Clinical Trials /

Ipatasertib Plus Non-Taxane Chemotherapy for Advanced or Metastatic Triple-Negative Breast Cancer

NCT04464174

Description:

This is a multicenter, open-label, non-comparative, three-arm, phase IIa trial of Ipatasertib (GDC-0068) in combination with non-taxane chemotherapy agents for taxane-pretreated unresectable locally advanced or metastatic triple-negative breast cancer patients

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ipatasertib Plus Non-Taxane Chemotherapy for Advanced or Metastatic Triple-Negative Breast Cancer
  • Official Title: A Multicenter, Open-Label, Non-Comparative, Three-Arm, Phase IIa Trial of Ipatasertib (GDC-0068) in Combination With Non-Taxane Chemotherapy Agents for Taxane-Pretreated Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer Patients

Clinical Trial IDs

  • ORG STUDY ID: MedOPP253
  • NCT ID: NCT04464174

Conditions

  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
IpatasertibGDC-0068Ipatasertib plus Eribulin
CapecitabineXelodaIpatasertib plus capecitabine
EribulinHalavenIpatasertib plus Eribulin
CarboplatinParaplatinIpatasertib plus carboplatin plus gemcitabine
GemcitabineGemzarIpatasertib plus carboplatin plus gemcitabine

Purpose

This is a multicenter, open-label, non-comparative, three-arm, phase IIa trial of Ipatasertib (GDC-0068) in combination with non-taxane chemotherapy agents for taxane-pretreated unresectable locally advanced or metastatic triple-negative breast cancer patients

Detailed Description

      Women age ≥ 18 years with triple-negative unresectable locally advanced or MBC that is not
      amenable to resection with curative intent.

      Patients must have received at least one, but not more than two, prior chemotherapeutic
      regimens for treatment of unresectable locally advanced and/or metastatic disease (at least
      one regimen must have contained a taxane).

      The number of patients to be included is 54 patients. The primary objective is to evaluate
      the safety and tolerability of ipatasertib (GDC-0068) in combination with capecitabine,
      eribulin, or carboplatin plus gemcitabine in patients with unresectable locally advanced or
      metastatic triple-negative breast cancer
    

Trial Arms

NameTypeDescriptionInterventions
Ipatasertib plus capecitabineExperimentalArm A: Ipatasertib (GDC-0068) 400 milligrams (mg) tablets administered orally once a day (noon) on Days 1-14 of each 21-day cycle plus capecitabine 1000 mg/m2 tablets orally twice a day (morning and evening; equivalent to 2000 mg/m2 total daily dose), for 14 days (followed by a 7-day rest period) every 21-day cycle.
  • Ipatasertib
  • Capecitabine
Ipatasertib plus EribulinExperimentalArm B: Ipatasertib (GDC-0068) 400 mg tablets administered orally once a day on Days 1-14 of each 21-day cycle plus eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) administered intravenously over 2 to 5 minutes on Days 1 and 8 of every 21-day cycle.
  • Ipatasertib
  • Eribulin
Ipatasertib plus carboplatin plus gemcitabineExperimentalArm C: Ipatasertib (GDC-0068) 400 mg tablets administered orally once a day on Days 1-14 of each 21-day cycle plus carboplatin AUC5 on Day 1 administered intravenously plus gemcitabine 1000 mg/m2 administered intravenously over 30 minutes on Days 1 and 8, every 21-day cycle.
  • Ipatasertib
  • Carboplatin
  • Gemcitabine

Eligibility Criteria

        Inclusion Criteria:

          1. Signed Informed Consent Form (ICF) prior to participation in any study-related
             activities.

          2. Female patients ≥ 18 years at the time of signing ICF.

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

          4. Life expectancy of ≥ 12 weeks.

          5. Histologically confirmed Triple Negative Breast Cancer (TNBC) per American Society of
             Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria based on
             local testing on the most recent analyzed biopsy. Triple-negative is defined as <1%
             expression for estrogen receptor (ER) and progesterone receptor (PgR) and negative for
             Human Epidermal Growth Factor Receptor 2 (HER2) (0-1+ by immunohistochemistry (IHC) or
             2+ and negative by in situ hybridization [ISH) test].

          6. Unresectable locally advanced or metastatic disease documented by computerized
             tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to
             resection with curative intent.

          7. Measurable or evaluable disease as per RECIST v.1.1. Patients with only bone lesions
             are also eligible.

          8. Refractory to or relapsed after one or two prior standard of care chemotherapy
             regimens for unresectable locally advanced or metastatic breast cancer (MBC). Earlier
             adjuvant or neoadjuvant therapy for more limited disease will be considered as one of
             the required prior regimens if the development of unresectable locally advanced or
             metastatic disease occurred within a 12-month period of time after completion of
             chemotherapy.

             Note: Exclusive tumor marker elevation will not be considered sufficient for diagnosis
             of disease progression.

          9. Prior therapy must have included a taxane in any combination or order and either in
             the early, locally advanced, or metastatic setting. Note: Exclusive prior taxane-based
             therapy as adjuvant or neoadjuvant treatment is also allowed if the patient had a
             disease-free interval of less than 12 months after completing this treatment.

         10. Eligible for one of the chemotherapy options (eribulin, capecitabine, carboplatin plus
             gemcitabine) as per local investigator assessment and slots availability. Patients
             treated with (neo)adjuvant platinum salts or capecitabine and who have relapsed more
             than one year after the last dose of either treatment may be allowed to be included in
             the treatment arm based on ipatasertib (GDC-0068) in combination with carboplatin plus
             gemcitabine and capecitabine, respectively.

         11. Previous treatment with androgen receptor antagonists, poly ADP-ribose Polymerase
             (PARP) inhibitors, and immunotherapy is allowed. Those patients who have previously
             received a PARP inhibitor will not be included in the carboplatin and gemcitabine arm
             unless PARP inhibitors were used in the early breast cancer setting and the period
             between the end of PARP inhibitor-based regimen and onset of metastatic disease is at
             least of 12 months.

         12. Resolution of all acute toxic effects of prior anti-cancer therapy to grade inferior
             or equal to 1 as determined by the NCI-CTCAE v.5.0 (except for alopecia or other
             toxicities not considered a safety risk for the patient at investigator's discretion).

         13. Willingness and ability to provide a tumor biopsy from a metastatic site or the
             primary breast tumor at the time of the inclusion in order to perform exploratory
             studies. If not feasible, patient eligibility should be evaluated by a Sponsor's
             qualified designee. Note: Subjects for whom tumor biopsies cannot be obtained (e.g.,
             inaccessible tumor or subject safety concern) may submit an archived metastatic tumor
             specimen only upon agreement from the Sponsor.

         14. Patients agree to give blood samples (liquid biopsy) at the time of inclusion, after
             two cycles of study treatment, and upon progression or study termination.

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

               1. Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil
                  count (ANC) > 1.5 x 109/L, platelet count > 100.0 x109/L, and hemoglobin > 9.0
                  g/dL.

               2. Hepatic: Serum albumin ≥ 3 g/dL; Bilirubin ≤ 1.5 times the upper limit of normal
                  (× ULN) (≤ 3 x ULN in the case of Gilbert's disease); aspartate transaminase
                  (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (in the case of liver metastases
                  ≤ 5 × ULN); alkaline phosphatase (ALP) ≤ 2 × ULN (≤ 5 × ULN in the case of liver
                  and/or bone metastases ≤ 5 × ULN).

               3. Renal: Serum creatinine < 1.5 × ULN or creatinine clearance ≥ 50 mL/min based on
                  Cockcroft−Gault glomerular filtration rate estimation.

               4. Coagulation: Partial Thromboplastin Time (PTT) (or activated Partial
                  Thromboplastin Time [aPTT]) and International Normalized Ratio (INR) ≤ 1.5 × ULN
                  (except for patients receiving anticoagulation therapy).

             Note: Patients receiving heparin treatment should have a PTT (or aPTT) ≤ 2.5 × 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 one to four days apart. Patients should be on a stable anticoagulant
             regimen.

         16. For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse), or to use a highly effective non-hormonal form of
             contraception, or two effective forms of contraception, as defined in the protocol
             during the treatment period and for at least 28 days after the last dose of
             ipatasertib (GDC-0068), three months after the last dose of eribulin, and six months
             after the last dose of carboplatin and gemcitabine or capecitabine, whichever occurs
             later, and agreement to refrain from donating eggs during this same period. Women of
             childbearing potential must have a negative serum pregnancy test before study
             treatment initiation.

        Exclusion Criteria:

          1. Inability to comply with study and follow-up procedures.

          2. Previous treatment with PI3K, mTOR, or AKT inhibitors.

          3. Known active uncontrolled or symptomatic central nervous system (CNS) metastases,
             carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms,
             cerebral edema, and/or progressive growth. Patients with a history of CNS metastases
             or cord compression are eligible if they have been definitively treated (e.g.,
             radiotherapy, stereotactic surgery), are clinically stable, and off anticonvulsants
             and steroids for at least two weeks before first dose of study treatment.

          4. Radiotherapy or limited-field palliative radiotherapy within seven days prior to study
             enrolment, or patients who have not recovered from radiotherapy-related toxicities to
             baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously
             irradiated.

          5. Major surgery (defined as requiring general anesthesia) or significant traumatic
             injury within 28 days of start of study drug, or patients who have not recovered from
             the side effects of any major surgery.

          6. Grade ≥ 2 peripheral neuropathy.

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

          8. History of type I or type II diabetes mellitus either requiring insulin or with a
             baseline fasting glucose > 150 mg/dL (8.3 mmol/L) or high hemoglobin A1c (HbA1c) as
             defined as > 7%. Patients who are on a stable dose of oral diabetes medication during
             at least weeks prior to initiation of study treatment are eligible for enrolment.

          9. Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,
             cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic
             infections (pneumocystis pneumonia or cytomegalovirus pneumonia).

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

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

         12. Known hypersensitivity reaction to any investigational or therapeutic compound or
             their incorporated substances.

         13. Patients have a concurrent malignancy or malignancy within five years of study
             enrollment with the exception of carcinoma in situ of the cervix, non-melanoma skin
             carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk
             of recurrence, discussion with the Medical Monitor is required.

         14. Current known infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV).
             Patients with past HBV infection or resolved HBV infection (defined as having a
             negative hepatitis B surface antibody [HBsAg] test and a positive hepatitis B core
             antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients
             positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is
             negative for HCV RNA.

         15. Active uncontrolled infection at the time of enrollment.

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

         17. Patients have an active cardiac disease or a history of cardiac dysfunction including
             any of the following:

               1. Unstable angina pectoris or documented myocardial infarction within six months
                  prior to study entry.

               2. Symptomatic pericarditis.

               3. Documented congestive heart failure (New York Heart Association functional
                  classification III- IV).

               4. Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated
                  acquisition (MUGA) scan or echocardiogram (ECHO).

         18. Patients have any of the following cardiac conduction abnormalities:

               1. Ventricular arrhythmias except for benign premature ventricular contractions.

               2. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
                  with medication.

               3. Conduction abnormality requiring a pacemaker.

               4. Other cardiac arrhythmia not controlled with medication.

         19. Patients have any other concurrent severe and/or uncontrolled medical condition that
             would, in the investigator's judgment contraindicate patient participation in the
             clinical study.

         20. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 14 days or five
             drug-elimination half-lives, whichever is longer, prior to initiation of study
             treatment.

         21. Pregnant, breastfeeding, or intending to become pregnant during the study or within 28
             days after the last dose of ipatasertib (GDC-0068), three months after the last dose
             of eribulin, and six months after the last dose of carboplatin and gemcitabine or
             capecitabine, whichever occurs later.

         22. Treatment with approved or investigational cancer therapy within 14 days prior to
             initiation of study drug.

         23. Concurrent participation in other interventional clinical trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability of ipatasertib (GDC-0068) in combination with capecitabine, eribulin, or carboplatin plus gemcitabine; as incidence of Adverse Events as assessed by the investigator, with severity determined through the use of NCI-CTCAE v.4.03
Time Frame:From baseline up to 15 months
Safety Issue:
Description:To evaluate the safety and tolerability of ipatasertib (400 mg) in combination with capecitabine, eribulin, or carboplatin plus gemcitabine

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:From baseline up to 15 months
Safety Issue:
Description:PFS, defined as the time from the date of inclusion to the date of the first documented progression or death due to any cause. If a patient has not had an event, PFS will be censored at the date of the last adequate tumor evaluation [see RECIST 1.1]) (Efficacy of ipatasertib (GDC-0068) in combination with capecitabine, eribulin, or carboplatin plus gemcitabine in the Intended To Treat (ITT) population and in each treatment arm).
Measure:Time to response (TTR)
Time Frame:From baseline up to 15 months
Safety Issue:
Description:TTR, defined as the time from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a Complete Response (CR) or Partial Response (PR), as determined locally by the investigator through the use of RECIST v.1.1.(Efficacy of ipatasertib (GDC-0068) in combination with capecitabine, eribulin, or carboplatin plus gemcitabine in the ITT population and in each treatment arm).
Measure:Overall response rate (ORR)
Time Frame:From baseline up to 15 months
Safety Issue:
Description:ORR, defined as a CR or PR, as determined locally by the investigator through the use of RECIST v.1.1.(Efficacy of ipatasertib (GDC-0068) in combination with capecitabine, eribulin, or carboplatin plus gemcitabine in the ITT population and in each treatment arm).
Measure:Duration of Response (DoR)
Time Frame:From baseline up to 15 months
Safety Issue:
Description:DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, as determined locally by the investigator through use of RECIST v.1.1.(Efficacy of ipatasertib (GDC-0068) in combination with capecitabine, eribulin, or carboplatin plus gemcitabine in the ITT population and in each treatment arm).
Measure:Clinical Benefit Rate (CBR)
Time Frame:From baseline up to 15 months
Safety Issue:
Description:CBR, defined as an objective response (CR or PR), or Stable Disease (SD) for at least 24 weeks, as determined locally by the investigator through the use of RECIST v.1.1(Efficacy of ipatasertib (GDC-0068) in combination with capecitabine, eribulin, or carboplatin plus gemcitabine in the ITT population and in each treatment arm).
Measure:Overall Survival (OS)
Time Frame:From baseline up to 15 months
Safety Issue:
Description:OS, defined as the time from treatment initiation to death from any cause, as determined locally by the investigator through use of RECIST v.1.1.(Efficacy of ipatasertib (GDC-0068) in combination with capecitabine, eribulin, or carboplatin plus gemcitabine in the ITT population and in each treatment arm).
Measure:Best percentage of change from baseline in the size of target tumor lesions
Time Frame:From baseline up to 15 months
Safety Issue:
Description:Best percentage of change from baseline in the size of target tumor lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, as determined locally by the investigator through use of RECIST v.1.1.(Efficacy of ipatasertib (GDC-0068) in combination with capecitabine, eribulin, or carboplatin plus gemcitabine in the ITT population and in each treatment arm).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:MedSIR

Last Updated

July 6, 2020