Clinical Trials /

GDC-0941 and Cisplatin in Treating Patients With Androgen Receptor-Negative Triple Negative Metastatic Breast Cancer

NCT01918306

Description:

This phase I/II trial study evaluates the tolerability and best tolerated dose of the PI3K inhibitor GDC-0941 when given with the chemotherapy cisplatin. This study will also examine how well the combination of GDC-0941 and cisplatin work in treating patients with androgen receptor negative triple negative metastatic breast cancer. Patients will be randomized to receive cisplatin alone or cisplatin with GDC-0941 in the phase II portion. Those receiving cisplatin alone can receive GDC-0941 upon progression of their disease. Cisplatin is a chemotherapy which has been shown to be effective in treating triple negative breast cancer. Preclinical studies show that adding a PI3K inhibitor such as GDC-0941 to cisplatin may be a more effective treatment for breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: GDC-0941 and Cisplatin in Treating Patients With Androgen Receptor-Negative Triple Negative Metastatic Breast Cancer
  • Official Title: A Phase Ib/II Trial of GDC-0941 (a PI3K Inhibitor) in Combination With Cisplatin in Patients With Androgen Receptor Negative Triple Negative Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: VICC BRE 1287
  • SECONDARY ID: NCI-2013-01319
  • NCT ID: NCT01918306

Conditions

  • Estrogen Receptor Negative Breast Cancer
  • Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
  • Triple Negative Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Triple-negative Breast Cancer

Interventions

DrugSynonymsArms
cisplatinPlatinol1PHIbA Arm A - cisplatin + GDC - 0941
GDC -09411PHIbA Arm A - cisplatin + GDC - 0941

Purpose

This phase I/II trial study evaluates the tolerability and best tolerated dose of the PI3K inhibitor GDC-0941 when given with the chemotherapy cisplatin. This study will also examine how well the combination of GDC-0941 and cisplatin work in treating patients with androgen receptor negative triple negative metastatic breast cancer. Patients will be randomized to receive cisplatin alone or cisplatin with GDC-0941 in the phase II portion. Those receiving cisplatin alone can receive GDC-0941 upon progression of their disease. Cisplatin is a chemotherapy which has been shown to be effective in treating triple negative breast cancer. Preclinical studies show that adding a PI3K inhibitor such as GDC-0941 to cisplatin may be a more effective treatment for breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of GDC-0941 when given in combination with
      cisplatin in patients with androgen receptor-negative (AR-) triple negative (TN) metastatic
      breast cancer (MBC): assessment of dose limiting toxicities (DLTs) during the first 4 weeks
      of treatment (cycle 1); determination of the maximally tolerated dose (MTD) and recommended
      phase II dose of GDC-0941 given in combination with cisplatin. (Phase IB)

      II. To evaluate the efficacy, as measured by the overall response rate (ORR), of cisplatin +
      GDC-0941 versus cisplatin alone in patients with AR- TN MBC. (Phase II)

      SECONDARY OBJECTIVES:

      I. To determine the clinical benefit rate (CBR) of cisplatin + GDC-0941 in patients with AR-
      TN MBC.

      II. To determine the time to disease progression (TTP) of cisplatin + GDC-0941 versus
      cisplatin alone in patients with AR- TN MBC.

      TERTIARY OBJECTIVES:

      I. To characterize pharmacokinetics of GDC-0941 when administered in combination with
      cisplatin.

      II. To explore predictors of response and mechanisms of resistance based on exploratory
      analysis of tumor tissue obtained through biopsies.

      III. To assess the prognostic effects of phosphatidylinositol-4,5-bisphosphate 3-kinase,
      catalytic subunit alpha (PIK3CA) mutations and phosphatase and tensin homolog (PTEN) loss on
      TTP and CBR.

      OUTLINE: This is a phase I, dose-deescalation study of PI3K inhibitor GDC-0941 followed by a
      randomized phase II study.

      PHASE I: Patients receive cisplatin intravenously (IV) over 1 hour on days 1, 8, and 15 and
      PI3K inhibitor GDC-0941 orally (PO) once daily (QD) on days 2-6, 9-13, 16-20, and 23-27.
      Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      PHASE II: Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive cisplatin IV over 1 hour on days 1, 8, and 15. Courses repeat every
      28 days in the absence of disease progression or unacceptable toxicity. Patients may
      crossover to Arm II upon disease progression.

      ARM II: Patients receive cisplatin as in Arm I and PI3K inhibitor GDC-0941 PO QD on days 2-6,
      9-13, 16-20, and 23-27. Courses repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
1PHIbA Arm A - cisplatin + GDC - 0941ExperimentalDetermine the safety and tolerability of GDC-0941 given in combination with cisplatin in patients with AR- TN MBC. Determination of the maximally tolerated dose (MTD) of GDC-0941. Cohort 1, 3 of 3 patients received: Cisplatin 25 mg/m2 IV D1, 8, 15 GDC-0941 260 mg PO, days 2-6, 9-13, 16-20, 23-27, 28 day cycle GDC-0941 dose to start at Max dose of 260mg. If no patient in the first cohort of 3 experiences a DLT, an additional cohort of 3 patients will be treated at the same dose level. If 1 patient experiences a DLT in the first cohort, an additional cohort of 3 patients will be treated at the same dose level. If ≤1 patient has a DLT in 6 treated at this same dose, this will be considered a tolerable dose to move to phase II If patients experience a DLT considered related to GDC-0941, the patient may remain on GDC-0941 and/or Cisplatin after resolution of the DLT. All such cases will be considered a DLT for the purposes of defining the MTD.
  • cisplatin
  • GDC -0941
1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1ExperimentalIf 2 or more patients in 3 or 6 patients treated at a given dose experience DLT, the dose will be de-escalated to the next lower dose level. Once the lowest dose level is reached, if a DLT occurs, the regimen will be considered too toxic and the corresponding cohort within the study will be discontinued. Determination of the maximally tolerated dose (MTD) of GDC-0941.
  • cisplatin
  • GDC -0941
2PHII1 Arm 1 - CisplatinActive ComparatorEvaluate the efficacy, as measured by the overall response rate (ORR), of Cisplatin +GDC-0941 versus Cisplatin alone in patients with AR- TN MBC. Patients will be randomized in a 1:1 fashion to arm 1: cisplatin, or arm 2: cisplatin + GDC-0941. Arm 1 Cisplatin Only Patient received: Cisplatin given intravenously (IV) over 1 hour for three consecutive weeks, then off one week (days 1, 8, and 15 of a 28 day cycle).
  • cisplatin
2PHII2 - Arm 2 - Cisplatin + GDC - 0941ExperimentalEvaluate the efficacy, as measured by the overall response rate (ORR), of Cisplatin +GDC-0941 versus Cisplatin alone in patients with AR- TN MBC. Patients are randomized in a 1:1 fashion to arm 1: cisplatin, or arm 2: cisplatin + GDC-0941. Arm 2 Cisplatin + GDC-0941 Patients received: Cisplatin given intravenously (IV) over 1 hour for three consecutive weeks, then off one week (days 1, 8, and 15 of a 28 day cycle). GDC-0941 260 mg PO, administered orally on days 2-6, 9-13, 16-20, 23-27 of a 28 day cycle.
  • cisplatin
  • GDC -0941
2PHIICOExperimentalArm 2: Crossover post-progression Patients who are randomized to Cisplatin alone (Arm 1) can crossover to receive Cisplatin + GDC-0941 upon disease progression. Patient received: Cisplatin given intravenously (IV) over 1 hour for three consecutive weeks, then off one week (days 1, 8, and 15 of a 28 day cycle). GDC-0941 260 mg PO, administered orally on days 2-6, 9-13, 16-20, 23-27 of a 28 day cycle.
  • cisplatin
  • GDC -0941

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must provide informed written consent.

          -  Patients must be <18 years of age.

          -  ECOG performance status 0-1.

          -  Clinical stage IV invasive mammary carcinoma, ER negative (defined as expression of ER
             in < 5% cells), PR negative (defined as expression of PR in < 5% cells), HER2 negative
             [acceptable FDA approved methods of HER2 analysis include IHC (0, 1+), fluorescence in
             situ hybridization (FISH) with HER2/CEN-17 ratio <2, and/or chromogenic in situ
             hybridization (CISH)] with HER2/CEN-17 ratio <2, as previously documented by
             histological analysis.

          -  Androgen receptor negativity, defined as < 10% of tumor cell nuclei with
             immunoreactivity for AR in a CLIA certified laboratory. See section 5.1.

          -  Measurable disease, defined as at least one lesion that can be accurately measured in
             at least one dimension by RECIST criteria 1.1, with radiologic scans within 21 days of
             day 1, cycle 1.

          -  Up to one prior chemotherapy regimens for metastatic disease.

          -  No prior treatment with cisplatin in the metastatic setting.

          -  Biopsy of a metastatic lesion in patients with reasonably accessible metastatic
             lesions (chest wall, skin, subcutaneous tissue, lymph nodes, skin, breast, bones,
             lung, and liver metastases). If a reasonably accessible site is available for biopsy,
             the patient must agree to biopsy.

          -  Life expectancy ≥ 6 months in the opinion of the investigator

          -  Patients must have adequate hematologic, hepatic, and renal function. All tests must
             be obtained less than 21 days from day 1 of study treatment. This includes:

               -  ANC >/=1500/mm3

               -  Platelet count >/=100,000/mm3

               -  Hemoglobin ≥ 9 g/dL

               -  Creatinine </=1.5X upper limits of normal (ULN)

               -  INR ≤ 2

               -  Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a
                  total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)

               -  AST and ALT ≤ 3 x ULN (or ≤ 5.0 x ULN if hepatic metastases are present)

               -  For patients without known Type II diabetes, the following is required at
                  screening:

                  o -Fasting blood glucose </= 135 mg/dL (7.49 mmol/L) and glycosylated hemoglobin
                  (HbA1c) <7.0 % or International Federation of Clinical Chemistry (IFCC) < 53
                  mmol/mol

               -  For patients with Type II diabetes receiving only oral anti-hyperglycemic therapy
                  (patients receiving insulin are not eligible), the following are required at
                  screening:

                    -  -HbA1c < 8.5 % or IFCC < 69.4 mmol/mol

                    -  -Stable regimen of oral anti-hyperglycemic therapy without insulin usage for
                       at least 3 weeks prior to first study treatment

                    -  -Fasting blood glucose levels </= 160 mg/dL (8.88 mmol/L) and no
                       hypoglycemia (BS <60) during home monitoring for at least 1 week prior to
                       study entry

          -  Patients must be able to swallow and retain oral medication.

          -  For patients who are not postmenopausal or surgically sterile (absence of ovaries
             and/or uterus), agreement to remain abstinent or to use two adequate methods of
             contraception, including at least one method with a failure rate of < 1% per year
             (e.g., hormonal implants, combined oral contraceptives, vasectomy/vasectomized
             partner, tubal ligation), during the treatment period and for at least 30 days after
             the last dose of GDC-0941 or 6 months after the last dose of cisplatin, whichever is
             longer; postmenopausal is defined as:

          -  Age >/= 60 years

          -  Age </= 60 years and amenorrheic for 12 months in the absence of chemotherapy,
             tamoxifen, toremifene, or ovarian suppression; and follicle stimulating hormone and
             estradiol in the postmenopausal range

          -  Patients may have received radiation therapy to painful bone metastases or areas of
             impending bone fracture as long as radiation therapy is completed ≥ 2 weeks prior to
             day 1 of cycle 1 of treatment. Patients who have received prior radiotherapy must have
             recovered from toxicity (≤ grade 1) induced by this treatment. Baseline radiologic
             scans must be obtained after completion of radiation.

          -  Patients must complete all screening assessments as outlined in the protocol.

        Exclusion Criteria:

          -  Any kind of malabsorption syndrome significantly affecting gastrointestinal function.

          -  Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,
             immunotherapy, hormonal therapy, biologic therapy) other than the ones specified in
             the protocol. Patients must have discontinued the above cancer therapies for 1 week
             prior to the first dose of study medication, as well as recovered from toxicity (to ≤
             than grade 1, except for alopecia) induced by previous treatments. Any investigational
             drugs should be discontinued 2 weeks prior to the first dose of study medication and
             radiotherapy must have been completed ≥ 2 weeks prior to initiation of study drug
             (Cycle 1, Day 1).

          -  Prior use of PI3K, or Akt inhibitors in the neoadjuvant, adjuvant, and metastatic
             setting for the treatment of cancer. These include, but are not limited to: GDC-0941,
             GDC-0980, GDC-0032, BEZ235, BKM120, LY294002, PIK-75, TGX-221, XL147, XL765, SF1126,
             PX-866, D-87503, D-106669, GSK615, CAL101. Patients who have received PI3K/Akt
             inhibitors previously for <4 weeks will be eligible.

          -  Pregnant or lactating women.

          -  Insulin-dependent diabetes. Patients with Type II diabetes must meet criteria outlined
             in Inclusion Criteria.

          -  Uncontrolled intercurrent illness including, but not limited to:

               -  -Ongoing or active infection requiring parenteral antibiotics

               -  -Impairment of lung function (COPD > grade 2, lung conditions requiring oxygen
                  therapy) or current dyspnea at rest

               -  -Symptomatic congestive heart failure (class III or IV of the New York Heart
                  Association classification for heart disease)

               -  -Known Left Ventricular Ejection Fraction (LVEF) < 50%.

               -  -Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within
                  6 months

               -  -Uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic blood
                  pressure > 100 mm Hg, found on two consecutive measurements separated by a 1 or 2
                  week period despite adequate medical support)

               -  -Clinically significant cardiac arrhythmia (multifocal premature ventricular
                  contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or
                  requires treatment [National Cancer Institute -Common Terminology Criteria for
                  Adverse Events, Version 4.0, grade 3]

               -  -QTcF ≥ 480 msec on screening EKG

               -  -Known history of QT/QTc prolongation or Torsades de Pointes (TdP)

               -  -ST depression or elevation of ≥ 1.5 mm in 2 or more leads

               -  -Diarrhea of any cause ≥ CTCAE grade 2

               -  -Active autoimmune disease that is not controlled by nonsteroidal or steroidal
                  (<10 mg of prednisone per day) anti inflammatory drugs or active inflammatory
                  disease, including small or large intestine inflammation such as active Crohn's
                  disease or ulcerative colitis, which requires immunosuppressive therapy

               -  -Psychiatric illness/social situations that would compromise patient safety or
                  limit compliance with study requirements including maintenance of a
                  compliance/pill diary

               -  -Symptomatic brain metastases (patients with a history of brain metastases must
                  be clinically stable for at least 2 weeks from completion of radiation treatment,
                  on a dose of steroids equivalent to <10 mg prednisone daily for at least one
                  week, and on a stable dose of therapeutic anticonvulsants)

               -  -Known history of chronic liver disease, including cirrhosis, current alcohol
                  abuse, or infection with hepatitis B virus or hepatitis C virus (active or
                  carrier), or renal failure

               -  -Known history of chronic pancreatitis

               -  -Conditions that affect lymphocyte counts, such as HIV infection or
                  immunosuppressive therapy

          -  Use of prohibited drugs
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose(MTD) of GDC-0941 and Recommended Phase II Dose of GDC-0941 Given in Combination With Cisplatin. - (Phase Ib)
Time Frame:4 weeks
Safety Issue:
Description:GDC-0941 dose will start at 260 mg (maximum dose). De-escalation of the intensity of the dose (if necessary) will proceed among cohorts of 3 patients according to a standard 3+3 algorithm beginning at the highest dose level of GDC-0941 260mg. MTD is defined as the highest dose at which a DLT is experienced >= 1 out of 6 patients. A cohort of 3 patients was initially enrolled in the GDC-0941 arm at dose 260mg PO days 2-6, 9-13, 16-20, 23-27 of 28 day cycle If no patient in the first cohort of 3 experiences a DLT, an additional cohort of 3 patients will be treated at the same dose level. If 1 patient experiences a DLT in the first cohort, an additional cohort of 3 patients will be treated at the same dose level. If ≤1 patient has a DLT in 6 treated at this same dose, this will be considered a tolerable dose to move to phase II. If 2 or more patients in 3 or 6 patients treated at a given dose experience DLT, the dose will be de-escalated to the next lower dose level.

Secondary Outcome Measures

Measure:Number of Patients With Dose-limiting Toxicities Per NCI Common Terminology for Adverse Events (CTCAE) - (Phase Ib)
Time Frame:During the first 4 weeks
Safety Issue:
Description:Number of patients with Grade 3 and 4 toxicities per NCI Common Terminology for Adverse Events (CTCAE) version 4.0 requirements.
Measure:Clinical Benefit Rate - (Phase II)
Time Frame:at 32 weeks
Safety Issue:
Description:Clinical Benefit Rate (CBR) is defined as complete response (CR) plus partial response (PR) plus stable disease (SD) for 6 months. Clinical Benefit Rate (CBR) is calculated with the corresponding 95% confidence intervals at the dose recommended for phase II. Response and progression will be evaluated using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 performed at baseline and every 8 weeks will be compared.
Measure:Time to Progression - (Phase II)
Time Frame:From time of randomization to disease progression, up to 104 weeks
Safety Issue:
Description:Time to Progression (TTP) is calculated with the corresponding 95% confidence interval at the dose recommended for phase II. TTP is defined as the time from randomization until objective tumor progression, this does not include deaths unrelated to disease progression.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Vanderbilt-Ingram Cancer Center

Trial Keywords

  • Triple Negative Breast Cancer
  • Estrogen receptor negative breast cancer
  • Metastatic breast cancer
  • Stage IV breast cancer
  • HER2 negative breast cancer

Last Updated

May 22, 2017