Clinical Trials /

Phase Ib/II Trial of coPANlisib in Combination With Trastuzumab in HER2-positive Breast Cancer. (Panther Study)

NCT02705859

Description:

This study is a Phase Ib/II open label, single arm, adaptive multi-centre trial of copanlisib in combination with trastuzumab in pretreated recurrent or metastatic HER2-positive breast cancer. Patients with HER2 positive, metastatic or incurable recurrent breast cancer, following disease progression during, or after, treatment with at least one systemic treatment regimen in the metastatic or recurrent setting, will be treated with copanlisib (at 30, 45 or 60 mg flat dosing IV weekly - depending on the maximum tolerated dose (MTD) determined in the Phase Ib part of the study) plus trastuzumab (4 mg/kg IV Cycle 1 Day 1 and then 2 mg/kg IV weekly starting from day 8).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase Ib/II Trial of coPANlisib in Combination With Trastuzumab in HER2-positive Breast Cancer. (Panther Study)
  • Official Title: Phase Ib/II Clinical Trial of Copanlisib in Combination With Trastuzumab in Pretreated Recurrent or Metastatic HER2-positive Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: ICORG 15-02
  • NCT ID: NCT02705859

Conditions

  • HER2 Positive Breast Cancer

Interventions

DrugSynonymsArms
CopanlisibBAY80-6946Single Arm
TrastuzumabHerceptinSingle Arm

Purpose

This study is a Phase Ib/II open label, single arm, adaptive multi-centre trial of copanlisib in combination with trastuzumab in pretreated recurrent or metastatic HER2-positive breast cancer. Patients with HER2 positive, metastatic or incurable recurrent breast cancer, following disease progression during, or after, treatment with at least one systemic treatment regimen in the metastatic or recurrent setting, will be treated with copanlisib (at 30, 45 or 60 mg flat dosing IV weekly - depending on the maximum tolerated dose (MTD) determined in the Phase Ib part of the study) plus trastuzumab (4 mg/kg IV Cycle 1 Day 1 and then 2 mg/kg IV weekly starting from day 8).

Detailed Description

      Phase Ib One of three dose levels of copanlisib is assigned at registration according to the
      dose escalation scheme.

      Phase II The copanlisib dose for the Phase II part of the trial will be based on the MTD
      established in the Phase Ib part of the study.

      Clinical and laboratory parameters will be assessed to evaluate disease response and toxicity
      of study therapy.

      Safety assessments will be performed throughout the study.

      Efficacy assessments (radiological examination) will be performed on all patients every 8
      weeks for the first 24 weeks and every 12 weeks thereafter.

      Following baseline cardiac assessment, cardiac safety monitoring will include physical exam
      (with New York Heart Association (NYHA) functional classification for patients with diagnosed
      congestive heart failure) during each cycle, Multigated acquisition (MUGA) scan or
      Echocardiogram (ECHO) and 12 lead Electrocardiogram (ECG) within 7 days of Day 1 of every
      third cycle starting at cycle 3 (Cycle 3, Cycle 6, etc.).
    

Trial Arms

NameTypeDescriptionInterventions
Single ArmOtherThis study is a Phase Ib/II open label, single arm, adaptive multi-centre trial. Patients with HER2-positive, metastatic or incurable recurrent breast cancer, following disease progression during, or after, treatment with at least one systemic treatment regimen in the metastatic or recurrent setting, will be treated with copanlisib (at 30, 45 or 60 mg flat dosing IV weekly - depending on the maximum tolerated dose (MTD) determined in the Phase Ib part of the study) plus trastuzumab (4 mg/kg IV Cycle 1 Day 1 and then 2 mg/kg IV weekly starting from day 8).
  • Copanlisib
  • Trastuzumab

Eligibility Criteria

        Inclusion Criteria:

        Patients are eligible to be included in the study only if they meet all of the following
        criteria:

          1. Adult women ≥18 years of age with histologically confirmed, recurrent, or metastatic,
             HER2-positive breast cancer.

             Eligible recurrent disease is recurrent disease that is considered incurable by the
             treating oncologist. Many local only recurrences are treated with curative intent; a
             treatment plan with curative intent for a local only recurrence would indicate that
             the patient is not eligible for this clinical trial. A local only recurrence must be
             considered incurable by the treating oncologist for the patient to be eligible.

          2. Documented HER2 overexpression by local laboratory (IHC 3+ or FISH or CISH positive).

          3. At least one measurable lesion according to RECIST criteria (Version 1.1). Patients
             with bone only disease are not eligible.

          4. Patient has received at least one trastuzumab based or TDM1-based treatment regimen in
             the setting of metastatic disease or incurable locoregional recurrence. A trastuzumab
             based or TDM1-based treatment regimen is considered as any treatment regimen that
             includes trastuzumab or TDM1.

             Patients must have had at least 1 line of therapy for metastatic and/or incurable
             locoregional recurrent disease to be eligible. A patient is eligible regardless of the
             period of time from adjuvant therapy so long as she has disease that is progressing
             after at least 1 line of trastuzumab-based therapy in the setting of metastatic
             disease and/or incurable locoregional recurrence.

          5. Disease progression during or following the most recent anticancer therapy.

          6. ECOG performance status ≤2.

          7. Life expectancy of at least 3 months.

          8. Availability of fresh tissue and/or archival tumour tissue at screening.

          9. 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 100 days 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: combined (oestrogen and progestogen
             containing) hormonal contraception associated with inhibition of ovulation (oral,
             intravaginal, transdermal) progestogen only hormonal contraception associated with
             inhibition of ovulation (oral, injectable and implantable), intrauterine device (IUD),
             intrauterine hormone releasing system (IUS), bilateral tubal occlusion, successfully
             vasectomised partner and sexual abstinence. In addition, the use of condoms by
             patients or their partners is required unless the woman has had a hysterectomy.

         10. 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 liver involvement). Alanine
             aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN for
             patients with liver involvement from breast cancer).

             Lipase ≤1.5 x ULN. Glomerular filtration rate (GFR) ≥30 mL/min/1.73m2 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 evidence of underlying
             abnormality in coagulation parameters exists. 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 predose 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. Absolute neutrophil count (ANC) ≥1 x 109/L. For patients
             with malignant bone marrow infiltration, ANC count ≥0.75 x 109/L.

             Fasting blood glucose <125 mg/dL (≤6.9 mmol/L) if not diabetic or <160 mg/dL (≤8.9
             mmol/L) if diabetic

         11. Left ventricular ejection fraction (LVEF), above the Institutions lower limit of
             normal, as determined by ECHO or MUGA.

         12. Patients must have recovered from clinically significant side effects associated with
             prior radiotherapy and chemotherapy.

             5.1.1 Additional criteria for Phase II:

         13. PIK3CA mutation confirmed by central laboratory.

         14. Phase Ib subjects (who are confirmed PIK3CA mutation carriers) must have been treated
             at the MTD in order to proceed with enrolment/registration to the Phase II study.

        Exclusion Criteria:

        Patients who meet any of the following criteria at the time of screening will be excluded
        from study registration:

          1. Known breast cancer involvement of the brain, unless adequately controlled as
             documented by baseline CT Scan (or PET CT/MRI if as per RECIST 1.1) that has not
             progressed since previous scans and that does not require corticosteroids for
             management of CNS symptoms

          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. Uncontrolled
             arterial hypertension (systolic blood pressure >160 mmHg or diastolic pressure >90
             mmHg despite optimal medical management).

          4. Uncontrolled Type I or II diabetes mellitus. Defined as HbA1c >8.5% or a fasting
             plasma glucose >8.9 mmol/L as determined during screening laboratory assessments.

          5. 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.

          6. Non-healing wound, ulcer, or bone fracture.

          7. Active, clinically serious infections >CTCAE Grade 2 (CTCAE v4.0).

          8. Known history of human immunodeficiency virus (HIV) infection.

          9. 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 laboratorial
             panel. Patients who test positive for HBsAg or 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.

         10. Patients with seizure disorder requiring medication.

         11. 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.

         12. Proteinuria of CTCAE Grade 3 or higher.

         13. History or concurrent condition of interstitial lung disease of any severity, and/or
             severely impaired lung function (as judged by the investigator).

         14. Concurrent diagnosis of pheochromocytoma.

         15. Pregnant or breast feeding patients. Women of childbearing potential must have a serum
             pregnancy test performed a maximum of 7 days before start of treatment, and a negative
             result must be documented before start of treatment.

         16. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior
             therapy/procedure, excluding alopecia, peripheral neuropathy, and bone marrow
             parameters.

         17. Known hypersensitivity to any of the test drugs, test drug classes, or excipients in
             the formulation.

         18. Substance abuse, medical, psychological or social conditions that may interfere with
             the patient's participation in the study or evaluation of the study results.

         19. Any illness or medical conditions that are unstable or could jeopardize the safety of
             patients and their compliance in the study.

         20. Patients permanently withdrawn from study participation will not be allowed to re
             enter the study.

             5.2.1 Excluded previous therapies and medications:

         21. Treatment with investigational drugs other than PI3K inhibitors less than 28 days
             before start of treatment.

         22. Ongoing immunosuppressive therapy.

         23. Radiotherapy or immunotherapy/chemotherapy less than 4 weeks before start of
             treatment.

         24. Myeloid growth factors less than 7 days before start of treatment.

         25. Blood or platelet transfusion less than 7 days before start of treatment.

         26. Ongoing systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone
             or equivalent. Previous corticosteroid therapy must be stopped or reduced to the
             allowed dose 7 days before performing the screening CT scan (or PET CT/MRI as per
             RECIST 1.1) and again prior to the first study drug administration. If a patient is on
             chronic corticosteroid therapy, corticosteroids should be de escalated to the minimum
             allowed dose before the screening. Patients may continue to use topical or inhaled
             corticosteroids.

         27. History of having received an allogeneic bone marrow or organ transplant.

         28. Major surgical procedure or significant traumatic injury (as judged by the
             investigator) less than 28 days before start of treatment. This does not include the
             study specific biopsy.

         29. Antiarrhythmic therapy (beta blockers or digoxin are permitted).

         30. Use of strong inhibitors of CYP3A4 is prohibited from Day 14 of Cycle 1 until the
             Safety follow up visit.

         31. Use of inducers of CYP3A4 is prohibited from Day 14 of Cycle 1 until the Safety follow
             up visit.

        Zoledronate or denosumab for patients with bone metastasis is allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose of copanlisib in combination with trastuzumab measured by the incidence of dose limiting toxicity (DLT) of copanlisib in combination with trastuzumab within the 1st cycle at each dose level.
Time Frame:1 year
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidences of adverse events and toxicities.
Time Frame:1.5 - 2 year
Safety Issue:
Description:
Measure:Overall survival
Time Frame:1.5 -2 year
Safety Issue:
Description:
Measure:Progression-Free Survival (PFS) assessed according to RECIST criteria version 1.1
Time Frame:1.5-2 year
Safety Issue:
Description:
Measure: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 year
Safety Issue:
Description:
Measure:Confirmed tumour response rate as assessed by RECIST criteria version 1.1.
Time Frame:1.5-2 year
Safety Issue:
Description:
Measure:Duration of response (DR) as assessed by RECIST criteria version 1.1.
Time Frame:1.5-2 year
Safety Issue:
Description:
Measure: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 4.0).
Time Frame:1.5-2 year
Safety Issue:
Description:
Measure:To assess the incidence of cardiotoxicity. Cardiac safety monitoring will include physical exam, (with NYHA functional classification for patients with diagnosed congestive heart failure) at each cycle, and MUGA scan or ECHO
Time Frame:1.5-2 year
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Cancer Trials Ireland

Last Updated

October 17, 2016