Clinical Trials /

Ipatasertib in Combination With Carboplatin, Carboplatin/Paclitaxel, or Capecitabine/Atezolizumab in Treating Patients With Metastatic Triple Negative Breast Cancer

NCT03853707

Description:

This phase I trial studies best dose of ipatasertib and how well it works with carboplatin with or without paclitaxel in treating patients with triple negative breast cancer that has spread to other places in the body (metastatic). Ipatasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, paclitaxel, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab will work better in treating patients with triple negative breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ipatasertib in Combination With Carboplatin, Carboplatin/Paclitaxel, or Capecitabine/Atezolizumab in Treating Patients With Metastatic Triple Negative Breast Cancer
  • Official Title: A Phase I/IB Study of Ipatasertib in Combination With Carboplatin, Carboplatin/Paclitaxel, or Capecitabine/Atezolizumab in Patients With Metastatic Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 18496
  • SECONDARY ID: NCI-2019-00465
  • SECONDARY ID: 18496
  • NCT ID: NCT03853707

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • Metastatic Triple-Negative Breast Carcinoma
  • Prognostic Stage IV Breast Cancer AJCC v8

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm C (ipatasertib, capecitabine, atezolizumab)
CapecitabineRo 09-1978/000, XelodaArm C (ipatasertib, capecitabine, atezolizumab)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm A (ipatasertib, carboplatin, paclitaxel)
IpatasertibGDC-0068, RG-7440Arm A (ipatasertib, carboplatin, paclitaxel)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm A (ipatasertib, carboplatin, paclitaxel)

Purpose

This phase I trial studies best dose of ipatasertib and how well it works with carboplatin with or without paclitaxel in treating patients with triple negative breast cancer that has spread to other places in the body (metastatic). Ipatasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, paclitaxel, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab will work better in treating patients with triple negative breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase II dose (RP2D) of ipatasertib plus
      carboplatin/paclitaxel (arm A), ipatasertib plus carboplatin (arm B), and ipatasertib,
      atezolizumab, and capecitabine (arm C) in patients with metastatic triple negative breast
      cancer (TNBC). (Phase I) II. To obtain initial evidence of activity by examining progression
      free survival for each dose regimen. (Phase IB)

      SECONDARY OBJECTIVES:

      I. To confirm the recommended phase II dose (RPIID) safety in expanded cohort by evaluating
      toxicities and confirm tolerability of the combinations.

      II. To obtain evidence of activity by examining response rate based on Response Evaluation
      Criteria in Solid Tumors (RECIST) 1.1.

      III. To evaluate clinical benefit rate (CBR), event-free survival, time-to-treatment failure
      and overall survival.

      IV. Further describe the cumulative toxicities (Common Terminology Criteria for Adverse
      Events [CTCAE] 5.0) of the combinations.

      V. To evaluate patient's quality of life (QOL).

      EXPLORATORY OBJECTIVES:

      I. To evaluate the progression-free survival and overall survival, based on the genomic
      alterations including PIK3CA/AKT/PTEN alterations and BRCA status.

      II. To study the association of TNBC messenger ribonucleic acid (mRNA) expression profiling
      including Vanderbilt molecular subtype and treatment response.

      III. To study the association of stool microbiome, calprotectin with diarrhea. IV. To study
      peripheral blood circulating tumor deoxyribonucleic acid (DNA). V. To study therapy
      resistance by analyzing tumor genomics and transcriptome analysis.

      VI. To study the profiles of peripheral blood mononuclear cells and its association with
      response to therapy.

      VII. To study genomic immune biomarkers and its association with response.

      OUTLINE: This is a phase I, dose-escalation trial of ipatasertib, followed by a phase II
      trial. Patients are randomized or assigned to 1 of 3 arms depending on available slots.

      ARM A: Patients receive ipatasertib orally (PO) once daily (QD) on days 1-28. Patients also
      receive carboplatin intravenously (IV) over 30 minutes and paclitaxel IV over 60 minutes on
      days 1, 8, and 15 or days 1 and 15. Cycles repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      ARM B: Patients receive ipatasertib PO QD on days 1-28. Patients also receive carboplatin IV
      over 30 minutes on days 1, 8, and 15 or days 1 and 15. Cycles repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      ARM C: Patients receive ipatasertib PO QD on days 1-21, capecitabine PO twice daily (BID) on
      days 1-7 and 15-21, and atezolizumab IV over 30-60 minutes on days 1 and 15. Cycles repeat
      every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 36 months.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (ipatasertib, carboplatin, paclitaxel)ExperimentalPatients receive ipatasertib PO QD on days 1-28. Patients also receive carboplatin IV over 30 minutes and paclitaxel IV over 60 minutes on days 1, 8, and 15 or days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Ipatasertib
  • Paclitaxel
Arm B (ipatasertib and carboplatin)Active ComparatorPatients receive ipatasertib PO QD on days 1-28. Patients also receive carboplatin IV over 30 minutes on days 1, 8, and 15 or days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Ipatasertib
Arm C (ipatasertib, capecitabine, atezolizumab)ExperimentalPatients receive ipatasertib PO QD on days 1-21, capecitabine PO BID on days 1-7 and 15-21, and atezolizumab IV over 30-60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Capecitabine
  • Ipatasertib

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent form

          -  Ability to comply with the study protocol, in the investigator's judgment

          -  Histologically or cytologically confirmed triple negative breast cancer defined by
             estrogen receptor (ER) or progesterone receptor (PR) =< 10% by immunohistochemistry
             (IHC) and HER2 negative defined by current American Society of Clinical
             Oncology/College of American Pathologists (ASCO/CAP) guideline

          -  Disease progression during or following treatment with 0-2 lines of chemotherapy
             and/or biological targeted therapy in the metastatic setting

          -  Measurable (Arm C only) or non-measurable (allowed for Arm A or B) but evaluable
             disease per RECIST version (v)1.1 (Previously irradiated lesions can be considered as
             measurable disease only if progressive disease has been unequivocally documented at
             that site since radiation.)

          -  Baseline tissue requirement:

               -  A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block
                  (preferred) or at least 20 x 5 um slides containing unstained, freshly cut,
                  serial sections must be collected along with an associated pathology report prior
                  to study enrollment

               -  If only 10-19 slides are available, the patient may still be eligible for the
                  study, after principal investigator approval has been obtained

               -  If archival tumor tissue is unavailable or is determined to be unsuitable for
                  required testing, tumor tissue must be obtained from a biopsy performed at
                  screening

               -  A biopsy may also be performed at screening if a patient's archival tissue test
                  results do not meet eligibility criteria

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          -  Life expectancy >= 3 months

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (1,500/uL) without granulocyte
             colony-stimulating factor support (obtained within 14 days prior to initiation of
             study treatment)

          -  Platelet count >= 100 x 10^9/L (100,000/uL) without transfusion (obtained within 14
             days prior to initiation of study treatment)

          -  Hemoglobin >= 9 mg/dL (9 mg/dL) (patients may be transfused to meet this criterion)
             (obtained within 14 days prior to initiation of study treatment)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
             limit of normal (ULN) (obtained within 14 days prior to initiation of study
             treatment), with the following exception:

               -  Patients with documented liver or bone metastases may have AST and ALT =< 5 x ULN

          -  Alkaline phosphatase (ALP) =< 2 x ULN (obtained within 14 days prior to initiation of
             study treatment), with the following exceptions:

               -  Patients with known liver involvement may have ALP =< 5 x ULN

               -  Patients with known bone involvement may have ALP =< 7 x upper limit (UL)

          -  Serum bilirubin =< 1.5 x ULN (obtained within 14 days prior to initiation of study
             treatment) with the following exception:

               -  Patients with known Gilbert disease: serum bilirubin level =< 3 x ULN

          -  Serum creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min (calculated using
             the Cockcroft-Gault formula) (obtained within 14 days prior to initiation of study
             treatment)

          -  Partial thromboplastin time (PTT) (or activated partial thromboplastin time [aPTT])
             and international normalized ratio (INR) =< 1.5 x ULN (except for patients receiving
             anticoagulation therapy) (obtained within 14 days prior to initiation of study
             treatment)

          -  Patients receiving heparin treatment should have a PTT (or aPTT) between 1.5 and 2.5 x
             ULN (or patient value before starting heparin treatment). Patients receiving coumarin
             derivatives should have an INR between 2.0 and 3.0 assessed in two consecutive
             measurements 1 to 4 days apart

          -  Fasting total glucose =< 150 mg/dL (obtained within 14 days prior to initiation of
             study treatment)

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per
             year during the treatment period and for 6 months after the last dose of study
             treatment. Women must refrain from donating eggs during this same period.

               -  A woman is considered to be of childbearing potential if she is post-menarcheal,
                  has not reached a postmenopausal state (>= 12 continuous months of amenorrhea
                  with no identified cause other than menopause), and has not undergone surgical
                  sterilization (removal of ovaries and/or uterus)

               -  Examples of contraceptive methods with a failure rate of < 1% per year include
                  bilateral tubal ligation, male sterilization, hormonal contraceptives that
                  inhibit ovulation, hormone- releasing intrauterine devices, and copper
                  intrauterine devices

               -  The reliability of sexual abstinence should be evaluated in relation to the
                  duration of the clinical trial and the preferred and usual lifestyle of the
                  patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post
                  ovulation methods) and withdrawal are not acceptable methods of contraception

          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
             a condom, and agreement to refrain from donating sperm, as defined below:

               -  With female partners of childbearing potential or pregnant female partners, men
                  must remain abstinent or use a condom during the treatment period and for 6
                  months after the last dose of study treatment to avoid exposing the embryo. Men
                  must refrain from donating sperm during this same period

               -  The reliability of sexual abstinence should be evaluated in relation to the
                  duration of the clinical trial and the preferred and usual lifestyle of the
                  patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post
                  ovulation methods) and withdrawal are not acceptable methods of contraception

        Exclusion Criteria:

          -  Inability to comply with study and follow-up procedures

          -  >= grade 3 toxicities from previous treatment, not recovered to =< grade 2 at study
             entry

          -  Prior exposure to PI3K/AKT/mTOR pathway inhibitors including but not limited to
             everolimus, ipatasertib, gedatolisib or alpelisib etc

          -  Prior exposure to carboplatin for treatment of metastatic TNBC not allowed; prior
             treatment of carboplatin as neoadjuvant or adjuvant therapy allowed if last dose of
             therapy completed >= 12 months prior to initiation of the current study

          -  Prior exposure to paclitaxel or nab-paclitaxel for treatment of metastatic TNBC not
             allowed for carboplatin/paclitaxel arm; prior treatment of paclitaxel or
             nab-paclitaxel as neoadjuvant or adjuvant therapy allowed if last dose of therapy
             completed >= 12 months prior to initiation of the current study

          -  Prior exposure to capecitabine for treatment of metastatic TNBC not allowed for Arm C;
             prior treatment of capecitabine as adjuvant therapy allowed if the last dose of
             therapy completed >= 12 months prior to initiation of the current study for Arm C

          -  Prior treatment with immune check point inhibitors for Arm C

          -  Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
             anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

          -  Prior treatment with systemic immunostimulatory agents (including, but not limited to,
             interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives
             (whichever is longer) prior to initiation of study treatment for Arm C

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

               -  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 for the study after Medical
                  Monitor confirmation has been obtained

               -  Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
                  for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose
                  corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
                  for the study

          -  Active autoimmune disorders requiring steroid dose higher than prednisone 10 mg daily
             for Arm C

          -  Active disease or receiving treatment for hepatitis B or C or human immunodeficiency
             virus (HIV) infection for Arm C

          -  Receipt of a live, attenuated vaccine within 4 weeks prior to enrollment (start of
             treatment), during treatment, or within 5 months following the last dose of
             atezolizumab for Arm C

          -  Known allergy or hypersensitivity to any component of carboplatin and/or paclitaxel or
             nab-paclitaxel, or capecitabine (5-FU) formulation (for patients planned for the
             respective arms)

          -  Known dihydropyrimidine dehydrogenase (DPD) deficiency in patients selected to receive
             capecitabine for Arm C

          -  Known severe allergic reactions to cisplatin or other platinum-containing compounds or
             mannitol (for patients planned for platinum-containing arms)

          -  History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or fusion proteins

          -  Known hypersensitivity to Chinese hamster ovary cell products or to any component of
             the atezolizumab formulation

          -  History of malabsorption syndrome or other condition that would interfere with enteral
             absorption or results in the inability or unwillingness to swallow pills

          -  Active infection requiring systemic anti-microbial treatment (including antibiotics,
             anti-fungals, and anti-viral agents)

          -  Severe infection within 4 weeks prior to initiation of study treatment, including, but
             not limited to, hospitalization for complications of infection, bacteremia, or severe
             pneumonia

          -  Known untreated or unstable brain metastasis or leptomeningeal metastasis from
             metastatic breast cancer

          -  Uncontrolled tumor-related pain

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures (once monthly or more frequently)

               -  Patients with indwelling catheters (e.g., PleurX) are allowed

          -  Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12
             mg/dL, or corrected calcium > ULN)

          -  Active or history of autoimmune disease or immune deficiency, including, but not
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
             antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome,
             or multiple sclerosis with the following exceptions:

               -  Patients with a history of autoimmune-related hypothyroidism who are on
                  thyroid-replacement hormone are eligible for the study.

               -  Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
                  are eligible for the study.

               -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis are
                  excluded) are eligible for the study provided all of following conditions are
                  met:

                    -  Rash must cover < 10% of body surface area

                    -  Disease is well controlled at baseline and requires only low-potency topical
                       corticosteroids

                    -  No occurrence of acute exacerbations of the underlying condition requiring
                       psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
                       agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids
                       within the previous 12 months

          -  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 (CT) scan

               -  History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

          -  Active tuberculosis

          -  Known HIV infection

          -  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 hepatitis B core antibody
                  [HBcAb] test, accompanied by a negative HBV deoxyribonucleic acid [DNA] test) are
                  eligible

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

          -  Prior allogeneic stem cell or solid organ transplantation

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to day 1 of cycle 1 or anticipation of need for a major surgical procedure
             during the course of the study

               -  Placement of a vascular access device is not considered major surgery

          -  Pregnant or breastfeeding, or intending to become pregnant during the study or within
             28 days after the last dose of ipatasertib, 5 months after the last dose of
             atezolizumab, and within 6 months after the last dose of paclitaxel, whichever occurs
             later

               -  Women of childbearing potential (who are not postmenopausal with >= 12 months of
                  non-therapy induced amenorrhea nor surgically sterile) must have a negative serum
                  pregnancy test result either within 96 hours prior to day 1 of cycle 1 treatment

          -  New York Heart Association class II, III, or IV heart failure; left ventricular
             ejection fraction < 50%; or active ventricular arrhythmia requiring medication

          -  Current unstable angina or history of myocardial infarction within 6 months prior to
             day 1 of cycle 1 and cerebrovascular accident within 3 months prior to day 1 of cycle
             1

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

          -  History or presence of an abnormal electrocardiogram (ECG) that is clinically
             significant in the investigator's opinion (including complete left bundle branch
             block, second- or third-degree heart block, or evidence of prior myocardial
             infarction)

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

          -  Treatment with approved or investigational cancer therapy within 14 days prior to day
             1 of cycle 1

          -  Patients with a prior diagnosis of malignancy except non-melanomatous skin cancer
             treated >= 5 years ago are eligible, provided that they have not received prior
             taxanes or carboplatin as part of their prior treatment regimen, and that they meet
             all eligibility criteria

          -  Any other disease, physical examination finding, or clinical laboratory finding that,
             in the investigator's opinion, gives reasonable suspicion of a disease or condition
             that contraindicates the use of an investigational drug or that may affec
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase II dose (RP2D) of ipatasertib (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:Tables will be created to summarize all toxicities and side effects by grade, attribution, dose, course (cycle 1 versus [vs] later cycles), organ and severity. Rates and associated 95% confidence limits will be estimated for dose-limiting toxicities (DLTs) at the RP2D, clinical benefit, response, and PIK3CA mutation rate.

Secondary Outcome Measures

Measure:RP2D safety in expanded cohort
Time Frame:Up to 28 days
Safety Issue:
Description:The safety of the RP2D in the expanded cohort will be done by evaluating toxicities and confirming the tolerability of the drug combinations. Tables will be created to summarize all toxicities and side effects by grade, attribution, dose, course (cycle 1 vs later cycles), organ and severity. Rates and associated 95% confidence limits will be estimated for (DLTs at the RP2D, clinical benefit, response, and PIK3CA mutation rate.
Measure:Evidence of activity by response rate
Time Frame:Up to 36 months
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Measure:Clinical benefit rate
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Event-free survival (EFS)
Time Frame:Up to 36 months
Safety Issue:
Description:Kaplan Meier methods will be used to estimate the median and 95% confidence limits.
Measure:Time-to-treatment failure (TTF)
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:Up to 36 months
Safety Issue:
Description:Kaplan Meier methods will be used to estimate the median and 95% confidence limits.
Measure:Incidence of adverse events
Time Frame:Up to 36 months
Safety Issue:
Description:Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Measure:Quality of life Questionnaire
Time Frame:Up to 6 months after radiographic disease progression
Safety Issue:
Description:Will be assessed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

April 8, 2020