Estrogen Receptor Negative Breast CancerPhase 1/2NCT01918306
GDC-0941 and Cisplatin in Treating Patients With Androgen Receptor-Negative Triple Negative Metastatic Breast Cancer
A Phase 1/2 study testing cisplatin, laboratory biomarker analysis and pharmacological study in people with Estrogen Receptor Negative Breast Cancer and Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, run by Vanderbilt-Ingram Cancer Center at 16 sites in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Estrogen Receptor Negative Breast Cancer, Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, Triple Negative Breast Cancer
- What is being tested?
- cisplatin, laboratory biomarker analysis and pharmacological study
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 16 sitesUnited States
- Study dates
- Sep 2013to Apr 2015
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 30Show fewer
- 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.
Who cannot join
- 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:
Show all 24Show fewer
- -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
Trial locations and contacts
16 sites in 1 country.
16 sites in 1 country
United States16 sites
University of Michigan
Ann Arbor, Michigan
Emory University
Atlanta, Georgia
John Hopkins University
Baltimore, Maryland
University of Alabama
Birmingham, Alabama
Dana Farber Cancer Institute
Boston, Massachusetts
University of North Carolina
Charlotte, North Carolina
University of Chicago
Chicago, Illinois
Baylor Breast Center
Houston, Texas
Indiana University
Indianapolis, Indiana
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37232
Memorial Sloan-Kettering Cancer Center
New York, New York
University of Pittsburgh
Pittsburgh, Pennsylvania
Mayo Clinic
Rochester, Minnesota
University of California, San Francisco
San Francisco, California
University of Washington
Seattle, Washington
Georgetown University
Washington D.C., District of Columbia
About this study
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
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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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:
- 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.
- 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
- Being tested
- cisplatin, laboratory biomarker analysis, pharmacological study, dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI, GDC -0941
- Keywords
- Triple Negative Breast Cancer, Estrogen receptor negative breast cancer, Metastatic breast cancer, Stage IV breast cancer, HER2 negative breast cancer
- Medical subject headings
- Triple Negative Breast Neoplasms, Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
cisplatinDrug
Also called Platinol
In 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.
In Arm II patients receive cisplatin as in Arm I and PI3K inhibitor GDC-0941 orally (PO) one time a day (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.
--------------------------------------------------------------------------------
laboratory biomarker analysisOther
correlative studies
correlative studies
dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRIProcedure or surgery
correlative studies
GDC -0941Drug
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
| Study group | Role | What they receive |
|---|---|---|
| 1PHIbA Arm A - cisplatin + GDC - 0941 | Experimental | Determine 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.
1. If 1 patient experiences a DLT in the first cohort, an additional cohort of 3 patients will be treated at the same dose level.
2. 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. Receives: Drug: cisplatin; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI; Drug: GDC -0941 |
| 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1 | Experimental | 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. 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. Receives: Drug: cisplatin; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI; Drug: GDC -0941 |
| 2PHII1 Arm 1 - Cisplatin | Active comparator | Evaluate 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). Receives: Drug: cisplatin; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI |
| 2PHII2 - Arm 2 - Cisplatin + GDC - 0941 | Experimental | Evaluate 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. Receives: Drug: cisplatin; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI; Drug: GDC -0941 |
| 2PHIICO | Experimental | Arm 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. Receives: Drug: cisplatin; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI; Drug: GDC -0941 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose(MTD) of GDC-0941 and Recommended Phase II Dose of GDC-0941 Given in Combination With Cisplatin. - (Phase Ib)
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.
Measured: 4 weeks
Percentage of Patients Achieving Overall Response - (Phase II)
The primary efficacy endpoint is overall response rate (ORR) of cisplatin + GDC-0941 versus cisplatin alone in patients with AR- TN MBC. ORR is defined as the percentage of subjects achieving complete response (CR) plus partial response (PR) as their best response by RECIST version 1.1 for targeted lesions and assessed by CT, MRI scan.
Objective responses, was estimated by the overall tumor burden at baseline (targeted lesions) in which subsequent measurements were performed every 8 weeks using the Solid Tumor Response Criteria (RECIST) v1.1 were compared. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Measured: at 8 weeks
Secondary outcomes (3)
Number of Patients With Dose-limiting Toxicities Per NCI Common Terminology for Adverse Events (CTCAE) - (Phase Ib)
Number of patients with Grade 3 and 4 toxicities per NCI Common Terminology for Adverse Events (CTCAE) version 4.0 requirements.
Measured: During the first 4 weeks
Clinical Benefit Rate - (Phase II)
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.
Measured: at 32 weeks
Time to Progression - (Phase II)
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.
Measured: From time of randomization to disease progression, up to 104 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Aug 2013 (estimated)
- Study startSep 2013
- Primary completionDec 2014
- Study completionApr 2015
Why it stopped: company stopped production of study drug due to excessive toxicities, lack of efficacy
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Estrogen Receptor Negative Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt-Ingram Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI), Genentech, Inc.
- Responsible party
- Principal investigator, Vandana Abramson, Vanderbilt-Ingram Cancer Center
- Investigators
- Vandana G. Abramson, MD, Principal investigator, Vanderbilt-Ingram Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01918306
- Sponsor's protocol ID
- VICC BRE 1287
- Other IDs
- NCI-2013-01319
- Status last verified
- May 2017
- First submitted
- 25 Jul 2013
- Last updated
- 27 Jun 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 27 Jun 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01918306
- Acronym / sponsor ID
- VICC BRE 1287
- 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
- Keywords
- Triple Negative Breast Cancer, Estrogen receptor negative breast cancer, Metastatic breast cancer, Stage IV breast cancer, HER2 negative breast cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: company stopped production of study drug due to excessive toxicities, lack of efficacy
- Enrolment
- 11 participants (actual)
- Lead sponsor
- Vanderbilt-Ingram Cancer CenterUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI), Genentech, Inc.
- Study start
- Sep 2013
- Primary completion
- Dec 2014 (actual)
- Study completion
- Apr 2015 (actual)
- First posted
- 7 Aug 2013 (estimated)
- Results
- Posted 27 Jun 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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:
- 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:
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| 1PHIbA Arm A - cisplatin + GDC - 0941 | Experimental | Drug: cisplatin, Other: laboratory biomarker analysis, Other: pharmacological study, Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI, Drug: GDC -0941Determine 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. 1. If 1 patient experiences a DLT in the first cohort, an additional cohort of 3 patients will be treated at the same dose level. 2. 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. |
| 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1 | Experimental | Drug: cisplatin, Other: laboratory biomarker analysis, Other: pharmacological study, Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI, Drug: GDC -0941If 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. |
| 2PHII1 Arm 1 - Cisplatin | Active comparator | Drug: cisplatin, Other: laboratory biomarker analysis, Other: pharmacological study, Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRIEvaluate 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). |
| 2PHII2 - Arm 2 - Cisplatin + GDC - 0941 | Experimental | Drug: cisplatin, Other: laboratory biomarker analysis, Other: pharmacological study, Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI, Drug: GDC -0941Evaluate 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. |
| 2PHIICO | Experimental | Drug: cisplatin, Other: laboratory biomarker analysis, Other: pharmacological study, Procedure: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI, Drug: GDC -0941Arm 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (30 listed)
- 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.
Key exclusion criteria (24 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| cisplatinAlso: PlatinolIn 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. In Arm II patients receive cisplatin as in Arm I and PI3K inhibitor GDC-0941 orally (PO) one time a day (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. -------------------------------------------------------------------------------- | Drug | 1PHIbA Arm A - cisplatin + GDC - 0941, 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1, 2PHII1 Arm 1 - Cisplatin, 2PHII2 - Arm 2 - Cisplatin + GDC - 0941, 2PHIICO |
| laboratory biomarker analysiscorrelative studies | Other | 1PHIbA Arm A - cisplatin + GDC - 0941, 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1, 2PHII1 Arm 1 - Cisplatin, 2PHII2 - Arm 2 - Cisplatin + GDC - 0941, 2PHIICO |
| pharmacological studycorrelative studies | Other | 1PHIbA Arm A - cisplatin + GDC - 0941, 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1, 2PHII1 Arm 1 - Cisplatin, 2PHII2 - Arm 2 - Cisplatin + GDC - 0941, 2PHIICO |
| dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRIcorrelative studies | Procedure or surgery | 1PHIbA Arm A - cisplatin + GDC - 0941, 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1, 2PHII1 Arm 1 - Cisplatin, 2PHII2 - Arm 2 - Cisplatin + GDC - 0941, 2PHIICO |
| GDC -0941Patients 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 | Drug | 1PHIbA Arm A - cisplatin + GDC - 0941, 1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1, 2PHII2 - Arm 2 - Cisplatin + GDC - 0941, 2PHIICO |
Primary outcome
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
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 1. 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. 2. If 1 patient experiences a DLT in the first cohort, an additional cohort of 3 patients will be treated at the same dose level. 3. 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. 4. 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.
Percentage of Patients Achieving Overall Response - (Phase II)
Time frame: at 8 weeks
The primary efficacy endpoint is overall response rate (ORR) of cisplatin + GDC-0941 versus cisplatin alone in patients with AR- TN MBC. ORR is defined as the percentage of subjects achieving complete response (CR) plus partial response (PR) as their best response by RECIST version 1.1 for targeted lesions and assessed by CT, MRI scan. Objective responses, was estimated by the overall tumor burden at baseline (targeted lesions) in which subsequent measurements were performed every 8 weeks using the Solid Tumor Response Criteria (RECIST) v1.1 were compared. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
3 secondary outcomes
Number of Patients With Dose-limiting Toxicities Per NCI Common Terminology for Adverse Events (CTCAE) - (Phase Ib)
Time frame: During the first 4 weeks
Clinical Benefit Rate - (Phase II)
Time frame: at 32 weeks
Time to Progression - (Phase II)
Time frame: From time of randomization to disease progression, up to 104 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jun 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Vanderbilt-Ingram Cancer Center, Find a Clinical TrialLink provided by the sponsor.
Related trials for Estrogen Receptor Negative Breast Cancer
RecruitingPhase 3
Testing Whether Hormone Therapy With Ribociclib is as Effective as Chemotherapy Followed by Hormone Therapy With Ribociclib for the Treatment of High Anatomic Stage Breast Cancer With Low Recurrence Risk, The RxFINE-Low Trial
Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8
Recruiting
Short-Term Reduced Dietary Protein in ER+/HER2- Breast Cancer Patients During Neoadjuvant Chemotherapy
Breast Cancer, Hormone Receptor Positive / HER2-negative Breast Cancer
Active, not recruitingObservational study
Longitudinal ctDNA Surveillance for Older Women With ER+ Breast Cancer Who Omit Surgery
Breast Cancer
Not yet recruiting
Prospective Study to Evaluate the Clinical Utility of ctDNA Tumor Fraction (TF) for Detection of Estrogen Receptor 1 (ESR1) Mutations in (Human Epidermal Growth Factor Receptor) HR+/HER2- Metastatic Breast Cancer (MBC)
Breast Cancer, Metastatic Breast Cancer
Recruiting
Signatera-Guided CDK4/6 Inhibitor Therapy in Breast Cancer
Breast Neoplasms, Carcinoma, Ductal, Breast
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vandana G. Abramson, MD principal investigator
Vanderbilt-Ingram Cancer Center
16 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing cisplatin, laboratory biomarker analysis and pharmacological study in people with Estrogen Receptor Negative Breast Cancer and Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, run by Vanderbilt-Ingram Cancer Center at 16 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 30 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 27 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jun 2017.