Clinical Trials /

Ipatasertib + Pertuzumab +Trastuzumab in Advanced HER2+ PI3KCA-mutant Breast Cancer Patients

NCT04253561

Description:

This is an open label, single arm, multicenter, phase Ib study to evaluate the safety and clinical activity of the combination of ipatasertib, trastuzumab and pertuzumab in patients with unresectable locally advanced or metastatic HER2-positive breast cancer with tumors harboring PIK3CA mutations, candidates to receive maintenance HP after first line treatment for metastatic disease with a taxane plus HP

Related Conditions:
  • Invasive Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ipatasertib + Pertuzumab +Trastuzumab in Advanced HER2+ PI3KCA-mutant Breast Cancer Patients
  • Official Title: A Phase Ib Study of Ipatasertib, an AKT Inhibitor, in Combination With Pertuzumab Plus Trastuzumab in Patients With PI3KCA-mutant, HER2-positive Locally Advanced or Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: SOLTI-1507
  • SECONDARY ID: 2019-001526-94
  • NCT ID: NCT04253561

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
IpatasertibGDC-0068Ipatasertib + Trastuzumab + Pertuzumab
TrastuzumabHerceptinIpatasertib + Trastuzumab + Pertuzumab
PertuzumabPerjectaIpatasertib + Trastuzumab + Pertuzumab

Purpose

This is an open label, single arm, multicenter, phase Ib study to evaluate the safety and clinical activity of the combination of ipatasertib, trastuzumab and pertuzumab in patients with unresectable locally advanced or metastatic HER2-positive breast cancer with tumors harboring PIK3CA mutations, candidates to receive maintenance HP after first line treatment for metastatic disease with a taxane plus HP

Detailed Description

      The main objective of the study is to assess whether the combination of ipatasertib and HP
      (+/- ET) is tolerable, especially in terms of the incidence and severity of diarrhea. For
      this purpose, up to a total of 25 patients will be enrolled in a staggered manner and
      evaluated.

      A 3-cohort, descending doses (400, 300, 200 mg) design will serve to establish the Maximun
      Toleraded Dose (MTD) and Recommended Phase 2 Dose (RP2D) of ipatasertib in combination with
      HP.

      The study will initially include 6 patients that will receive ipatasertib plus HP at Dose
      Level 1.

      If ≤1 DLTs are observed, this dose will be deemed safe, and the trial will enroll at least
      additional 19 patients to further assess safety and preliminary efficacy of the combination.

      If ≥2 DLT occurs in the first 6 patients, a decision will be made of whether expand Dose
      Level 1 to 10 additional patients or to de-escalate ipatasertib to the next lower dose level.
      In the case of de-escalation, the same rules will apply for enrollment and expansion of Dose
      level -1. The minimum ipatasertib dose explored will be Dose level -2.

      Dose reductions of pertuzumab and trastuzumab will not be allowed.

      If all inclusion criteria and no exclusion criteria are met, patients will be enrolled in the
      trial and will start treatment with oral (PO) ipatasertib once a day (QD) D1-21 in 28-days
      cycles, together with pertuzumab 420 mg intravenous (IV) every 21 days (Q21d) and trastuzumab
      600 mg subcutaneous (SC) Q21d.

      Patients with hormone receptor positive (HR+) tumors (defined as ER and/or PgR expression in
      >1% of tumor cells) will also receive endocrine therapy either an Aromatase Inhibitor (AI),
      tamoxifen or fulvestrant +/- Luteinizing Hormone-Releasing Hormone (LHRH) analogues,
      according to Investigator's decision.

      Patients will also start loperamide (2 mg twice a day [BID] or 4 mg QD) as prophylaxis for
      diarrhea in the first cycle
    

Trial Arms

NameTypeDescriptionInterventions
Ipatasertib + Trastuzumab + PertuzumabExperimentalIpatasertib will be given from Day 1 to Day 21 in every 28-day cycles. The starting dose is 400 mg orally (PO) QD and may be decreased to 300 mg QD and further to 200 mg QD (dose levels 1, - 1 and -2, respectively). Pertuzumab will be given IV every 21 days at the dose of 420 mg. Trastuzumab will be given SC every 21 days at the dose of 600mg. Intravenous (IV) Trastuzumab
  • Ipatasertib
  • Trastuzumab
  • Pertuzumab

Eligibility Criteria

        Inclusion Criteria:

          1. Written and signed informed consent for all study procedures according to local
             regulatory requirements prior to beginning of specific protocol procedures.

          2. Female (pre- or postmenopausal) or male patients.

          3. Age ≥ 18 years.

          4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

          5. Confirmed HER2-positive invasive breast cancer by central determination defined by
             American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)
             clinical practice guidelines. (Wolff el al. Arch Pathol Lab Med-Vol 142, November
             2018;).

          6. Known hormone receptor status, as assessed locally, defined by ASCO/CAP clinical
             practice guidelines. ER/PR positivity is defined as the presence of ≥ 1% of tumor
             cells with nuclear staining (Hammond et al. JCO 2010).

          7. Histologically confirmed, locally advanced or metastatic adenocarcinoma of the breast.

               1. Patients with unresectable locally advanced disease must have recurrent or
                  progressive disease, which must not be amenable to resection with curative
                  intent. Patients with available standard curative options are not eligible.

               2. For patients with bilateral breast cancer, HER2-positivity must be demonstrated
                  in both locations or in a metastatic biopsy.

          8. Patient must be a candidate to receive maintenance HP after first line treatment for
             metastatic disease with at least 4 cycles of taxane plus HP.

          9. Prior taxane must have been discontinued for a reason other than progressive disease.

         10. Patients may or may not have received neo/adjuvant therapy but must have a
             disease-free interval from completion of anti-HER2 therapy to metastatic diagnosis ≥6
             months.

         11. PIK3CA mutation identified and confirmed in tumor tissue or plasma ctDNA by central
             determination.

         12. Start of treatment with ipatasertib plus HP no later than 9 weeks after last dose of
             taxane plus HP (i.e., maximum of 2 HP administrations with no taxane).

         13. Willingness and ability to provide archived formalin fixed paraffin embedded (FFPE)
             tissue block.

         14. Measurable or non-measurable (but evaluable) disease, as per RECIST 1.1 criteria.

         15. No baseline diarrhea or diarrhea grade ≤1 within the last 28 days.

         16. Adequate hematologic and organ function within 14 days before the first study
             treatment on Day 1 of Cycle 1, defined by the following:

               1. Neutrophils (ANC ≥1500/μL)

               2. Hemoglobin ≥9 g/dL (with no need for transfusions in the last 14 days).

               3. Platelet count ≥75,000/μL

               4. Serum albumin ≥3 g/dL

               5. Total bilirubin ≤1.5x the upper limit of normal (ULN), with the exception:
                  patients with known Gilbert syndrome who have serum bilirubin ≤3x ULN.

               6. AST and ALT ≤2.5x ULN, with the following exception: patients with documented
                  liver or bone metastases who may have AST and ALT ≤5x ULN.

               7. ALP ≤2x ULN, with the following exceptions:

                    -  Patients with known liver involvement who may have ALP ≤5x ULN.

                    -  Patients with known bone involvement who may have ALP ≤7x ULN.

               8. PTT (or aPTT) and INR ≤1.5x ULN (except for patients receiving anticoagulation
                  therapy).

                    -  Patients receiving heparin treatment should have a PTT (or aPTT) between 1.5
                       and 2.5x ULN.

                    -  Patients receiving coumarin derivatives should have an INR between 2.0 and
                       3.0 assessed in two consecutive measurements 1 to 4 days apart.

               9. Serum creatinine <1.5x ULN or creatinine clearance ≥50 mL/min based on
                  Cockcroft-Gault glomerular filtration rate estimation:

                  (140 - age) x (weight in Kg) x 0.85 (if female)/72 x (serum creatinine in mg/dL)

              10. Fasting total serum glucose ≤150mg/dL and glycosylated hemoglobin (HbA1C) ≤7.5%

         17. Life expectancy of at least 6 months.

         18. Baseline left ventricular ejection fraction (LVEF) ≥50% measured by echocardiography
             (ECHO) or Multiple Gate Acquisition (MUGA) scan.

         19. Negative β-HCG pregnancy test (serum) for premenopausal women of reproductive capacity
             (those who are biologically capable of having children) and for women less than 12
             months after the menopause. All subjects who are biologically capable of having
             children must agree and commit to the use of a reliable method of birth control from 2
             weeks before administration of the first dose of investigational product until 28 days
             after the last dose of investigational product.

         20. Absence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule; those
             conditions should be discussed with the patient before registration in the trial.

        Exclusion Criteria:

          1. Last dose of taxane plus HP given more than 9 weeks prior to C1D1.

          2. Prior malignancy within 3 years prior to randomization, except curatively treated
             non-melanoma skin, carcinoma in situ of the cervix or Stage I uterine cancer.

          3. Brain metastases that have not been treated previously, are progressive, or require
             any type of therapy (e.g., radiation, surgery, or steroids) to control symptoms within
             30 days prior to the first study treatment dose.

          4. Radiotherapy for metastatic sites of disease outside of the brain performed within 14
             days prior to study enrollment and/or radiation of >30% of marrow-bearing bone.

          5. Symptomatic hypercalcemia requiring use of bisphosphonate or RANKL inhibitors therapy
             within 21 days prior to the first study treatment. Patients who receive bisphosphonate
             therapy specifically to prevent skeletal events are eligible if they have been
             initiated prior to the treatment to study.

          6. Cardiopulmonary dysfunction as defined by:

               1. Inadequately controlled angina or serious cardiac arrhythmia not controlled by
                  adequate medication.

               2. Inadequate LVEF at baseline, as defined as LVEF <50% by either ECHO or MUGA scan.

               3. History of symptomatic congestive heart failure (CHF): Grade ≥3 per NCI CTCAE
                  version 4.03 or Class ≥II New York Health Association (NYHA) criteria.

               4. History of a decrease in LVEF to <40% or symptomatic CHF with prior trastuzumab
                  or HP treatment.

               5. History of myocardial infarction within 6 months prior to randomization.

               6. Current dyspnea at rest due to complications of advanced malignancy, or other
                  disease requiring continuous oxygen therapy.

          7. Congenital long QT syndrome or screening QT interval corrected using Fridericia's
             formula (QTcF) > 480 milliseconds.

          8. Concurrent, serious, uncontrolled infections or current known infection with HIV
             (testing is not mandatory).

          9. History of intolerance, including Grade 3-4 infusion reaction or hypersensitivity, to
             trastuzumab or pertuzumab.

         10. Known hypersensitivity to any of the study drugs, including excipients.

         11. Known clinically significant history of liver disease consistent with Child-Pugh Class
             B or C, including active viral or other hepatitis (e.g., positive for hepatitis B
             surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), current
             drug or alcohol abuse, or cirrhosis.

               -  Patients with past hepatitis B virus (HBV) infection or resolved HBV infection
                  (defined as having a negative HBsAg test and a positive antibody to hepatitis B
                  core antigen [HBcAg] antibody test) are eligible.

               -  Patients positive for HCV antibody are eligible only if polymerase chain reaction
                  (PCR) is negative for HCV RNA

         12. History of Type I or Type II diabetes mellitus requiring insulin. Patients who are on
             stable dose of oral diabetes medication > 2 weeks prior to initiation of study
             treatment are eligible for enrollment.

         13. Grade ≥2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia.

         14. History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative
             colitis) or active bowel inflammation (e.g., diverticulitis).

         15. Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,
             cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic
             infections (Pneumocystis pneumonia or Cytomegalovirus pneumonia).

         16. Need for chronic corticosteroid therapy of >10 mg of prednisone per day or an
             equivalent dose of other anti-inflammatory corticosteroids for a chronic disease.

         17. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with
             indwelling catheters (e.g., PleurX®) are allowed.

         18. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5
             drug-elimination half-lives, whichever is longer, prior to initiation of study drug.

         19. Prior treatment with an AKT inhibitor. Prior PI3K or mTOR inhibitors are allowed.

         20. Current severe, uncontrolled systemic disease (e.g. clinically significant
             cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone
             fractures).

         21. Unresolved, clinically significant toxicity from prior therapy, except for alopecia
             and Grade 1 peripheral neuropathy.

         22. Major surgical procedure or significant traumatic injury within 28 days prior to
             enrollment.

         23. Assessment by the investigator to be unable or unwilling to comply with the
             requirements of the protocol.

         24. History of significant comorbidities that, in the judgment of the investigator, may
             interfere with the conduction of the study, the evaluation of response, or with
             informed consent.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To define the Recommended Phase 2 Dose (RP2D) of ipatasertib when used in combination with HP (+/- ET)
Time Frame:From baseline to the end of cycle 1, up to 28 days
Safety Issue:
Description:The RP2D will be the dose level of ipatasertib at which no more than 1 subject of the study experiences a Dose Limiting Toxicity (DLT) defined by the protocol study.

Secondary Outcome Measures

Measure:To evaluate the safety of the combination of ipatasertib with HP (+/- endocrine therapy [ET]).
Time Frame:Toxicities will be assessed during the whole treatment period (from baseline until lasts until 6 months after a patients' final treatment which is defined as the end of the Treatment Phase of the study).
Safety Issue:
Description:Number of patients with adverse events (AEs) and severe adverse events (SAEs) as per NCI CTCAE v4.03 of the combination of ipatasertib plus HP (+/- ET), with a special emphasis on the onset and severity of diarrhea.
Measure:To evaluate the tolerability of the combination of ipatasertib with HP (+/- endocrine therapy [ET]).
Time Frame:Toxicities will be assessed during the whole treatment period (from baseline until lasts until 6 months after a patients' final treatment which is defined as the end of the Treatment Phase of the study).
Safety Issue:
Description:Quantification of dose interruptions, reductions and dose intensity
Measure:Objective Response Rate (ORR) of the combination of ipatasertib with HP (+/- ET) as maintenance therapy after first line treatment for HER2-positive metastatic BC with a taxane plus HP.
Time Frame:From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to 20 months .
Safety Issue:
Description:Proportion of patients who have a complete response (CR) or partial response (PR), as determined by the investigator through use of RECIST v1.1.
Measure:Duration of Response (DoR) to the combination of ipatasertib with HP (+/- ET) as maintenance therapy after first line treatment for HER2-positive metastatic BC with a taxane plus HP.
Time Frame:From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to 20 months .
Safety Issue:
Description:Time from the first occurrence of a documented Objective Response (OR) to disease progression, according to RECIST v1.1, or death from any cause, whichever occurs first.
Measure:Clinical Benefit Rate (CBR) of the combination of ipatasertib with HP (+/- ET) as maintenance therapy after first line treatment for HER2-positive metastatic BC with a taxane plus HP.
Time Frame:From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to 20 months .
Safety Issue:
Description:Percentage of patients achieving confirmed CR, PR or stable disease (SD) for at least 24 weeks after the beginning of the study treatment by RECIST v1.1.
Measure:Progression-free survival (PFS) to the combination of ipatasertib with HP (+/- ET) as maintenance therapy after first line treatment for HER2-positive metastatic BC with a taxane plus HP.
Time Frame:From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to 20 months .
Safety Issue:
Description:Time from the commencement of study treatment (Day 1) to the occurrence of PD, as determined by the investigator via RECIST v1.1, or death from any cause, whichever occurs first.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:SOLTI Breast Cancer Research Group

Last Updated

April 30, 2020