Panitumumab, Gemcitabine and Carboplatin in Triple-Negative Metastatic Breast Cancer

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT00894504
• Collaborator: Amgen (Industry), Eli Lilly and Company (Industry)
• Enrollment: 71
• Locations: 17
• Arm: 1
• Duration (Months): 55
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

In this Phase II trial, the investigators will evaluate the combination of gemcitabine, carboplatin, and panitumumab in the treatment of patients with metastatic triple-negative breast cancer. In addition, to assess the efficacy of this combination, tumor tissue will be examined for the presence of various markers, including K-ras and PI3K-activating mutations, EGFR, PTEN, and p53. Correlation of tumor response with marker expression may define a patient subset that is particularly responsive to treatment with a panitumumab-containing combination.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Panitumumab; Drug: Carboplatin; Drug: Gemcitabine	Phase 2

Detailed Description

All patients will receive a pre-emptive skin care regimen during panitumumab therapy to reduce skin toxicity. Treatment cycles will be repeated every 14 days (2 weeks). During each treatment, panitumumab will be administered first, then carboplatin, then gemcitabine. All drugs will be administered according to standard guidelines. Patients will be re-evaluated for response after completion of 3 cycles (6 weeks) of treatment. Patients with objective response or stable disease will continue treatment. Subsequent re-evaluations will occur every 6 weeks. Patients will continue treatment with all three drugs until tumor progression, or until unacceptable toxicity occurs. If patients experience toxicity caused by gemcitabine/carboplatin and are continuing to benefit from treatment, panitumumab can be continued as a single agent (at the same dose and schedule), at the discretion of the investigator, until disease progression occurs.

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Panitumumab, Gemcitabine, and Carboplatin in Triple-Negative Metastatic Breast Cancer
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Panitumumab/Gemcitabine/Carboplatin Systemic therapy

Drug: Panitumumab; 6 mg/kg IV on Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks); Other Names: Systemic Therapy Vectibix ; Drug: Carboplatin; AUC=2.5 IV, Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks); Other Names: Systemic Therapy Paraplatin ; Drug: Gemcitabine; 1500 mg/m2 IV, Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks); Other Names: Systemic Therapy Gemzar

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [every 6 weeks until treatment discontinuation]

   Measured from Day 1 of study drug administration to disease progression - defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as a 20% increase in the sum of the longest diameter of target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions

Secondary Outcome Measures

1. Objective Response Rate and Clinical Benefit Rate [every 6 weeks until treatment discontinuation]

   Estimated as the proportion of subjects who meet the criteria for complete or partial response (CR or PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 - for target lesions assessed by MRI: Complete Response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as >=30% decrease in the sum of the longest diameter of target lesions.

2. Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity [every 6 weeks until discontinuation of treatment, expected average of 18 months]

   Assessments made through analysis of treatment-related adverse events and serious adverse events

3. Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab [18 months]

   Median PFS (95% CI), months, reported by biomarker expression/mutation status for: EGFR, p53, PTEN, PIK3CA, KRAS

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Female patients >=18 years of age.

2. Histologically or cytologically confirmed diagnosis of unresectable locally advanced or stage IV breast cancer.

3. No more than 1 prior treatment regimen for metastatic breast cancer.

4. Estrogen receptor and progesterone receptor negative (defined as <10% staining by IHC).

5. Paraffin-embedded tumor tissue (from the primary tumor or metastasis) for biomarker testing. (In the absence of paraffinembedded tissue, unstained paraffin-embedded tumor slides are acceptable).

6. Measurable disease, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines

7. HER2 negative tumors. HER2 negativity must be confirmed by one of the following:

• FISH-negative (FISH ratio <2.2), or

• IHC 0-1+, or

• IHC 2-3+ AND FISH-negative (FISH ratio <2.2)

1. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1.

2. Absolute neutrophil count (ANC) >=1.5 × 109/L; platelet count >=100 × 109/L; hemoglobin >=9.0 g/dL.

3. Creatinine <=1.5 mg/dL, or creatinine clearance >=40 mL/min (as calculated by the Cockcroft-Gault method, as follows: Female creatinine clearance = (140 - age) × (weight in kg) × 0.85 (serum creatinine × 72)

4. Adequate hepatic function, defined as follows: total bilirubin <=1.5 x ULN; aspartate aminotransferase (AST) <=3 × ULN (or <= 5 x ULN if liver metastases); alanine aminotransferase (ALT) <=3 x ULN (or <=5 x ULN if liver metastases).

5. Magnesium level >= the institutional lower limit of normal (LLN).

6. Women of childbearing potential must agree to use adequate contraception (per institutional standard of care) during treatment and until 6 months after the last administration of investigational products.

Exclusion Criteria:

1. Patients with brain metastases are not eligible.

2. History of another primary cancer, with the exception of the following:

• Curatively treated in situ cervical cancer;

• Curatively resected non-melanoma skin cancer;

• Other primary solid tumor curatively treated with no known active disease present and no treatment administered for >=5 years prior to study enrollment.

1. History of interstitial lung disease (e.g., pneumonitis, pulmonary fibrosis), or any evidence of interstitial lung disease on the CT scan of the chest performed at the baseline visit.

2. Prior anti-EGFR antibody therapy (e.g., cetuximab), or treatment with small-molecule EGFR inhibitors (e.g., gefitinib, erlotinib, lapatinib).

3. Radiotherapy <=14 days prior to study enrollment. Any acute effects of radiotherapy must be resolved prior to the administration of study drugs.

4. Systemic chemotherapy, hormonal therapy, immunotherapy, or experimental or approved proteins/antibodies (e.g., bevacizumab) <=21 days prior to study enrollment.

5. Prior therapy with gemcitabine or carboplatin in the metastatic setting is not permitted. Patients who received gemcitabine or carboplatin as part of adjuvant therapy are eligible, as long as recurrence was first documented >12 months after the last exposure to the drug(s).

6. Major surgery within 28 days or minor surgery within 14 days of study enrollment.

7. Requirement of chronic use of immunosuppressive agents (e.g., methotrexate, cyclosporine).

8. Any investigational agent or therapy <=30 days prior to study enrollment.

9. Uncontrolled or intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.

10. History of any medical or psychiatric condition or laboratory abnormality that, in the opinion of the investigator, may increase the risks associated with the study participation or administration of the investigational products, or that may interfere with the interpretation of the results.

11. Unwillingness or inability to comply with study requirements.

12. Women who are pregnant or breastfeeding.

13. Patients with known human immunodeficiency virus (HIV), hepatitis C virus, and/or acute or chronic hepatitis B virus infection.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Los Robles	Thousand Oaks	California	United States	91360
2	Aventura Hospital and Medical Center	Aventura	Florida	United States	33180
3	Florida Cancer Specialists	Ft. Myers	Florida	United States
4	Providence Medical Group	Terre Haute	Indiana	United States	47802
5	Norton Cancer Institute	Louisville	Kentucky	United States	40207
6	Center for Cancer and Blood Disorders	Bethesda	Maryland	United States	20817
7	National Capital Clinical Research Consortium	Bethesda	Maryland	United States	20817
8	St. Louis Cancer Care	Chesterfield	Missouri	United States	63017
9	Research Medical Center	Kansas	Missouri	United States	64132
10	Nebraska Methodist Cancer Center	Omaha	Nebraska	United States	68114
11	Atlantic Health System	Morristown	New Jersey	United States	07960
12	Oncology Hematology Care	Cincinnati	Ohio	United States	45242
13	Chattanooga Oncology Hematology Associates	Chattanooga	Tennessee	United States	37404
14	Family Cancer Center	Collierville	Tennessee	United States	38119
15	Tennessee Oncology	Nashville	Tennessee	United States	37203
16	Texas Health Physician Group	Dallas	Texas	United States	76011
17	Peninsula Cancer Institute	Newport News	Virginia	United States	23601

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Amgen
• Eli Lilly and Company

Investigators

• Study Chair: Denise A Yardley, M.D., SCRI Development Innovations, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT00894504
• Other Study ID Numbers: SCRI BRE 126
• First Posted: May 7, 2009
• Last Update Posted: May 15, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by SCRI Development Innovations, LLC: Metastatic Breast Cancer; Triple Negative; Panitumumab; Vectibix; Gemcitabine; Gemzar; Carboplatin
• Additional relevant MeSH terms: Breast Neoplasms; Gemcitabine; Carboplatin; Panitumumab

Study Results

Participant Flow

Arm/Group Title	Panitumumab/Gemcitabine/Carboplatin
Arm/Group Description	Treatment cycles are repeated every 14 days (2 weeks) Panitumumab: 6mg/kg intravenous (IV), Day 1 of each 2-week treatment cycle. Gemcitabine: 1500mg/m2 IV, Day 1 of each 2-week treatment cycle Carboplatin: Area Under the Curve (AUC) = 2.5 IV, Day 1 of each 2-week treatment cycle
Period Title: Overall Study
STARTED	71
COMPLETED	0
NOT COMPLETED	71

Baseline Characteristics

Arm/Group Title	Panitumumab/Gemcitabine/Carboplatin
Arm/Group Description	Panitumumab - 6 mg/kg IV on Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks) Carboplatin - AUC=2.5 IV, Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks) Gemcitabine - 1500 mg/m2 IV, Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks)
Overall Participants	71
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	54
Sex: Female, Male (Count of Participants)
Female	71 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	71 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	Measured from Day 1 of study drug administration to disease progression - defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as a 20% increase in the sum of the longest diameter of target lesions and/or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions
Time Frame	every 6 weeks until treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panitumumab/Gemcitabine/Carboplatin
Arm/Group Description	Panitumumab - 6 mg/kg IV on Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks) Carboplatin - AUC=2.5 IV, Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks) Gemcitabine - 1500 mg/m2 IV, Day 1 of each 2-week treatment cycle for 3 cycles (6 weeks)
Measure Participants	71
Median (95% Confidence Interval) [Months]	4.4

2. Secondary Outcome

Title	Objective Response Rate and Clinical Benefit Rate
Description	Estimated as the proportion of subjects who meet the criteria for complete or partial response (CR or PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 - for target lesions assessed by MRI: Complete Response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as >=30% decrease in the sum of the longest diameter of target lesions.
Time Frame	every 6 weeks until treatment discontinuation

Outcome Measure Data

Analysis Population Description

All evaluable patients per RECIST v 1.1

Arm/Group Title	Panitumumab/Gemcitabine/Carboplatin
Arm/Group Description	Systemic therapy
Measure Participants	69
Clinical benefit rate (CR + PR + SD>6 months)	32 45.1%
Objective response rate (CR + PR)	30 42.3%

3. Secondary Outcome

Title	Number of Treatment-related Toxicities Occurring in ≥10% of Patients as a Measure of Tolerability and Toxicity
Description	Assessments made through analysis of treatment-related adverse events and serious adverse events
Time Frame	every 6 weeks until discontinuation of treatment, expected average of 18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm/Group 1
Arm/Group Description
Measure Participants	71
Neutropenia	32 45.1%
Thrombocytopenia	32 45.1%
Leukopenia	25 35.2%
Anemia	20 28.2%
Rash	50 70.4%
Fatigue	37 52.1%
Nausea/vomiting	36 50.7%
Dry skin	21 29.6%
Hypomagnesemia	18 25.4%
Mucositis/stomatitis	16 22.5%
Constipation	15 21.1%
Dyspnea	12 16.9%
Pruritis	12 16.9%
Anorexia	10 14.1%
Diarrhea	9 12.7%
AST/ALT increased	9 12.7%
Alopecia	7 9.9%
Dyspepsia	7 9.9%
Myalgia	7 9.9%

4. Secondary Outcome

Title	Correlation of Biomarker Expressions of EGFR, K-ras, p53, PTEN Expression, and PI3K in Triple-negative Breast Cancer With Response to Treatment With the Combination of Gemcitabine, Carboplatin, and Panitumumab
Description	Median PFS (95% CI), months, reported by biomarker expression/mutation status for: EGFR, p53, PTEN, PIK3CA, KRAS
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Excludes patients in the following categories due to insufficient data: PTEN status unknown, PIK3CA Status unknown and KRAS no mutation

Arm/Group Title	EGFR Normal	EGFR Amplified	p53 Normal	p53 Loss	PTEN Normal	PTEN Loss	PIK3CA No Mutation	PIK3CA Mutation(s)
Arm/Group Description
Measure Participants	56	12	34	34	62	5	55	12
Median (95% Confidence Interval) [months]	4.57	3.42	4.16	5.32	4.4	2.91	4.37	4.73

Adverse Events

Arm/Group Title	Panitumumab/Gemcitabine/Carboplatin
Arm/Group Description
All Cause Mortality
	Panitumumab/Gemcitabine/Carboplatin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Panitumumab/Gemcitabine/Carboplatin
	Affected / at Risk (%)	# Events
Total	10/71 (14.1%)
Cardiac disorders
ATRIAL FIBRILLATION	1/71 (1.4%)	1
CARDIAC TAMPONADE	1/71 (1.4%)	1
PERICARDIAL EFFUSION	1/71 (1.4%)	2
SUPRAVENTRICULAR TACHYCARDIA	1/71 (1.4%)	1
Gastrointestinal disorders
DIARRHOEA	1/71 (1.4%)	1
NAUSEA	1/71 (1.4%)	1
VOMITING	1/71 (1.4%)	1
General disorders
CHEST PAIN	1/71 (1.4%)	1
Infections and infestations
PNEUMONIA	1/71 (1.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MALIGNANT PLEURAL EFFUSION	1/71 (1.4%)	1
Nervous system disorders
HEPATIC ENCEPHALOPATHY	1/71 (1.4%)	1
Renal and urinary disorders
HAEMORRHAGE URINARY TRACT	1/71 (1.4%)	1
HYDRONEPHROSIS	1/71 (1.4%)	1
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	2/71 (2.8%)	2
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	1/71 (1.4%)	3
Vascular disorders
EMBOLISM	1/71 (1.4%)	1
Other (Not Including Serious) Adverse Events
	Panitumumab/Gemcitabine/Carboplatin
	Affected / at Risk (%)	# Events
Total	70/71 (98.6%)
Blood and lymphatic system disorders
ANAEMIA	16/71 (22.5%)	46
LEUKOPENIA	18/71 (25.4%)	114
NEUTROPENIA	24/71 (33.8%)	121
THROMBOCYTOPENIA	25/71 (35.2%)	54
Cardiac disorders
TACHYCARDIA	6/71 (8.5%)	8
Eye disorders
DRY EYE	4/71 (5.6%)	4
Gastrointestinal disorders
CONSTIPATION	28/71 (39.4%)	41
DIARRHOEA	13/71 (18.3%)	26
DYSPEPSIA	7/71 (9.9%)	9
GASTROOESOPHAGEAL REFLUX DISEASE	5/71 (7%)	6
NAUSEA	38/71 (53.5%)	56
STOMATITIS	7/71 (9.9%)	8
VOMITING	17/71 (23.9%)	28
General disorders
FATIGUE	45/71 (63.4%)	109
MUCOSAL INFLAMMATION	9/71 (12.7%)	22
OEDEMA PERIPHERAL	5/71 (7%)	5
PYREXIA	7/71 (9.9%)	8
Investigations
ALANINE AMINOTRANSFERASE INCREASED	7/71 (9.9%)	40
ASPARTATE AMINOTRANSFERASE INCREASED	10/71 (14.1%)	32
BLOOD ALKALINE PHOSPHATASE INCREASED	6/71 (8.5%)	20
WHITE BLOOD CELL COUNT DECREASED	4/71 (5.6%)	19
Metabolism and nutrition disorders
DECREASED APPETITE	13/71 (18.3%)	26
DEHYDRATION	7/71 (9.9%)	8
HYPERGLYCAEMIA	4/71 (5.6%)	17
HYPOCALCAEMIA	4/71 (5.6%)	6
HYPOKALAEMIA	8/71 (11.3%)	14
HYPOMAGNESAEMIA	16/71 (22.5%)	29
Musculoskeletal and connective tissue disorders
ARTHRALGIA	4/71 (5.6%)	5
BACK PAIN	5/71 (7%)	6
BONE PAIN	6/71 (8.5%)	8
MUSCULOSKELETAL PAIN	4/71 (5.6%)	21
MYALGIA	7/71 (9.9%)	8
PAIN IN EXTREMITY	5/71 (7%)	6
Nervous system disorders
DIZZINESS	5/71 (7%)	6
DYSGEUSIA	6/71 (8.5%)	6
HEADACHE	6/71 (8.5%)	8
PERIPHERAL SENSORY NEUROPATHY	8/71 (11.3%)	10
Psychiatric disorders
ANXIETY	7/71 (9.9%)	8
DEPRESSION	4/71 (5.6%)	4
INSOMNIA	12/71 (16.9%)	12
Renal and urinary disorders
DYSURIA	5/71 (7%)	5
Respiratory, thoracic and mediastinal disorders
COUGH	10/71 (14.1%)	13
DYSPNOEA	14/71 (19.7%)	21
Skin and subcutaneous tissue disorders
ACNE	6/71 (8.5%)	11
ALOPECIA	7/71 (9.9%)	7
DERMATITIS ACNEIFORM	8/71 (11.3%)	17
DRY SKIN	24/71 (33.8%)	28
EXFOLIATIVE RASH	6/71 (8.5%)	13
PRURITUS	11/71 (15.5%)	13
RASH	31/71 (43.7%)	55

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites