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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 11
- 试验地点
- 16
- 主要终点
- Maximum Tolerated Dose(MTD) of GDC-0941 and Recommended Phase II Dose of GDC-0941 Given in Combination With Cisplatin. - (Phase Ib)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Open label
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must provide informed written consent.
- •Patients must be <18 years of age.
- •ECOG performance status 0-
- •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.
- •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
- •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)
- •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.
排除标准
- •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, CAL
- •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
研究组 & 干预措施
1PHIbA Arm A - cisplatin + GDC - 0941
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.
- 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.
干预措施: cisplatin (Drug)
1PHIbA Arm A - cisplatin + GDC - 0941
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.
- 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.
干预措施: laboratory biomarker analysis (Other)
1PHIbA Arm A - cisplatin + GDC - 0941
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.
- 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.
干预措施: pharmacological study (Other)
1PHIbA Arm A - cisplatin + GDC - 0941
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.
- 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.
干预措施: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI (Procedure)
1PHIbA Arm A - cisplatin + GDC - 0941
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.
- 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.
干预措施: GDC -0941 (Drug)
1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1
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.
干预措施: cisplatin (Drug)
1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1
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.
干预措施: laboratory biomarker analysis (Other)
1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1
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.
干预措施: pharmacological study (Other)
1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1
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.
干预措施: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI (Procedure)
1PHIbB - Arm B - Cisplatin + GDC 0941 dose level -1
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.
干预措施: GDC -0941 (Drug)
2PHII1 Arm 1 - Cisplatin
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).
干预措施: cisplatin (Drug)
2PHII1 Arm 1 - Cisplatin
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).
干预措施: laboratory biomarker analysis (Other)
2PHII1 Arm 1 - Cisplatin
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).
干预措施: pharmacological study (Other)
2PHII1 Arm 1 - Cisplatin
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).
干预措施: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI (Procedure)
2PHII2 - Arm 2 - Cisplatin + GDC - 0941
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.
干预措施: cisplatin (Drug)
2PHII2 - Arm 2 - Cisplatin + GDC - 0941
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.
干预措施: laboratory biomarker analysis (Other)
2PHII2 - Arm 2 - Cisplatin + GDC - 0941
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.
干预措施: pharmacological study (Other)
2PHII2 - Arm 2 - Cisplatin + GDC - 0941
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.
干预措施: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI (Procedure)
2PHII2 - Arm 2 - Cisplatin + GDC - 0941
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.
干预措施: GDC -0941 (Drug)
2PHIICO
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.
干预措施: cisplatin (Drug)
2PHIICO
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.
干预措施: laboratory biomarker analysis (Other)
2PHIICO
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.
干预措施: pharmacological study (Other)
2PHIICO
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.
干预措施: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI (Procedure)
2PHIICO
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.
干预措施: GDC -0941 (Drug)
结局指标
主要结局
Maximum Tolerated Dose(MTD) of GDC-0941 and Recommended Phase II Dose of GDC-0941 Given in Combination With Cisplatin. - (Phase Ib)
时间窗: 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)
时间窗: 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.
次要结局
- Number of Patients With Dose-limiting Toxicities Per NCI Common Terminology for Adverse Events (CTCAE) - (Phase Ib)(During the first 4 weeks)
- Clinical Benefit Rate - (Phase II)(at 32 weeks)
- Time to Progression - (Phase II)(From time of randomization to disease progression, up to 104 weeks)
研究者
Vandana Abramson
Assistant Professor of Medicine; Medical Oncologist
Vanderbilt-Ingram Cancer Center