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Estrogens

Cisplatin

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.

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.

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).

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.

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.

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.

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cisplatin

laboratory biomarker analysis

pharmacological study

dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI

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

GDC -0941

Vandana G. Abramson, MD

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.

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.

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

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

Examining tumor tissue for PI3K mutations and correlating this statistically with clinical outcomes including time to tumor progression.

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.

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.

Number of patients with Grade 3 and 4 toxicities per NCI Common Terminology for Adverse Events (CTCAE) version 4.0 requirements.

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.

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.

National Cancer Institute (NCI)

Genentech, Inc.

Vanderbilt-Ingram Cancer Center

Assistant Professor of Medicine; Medical Oncologist

Patients cohort 1 receive cisplatin and PI3K inhibitor GDC-0941. Courses repeat in the absence of disease progression or unacceptable toxicity.

cisplatin: 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.

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.

If no patients in Cohort 1 experienced DLT's after 4 weeks, all patients in Cohort 2 will receive cisplatin and PI3K inhibitor GDC-0941, GDC-0941dose not to exceed 260mg.

If 1 patient experiences a DLT in the first cohort, an additional cohort of 3 patients will be treated at the same dose level in cohort 2.

If ≤1 patient has a DLT in 6 (cohort 1 and 2) treated at this same dose, this will be considered a tolerable dose to move to phase II.

1PHIbA - Arm A - Cisplatin + GDC - 0941 Dose Level 1

If 2 or more patients in 3 or 6 patients (cohort 1 and 2) treated at a given dose 260 mg experience DLT, the dose will be de-escalated to the next lower dose level.

1PHIbB - Arm B - Cisplatin + GDC -0941 Dose Level -1

Patients receive cisplatin in Arm I. Patients may crossover to Arm II upon disease progression.

cisplatin:patients received 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.

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laboratory biomarker analysis: correlative studies

pharmacological study: correlative studies

dynamic contrast-enhanced MRI, diffusion-weighted MRI \& chemical exchange saturation transfer MRI: correlative studies

2PHII 1 - Arm 1 - Cisplatin Only

Patients receive Cisplatin and PI3K inhibitor GDC-0941. Courses repeat in the absence of disease progression or unacceptable toxicity.

cisplatin: patients received 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 receive 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.

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laboratory biomarker analysis: correlative studies

pharmacological study: correlative studies

dynamic contrast-enhanced MRI, diffusion-weighted MRI \& chemical exchange saturation transfer MRI: correlative studies

GDC -0941: Patients receive cisplatin as in Arm I and PI3K

2PHII2 - Arm 2 - Cisplatin and GDC-0941

Crossover patient received Cisplatin and PI3K inhibitor GDC-0941 after found to have disease progression in Cisplatin only arm. Courses repeat in the absence of disease progression or unacceptable toxicity.

cisplatin: patients received 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.

patient received 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 analysis: correlative studies

pharmacological study: correlative studies

dynamic contrast-enhanced MRI, diffusion-weighted MRI \& chemical exchange saturation transfer MRI: correlative studies

2PHIICO - Crossover to Arm 2 - Cistplatin + GDC -0941

Patients receive cisplatin in Arm I. Patients may crossover to Arm II upon disease progression.

cisplatin: 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.

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laboratory biomarker analysis: correlative studies

pharmacological study: correlative studies

dynamic contrast-enhanced MRI, diffusion-weighted MRI \& chemical exchange saturation transfer MRI: correlative studies

Patients receive cisplatin as in Arm I and PI3K inhibitor GDC-0941. Courses repeat in the absence of disease progression or unacceptable toxicity.

cisplatin: 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.

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GDC -0941: 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

Cisplatin and GDC-0941

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

One participant that is listed in Cisplatin and GDC-0941 arm is a Crossover patient from the Cisplatin only arm.

Dr. Vandana Abramson

Patients receive cisplatin and PI3K inhibitor GDC-0941. Courses repeat in the absence of disease progression or unacceptable toxicity.

cisplatin: 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.

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.

1PHIbA -Cisplatin and GDC-0941

A cohort of 3 was enrolled at dose 260mg. No DLT was found. Then a second cohort of 260mg was enrolled. One of them experienced DLT.

Maximum Tolerated Dose(MTD) of GDC-0941 and Recommended Phase II Dose of GDC-0941 Given in Combination With Cisplatin. - (Phase Ib)

Patients receive cisplatin in Arm I. Patients may crossover to Arm II upon disease progression.

cisplatin:patients received 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.

laboratory biomarker analysis: correlative studies

pharmacological study: correlative studies

dynamic contrast-enhanced MRI, diffusion-weighted MRI \& chemical exchange saturation transfer MRI: correlative studies

2PHII1 Arm 1 Cisplatin

Patients receive Cisplatin and PI3K inhibitor GDC-0941. Courses repeat in the absence of disease progression or unacceptable toxicity.

cisplatin: patients received 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 receive 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 analysis: correlative studies

pharmacological study: correlative studies

dynamic contrast-enhanced MRI, diffusion-weighted MRI \& chemical exchange saturation transfer MRI: correlative studies

2PHII2 Arm 2 - Cisplatin and GDC-0941

Crossover patient received Cisplatin and PI3K inhibitor GDC-0941 after found to have disease progression in Cisplatin only arm. Courses repeat in the absence of disease progression or unacceptable toxicity.

cisplatin: patients received 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 receive 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 analysis: correlative studies

pharmacological study: correlative studies

dynamic contrast-enhanced MRI, diffusion-weighted MRI \& chemical exchange saturation transfer MRI: correlative studies

2PHIICO - Crossover to Arm 2 - Cisplatin and GDC-0941

Phase 1-Initial and Max tolerated dose of GCD-0941 was the same, no dose de-escalation occurred. Phase 2, 1 of the 2 patients from the Cisplatin only arm did crossover to the Crossover Cisplatin and GDC-0941 arm. 3 patients randomized to Cisplatin + GDC -0941 arm, and 1 crossover patient, for a total of 4 patients who received Cisplatin+GDC-0941.

Percentage of Patients Achieving Overall Response - (Phase II)

Starting dose of GDC - 0941 260mg. 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. (Highest dose = 260mg)

In cohort 1 patients received 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 also received 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.

1PHIbA - Cisplatin and GDC-0941 Cohort 1

Starting dose of GDC - 0941 260mg, no DLT's experienced in cohort 1. Therefore no de-escalation of the intensity of the dose was necessary. An additional cohort of 3 patients will be treated at the same dose level beginning at the highest dose level. (Highest dose = 260mg)

In cohort 2, patients received 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 also received 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.

≤1 patient has a DLT in 6 treated at this same dose, this will be considered a tolerable dose to move to phase II.

1 PHIbA - Arm 1 - Cisplatin and GDC-0941Cohort 2

1PHIbB - Arm B - Cistplatin + GDC -0941 Dose Level -1

Less than 2 patients in cohort 1 and 2 experienced DLT, therefore no patients enrolled in arm 1PHIbB.

Number of Patients With Dose-limiting Toxicities Per NCI Common Terminology for Adverse Events (CTCAE) - (Phase Ib)

Patients receive Cisplatin in Arm I. Patients may crossover to Arm II upon disease progression.

Cisplatin: patients received 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.

laboratory biomarker analysis: correlative studies

pharmacological study: correlative studies

dynamic contrast-enhanced MRI, diffusion-weighted MRI \& chemical exchange saturation transfer MRI: correlative studies

2 PHII1 - ARM 1 Cisplatin

2PHII2 - ARM 2 - Cisplatin and GDC-0941

2PHIICO - Crossover to 2 - Cisplatin + GDC-0941

Study closed early and response and progression were not evaluated at 32 weeks.

Clinical Benefit Rate - (Phase II)

2PHII1 - Arm 1 - Cisplatin

2PHIICO - Crossover to Arm 2 - Cistplatin + GDC - 0941

Time to Progression - (Phase II)

Correlation of the Presence of PIK3CA Mutations in the Tumor With Time to Tumor Progression.

1PHIbA - Arm A - Cisplatin + GDC -0941 Dose Level 1 Cohort 1&2

Patients receive cisplatin in Arm I. Patients may crossover to Arm II upon disease progression.

cisplatin: 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.

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laboratory biomarker analysis: correlative studies

pharmacological study: correlative studies

dynamic contrast-enhanced MRI, diffusion-weighted MRI \& chemical exchange saturation transfer MRI: correlative studies

2PHII1 - Arm 1 - Cisplatin Only

Overall Study

Gemcitabine

Paclitaxel

Carboplatin

Hormones

Albumin-Bound Paclitaxel

Progesterone

Tubulin Modulators

Antimitotic Agents

Antimetabolites

Treatment Arm A: nab-Paclitaxel 125 mg/m\^2 by intravenous (IV) administration over 30 minutes, followed by gemcitabine 1000 mg/m\^2 on Days 1 and 8 of each 21-day cycle by IV administration over 30 minutes

Treatment Arm B: nab-Paclitaxel 125 mg/m\^2 on Days 1 and 8 by IV administration followed by carboplatin at an Area Under the Curve (AUC) of 2 on Days 1 and 8 of each 21-day cycle by IV administration

Treatment Arm C: Gemcitabine 1000 mg/m\^2 on Days 1 and 8 by IV administration followed by carboplatin AUC 2 on Days 1 and 8 of each 21-day cycle by IV administration

nab-Paclitaxel 125 mg/m\^2 by IV administration over 30 minutes on Days 1 and 8 of each 21-day treatment cycle.

nab-Paclitaxel

Carboplatin at an AUC of 2 on Days 1 and 8 of each 21-day cycle by IV administration

Gemcitabine 1000 mg/m\^2 on Days 1 and 8 of each 21-day treatment cycle.

Ileana Elias, M.D.

The purpose of this study is to compare the safety and efficacy of nab-paclitaxel in combination with either gemcitabine or carboplatin to the combination of gemcitabine and carboplatin as first line treatment in female subjects with triple negative metastatic breast cancer (TNMBC) or metastatic triple negative breast cancer.

ABI-007-MBC- 001 is a Phase 2/3, multicenter, open-label, randomized, study that will compare the safety and efficacy of weekly nab-paclitaxel in combination with gemcitabine or carboplatin to the combination of gemcitabine and carboplatin as first line therapy in female subjects with Estrogen Receptor (ER), Progesterone Receptor (PgR), and human epidermal growth factor receptor 2 (HER2) negative (triple negative) metastatic breast cancer (TNMBC) or metastatic triple negative breast cancer. In the phase 2 portion of the study, the combinations of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus carboplatin will be evaluated, and a comparator arm of gemcitabine combined with carboplatin will be used. In the phase 3 portion of the study, the selected nab-paclitaxel combination treatment will be compared to gemcitabine combined with carboplatin to evaluate progression free survival, safety and tolerability, overall survival, disease control rate and duration of response in women with metastatic triple negative breast cancer.

Due to changes in the treatment landscape since the initiation of this trial, the decision was made not to proceed to the Phase 3 portion of the study.

Evaluate Risk/Benefit of Nab Paclitaxel in Combination With Gemcitabine and Carboplatin Compared to Gemcitabine and Carboplatin in Triple Negative Metastatic Breast Cancer (or Metastatic Triple Negative Breast Cancer)

A Phase 2/3, Multi-Center, Open-Label, Randomized Study of Weekly Nab®-Paclitaxel in Combination With Gemcitabine or Carboplatin, Compared to Gemcitabine/Carboplatin, as First Line Treatment in Subjects With ER, PgR, and HER2 Negative (Triple Negative) Metastatic Breast Cancer

PFS was defined as the time from the date of randomization to the date of disease progression or death from any cause on or prior to the data cutoff date for the statistical analysis, whichever occurred earlier. Tumor responses were assessed every 6 weeks using, Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and defined as: Complete response (CR) is the disappearance of all target lesions; Partial response (PR) occurs when at least a 30% decrease in the sum of diameters of target lesions from baseline; Stable disease is neither sufficient shrinkage to qualify for a PR nor sufficient increase of lesions to qualify for Progressive disease (PD); Progressive Disease- is at least a 20% increase in the sum of diameters of target lesions from nadir.

Percentage of participants with an Objective Complete or Partial Overall Response according to RECIST 1.1 and defined as: Complete response-disappearance of all target lesions; partial response at least a 30% decrease in the sum of diameters of target lesions from baseline; stable disease-neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for Progressive disease (PD)• Progressive Disease- At least a 20% increase in the sum of diameters of target lesions from nadir.

The percentage of participants who initiated Cycle 6 receiving doublet combination therapy regardless of the need for dose modifications.

Overall survival was defined as the time from the date of randomization to the date of death (from any cause).

Treatment-emergent adverse events (TEAEs) were defined as any AEs that began or worsened with the onset date on or after the date of the first dose of IP through 28 days after the last dose. A serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was graded based on the participant's symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity as follows: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death.

The number of participants with dose modifications occurring during the treatment period. Dose reductions and interruptions are typically caused by clinically significant laboratory abnormalities and /or treatment emergent adverse events/toxicities.

Treatment-emergent adverse events (TEAEs) were defined as any AEs that begin or worsen with an onset date on or after the date of the first dose of IP through 28 days after the last dose.

Celgene

Maximum treatment duration of study drug exposure was 108.3 weeks for Arm A, 83 weeks for Arm B and 110.1 weeks for Arm C

Participants received nab-Paclitaxel 125 mg/m\^2 on Days 1 and 8 by intravenous (IV) administration followed by gemcitabine 1000 mg/m\^2 on Days 1 and 8 by IV administration in each 21-day treatment cycle.

Arm A: Nab-Paclitaxel + Gemcitabine

Participants received nab-Paclitaxel 125 mg/m\^2 on Days 1 and 8 by IV administration followed by Carboplatin AUC 2 on Days 1 and 8 in each 21-day treatment cycle.

Arm B: Nab-Paclitaxel + Carboplatin

Participants received Gemcitabine 1000 mg/m\^2 on Days 1 and 8 by IV administration, followed by carboplatin AUC 2 on Days 1 and 8 by IV administration in each 21-day treatment cycle.

Arm C: Gemcitabine + Carboplatin

Participants received nab-Paclitaxel 125 mg/m\^2 on Days 1 and 8 by intravenous (IV) administration followed by gemcitabine 1000 mg/m\^2 on Days 1 and 8 by IV administration in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

Arm A: Nab-Paclitaxel Plus (+) Gemcitabine

Participants received nab-Paclitaxel 125 mg/m\^2 on Days 1 and 8 by IV administration followed by carboplatin area under the curve 2 (AUC 2) on Days 1 and 8 in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

Participants received gemcitabine 1000 mg/m\^2 on Days 1 and 8 by IV administration, followed by carboplatin AUC 2 on Days 1 and 8 by IV administration in each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment.

Black or African American

White

Unknown or Not Reported

Race

0 = Fully Active

1 = Restrictive but ambulatory

2 = Ambulatory but unable to work

Missing

ECOG performance status is used by doctors and researchers to assess how a subject's disease is progressing, assess how the disease affects the daily living activities of the subject and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, No self-care (Least Favorable Activity)

Eastern Cooperative Oncology Group (ECOG) Performance Status

≤ 1 year

> 1 year

Disease Free Interval is defined as period of being absent of disease less than or equal to one year or free of disease greater than one year.

Disease Free Interval by Clinical Interpretation

Time from Diagnosis to First Documented Disease/Relapse

Time from First Documented Metastatic Disease/Relapse to Study Randomization

Time from Primary Diagnosis to Randomization

Lymph Nodes(s)

Lung/Thoracic

Bone

Liver

Right/Left Breast

Skin/Soft Tissue

Other

Abdomen/Peritoneal

Current Sites of Metastasis

Stage 0

Stage IA

Stage IB

Stage IIA

Stage IIB

Stage IIIA

Stage IIIB

Stage IIIC

Stage IV

Invasive breast cancer stages:

* Stage 0-Stage 0 = noninvasive ductal carcinoma in situ
* Stage Ia-cancer cells are breaking through to or invading normal surrounding breast tissue.
* Stage IIa-breast tumor about 2cm and involvement of ancillary lymph nodes.
* Stage IIb-a larger tumor than earlier phases.
* Stage IIIa-axillary lymph nodes clumping together.
* Stage IIIb-spread further to the skin, breast bone or chest wall.
* Stage IIIc-expanded involvement of lymph nodes.
* Stage IV-cancer that has spread beyond the breast and nearby lymph nodes to other organs of the body.

Stage of Primary Diagnosis

Triple-Negative Breast Cancer defined as estrogen receptor (ER) negative, progesterone receptor (PgR) negative, and human epidermal growth factor receptor 2 (HER2) negative.

Triple-Negative Breast Cancer (TNBC) at Primary Diagnosis

Triple-Negative at Latest Diagnosis

Intent-to-treat (ITT) population includes all randomized participants regardless of whether they received any IP or had any efficacy assessments collected.

Due to changes in the treatment landscape since the trial initiation, including the initiation of trials with immunotherapy drugs, successful enrollment of the Phase 3 part was considered unlikely and was not conducted; no safety signals were raised.

Anne McClain, Senior Manager Clinical Trial Disclosure

For stratified analysis, the stratified log-rank test and stratified Cox proportional hazards model were used, where the stratification factor is the disease free interval (\<= 1 year; \> 1 year).

Participants received nab-Paclitaxel 125 mg/m\^2 on Days 1 and 8 by intravenous (IV) administration followed by gemcitabine 1000 mg/m\^2 on Days 1 and 8 by IV administration of each 21-day treatment cycle. Participants continued treatment until progressive disease (PD), unacceptable toxicity, required palliative radiotherapy or surgical intervention of lesion(s), withdrawal from study treatment, withdrawal of study consent, participant refusal or the investigator felt it was no longer in the best interest of the participant to continue on treatment

ITT includes all randomized participants regardless of whether they received any IP or had any efficacy assessments collected. Those who did not have disease progression or had not died as of the data cutoff date were censored at the time of the last radiologic assessment prior to the data cutoff date.

Kaplan-Meier Estimates of Progression-Free Survival (PFS) Based on Investigator Assessment.

Percentage of Participants With an Objective Complete or Partial Overall Response by Investigator Assessment.

Percentage of Participants Who Initiated Cycle 6 Receiving Doublet Combination Therapy

Hazard ratios and associated two-sided 95% confidence intervals were estimated using stratified Cox proportional hazard model. The stratification factor is the disease free interval (≤ 1 year; \> 1 year).

The ITT population includes all randomized participants regardless of whether the participant received any Investigational Product (IP) or had any efficacy assessments collected.

Kaplan-Meier Estimates of Overall Survival

Any TEAE

Any Grade 3 or Higher TEAE

Treatment-related TEAE

Treatment-related, Grade 3 or Higher TEAE

Serious TEAE

Treatment-related Serious TEAE

TEAE Leading to Discontinuation (D/C) of IP

Treatment Related (TR) TEAE Leading to D/C of IP

TEAE Leading to Dose Reduction (DR) of IP

Treatment related TEAE Leading to DR of IP

TEAE Leading to Dose Interruption (DI) of IP

The safety population includes all randomized participants who received at least 1 dose of IP.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
GDC-0941 and Cisplatin in Treating Patients With Androgen Receptor-Negative Triple Negative Metastatic Breast Cancer	NCT01918306	Estrogen Recept... Human Epidermal... Triple Negative... Recurrent Breas... Stage IV Breast... Triple-negative...	cisplatin laboratory biom... pharmacological... dynamic contras... GDC -0941	18 Years -	Vanderbilt-Ingram Cancer Center
GDC-0941 and Cisplatin in Treating Patients With Androgen Receptor-Negative Triple Negative Metastatic Breast Cancer	NCT01918306	Estrogen Recept... Human Epidermal... Triple Negative... Recurrent Breas... Stage IV Breast... Triple-negative...	cisplatin laboratory biom... pharmacological... dynamic contras... GDC -0941	18 Years -	Vanderbilt-Ingram Cancer Center
Evaluate Risk/Benefit of Nab Paclitaxel in Combination With Gemcitabine and Carboplatin Compared to Gemcitabine and Carboplatin in Triple Negative Metastatic Breast Cancer (or Metastatic Triple Negative Breast Cancer)	NCT01881230	Breast Tumor Breast Cancer Cancer of the B... Estrogen Recept... HER2- Negative ... Progesterone Re... Recurrent Breas... Stage IV Breast... Triple-negative... Triple-negative... Metastatic Brea...	nab-Paclitaxel Carboplatin Gemcitabine	18 Years -	Celgene
Phase II Short-term Adjuvant Therapy and Biomarker Studies With Targeted Agents in Women With Estrogen Receptor Negative Breast Cancer	NCT01471106	Breast Cancer	Dasatinib	18 Years -	M.D. Anderson Cancer Center
Phase II Short-term Adjuvant Therapy and Biomarker Studies With Targeted Agents in Women With Estrogen Receptor Negative Breast Cancer	NCT01471106	Breast Cancer	Dasatinib	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for estrogen receptor negative breast cancer