Clinical Trials /

Testing the Addition of Copanlisib to Eribulin for the Treatment of Advanced-Stage Triple Negative Breast Cancer

NCT04345913

Description:

This phase I/II trial studies the side effects and best dose of copanlisib and how well it works when given together with eribulin in treating patients with triple negative breast cancer that has spread to other places in the body (advanced stage). Copanlisib stops the growth of a protein called PI3K, which is often changed in tumor cells and causes resistance to treatment. Chemotherapy drugs, such as eribulin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving copanlisib and eribulin may work better in treating advanced stage triple negative breast cancer compared to eribulin alone.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of Copanlisib to Eribulin for the Treatment of Advanced-Stage Triple Negative Breast Cancer
  • Official Title: A Phase I/II Trial Evaluating the Safety and Efficacy of Eribulin in Combination With Copanlisib in Patients With Metastatic Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-02319
  • SECONDARY ID: NCI-2020-02319
  • SECONDARY ID: 10382
  • SECONDARY ID: 10382
  • SECONDARY ID: UM1CA186704
  • NCT ID: NCT04345913

Conditions

  • Anatomic Stage III Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • Anatomic Stage IIIB Breast Cancer AJCC v8
  • Anatomic Stage IIIC Breast Cancer AJCC v8
  • Anatomic Stage IV Breast Cancer AJCC v8
  • Metastatic Breast Carcinoma
  • Prognostic Stage III Breast Cancer AJCC v8
  • Prognostic Stage IIIA Breast Cancer AJCC v8
  • Prognostic Stage IIIB Breast Cancer AJCC v8
  • Prognostic Stage IIIC Breast Cancer AJCC v8
  • Prognostic Stage IV Breast Cancer AJCC v8
  • Triple-Negative Breast Carcinoma
  • Unresectable Breast Carcinoma

Interventions

DrugSynonymsArms
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 DihydrochloridePhase I (eribulin, copanlisib)
Eribulin MesylateB1939 Mesylate, E7389, ER-086526, Halaven, Halichondrin B AnalogPhase I (eribulin, copanlisib)

Purpose

This phase I/II trial studies the side effects and best dose of copanlisib and how well it works when given together with eribulin in treating patients with triple negative breast cancer that has spread to other places in the body (advanced stage). Copanlisib stops the growth of a protein called PI3K, which is often changed in tumor cells and causes resistance to treatment. Chemotherapy drugs, such as eribulin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving copanlisib and eribulin may work better in treating advanced stage triple negative breast cancer compared to eribulin alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety, toxicity profile, dose limiting toxicity (DLT), maximum tolerated
      dose (MTD) and recommended phase 2 dose (RP2D) of copanlisib hydrochloride (copanlisib) in
      combination with eribulin mesylate (eribulin) in metastatic triple negative breast cancer
      (TNBC). (Phase I) II. To compare progression free survival (PFS) between eribulin and
      eribulin plus copanlisib arms in patients with metastatic TNBC treated with prior taxane and
      anthracycline. (Phase II)

      SECONDARY OBJECTIVES:

      I. To determine the objective response rate (ORR) and clinical benefit rate (CBR) of the
      combination. (Phase I) II. To observe and record anti-tumor activity. (Phase I) III. To
      compare the ORR, CBR (complete response [CR]+partial response [PR]+stable disease [SD] >= 24
      weeks) and safety of eribulin and eribulin plus copanlisib arms. (Phase II) IV. To compare
      the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors
      harboring mutations in PIK3CA/ PTEN or with loss of PTEN expression by immunohistochemistry
      (IHC) on baseline tumor biopsy. (Phase II) V. To compare the ORR, CBR, PFS of eribulin and
      eribulin plus copanlisib arms in patients with tumors lacking PIK3CA/ PTEN pathway
      alterations. (Phase II) VI. To compare the ORR, CBR, PFS of eribulin and eribulin plus
      copanlisib arms in patients with tumors harboring loss of PTEN expression by IHC in
      pre-treatment metastatic site (in patients with available tissue from metastatic site).
      (Phase II) VII. To compare PTEN IHC results between paired archival primary tumor vs.
      baseline tumor biopsies. (Phase II) VIII. To assess targeted inhibition by copanlisib and
      eribulin by measuring treatment induced changes in phosphorylated (phospho)-AKT (T308),
      phospho-AKT (S473), phospho-histone H3, and inhibition of apoptosis (cleaved caspase 3)
      between post-treatment tumor (C2D1-2) versus baseline. (Phase II) IX. To compare the ORR,
      CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors harboring
      mutations in PIK3CA/PTEN by circulating tumor-derived deoxyribonucleic acid (ctDNA) at
      baseline, and potential changes over time. (Phase II)

      EXPLORATORY OBJECTIVES:

      I. To compare PTEN IHC results between paired baseline tumor biopsy versus at time of disease
      progression.

      II. Assess baseline (pre-treatment) tumor tissue mutation or gene expression profiles to
      correlate treatment response.

      III. Assess intrinsic and adaptive resistance mechanisms by analyzing pre and post treatment
      biopsies for gene expression and proteomic changes.

      IV. Determine circulating tumor DNA (ctDNA) mutation profiles at baseline and changes in
      mutation profile and variant allele frequencies (VAFs) on cycle 2 day 1 (C2D1) and at disease
      progression compared to baseline to correlate with treatment response.

      V. Assess circulating biomarkers predictive of treatment response. VI. Assess plasma and
      serum proteomics and metabolomics predictive of treatment response.

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

      PHASE I: Patients receive copanlisib intravenously (IV) over 60 minutes and eribulin IV over
      2-5 minutes on days 1 and 15 or days 1 and 8. Cycles repeat every 21 or 28 days in the
      absence of disease progression or unacceptable toxicity.

      PHASE II. Patients are randomized to 1 of 2 groups.

      GROUP I: Patients receive eribulin IV over 2-5 minutes on days 1 and 8. Cycles repeat every
      21 days in the absence of disease progression or unacceptable toxicity.

      GROUP II: Patients receive copanlisib IV over 60 minutes on days 1 and 8 and eribulin IV over
      2-5 minutes on days 1 and 8 or days 1 and 15. Cycles repeat every 21 or 28 days in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I (eribulin, copanlisib)ExperimentalPatients receive copanlisib IV over 60 minutes and eribulin IV over 2-5 minutes on days 1 and 15 or days 1 and 8. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.
  • Copanlisib Hydrochloride
  • Eribulin Mesylate
Phase II, Group I (eribulin)Active ComparatorPatients receive eribulin IV over 2-5 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Eribulin Mesylate
Phase II, Group II (eribulin, copanlisib)ExperimentalPatients receive copanlisib IV over 60 minutes on days 1 and 8 and eribulin IV over 2-5 minutes on days 1 and 8 or days 1 and 15. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.
  • Copanlisib Hydrochloride
  • Eribulin Mesylate

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have metastatic or unresectable carcinoma of the breast that is estrogen
             receptor (ER) negative (less than 10%), progesterone receptor (PR) negative (less than
             10%), and HER2 negative/unamplified

          -  Patients must have had prior treatment with an anthracycline and taxane, unless
             contraindicated

          -  Patients must have progressed on at least one and not more than five prior
             chemotherapy regimens, including in the neoadjuvant, adjuvant, and metastatic settings

          -  All patients must agree to provide archival tumor material (most recent archival tumor
             tissue immediately prior to enrollment is strongly preferred) 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 PTEN and PIK3CA analysis

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 8.0 g/dL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (=< 3 x
             institutional ULN for patients with Gilbert syndrome)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) /
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
             institutional ULN

          -  Lipase =< 1.5 x ULN

          -  Creatinine < 1.5 mg/dL AND glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2

          -  Partial thromboplastin time (PTT) =< 1.5 x ULN

          -  International normalized ratio (INR) =< 1.5 x ULN

          -  Patients with history of known type I or type II diabetes must have a fasting glucose
             level of < 120 mg/dL on at least 2 separate occasions or glycosylated hemoglobin
             measurement (HbA1c) < 8.5% at screening within 14 days prior to registration

          -  Patients who are therapeutically treated with an agent such as warfarin or heparin
             will be allowed to participate provided that their medication dose and INR/PTT is
             stable

          -  Prophylactic antiemetics may be administered according to standard practice. The
             routine use of standard antiemetics, including 5-HT3 blockers, such as granisetron,
             ondansetron, or an equivalent agent, is allowed as needed, as long as corrected QT
             (QTc) interval on baseline electrocardiogram (ECG) < 480 msec. The use of
             corticosteroids as antiemetics prior to copanlisib administration will not be allowed

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

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial
             provided they are on a stable regimen of anti-retroviral therapy (ART) with no
             medications otherwise prohibited by this protocol (e.g. drug-drug interactions)

          -  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 treated brain metastases are eligible if follow-up brain imaging after
             central nervous system (CNS)-directed therapy shows no evidence of progression. For
             patients with history of treated brain metastases, brain scans will be performed
             within 6 weeks of study enrollment. During study enrollment in the phase 2 portion of
             the study, brain MRI will be performed every 12 weeks or sooner if
             clinically-indicated in all patients with history of known brain metastases

          -  For phase 1 portion of the study only: patients with new or progressive brain
             metastases (active brain metastases) or leptomeningeal disease are eligible if the
             treating physician determines that immediate CNS specific treatment is not required
             and is unlikely to be required during the first cycle of therapy. This is not allowed
             for phase 2 portion of the study

          -  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

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class 2B or better. Patients with history
             of known congestive heart failure (left ventricular ejection fraction [LVEF] < 50%)
             must have documented LVEF >= 50% within 12 months of study enrollment

          -  Patients must have archival tissue available for research

          -  Known mutation status for PIK3CA and PTEN from archival tumor tissue analysis

          -  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 must agree to use adequate contraception (hormonal or barrier method of
             birth control; abstinence) prior to study entry and for the duration of study
             participation, and for 1 month after the last dose of study medication. 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 3.5 months after completion of
             study treatment

          -  Ability to understand and the willingness to sign a written informed consent document.
             Participants with impaired decision-making capacity (IDMC) who have a
             legally-authorized representative (LAR) and/or family member available will also be
             eligible

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 3 weeks

          -  Patients who have had prior treatment with nitrosoureas or mitomycin C

          -  Patients who have had prior treatment with eribulin

          -  Patients who have had prior treatment with PI3K/mTOR/AKT pathway inhibitor

          -  Clinically significant ECG abnormality, including prolonged corrected QT (QTc)
             interval > 480 msec or history of risk factors for Torsades de Pointes (TdP) (i.e.
             congestive heart failure, hypokalemia, hypomagnesemia, bradyarrhythmias, family
             history of long QT syndrome)

          -  Patients with pre-existing neuropathy of grade 2 or higher

          -  Myeloid growth factors within 14 days prior to treatment start

          -  Platelet transfusion within 7 days prior to treatment start

          -  Patients 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

          -  Patients who are receiving any other investigational agents

          -  Immunosuppressive therapy is not allowed while on study

          -  Known tumor AKT mutation from archival tumor tissue analysis

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

          -  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/magnetic resonance imaging (CT/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

          -  Patients with uncontrolled intercurrent illness

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

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

          -  Patients with active, clinically serious infections > grade 2 (Common Terminology
             Criteria for Adverse Events Version 5.0 [CTCAEv5.0]) (viral, bacterial or fungal
             infection)

          -  History of known Pneumocystis jiroveci pneumonia (PJP) infection

          -  Patients with 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

          -  Concurrent diagnosis of pheochromocytoma due to risk of hypertension with copanlisib

          -  Uncontrolled hypertension (defined as blood pressure >= 150/90 mm/Hg) despite optimal
             medical management (per investigator's opinion)

          -  Proteinuria estimated by urine protein/creatinine ratio > 3.5 on random urine sample

          -  Patients with history of or current autoimmune disease

          -  Patients with congenital QT prolongation

          -  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

          -  Pregnant women are excluded from this study because copanlisib is a PI3K inhibitor
             agent and eribulin is an anti-tubulin 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 and
             eribulin, breastfeeding should be discontinued if the mother is treated with
             copanlisib and/or eribulin. 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:Maximum tolerated dose (MTD) (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:The maximum tolerated dose (MTD) is defined as the highest dose level at which at most 1 of 6 patients experience a dose limiting toxicity (DLT) during the observation window.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR) (Phase I)
Time Frame:Up to 3 years
Safety Issue:
Description:The objective response rate (ORR) is defined as the proportion of patients with complete response, partial response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Measure:Clinical benefit rate (CBR) (Phase I)
Time Frame:Up to 3 years
Safety Issue:
Description:CBR defined as the proportion of patients with toxicity in each arm, in the overall population, and by PTEN/PIK3CA mutation status based on archival tumor tissue next generation sequencing.
Measure:PFS (Phase I)
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years
Safety Issue:
Description:PFS is defined from date of treatment start to date of progression or death. Patients who have not experienced progression or death will be censored at last follow up.
Measure:ORR (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:Measured in the overall population by treatment arm; by treatment arm in patients with triple negative breast cancer (TNBC) harboring mutations in PIK3CA/ PTEN or loss of PTEN expression by immunohistochemistry (IHC) of baseline (pre-treatment) biopsy; and by treatment arm in patients with TNBC harboring mutations in PIK3CA/ PTEN by circulating tumor deoxyribonucleic acid (ctDNA) at baseline (pre-treatment) biopsy and potential changes over time.
Measure:CBR (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:Measured in the overall population by treatment arm, in patients with TNBC harboring mutations in PIK3CA/ PTEN or loss of PTEN expression by IHC of baseline (pre-treatment) biopsy, by treatment arm in patients with TNBC harboring mutations in PIK3CA/ PTEN by ctDNA at baseline (pre-treatment) biopsy and potential changes over time.
Measure:PFS (Phase II)
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years
Safety Issue:
Description:Measured by treatment arm in patients with TNBC harboring mutations in PIK3CA/ PTEN or loss of PTEN expression by IHC of baseline (pre-treatment) biopsy and by treatment arm in patients with TNBC harboring mutations in PIK3CA/ PTEN by ctDNA at baseline (pre-treatment) biopsy and potential changes over time. PFS will be estimated using the Kaplan-Meier product limit estimator.
Measure:Target inhibition of PI3K pathway and mitotic arrest
Time Frame:Up to 3 years
Safety Issue:
Description:Using phospho-AKT and phospho-histone H3 with eribulin plus copanlisib versus eribulin alone.

Details

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

Last Updated

April 14, 2020