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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

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ClinicalTrials.gov Identifier: NCT04108858
Recruitment Status : Recruiting
First Posted : September 30, 2019
Last Update Posted : June 21, 2022
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Anatomic Stage IV Breast Cancer AJCC v8 HER2-Positive Breast Carcinoma Metastatic Breast Carcinoma Drug: Copanlisib Biological: Pertuzumab Biological: Trastuzumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 6, 2019
Estimated Primary Completion Date : June 30, 2022
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Phase I, Phase II Arm I (copanlisib, trastuzumab, pertuzumab)
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.
Drug: Copanlisib
Given IV

Biological: Pertuzumab
Given IV

Biological: Trastuzumab
Given IV

Active Comparator: Phase II Arm II (trastuzumab, pertuzumab)
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.
Biological: Pertuzumab
Given IV

Biological: Trastuzumab
Given IV




Primary Outcome Measures :
  1. Incidence of adverse events and serious adverse events (Phase Ib) [ Time Frame: Up to 3 months ]
    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.

  2. Incidence of dose limiting toxicities (DLTs) (Phase Ib) [ Time Frame: Up to 3 months ]
    Will measure the incidence of DLTs to determine recommended phase 2 dose. Will tabulate the toxicity data by grade, severity and dose level.

  3. Progression-free survival (PFS) (Phase II) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 months ]
    The statistical test for the primary analysis will be the partial likelihood ratio test of a stratified Cox PH model with treatment group as a covariate.


Secondary Outcome Measures :
  1. PFS (Phase Ib) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 months ]
  2. Overall survival (OS) (Phase Ib) [ Time Frame: Up to 3 months ]
    Will use the Kaplan-Meier method to estimate OS.

  3. OS (Phase II) [ Time Frame: Up to 3 months ]
    Will use the Kaplan-Meier method to estimate OS.

  4. Incidence of adverse events and serious adverse events (Phase II) [ Time Frame: Up to 3 months ]
    The descriptions and grading scales found in the revised NCI CTCAE version 5.0 will be utilized for AE reporting. Will tabulate the toxicity data by grade, severity and dose level.


Other Outcome Measures:
  1. Number of induction cycles (Phase II) [ Time Frame: Up to 3 months ]
    Will correlate PFS and OS with number of induction cycles. Will assess the extent to which treatment effects (measured as hazard ratio for time to progression and odds ratio for response) depend on number of induction cycles (using product terms in logistic and Cox PH regression models).

  2. Hormone receptor (HR) status (estrogen receptor [ER] and progesterone receptor [PR]) (Phase II) [ Time Frame: Up to 3 months ]
    Will correlate PFS and OS with hormone receptor status (ER and PR). Will assess the extent to which treatment effects (measured as hazard ratio for time to progression and odds ratio for response) depend on HR status (using product terms in logistic and Cox PH regression models).

  3. Molecular alteration analysis (Phase II) [ Time Frame: Up to 3 months ]
    Will correlate PFS and OS with molecular alterations identified through whole exome sequencing and ribonucleic acid sequencing in tumor tissue, as well as circulating tumor deoxyribonucleic acid analysis.

  4. Change in expression of pharmacodynamics markers downstream of PI3K inhibition (Phase II) [ Time Frame: Baseline up to 3 months ]
    Will correlate PFS and OS with change in expression of pharmacodynamics markers downstream of PI3K inhibition.

  5. Change in expression of genes involved in alternate signaling pathways identified through reverse phase protein array (RPPA) (Phase II) [ Time Frame: Baseline up to 3 months ]
    Will correlate PFS and OS with change in expression of genes involved in alternate signaling pathways identified through RPPA.



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

Inclusion Criteria:

  • Phase 1B: Any prior number of lines of therapy in metastatic setting is allowed, provided patients are considered candidates for trastuzumab and pertuzumab combination or on maintenance trastuzumab and pertuzumab (with or without prior chemotherapy) as long as dose limiting toxicity (DLT) can be determined. For Phase 2:Patients should have only received first line of induction chemotherapy (taxane) with trastuzumab and pertuzumab in the metastatic setting
  • Presence of actionable mutation in either PIK3CA or PTEN on molecular testing
  • For Phase 2-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 patients with any ER/PR status 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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
  • 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 (ER+ and / PR+) breast cancer patients will be allowed to continue endocrine therapy as clinically indicated while participating in the study.
  • 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 ribonucleic acid (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
  • Prior exposure to any PI3K, AKT or mTOR inhibitors. 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
  • Patients are eligible to receive standard of care therapy that would confer clinical benefit to the patient

Information from the National Library of Medicine

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

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04108858


Locations
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United States, California
Los Angeles County-USC Medical Center Recruiting
Los Angeles, California, United States, 90033
Contact: Site Public Contact    323-865-0451      
Principal Investigator: Irene Kang         
USC / Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Site Public Contact    323-865-0451      
Principal Investigator: Irene Kang         
United States, Colorado
University of Colorado Hospital Active, not recruiting
Aurora, Colorado, United States, 80045
United States, Oklahoma
University of Oklahoma Health Sciences Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Site Public Contact    405-271-8777    ou-clinical-trials@ouhsc.edu   
Principal Investigator: Wajeeha Razaq         
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Site Public Contact    877-632-6789    askmdanderson@mdanderson.org   
Principal Investigator: Senthilkumar Damodaran         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Senthilkumar Damodaran University of Texas MD Anderson Cancer Center LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04108858    
Other Study ID Numbers: NCI-2019-06461
NCI-2019-06461 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MDACC# 2020-0260
10296 ( Other Identifier: University of Texas MD Anderson Cancer Center LAO )
10296 ( Other Identifier: CTEP )
UM1CA186688 ( U.S. NIH Grant/Contract )
First Posted: September 30, 2019    Key Record Dates
Last Update Posted: June 21, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Trastuzumab
Pertuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents