between the FPC arm vs. FP arm by two sample t-test or Wilcoxon rank sum test as appropriate.
Measure:Effectiveness of fulvestrant, abemaciclib, and copanlisib (FAC)
Time Frame:Up to 5 years
Safety Issue:
Description:FAC will be evaluated for inhibition of AKT phosphorylation, reduction of cyclin D1, and effectiveness, compared to fulvestrant and abemaciclib, in inhibiting Rb phosphorylation. Balance/imbalance of biomarker distribution between arms will be examined by Fisher's exact test or two sample t-test. Prognostic effect of biomarker for PFS will be examined by the KM method or/and Cox proportional hazard model and for ORR using logistic regression model. Predictive effect of biomarker will be measured along multiple time points, generalized linear mixed effects model will be used to model longitudinal trajectories along time with the inference focus on the arm factor, without and with adjustment for other covariates. Two sample t-test or Wilcoxon rank sum test will be applied to compare time-matched biomarkers between the two arms or two patients' subsets. Paired sample t-test or Wilcoxon signed rank test will be applied to compare subject-specific biomarkers between two time points.

Details

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

Last Updated