Clinical Trials /

Testing the Addition of an Anti-cancer Drug, Copanlisib, to the Usual Maintenance Treatment (Trastuzumab and Pertuzumab) After Initial Chemotherapy in a Phase Ib/II Trial for Advanced HER2 Positive Breast Cancer

NCT04108858

Description:

This phase Ib/II trial studies the side effects and best dose of copanlisib when given together with trastuzumab and pertuzumab and to see how well they work after induction treatment in treating patients with HER2 positive stage IV breast cancer with PIK3CA or PTEN mutation. Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Trastuzumab is a form of "targeted therapy" because it works by attaching itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Monoclonal antibodies, such as pertuzumab, may kill tumor cells that are left after chemotherapy. The addition of copanlisib to the usual treatment (trastuzumab and pertuzumab) could shrink the cancer or stabilize it for longer duration as compared to the usual treatment alone.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anti-cancer Drug, Copanlisib, to the Usual Maintenance Treatment (Trastuzumab and Pertuzumab) After Initial Chemotherapy in a Phase Ib/II Trial for Advanced HER2 Positive Breast Cancer
  • Official Title: Phase Ib/II Trial of Copanlisib in Combination With Trastuzumab and Pertuzumab After Induction Treatment of HER2 Positive (HER2+) Metastatic Breast Cancer (MBC) With PIK3CA Mutation or PTEN Mutation

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-06461
  • SECONDARY ID: NCI-2019-06461
  • SECONDARY ID: 10296
  • SECONDARY ID: 10296
  • SECONDARY ID: UM1CA186688
  • NCT ID: NCT04108858

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • ERBB2 Gene Amplification
  • HER2 Positive Breast Carcinoma
  • Metastatic Breast Carcinoma
  • PIK3CA Gene Mutation
  • PTEN Gene Mutation

Interventions

DrugSynonymsArms
CopanlisibBAY 80-6946, PI3K Inhibitor BAY 80-6946Phase I, Phase II Arm I (copanlisib, trastuzumab, pertuzumab)
Pertuzumab2C4, 2C4 Antibody, MoAb 2C4, Monoclonal Antibody 2C4, Omnitarg, Perjeta, rhuMAb2C4, RO4368451Phase I, Phase II Arm I (copanlisib, trastuzumab, pertuzumab)
TrastuzumabABP 980, ALT02, Anti-c-ERB-2, Anti-c-erbB2 Monoclonal Antibody, Anti-ERB-2, Anti-erbB-2, Anti-erbB2 Monoclonal Antibody, Anti-HER2/c-erbB2 Monoclonal Antibody, Anti-p185-HER2, c-erb-2 Monoclonal Antibody, HER2 Monoclonal Antibody, Herceptin, Herceptin Biosimilar PF-05280014, Herceptin Trastuzumab Biosimilar PF-05280014, Herzuma, MoAb HER2, Monoclonal Antibody c-erb-2, Monoclonal Antibody HER2, Ogivri, Ontruzant, PF-05280014, rhuMAb HER2, RO0452317, SB3, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar ALT02, trastuzumab biosimilar EG12014, Trastuzumab Biosimilar HLX02, Trastuzumab Biosimilar PF-05280014, Trastuzumab Biosimilar SB3, Trastuzumab-dkst, Trastuzumab-dttb, Trastuzumab-pkrb, Trastuzumab-QYYP, TrazimeraPhase I, Phase II Arm I (copanlisib, trastuzumab, pertuzumab)

Purpose

This phase Ib/II trial studies the side effects and best dose of copanlisib when given together with trastuzumab and pertuzumab and to see how well ithey work after induction treatment in treating patients with HER2 positive stage IV breast cancer with PIK3CA or PTEN mutation. Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Trastuzumab is a form of "targeted therapy" because it works by attaching itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Monoclonal antibodies, such as pertuzumab, may kill tumor cells that are left after chemotherapy. The addition of copanlisib to the usual treatment (trastuzumab and pertuzumab) could shrink the cancer or stabilize it for longer duration as compared to the usual treatment alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and recommended phase 2 dose (RP2D) of the combination of
      copanlisib, trastuzumab and pertuzumab in patients with metastatic epidermal growth factor
      receptor 2 (HER2)-positive breast cancer. (Phase Ib) II. To assess the benefit of adding
      copanlisib to trastuzumab and pertuzumab in HER2-positive metastatic breast cancer patients
      with PIK3CA mutations or PTEN mutation receiving maintenance therapy after induction
      treatment, as measured by progression free survival (PFS). (Phase II)

      SECONDARY OBJECTIVES:

      I. To assess the benefit of adding copanlisib to trastuzumab and pertuzumab in HER2-positive
      metastatic breast cancer patients with PIK3CA mutations or PTEN mutation receiving
      maintenance therapy after induction treatment, as measured by overall survival (OS). (Phase
      II) II. To evaluate the safety of copanlisib given at the RP2D in combination with
      trastuzumab and pertuzumab. (Phase II)

      EXPLORATORY OBJECTIVES:

      I. To correlate PFS and OS of the patients who receive the triplet combination with:

      Ia. The number of induction cycles. Ib. Hormone receptor status (ER and PR). Ic. PTEN loss.
      Id. PIK3CA mutations or PTEN mutations. (Phase Ib)

      II. To assess PTEN immunohistochemistry (IHC), Ki-67 IHC and cleaved caspase-3 IHC and to
      perform molecular profiling assays on malignant and normal tissues, including, but not
      limited to, whole exome sequencing (WES) and messenger ribonucleic acid (RNA) sequencing
      (RNAseq), in order to:

      IIa. Identify potential predictive and prognostic biomarkers associated with treatment
      outcomes (PFS and OS) with the addition of copanlisib to dual HER2-targeted treatment.

      IIb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based
      assessment platforms.

      III. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
      Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
      and future research; specimens will be annotated with key clinical data, including
      presentation, diagnosis, staging, summary treatment, and if possible, outcome.

      IV. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA
      analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical
      Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.

      OUTLINE:

      PHASE I: Patients receive copanlisib intravenously (IV) over 60 minutes on days 1 and 8.
      Patients also receive trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60 minutes
      on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable
      toxicity.

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

      ARM I: Patients receive copanlisib IV over 60 minutes on days 1 and 8. Patients also receive
      trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60 minutes on day 1. Cycles
      repeat every 21 days in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60
      minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up within 30 days and at 3 months.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I, Phase II Arm I (copanlisib, trastuzumab, pertuzumab)ExperimentalPatients receive copanlisib IV over 60 minutes on days 1 and 8. Patients also receive trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Copanlisib
  • Pertuzumab
  • Trastuzumab
Phase II Arm II (trastuzumab, pertuzumab)Active ComparatorPatients receive trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Pertuzumab
  • Trastuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  PHASE IB/SAFETY RUN-IN ONLY: Molecular biomarker selection will not be mandated

          -  PHASE IB/SAFETY RUN-IN ONLY: Patients will be enrolled after completion of induction
             chemotherapy with any taxane, trastuzumab and pertuzumab; or after progression on any
             prior treatment. The last dose of prior treatment should be at least 3 weeks before
             the start of the trial

          -  PHASE II ONLY: Presence of actionable mutation in either PIK3CA gene or PTEN gene on
             molecular testing, in primary or metastatic tumor at Clinical Laboratory Improvement
             Act (CLIA) certified laboratory. Results of molecular testing will be reviewed to
             confirm eligibility by MD Anderson Precision Oncology Decision Support team and
             captured in patient's record

          -  PHASE II ONLY: Patients must be within 8 weeks of completion of first-line induction
             chemotherapy (i.e., 4-8 cycles of any taxane, trastuzumab and pertuzumab) without
             evidence of progression. Patients may receive up to 2 doses of HER2 targeted treatment
             between end of induction treatment and start of trial, while eligibility is being
             confirmed

          -  Clinical stage IV as assessed by American Joint Committee on Cancer (AJCC) (8th
             edition, anatomic staging) guidelines with known metastatic disease (Edge and Compton,
             2010; Amin et al., 2017)

          -  HER2+ breast cancer as assessed by the American Society of Clinical Oncology
             (ASCO)-College of American Pathologists (ASCO-CAP) guidelines (Wolff et al., 2013;
             Wolff et al., 2018). HER2 testing of metastasis will be required. Positive HER2 test
             result is defined as:

               -  IHC 3+ based on circumferential membrane staining that is complete, intense

               -  In situ hybridization (ISH) positive based on:

                    -  Single-probe average HER2 copy number >= 6.0 signals/cell

                    -  Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number >= 4.0
                       signals/cell

                    -  Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number < 4.0
                       signals/cell unless HER2 by immunohistochemistry (IHC) is 2+ or less

                    -  Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0
                       signals/cell

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count (ANC) >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 9 g/dL

          -  Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram or multigated
             acquisition scan (MUGA)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) OR direct bilirubin
             =< ULN for subjects with total bilirubin levels > 1.5 x ULN

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN OR =< 5 x ULN for subjects with liver metastases

          -  Creatinine =< 1.5 x institutional ULN OR measured or calculated creatinine clearance
             >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (glomerular
             filtration rate [GFR] can also be used in place of creatinine or creatinine clearance
             [CrCl]). Creatinine clearance should be calculated per institutional standard

          -  International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless
             patient is receiving anticoagulation as long as PT or partial thromboplastin time
             (PTT) is within therapeutic range of intended use of anticoagulants

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving
             anticoagulation as long as PT or PTT is within therapeutic range of intended use of
             anticoagulants

          -  Patients with treated brain metastases are eligible if follow-up brain imaging 30 days
             after central nervous system (CNS)-directed therapy shows no evidence of progression

          -  Patients who are therapeutically treated with anticoagulation including warfarin will
             be allowed to participate provided that their medication dose and INR/PTT is stable.
             Due to interaction of copanlisib with warfarin, patients who are on warfarin should be
             monitored closely while on this trial

          -  Women of child-bearing potential MUST have a negative serum or urine human chorionic
             gonadotropin (HCG) test unless prior tubal ligation (>= 1 year before screening),
             total hysterectomy or menopause (defined as 12 consecutive months of amenorrhea).
             Patients should not become pregnant or breastfeed while on this study

          -  Patients and their partners, if sexually active and of childbearing potential, must
             agree to the use of two highly effective forms of contraception in combination
             throughout the period of taking study treatment and for 7 months after last dose of
             study drug(s) to prevent pregnancy in the study patient or partner

          -  Hormone receptor positive breast cancer patients will be allowed to continue endocrine
             therapy as indicated while participating in this clinical trial

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Known active hepatitis B or hepatitis C infection. All patients must be screened for
             hepatitis B virus (HBV) and hepatitis C virus (HCV) up to 28 days prior to study drug
             start using the routine hepatitis virus lab panel. For patients with evidence of
             chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on
             non-CYP3A4-interactive suppressive therapy, if indicated. Patients with a history of
             hepatitis C virus (HCV) infection must have been treated and cured. Patients positive
             for anti-HCV antibody will be eligible if they are negative for HCV RNA

          -  Human immunodeficiency virus (HIV)-positive patients, unless they have CD4 counts >
             500 cells/mm^3 in the past 6 months and do not require CYP3A4-interactive
             antiretroviral therapy

          -  Active infection requiring IV antibiotics or other uncontrolled intercurrent illness
             requiring hospitalization

          -  Inability to comply with the study and follow-up procedures

          -  History of cerebrovascular accident (CVA), myocardial infarction, symptomatic
             congestive heart failure, cardiac arrhythmia, or unstable angina within the previous 6
             months before starting therapy

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > grade 1) with the following exceptions: alopecia
             (any grade is acceptable); neuropathy must have resolved to =< grade 2. Congestive
             heart failure (CHF) due to prior anti-cancer therapy must have been =< grade 1 in
             severity at the time of occurrence, and must have resolved completely

          -  Current uncontrolled hypertension (>= 150/90)

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer

          -  Has a known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Patients with uncontrolled type I or II diabetes mellitus (DM); uncontrolled DM is
             defined as glycosylated hemoglobin (HbA1c) > 8.5% and a fasting blood glucose of > 120
             mg/dL within 14 days prior to trial entry

          -  Immunosuppressive therapy is not allowed while on study

          -  Patients who are receiving any other investigational agents

          -  Patients with leptomeningeal disease or active untreated brain metastases

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to copanlisib, PI3K inhibitors, or HER2 inhibitors

          -  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

               -  Because the lists of these agents are constantly changing, 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

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events and serious adverse events (Phase Ib)
Time Frame:Up to 3 months
Safety Issue:
Description:The descriptions and grading scales found in the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event (AE) reporting.

Secondary Outcome Measures

Measure:PFS (Phase Ib)
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 months
Safety Issue:
Description:
Measure:Overall survival (OS) (Phase Ib)
Time Frame:Up to 3 months
Safety Issue:
Description:Will use the Kaplan-Meier method to estimate OS.
Measure:OS (Phase II)
Time Frame:Up to 3 months
Safety Issue:
Description:Will use the Kaplan-Meier method to estimate OS.
Measure:Incidence of adverse events and serious adverse events (Phase II)
Time Frame:Up to 3 months
Safety Issue:
Description:The descriptions and grading scales found in the revised NCI CTCAE version 5.0 will be utilized for AE reporting.

Details

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

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