Clinical Trials /

Ipatasertib + Atezolizumab to Prevent Recurrence in TNBC

NCT04434040

Description:

The purpose of this study is to determine if a combination of two drugs ipatasertib and atezolizumab works as a treatment for residual cancer in the breast or lymph nodes and have circulating tumor DNA in the blood. This research study involves the following investigational drugs: - Ipatasertib - Atezolizumab

Related Conditions:
  • Invasive Breast Carcinoma
Recruiting Status:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ipatasertib + Atezolizumab to Prevent Recurrence in TNBC
  • Official Title: Combination Ipatasertib and Atezolizumab to Prevent Recurrence in Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 20-028
  • NCT ID: NCT04434040

Conditions

  • Breast Cancer
  • Triple Negative Breast Cancer
  • Residual Cancer
  • Circulating Tumor DNA

Interventions

DrugSynonymsArms
AtezolizumabTecentriqAtezolizumab and Ipatasertib
IpatasertibGDC-0068Atezolizumab and Ipatasertib

Purpose

The purpose of this study is to determine if a combination of two drugs ipatasertib and atezolizumab works as a treatment for residual cancer in the breast or lymph nodes and have circulating tumor DNA in the blood. This research study involves the following investigational drugs: - Ipatasertib - Atezolizumab

Detailed Description

      This is an open label single-arm phase II study to evaluate the combination therapy of the
      AKT inhibitor, ipatasertib, and the anti-PD-L1 antibody, atezolizumab, in patients with
      triple negative breast cancer.

      The research study procedures include screening for eligibility and study treatment including
      laboratory evaluations, stool collection and follow up visits.

      This research study involves the following investigational drugs:

        -  Ipatasertib

        -  Atezolizumab

      Participants will receive study treatment for 24 weeks and will be followed for every 6
      months for 3 years.

      It is expected that about 40 people will take part in this research study.

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug to learn whether the drug or drug combination
      works in treating a specific disease. "Investigational" means that the drug combination is
      being studied.

      The U.S. Food and Drug Administration (FDA) has not approved atezolizumab (Tecentriq) for
      residual triple negative breast cancer but it has been approved for advanced triple negative
      breast cancer and other cancers. Atezolizumab is a protein that affects your immune system by
      blocking the PD-L1 pathway. The PD-L1 pathway controls your body's natural immune response,
      but for some types of cancer the immune system does not work as it should and is prevented
      from attacking tumors. Atezolizumab works by blocking the PD-L1 pathway, which may help your
      immune system identify and catch tumor cells.

      The U.S. Food and Drug Administration (FDA) has not approved ipatasertib as a treatment for
      any disease.

      Ipatasertib is a drug that inhibits (stops) an enzyme called Akt in cancer cells. It is
      thought that inhibiting Akt may make cancer cells more sensitive to treatment, especially in
      combination with a drug that activates the immune system, like atezolizumab.
    

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab and IpatasertibExperimentalPatients will receive the following treatment: Atezolizumab and Ipatasertib treatment will continue for 6 cycles (24 total weeks), with evaluations done at 12 and 24 weeks. Atezolizumab intravenously (IV) at a pre-determined dose on days 1 and 15 in a 28-day cycle Ipatasertib: Oral daily at a pre-determined dose daily on days 1-21, followed by one week off (3 weeks on, 1 week off) in a 28 day cycle (with daily prophylactic loperamide for first cycle)
  • Atezolizumab
  • Ipatasertib

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed residual invasive breast cancer, in the breast and/or lymph
             node(s), following neoadjuvant chemotherapy. In the absence of residual invasive
             disease in the breast, lymph node must contain at least 2mm of invasive disease.

          -  HER2 negative by local pathology assessed according to current ASCO/CAP guidelines:

               -  In situ hybridization non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe
                  average HER2 gene copy number < 4 signals/cell), OR

               -  Immunohistochemistry (IHC) 0 or IHC 1+.

               -  NOTE: If more than one test result is available and not all results meet the
                  inclusion criterion definition, all results should be discussed with the
                  Principal Investigator to establish eligibility

          -  ER and PR negative defined as < 1% of cells expressing hormonal receptors via IHC
             analysis by local laboratory assessment.

          -  Patients must have received neoadjuvant chemotherapy prior to breast surgery.
             Investigational agents as part of the neoadjuvant regimen are allowed, with the
             exception of PI3K/Akt/mTor inhibitors and/or immune checkpoint inhibitors.

          -  Patients must be within 12 months of last therapy (definitive breast surgery,
             radiation and/or all intended adjuvant therapy). Definitive breast surgery includes
             lumpectomy or mastectomy with pathologically clear margins (i.e. no ink on tumor). For
             patients undergoing lumpectomy, this must be followed by whole breast irradiation.
             Definitive surgery also includes axillary surgery, either sentinel lymph node biopsy
             or axillary lymph node dissection at the discretion of the attending surgeon.

          -  Evidence of circulating tumor cfDNA in blood sample collected after completion of all
             local and systemic neoadjuvant and adjuvant therapy (preoperative and postoperative
             chemotherapy, surgery and radiation), confirmed by central testing. Detection of any
             tumor specific mutations (TSMs) within the sample will be considered positive for
             purposes of study eligibility.

          -  Concurrent receipt of bone modifying agents (bisphosphonates or rank-ligand
             inhibitors)is allowed.

          -  ECOG Performance Status of 0 or 1

          -  Men and women, age ≥ 18 years

          -  Adequate hematologic and organ function defined by the following:

               -  ANC ≥ 1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor support

               -  WBC count ≥ 2.5 × 109/L (2500/μL)

               -  Absolute Lymphocyte count ≥ 0.5 × 109/L (500/μL)

               -  Platelet count ≥ 100 × 109/L (100,000/μL)

               -  Hemoglobin ≥ 90 g/L (9.0 g/dL), with or without transfusion

               -  AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 × institutional upper limit of
                  normal (ULN).

               -  Serum bilirubin ≤ 1.5 × institutional ULN with the following exception:

                    -  Patients with known Gilbert syndrome: serum bilirubin level ≤ 3 ×
                       institutional ULN

               -  Serum creatinine < 1.5 x institutional ULN

               -  Serum albumin ≥ 25 g/L (2.5 g/dL)

               -  Fasting glucose < 150 mg/dL and hemoglobin (HBA1c) < 7.5%

               -  For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 ×
                  institutional ULN

               -  For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

          -  Women of childbearing potential (pre-menopausal) must have a negative serum or urine
             pregnancy test within 7 days prior to start of therapy. A woman is defined as
             premenopausal if she is less than 12 months from last menstrual period with no
             identified cause other than menopause (medication induced amenorrhea is not
             acceptable). Pregnancy test is not required in women who are surgically sterile via
             bilateral salpingooophorectomy or hysterectomy.

          -  Women of childbearing potential and men must agree to use adequate contraception for
             the duration of protocol treatment and for 28 days after last dose of ipatasertib and
             5 months after stopping atezolizumab. Hormonal contraceptives are not acceptable (see
             section 5.6).

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Patients must be willing to provide archival tissue for research purposes.

        Exclusion Criteria:

          -  Clinical evidence of metastatic disease

          -  Residual DCIS or LCIS alone without invasive cancer OR pT0N0i and pT0N1mic residual
             disease

          -  Prior treatment with an immune checkpoint inhibitor is permitted in the neoadjuvant
             setting and prohibited in the adjuvant setting.

          -  Concurrent enrollment on another investigational therapy trial

          -  Prior treatment-related toxicity must be resolved to ≤ Grade 1 with the exception of
             alopecia and peripheral neuropathy, prior to study enrollment.

          -  Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation
             of study treatment, or anticipation of need for a major surgical procedure during the
             study

          -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
             of study treatment Patients receiving prophylactic antibiotics (e.g., to prevent a
             urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
             eligible for the study.

          -  Intercurrent illness including, but not limited to: ongoing or active infection
             requiring systemic therapy, active tuberculosis, serious liver disease such as
             cirrhosis, active bleeding diathesis, uncontrolled Type I or Type II diabetes
             mellitus, Grade ≥ 2 uncontrolled or untreated hypercholesterolemia,
             Hypertriglyceridemia or hypercalcemia

          -  Cardiovascular disease including: congestive heart failure of New York Heart
             Association Class III or IV, myocardial infarction (<6 months prior to enrollment)
             unstable angina pectoris, serious uncontrolled cardiac arrhythmia or any other
             clinically significant cardiac disease, in the opinion of the investigator

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
             active pneumonitis on screening chest computed tomography scan. History of radiation
             pneumonitis in the radiation field (fibrosis) is permitted.

          -  Active (acute or chronic) autoimmune disease of any type except hypothyroidism on a
             thyroid-replacement hormone,or celiac disease, or well-controlled psoriasis, eczema,
             lichen simplex chronicus or vitiligo.

          -  Impairment of gastrointestinal function or active gastrointestinal disease that may
             significantly alter the absorption of the study agents (e.g., ulcerative disease,
             uncontrolled nausea(> grade 2), vomiting (> grade 2), diarrhea (> grade 2),
             malabsorption syndrome or small bowel resection).

          -  Congenital long QT syndrome or screening QT interval corrected through use of
             Fridericia's formula >480 ms.

          -  Participants known to be positive for the human immunodeficiency virus (HIV),
             Hepatitis B antigen (HepBsAg), or Hepatitis C virus (HCV) RNA are ineligible.

          -  History of prior invasive breast cancer in either breast.

          -  Participants with history of prior malignancy other than breast cancer are eligible if
             they have been disease-free for at least 5 years prior to enrollment with the
             exception of patients with thyroid cancer that has been definitively treated without
             spread to regional lymph nodes.

          -  Treatment with strong CYP3A4 inducers within 4 weeks or 5 drug-elimination half-lives,
             whichever is longer, prior to initiation of study drug.

          -  Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
             treatment, or anticipation of need for such a vaccine while on protocol treatment

          -  Known allergy or hypersensitivity to any of the study drugs or any of their
             excipients, including chimeric or humanized antibodies or fusion proteins and Chinese
             hamster ovary cell products or recombinant human antibodies

          -  Treatment with systemic immunosuppressive medication (including, but not limited to,
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti−tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study
             treatment, or anticipation of need for systemic immunosuppressive medication during
             the course of the study, with the following exceptions:

               -  Patients who received acute, low-dose systemic immunosuppressant medication or a
                  one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
                  corticosteroids for a contrast allergy) are eligible. o Patients who received
                  mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic
                  obstructive pulmonary disease or asthma, or low-dose corticosteroids for
                  orthostatic hypotension or adrenal insufficiency are eligible for the study.

          -  Pregnant women are excluded from this study because the effects of ipatasertib and
             atezolizumab on a developing fetus are unknown. Breastfeeding should be discontinued
             prior to entry onto the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of undetectable circulating tumor cfDNA- 6 Cycles
Time Frame:24 Weeks
Safety Issue:
Description:Clearance of tumor cfDNA after 24 weeks, it will be tested using a one-sided one-sample binomial exact test (alpha 5%) against a null hypothesis value of 7% false negatives.

Secondary Outcome Measures

Measure:Rate of undetectable circulating tumor cfDNA - 3 Cycles
Time Frame:12 weeks
Safety Issue:
Description:Proportion of patients with undetectable circulating tumor cfDNA after 3 cycles of combination therapy
Measure:Number of Participants With Treatment-Related Adverse Events
Time Frame:12 Weeks
Safety Issue:
Description:Type, incidence and severity of adverse events (AEs) as graded by NCI CTCAE v5 criteria by 12 and 24 weeks.
Measure:Number of Participants With Treatment-Related Adverse Events
Time Frame:24 Weeks
Safety Issue:
Description:Type, incidence and severity of adverse events (AEs) as graded by NCI CTCAE v5 criteria by 12 and 24 weeks.
Measure:Invasive disease-free survival (iDFS) Rate
Time Frame:3 years
Safety Issue:
Description:Estimated disease-free survival (iDFS) Rate with 90% CI
Measure:Distant metastasis free survival (DMFS) Rate
Time Frame:3 years
Safety Issue:
Description:Estimated metastasis free survival (DMFS) rate with 90% CI
Measure:Overall survival (OS) Rate
Time Frame:3 years
Safety Issue:
Description:Estimate overall survival rate with 90% CI
Measure:3-year recurrence rate
Time Frame:3 Years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Breast Cancer
  • Triple Negative Breast Cancer
  • Residual Cancer
  • Circulating Tumor DNA

Last Updated

June 14, 2020