Clinical trial NCT01918306
Conditions: Estrogen Receptor Negative Breast Cancer Human Epidermal Growth Factor 2 Negative Carcinoma of Breast Triple Negative Breast Cancer Recurrent Breast Cancer Stage IV Breast Cancer Triple-negative Breast Cancer
Keywords: Triple Negative Breast Cancer Estrogen receptor negative breast cancer Metastatic breast cancer Stage IV breast cancer HER2 negative breast cancer
Sponsor: Vanderbilt-Ingram Cancer Center
Start date: 2013-09-01; Completion date: 2015-04-01
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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 breast cancer. Patients will be randomized to receive cisplatin alone or cisplatin with GDC-0941 in the phase II portion. Those receiving cisplatin alone can receive GDC-0941 upon progression of their disease. Cisplatin is a chemotherapy which has been shown to be effective in treating triple negative breast cancer. Preclinical studies show that adding a PI3K inhibitor such as GDC-0941 to cisplatin may be a more effective treatment for breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

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

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

SECONDARY OBJECTIVES:

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

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

TERTIARY OBJECTIVES:

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

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

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

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

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

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

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

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

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

Arms: arm 1: 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. arm 2: 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. arm 3: 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). arm 4: 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 5: 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.
Interventions: intervention 1: cisplatin intervention 2: laboratory biomarker analysis intervention 3: pharmacological study intervention 4: dynamic contrast-enhanced MRI, diffusion-weighted MRI & chemical exchange saturation transfer MRI intervention 5: GDC -0941
Intervention descriptions: intervention 1: 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.

\-------------------------------------------------------------------------------- intervention 2: correlative studies intervention 3: correlative studies intervention 4: correlative studies intervention 5: 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

Protocol documents: