Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Copanlisib in Combination With T-DM1 in Pretreated Unresectable Locally Advanced or Metastatic HER2-positive Breast Cancer (Panthera)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04042051
Recruitment Status : Recruiting
First Posted : August 1, 2019
Last Update Posted : November 13, 2019
Sponsor:
Information provided by (Responsible Party):
Cancer Trials Ireland

Brief Summary:

This study is a Phase 1b open label, single arm, adaptive multi-centre trial of copanlisib in combination with trastuzumab emtansine (T-DM1) in pretreated locally advanced or metastatic HER2-positive breast cancer.

Patients with unresectable locally advanced or metastatic HER2-positive breast cancer who previously received trastuzumab and a taxane, separately or in combination, will be treated with copanlisib (to the dose escalation scheme) plus trastuzumab emtansine 3.6mg/kg IV on day 1 of a 21-day cycle.


Condition or disease Intervention/treatment Phase
HER2-positive Breast Cancer Metastatic Breast Cancer Locally Advanced Breast Cancer Unresectable Breast Cancer Drug: Copanlisib Drug: Trastuzumab emtansine Phase 1

Detailed Description:

This study is a phase Ib open label, single arm, adaptive multi-centre trial. Patients with unresectable locally advanced or metastatic HER2-positive breast cancer who previously received trastuzumab and a taxane, separately or in combination, will be treated with copanlisib plus trastuzumab emtansine 3.6mg/kg IV on day 1 of a 21-day cycle.

3 to 6 patients will be enrolled per dose level. All patients in each level must have completed at least the first cycle of therapy before enrolment in the next dose level begins. Patients not completing the first cycle for a reason other than toxicity will be replaced.

Copanlisib will start at a low level and dose escalations will be performed in cohorts of 3 patients according to a standard 3+3 algorithm.

Dose escalation and determination of maximum tolerated dose (MTD) will be based on occurrences of Dose Limiting Toxicities (DLT).

The first cohort of 3 patients will commence at dose level 1. All patients in each cohort will be observed for one cycle on the specified dose:

  • If none of 3 patients at a given dose level experiences a DLT, accrual will continue to the next dose level according to the protocol.
  • If 1 of 3 patients experiences a DLT at a given dose level, 3 additional patients will be treated at the same dose. If no additional patient has a DLT in this cohort, accrual will continue to the next dose level according to the protocol.
  • If 2 or more patients in 3 or 6 patients treated at a given dose experience a DLT, the dose will be de-escalated to the next lower dose level, which will define the MTD.

If 2 or more patients in 3 or 6 patients treated at the -1 dose level experience DLT, the trial will be stopped.

Primary Objective:

1. To determine the Maximum Tolerated Dose (MTD), for copanlisib in combination with trastuzumab emtansine (T-DM1) in patients with pretreated unresectable locally advanced or metastatic HER2-positive breast cancer.

Secondary Objectives:

  1. To evaluate the safety and tolerability of this regimen.
  2. To evaluate efficacy measures in patients treated with this regimen.
  3. To assess the incidence of cardiotoxicity in patients treated with this regimen.

Exploratory Objectives:

  1. To examine for predictive biomarkers in tumour tissue and blood.
  2. To examine molecular tumour adaptation to clinical trial therapy.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib Clinical Trial of Copanlisib in Combination With Trastuzumab Emtansine (T-DM1) in Pretreated Unresectable Locally Advanced or Metastatic HER2-positive Breast Cancer "Panthera"
Actual Study Start Date : November 12, 2019
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : March 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Single Arm
This study is a phase Ib open label, single arm, adaptive multi-centre trial. Patients with unresectable locally advanced or metastatic HER2-positive breast cancer who previously received trastuzumab and a taxane, separately or in combination, will be treated with copanlisib (as assigned at registration according to the dose escalation scheme) plus trastuzumab emtansine 3.6mg/kg IV on day 1 of a 21-day cycle.
Drug: Copanlisib
Copanlisib is supplied as lyophilized preparation in a 6mL injection vial. The total amount of copanlisib per vial is 60mg. The solution for IV infusions is obtained after reconstitution with normal saline solution. Copanlisib will be administered on Days 1 (and 8 and 15 [according to the dose escalation scheme]) of each 21-day cycle. Copanlisib will be administered first over 60 minutes followed by the infusion of trastuzumab emtansine.
Other Name: BAY 80-6946

Drug: Trastuzumab emtansine
Trastuzumab emtansine 3.6mg/kg IV infusion on Day 1 of each 21-day treatment cycle.
Other Name: Kadcyla




Primary Outcome Measures :
  1. To determine the incidence of dose limiting toxicity (DLT) of copanlisib in combination with trastuzumab emtansine within the 1st cycle at each dose level. [ Time Frame: 1.5 years ]

Secondary Outcome Measures :
  1. Clinical Benefit Rate (CBR) is defined as complete response (CR) or partial response (PR) at any time-point on the study; or stable disease (SD) lasting at least 24 weeks based on radiological assessment. [ Time Frame: 1.5-2.5 years ]
  2. Overall Survival (OS). [ Time Frame: 1.5-2.5 years ]
  3. Progression-Free Survival (PFS) assessed according to RECIST criteria version 1.1. [ Time Frame: 1.5-2.5 years ]
  4. Time to Treatment Failure (TTF) is defined as time from registration to discontinuation of therapy or add-on of new anti-cancer therapy for any reason (including death, progression and toxicity). [ Time Frame: 1.5-2.5 years ]
  5. Confirmed tumour response rate as assessed by RECIST criteria version 1.1 [ Time Frame: 1.5-2.5 years ]
  6. Duration of response (DR) as assessed by standard RECIST criteria version 1.1. [ Time Frame: 1.5-2.5 years ]
  7. To evaluate the safety and tolerability of this regimen as measured by incidence of adverse events reported and toxicity evaluation as per the NCI Common Terminology Criteria for Adverse Events (CTCAE version 5.0). [ Time Frame: 1.5-2.5 years ]
  8. To assess the incidence of cardiotoxicity in patients treated with this regimen. [ Time Frame: 1.5-2.5 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent must be provided before any study-specific tests or procedures are performed.
  2. Adult women ≥ 18 years of age.
  3. Histologically confirmed HER2-positive breast cancer:

    • Documented HER2 overexpression by local laboratory defined as a score of 3+ by IHC or a ratio of ≥ 2.0 by ISH.
    • HER2-positive on diagnostic breast biopsy or surgical breast resection sample or metastatic disease site biopsy.
  4. Patient with unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination.
  5. Patient has received prior therapy for locally advanced or metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.
  6. At least one measurable lesion according to RECIST criteria (Version 1.1). Patients with bone only disease are eligible if lesion(s) can be accurately assessed by CT/MRI according to RECIST (Version 1.1).
  7. ECOG performance status ≤ 2.
  8. Life expectancy of at least 3 months.
  9. Availability of fresh tissue and/or archival tumour tissue at screening.
  10. Women of childbearing potential must agree to use a highly effective method of contraception when sexually active. This applies from signing of the informed consent form until at least 7 months after the last study drug administration. The investigator or a designated associate is required to advise the patient how to achieve an adequate birth control. Highly effective contraception is defined in the study as methods that achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include:

    i. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).

    ii. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable and implantable).

    iii. Intrauterine device (IUD). iv. Intrauterine hormone-releasing system (IUS). v. Bilateral tubal occlusion. vi. Successfully vasectomised partner. vii. Sexual abstinence.

    Postmenopausal women defined as follows:

    • Woman 60 years of age or older, OR
    • Woman younger than 60 years of age with spontaneous cessation of menses for at least 12 consecutive months prior to registration, OR
    • Prior bilateral oophorectomy, OR
    • Woman younger than 60 years of age who have had a prior hysterectomy (without bilateral oophorectomy) AND who have an FSH level in the postmenopausal range (or >34.4 IU/L if institutional range is not available).
  11. Adequate baseline laboratory values collected no more than 14 days before starting study treatment:

    • Total bilirubin ≤ 1.5 x ULN (< 3 x ULN for patients with metastatic disease in the liver)
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN (≤ 5 x ULN for patients with liver involvement by breast cancer).
    • Lipase ≤ 1.5 x ULN.
    • Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula. If not on target, this evaluation may be repeated once after at least 24 hours either according to the MDRD abbreviated formula or by 24 hour sampling. If the later result is within acceptable range, it may be used to fulfil the inclusion criteria instead.
    • International normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior underlying coagulopathy disorder. Close monitoring of these patients (Day 15 of Cycle 1 and Day 1 of each cycle) will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.
    • Platelet count ≥ 75 x 109/L. For patients with breast cancer bone marrow infiltration, platelet count ≥ 50 x 109/L.
    • Haemoglobin (Hb) ≥ 8 g/dL.
    • Fasting blood glucose ≤6.0 mmol/L if not diabetic or ≤8.9 mmol/L if diabetic.
    • Absolute neutrophil count (ANC) ≥ 1 x 109/L. For patients with malignant bone marrow infiltration, ANC count ≥ 0.75 x 109/L.
  12. Left ventricular ejection fraction (LVEF), at or above the Institutions lower limit of normal, as determined by ECHO or MUGA.
  13. Patients must have recovered from clinically significant side effects associated with prior radiotherapy and chemotherapy with the exception of fatigue or neuropathy.

Exclusion Criteria:

  1. Known breast cancer involvement of the brain, unless adequately controlled based on the clinical judgement of the treating physician.
  2. Congestive heart failure > New York Heart Association (NYHA) class II.
  3. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before registration.
  4. Uncontrolled arterial hypertension despite optimal medical management (per investigator's opinion).
  5. Uncontrolled Type I or II diabetes mellitus. Defined as HbA1c > 8.5% as determined during screening laboratory assessments.
  6. 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 registration.
  7. Non-healing wound, ulcer, or bone fracture.
  8. Active, clinically serious infections > Grade 2 (CTCAE v5.0).
  9. Known history of human immunodeficiency virus (HIV) infection.
  10. 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 laboratory panel Patients who test positive for Hepatitis B surface Antigen (HBsAg) or Hepatitis B core Antigen (HBcAb) will be eligible if they are negative for HBV-DNA; patients who test positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.
  11. Patients with CMV PCR positive.
  12. Patients with seizure disorder requiring medication.
  13. Patients with evidence or history of bleeding diathesis. Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study treatment.
  14. Proteinuria of Grade 3 or higher (CTCAE v5.0). Patient will be excluded if > 2+ on urinalysis (unless 24 hr collection shows 24 hour urinary protein < 3.5g/24hrs).
  15. History or concurrent condition of interstitial lung disease of any severity, and/or severely impaired lung functions (as judged by the investigator).
  16. Concurrent diagnosis of pheochromocytoma.
  17. Pregnant or breast-feeding patients. Women of childbearing potential must have a serum or urine pregnancy test within 7 days of first dose, and a negative result must be documented before start of treatment.
  18. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia, peripheral neuropathy, and bone marrow parameters.
  19. Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation.
  20. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
  21. Any illness or medical conditions that are unstable or could jeopardise the safety of patients and their compliance in the study.
  22. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.

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): NCT04042051


Contacts
Layout table for location contacts
Contact: Cancer Trials Ireland Dublin 11, Ireland +353 1 6677211 info@cancertrials.ie

Locations
Layout table for location information
Ireland
Cancer Trials Ireland Investigative Site Not yet recruiting
Cork, Ireland
Cancer Trials Ireland Investigative Site Not yet recruiting
Dublin 4, Ireland
Cancer Trials Ireland Investigative Site Recruiting
Dublin 9, Ireland
Spain
Cancer Trials Ireland Investigative Site Not yet recruiting
Seville, Spain
Sponsors and Collaborators
Cancer Trials Ireland
Investigators
Layout table for investigator information
Study Director: Cancer Trials Ireland Dublin 11, Ireland Cancer Trials Ireland

Layout table for additonal information
Responsible Party: Cancer Trials Ireland
ClinicalTrials.gov Identifier: NCT04042051     History of Changes
Other Study ID Numbers: CTRIAL-IE 17-13
First Posted: August 1, 2019    Key Record Dates
Last Update Posted: November 13, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Cancer Trials Ireland:
HER2
HER2-positive
Metastatic
Breast
Cancer
Additional relevant MeSH terms:
Layout table for MeSH terms
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Trastuzumab
Ado-trastuzumab emtansine
Maytansine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action