Carboplatin With or Without Atezolizumab in Treating Patients With Stage IV Triple Negative Breast Cancer

A Phase II Trial of Atezolizumab (Anti-PDL1) With Carboplatin in Patients With Metastatic Triple Negative Breast Cancer

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03206203

Enrollment

106

Registered

2017-07-02

Start date

2017-08-29

Completion date

2023-10-04

Last updated

2024-12-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Triple Negative Breast Cancer, Stage IV Breast Cancer, HER2 Negative, Invasive Breast Cancer

Brief summary

This randomized phase II trial studies how well carboplatin with or without atezolizumab works in treating patients with stage IV triple negative breast cancer. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Giving carboplatin with atezolizumab may work better in treating patients with stage IV triple negative breast cancer

Detailed description

Primary objective: To evaluate the efficacy, as measured by progression free survival (PFS) of carboplatin + atezolizumab (using irRECIST) versus carboplatin alone (using RECIST) in patients with triple negative metastatic breast cancer Secondary objectives: * To determine overall response rate. * To evaluate the efficacy, as measured by clinical benefit rate, of carboplatin + atezolizumab (using irRECIST) versus carboplatin (using RECIST) alone in patients with triple negative metastatic breast cancer. Clinical benefit rate is defined as complete response plus partial response plus stable disease for 6 months. * To determine the duration of response for patients achieving a partial or complete response. * To evaluate the overall survival (OS) of carboplatin + atezolizumab versus carboplatin alone in patients with triple negative metastatic breast cancer. TERTIARY OBJECTIVES: * To perform the following correlative studies from biopsies taken at baseline: 1. Tumor infiltrating lymphocyte frequency and phenotype (TILs) at baseline 2. PD-L1 expression from the baseline pre-treatment tissue and at progression lesion, performed by IHC (SP142 clone) 3. HER2 (IHC, FISH) and ER/PR levels (IHC) from a metastatic site 4. Perform RNA-seq to determine non-synonymous mutation burden in expressed genes and gene expression to assign a triple negative subtype at baseline for correlations with clinic outcome 5. Immune phenotyping (IHC) for markers of T cell subsets and activation (CD4, CD8, FoxP3, CD25, Glut1) and exhaustion (PD1, CTLA4) and test feasibility of flow cytometric analyses to include additional markers * To assess the effect of BRCA mutations on response to the study drugs * To evaluate the effect of steroids on the efficacy of atezolizumab To assess the prognostic effects of TILs on PFS and CBR in patients receiving atezolizumab

Interventions

DRUGAtezolizumab

Given by vein

DRUGCarboplatin

Given by vein

OTHERLaboratory Biomarker

Correlative study

OTHERQuality-of-Life Assessment

Ancillary studies

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Patients must provide informed written consent * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Clinical stage IV ER, PR, HER2 negative invasive mammary carcinoma, previously documented by histological analysis and that meets the following criteria: * HER2 negativity is defined as any of the following by local laboratory assessment: In-situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 \< 2.0 or single probe average HER2 gene copy number \< 4 signals/cell), or IHC 0 or IHC 1+ (if more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the protocol chair to establish eligibility of the patient) * ER and PR negativity are defined as =\< 5% of cells expressing hormonal receptors via IHC analysis * Willing to undergo biopsy of a metastatic lesion (in patients with reasonably accessible metastatic lesions such as chest wall, skin, subcutaneous tissue, lymph nodes, bones, peripheral lung, and liver metastases) * Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension by RECIST criteria version (v)1.1 * Zero or one prior chemotherapy regimens for metastatic disease * No prior treatment with carboplatin * Absolute neutrophil count (ANC) \>= 1500/mm\^3 (without granulocyte colony-stimulating factor \[G-CSF\] support within 2 weeks prior to cycle 1, day 1) * Lymphocyte count \>= 500/uL * Platelet count \>= 100,000/mm\^3 (without transfusion within 2 weeks prior to cycle 1, day 1) * Hemoglobin \>= 9.0 g/dL \* Patients may be transfused or receive erythropoietic treatment to meet this criterion * Calculated creatinine clearance \>= 30 mL/min using the Calvert Formula * Bilirubin =\< 2.5 x upper limits of normal if no liver metastases present; serum total bilirubin must be =\< 3 x upper limits of normal for patients with Gilbert disease; total bilirubin =\< 5 x upper limits of normal if liver metastases present * Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) =\< 2.5 x upper limits of normal if no liver metastases present; SGOT, SGPT =\< 5 x upper limits of normal if liver metastases present * Alkaline phosphatase =\< 2.5 x upper limits of normal if no liver metastases present; alkaline phosphatase =\< 5 x upper limits of normal if liver metastases present * For patients who are not postmenopausal (women) or surgically sterile (absence of ovaries and/or uterus or vasectomy), agreement to remain abstinent or to use two adequate methods of contraception (e.g., condoms, diaphragm, vasectomy/vasectomized partner, tubal ligation), during the treatment period and for at least 30 days after the last dose of study treatment; hormone based oral contraceptives are not allowed on study; 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; or follicle stimulating hormone and estradiol in the postmenopausal range * Subjects must complete all baseline screening assessments

Exclusion criteria

* CANCER-SPECIFIC

Design outcomes

Primary

Measure	Time frame	Description
Progression Free Survival (PFS)	Up to 3 years.	The PFS is defined as the time from the first day of treatment to the first observation of disease progression (RECIST V1.1) or death of any cause. Those without events were censored at the last follow up. The median PFS time will be estimated using the Kaplan-Meier method with 95% confidence intervals.

Secondary

Measure	Time frame	Description
Overall Survival (OS)	Up to 3 years.	OS is defined as the time from first day of treatment to death. Those alive were censored at the last follow up. The median and OS time and corresponding 95% confidence intervals were estimated using Kaplan-meier method.
Overall Response Rate (ORR)	Up to 3 years	Patient response to treatment was evaluated by RECIST V1.1. The ORR (CR + PR) and corresponding 95% confidence intervals (exact) were estimated among evaluable patients.
Clinical Benefit Rate (CBR)	Up to 3 years	Patient response to treatment was evaluated by RECIST 1.1. The CBR (CR + PR+stable disease ≥ 6 months) and corresponding 95% confidence intervals (exact) were estimated among evaluable patients.
Duration of Response (DOR)	Up to 3 years	DOR was defined as the time from CR or PR to progression using RECIST V1.1. The median DOR and corresponding 95% confidence intervals was estimated uisng Kaplan-Meier method.

Other

Measure	Time frame	Description
Changes in Gene Expression in Tumor Tissue as Assessed by Ribonucleic Acid-sequencing (RNA-seq)	Baseline and upon disease progression, assessed for up to 3 years	Statistics will be primarily descriptive.
Assignment of a Triple Negative Subtype in Tumor Tissue as Assessed by Ribonucleic Acid-sequencing (RNA-seq)	Baseline and upon disease progression, assessed for up to 3 years	Statistics will be primarily descriptive.
Define Mutations Present in the Tumors as Assessed by Ribonucleic Acid-sequencing (RNA-seq)	Baseline and upon disease progression, assessed for up to 3 years	Statistics will be primarily descriptive.
Somatic Single Nucleotide Polymorphisms (SNPs) and Structural Variants in Tumor Tissue and Blood as Assessed by Whole Exome Sequencing (WES)	Up to 3 years	Statistics will be primarily descriptive.
Status of p53, BRCA1/2, PIK3CA, PTEN, INPP4B and Other Mutations	Up to 3 years.	Statistics will be primarily descriptive.

Countries

United States

Participant flow

Recruitment details

Participants were enrolled onto this study at 6 academic medical centers from August 2017 to October 2020.

Participants by arm

Arm	Count
Arm 1 (Atezolizumab, Carboplatin) Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Atezolizumab: Given by vein Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	56
Arm 2 (Carboplatin) Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression. Carboplatin: Given by vein Laboratory Biomarker: Correlative study Quality-of-Life Assessment: Ancillary studies	31
Cross-Over Patients on Arm 2 have the option to cross-over to Arm 1 upon disease progression and receive atezolizumab by IV over 30-60 minutes	19
Total	106

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Optional Cross-Over	Death	0	0	14
Optional Cross-Over	Refused follow-up	0	0	2
Treatment	Cross over to Arm 1	0	19	0
Treatment	Death	38	26	0
Treatment	Disease progression	0	1	0
Treatment	Lost to Follow-up	4	0	0
Treatment	N/A in Follow-Up	8	1	0
Treatment	Refused follow-up	0	1	0
Treatment	Withdrawal by Subject	1	0	0

Baseline characteristics

Characteristic	Arm 1 (Atezolizumab, Carboplatin)	Arm 2 (Carboplatin)	Cross-Over	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	14 Participants	9 Participants	3 Participants	26 Participants
Age, Categorical Between 18 and 65 years	42 Participants	22 Participants	16 Participants	80 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	0 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	28 Participants	18 Participants	9 Participants	55 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	27 Participants	13 Participants	10 Participants	50 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	8 Participants	9 Participants	3 Participants	20 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants	4 Participants	3 Participants	12 Participants
Race (NIH/OMB) White	42 Participants	18 Participants	13 Participants	73 Participants
Region of Enrollment United States	56 participants	31 participants	19 participants	106 participants
Sex: Female, Male Female	56 Participants	31 Participants	19 Participants	106 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	38 / 56	26 / 50	14 / 19
other Total, other adverse events	54 / 56	30 / 50	19 / 19
serious Total, serious adverse events	23 / 56	11 / 50	12 / 19

Outcome results

Primary

Progression Free Survival (PFS)

The PFS is defined as the time from the first day of treatment to the first observation of disease progression (RECIST V1.1) or death of any cause. Those without events were censored at the last follow up. The median PFS time will be estimated using the Kaplan-Meier method with 95% confidence intervals.

Time frame: Up to 3 years.

Population: Randomized patients received treatments.

Arm	Measure	Value (MEDIAN)
Arm 1 (Atezolizumab, Carboplatin)	Progression Free Survival (PFS)	4.1 months
Arm 2 (Carboplatin)	Progression Free Survival (PFS)	2.2 months

Secondary

Clinical Benefit Rate (CBR)

Patient response to treatment was evaluated by RECIST 1.1. The CBR (CR + PR+stable disease ≥ 6 months) and corresponding 95% confidence intervals (exact) were estimated among evaluable patients.

Time frame: Up to 3 years

Population: Randomized patients who received treatment and evaluated response with evaluable result.

Arm	Measure	Value (NUMBER)
Arm 1 (Atezolizumab, Carboplatin)	Clinical Benefit Rate (CBR)	38.9 percentage of participants
Arm 2 (Carboplatin)	Clinical Benefit Rate (CBR)	20.0 percentage of participants

Secondary

Duration of Response (DOR)

DOR was defined as the time from CR or PR to progression using RECIST V1.1. The median DOR and corresponding 95% confidence intervals was estimated uisng Kaplan-Meier method.

Time frame: Up to 3 years

Population: Randomized patients who received treatment and had CR or PR.

Arm	Measure	Value (MEDIAN)
Arm 1 (Atezolizumab, Carboplatin)	Duration of Response (DOR)	11.6 months
Arm 2 (Carboplatin)	Duration of Response (DOR)	14.8 months

Secondary

Overall Response Rate (ORR)

Patient response to treatment was evaluated by RECIST V1.1. The ORR (CR + PR) and corresponding 95% confidence intervals (exact) were estimated among evaluable patients.

Time frame: Up to 3 years

Population: Randomized patients who received treatments and evaluated for response with evaluanble result.

Arm	Measure	Value (NUMBER)
Arm 1 (Atezolizumab, Carboplatin)	Overall Response Rate (ORR)	31.5 percentage of participants
Arm 2 (Carboplatin)	Overall Response Rate (ORR)	8.9 percentage of participants

Secondary

Overall Survival (OS)

OS is defined as the time from first day of treatment to death. Those alive were censored at the last follow up. The median and OS time and corresponding 95% confidence intervals were estimated using Kaplan-meier method.

Time frame: Up to 3 years.

Population: Randomized patients who received treatment.

Arm	Measure	Value (MEDIAN)
Arm 1 (Atezolizumab, Carboplatin)	Overall Survival (OS)	12.6 months
Arm 2 (Carboplatin)	Overall Survival (OS)	7.0 months

Other Pre-specified