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Phase I/IIa Trial of Gemcitabine Plus Trastuzumab and Pertuzumab in Previously Treated Metastatic HER2+ Breast Cancer

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ClinicalTrials.gov Identifier: NCT02139358
Recruitment Status : Active, not recruiting
First Posted : May 15, 2014
Results First Posted : July 20, 2018
Last Update Posted : September 10, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Breast Cancer
Interventions Drug: Gemcitabine
Drug: Trastuzumab
Drug: Pertuzumab
Enrollment 15
Recruitment Details Participants were enrolled at Moffitt Cancer Center October 2014 through October 2016.
Pre-assignment Details  
Arm/Group Title Dose Escalation / Phase II Treatment
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Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.

Gemcitabine: The Phase I trial will start at the recommended phase II dose (RP2D) for gemcitabine but will have a de-escalation dose levels in the event that an unacceptable toxicity requires dose reduction. Dose level 0 = gemcitabine (1200mg/m2) IV D1,8 q21 days; Dose level -1 = gemcitabine (1000 mg/m^2) IV D1,8 q21 days; Dose level -2 = gemcitabine (850 mg/m^2) IV D1,8 q21 days. The RP2D will be the dose level where 0-1 dose limiting toxicities (DLTs) in six patients occur.

Trastuzumab: Trastuzumab will be given using an 8 mg/kg loading dose on cycle one, day one (C1D1), followed by 6 mg/kg IV on subsequent cycles every (q) 21 days.

Pertuzumab: Pertuzumab will be given using an 840 mg IV loading dose on C1D1, followed by 420 mg IV on subsequent cycles q21 days.
Period Title: Overall Study
Started 15
Completed 15
Not Completed 0
Arm/Group Title Dose Escalation / Phase II Treatment
Hide Arm/Group Description Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Overall Number of Baseline Participants 15
Hide Baseline Analysis Population Description
All participants
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 15 participants
58.2
(46 to 68)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants
Female
15
 100.0%
Male
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants
Hispanic or Latino
2
  13.3%
Not Hispanic or Latino
12
  80.0%
Unknown or Not Reported
1
   6.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
1
   6.7%
White
12
  80.0%
More than one race
0
   0.0%
Unknown or Not Reported
2
  13.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 15 participants
15
1.Primary Outcome
Title Phase I: Recommended Phase II Dose (RP2D)
Hide Description The RP2D dose in mg/m^2 of gemcitabine along with standard doses of pertuzumab (840 mg loading/420 mg maintenance) and Herceptin (8 mg/kg loading, 6 mg/kg maintenance). Safety data to be described using Common Terminology Criteria for Adverse Events (CTCAE) 4.0 terminology. Any participant who receives any dose of the study treatment will be evaluated for the safety/toxicity endpoints in the trial.
Time Frame 6 Months
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Hide Analysis Population Description
All participants enrolled during Phase 1
Arm/Group Title Dose Escalation / Phase II Treatment
Hide Arm/Group Description:
Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Overall Number of Participants Analyzed 6
Measure Type: Number
Unit of Measure: dose in mg/m^2
1200
2.Primary Outcome
Title Phase II: Objective Response Rate (ORR)
Hide Description Objective Response Rate: Response according to Response Evaluation in Solid Tumors (RECIST) 1.1 for the combination of gemcitabine+trastuzumab+pertuzumab at the recommended phase II dose. Complete Response (CR): Disappearance of all evidence of tumor for at least two cycles of therapy. Tumor markers must be normal. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of target lesions, taking a reference the baseline sum longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the beginning of treatment or the appearance of one or more new lesions.
Time Frame Up to 36 Months
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Hide Analysis Population Description
All participants who have undergone 2 treatment cycles followed by a response scan and have documented best response data available.
Arm/Group Title Dose Escalation / Phase II Treatment
Hide Arm/Group Description:
Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Overall Number of Participants Analyzed 10
Measure Type: Count of Participants
Unit of Measure: Participants
Complete Response
1
  10.0%
Partial Response
1
  10.0%
Stable Disease
8
  80.0%
3.Secondary Outcome
Title Phase II: Progression Free Survival (PFS)
Hide Description Median progression free survival (in months) for all participants evaluable for response. The time-to-event data will be summarized using Kaplan-Meir curve method for all patients who are evaluable for the ORR endpoint. Progressive disease (PD): At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the beginning of treatment or the appearance of one or more new lesions.
Time Frame Up to 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants
Arm/Group Title Dose Escalation / Phase II Treatment
Hide Arm/Group Description:
Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Overall Number of Participants Analyzed 15
Median (95% Confidence Interval)
Unit of Measure: months
6.4883
(2.7807 to 9.0372)
4.Secondary Outcome
Title Overall Survival (OS)
Hide Description Median overall survival (in months) for all participants evaluable for response. The length of time from the start of treatment that participants are still alive.
Time Frame Up to 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants
Arm/Group Title Dose Escalation / Phase II Treatment
Hide Arm/Group Description:
Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Overall Number of Participants Analyzed 15
Median (95% Confidence Interval)
Unit of Measure: months
11.3545
(6.2897 to 14.0028)
Time Frame 3 years, 7 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Dose Escalation / Phase II Treatment
Hide Arm/Group Description Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
All-Cause Mortality
Dose Escalation / Phase II Treatment
Affected / at Risk (%)
Total   2/15 (13.33%)    
Show Serious Adverse Events Hide Serious Adverse Events
Dose Escalation / Phase II Treatment
Affected / at Risk (%) # Events
Total   7/15 (46.67%)    
Cardiac disorders   
Cardiac arrest * 1  1/15 (6.67%)  1
Chest pain - cardiac * 1  1/15 (6.67%)  1
Gastrointestinal disorders   
Diarrhea * 1  1/15 (6.67%)  1
Duodenal hemorrhage * 1  1/15 (6.67%)  1
General disorders   
Fatigue * 1  1/15 (6.67%)  1
Fever * 1  1/15 (6.67%)  1
Sudden death NOS * 1  1/15 (6.67%)  1
Infections and infestations   
Sepsis * 1  1/15 (6.67%)  1
Skin infection * 1  1/15 (6.67%)  1
Investigations   
Neutrophil count decreased * 1  1/15 (6.67%)  1
Platelet count decreased * 1  1/15 (6.67%)  1
Metabolism and nutrition disorders   
Dehydration * 1  1/15 (6.67%)  1
Respiratory, thoracic and mediastinal disorders   
Dyspnea * 1  2/15 (13.33%)  2
Pleural effusion * 1  1/15 (6.67%)  1
Respiratory failure * 1  1/15 (6.67%)  2
Respiratory, thoracic and mediastinal disorders - Other, Pneumonia * 1  1/15 (6.67%)  1
Skin and subcutaneous tissue disorders   
Rash maculo-papular * 1  1/15 (6.67%)  1
1
Term from vocabulary, CTCAE (4.0)
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Dose Escalation / Phase II Treatment
Affected / at Risk (%) # Events
Total   15/15 (100.00%)    
Blood and lymphatic system disorders   
Anemia * 1  11/15 (73.33%)  39
Cardiac disorders   
Sinus tachycardia * 1  3/15 (20.00%)  5
Chest pain - cardiac * 1  1/15 (6.67%)  1
Left ventricular systolic dysfunction * 1  1/15 (6.67%)  1
Palpitations * 1  1/15 (6.67%)  1
Ear and labyrinth disorders   
Tinnitus * 1  1/15 (6.67%)  1
Eye disorders   
Blurred vision * 1  1/15 (6.67%)  1
Dry eye * 1  1/15 (6.67%)  1
Eye pain * 1  1/15 (6.67%)  1
Gastrointestinal disorders   
Diarrhea * 1  10/15 (66.67%)  13
Nausea * 1  9/15 (60.00%)  11
Vomiting * 1  5/15 (33.33%)  6
Abdominal pain * 1  2/15 (13.33%)  2
Dysphagia * 1  2/15 (13.33%)  2
Constipation * 1  1/15 (6.67%)  1
Dry mouth * 1  1/15 (6.67%)  1
Duodenal hemorrhage * 1  1/15 (6.67%)  1
Duodenal ulcer * 1  1/15 (6.67%)  1
Dyspepsia * 1  1/15 (6.67%)  1
Fecal incontinence * 1  1/15 (6.67%)  1
Mucositis oral * 1  1/15 (6.67%)  1
Oral pain * 1  1/15 (6.67%)  1
General disorders   
Fatigue * 1  10/15 (66.67%)  12
Infusion related reaction * 1  3/15 (20.00%)  3
Pain * 1  3/15 (20.00%)  4
Edema limbs * 1  2/15 (13.33%)  3
Fever * 1  2/15 (13.33%)  2
Chills * 1  1/15 (6.67%)  1
Malaise * 1  1/15 (6.67%)  1
Non-cardiac chest pain * 1  1/15 (6.67%)  1
Infections and infestations   
Skin infection * 1  2/15 (13.33%)  2
Papulopustular rash * 1  1/15 (6.67%)  1
Sinusitis * 1  1/15 (6.67%)  1
Tooth infection * 1  1/15 (6.67%)  2
Upper respiratory infection * 1  1/15 (6.67%)  1
Injury, poisoning and procedural complications   
Bruising * 1  1/15 (6.67%)  1
Fracture * 1  1/15 (6.67%)  1
Wound dehiscence * 1  1/15 (6.67%)  2
Investigations   
Neutrophil count decreased * 1  12/15 (80.00%)  47
Lymphocyte count decreased * 1  10/15 (66.67%)  19
Platelet count decreased * 1  9/15 (60.00%)  24
White blood cell decreased * 1  9/15 (60.00%)  48
Alanine aminotransferase increased * 1  6/15 (40.00%)  12
Aspartate aminotransferase increased * 1  6/15 (40.00%)  17
Alkaline phosphatase increased * 1  2/15 (13.33%)  3
Creatinine increased * 1  1/15 (6.67%)  2
Ejection fraction decreased * 1  1/15 (6.67%)  1
Electrocardiogram QT corrected interval prolonged * 1  1/15 (6.67%)  1
Metabolism and nutrition disorders   
Anorexia * 1  6/15 (40.00%)  7
Hypoalbuminemia * 1  6/15 (40.00%)  8
Hypocalcemia * 1  5/15 (33.33%)  8
Hypokalemia * 1  5/15 (33.33%)  10
Dehydration * 1  2/15 (13.33%)  2
Hypernatremia * 1  2/15 (13.33%)  2
Hyponatremia * 1  2/15 (13.33%)  2
Hypophosphatemia * 1  2/15 (13.33%)  2
Hypercalcemia * 1  1/15 (6.67%)  1
Hypermagnesemia * 1  1/15 (6.67%)  1
Musculoskeletal and connective tissue disorders   
Myalgia * 1  6/15 (40.00%)  7
Pain in extremity * 1  4/15 (26.67%)  6
Bone pain * 1  3/15 (20.00%)  3
Arthralgia * 1  2/15 (13.33%)  2
Back pain * 1  2/15 (13.33%)  3
Generalized muscle weakness * 1  1/15 (6.67%)  1
Musculoskeletal and connective tissue disorder - Other, Right wrist swelling * 1  1/15 (6.67%)  1
Neck pain * 1  1/15 (6.67%)  1
Osteoporosis * 1  1/15 (6.67%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Cervical polyp * 1  1/15 (6.67%)  1
Neoplasms benign, malignant and unspecified and polyps) - Other, Goiter with thyroid modules * 1  1/15 (6.67%)  1
Nervous system disorders   
Dizziness * 1  4/15 (26.67%)  4
Peripheral sensory neuropathy * 1  3/15 (20.00%)  3
Headache * 1  2/15 (13.33%)  2
Somnolence * 1  2/15 (13.33%)  2
Dysphasia * 1  1/15 (6.67%)  1
Psychiatric disorders   
Depression * 1  1/15 (6.67%)  1
Insomnia * 1  1/15 (6.67%)  1
Restlessness * 1  1/15 (6.67%)  1
Renal and urinary disorders   
Cystitis noninfective * 1  1/15 (6.67%)  1
Hematuria * 1  1/15 (6.67%)  1
Proteinuria * 1  1/15 (6.67%)  1
Urinary frequency * 1  1/15 (6.67%)  1
Urinary tract pain * 1  1/15 (6.67%)  1
Reproductive system and breast disorders   
Vaginal inflammation * 1  1/15 (6.67%)  1
Vaginal pain * 1  1/15 (6.67%)  1
Respiratory, thoracic and mediastinal disorders   
Dyspnea * 1  6/15 (40.00%)  8
Allergic rhinitis * 1  2/15 (13.33%)  2
Epistaxis * 1  2/15 (13.33%)  4
Nasal congestion * 1  2/15 (13.33%)  2
Aspiration * 1  1/15 (6.67%)  1
Cough * 1  1/15 (6.67%)  1
Pleural effusion * 1  1/15 (6.67%)  1
Respiratory failure * 1  1/15 (6.67%)  1
Sore throat * 1  1/15 (6.67%)  1
Wheezing * 1  1/15 (6.67%)  1
Skin and subcutaneous tissue disorders   
Pruritus * 1  3/15 (20.00%)  4
Rash acneiform * 1  2/15 (13.33%)  2
Rash maculo-papular * 1  2/15 (13.33%)  2
Skin and subcutaneous tissue disorders - Other, Left chest wall - Abnormal sensation * 1  1/15 (6.67%)  1
Skin and subcutaneous tissue disorders - Other, Rash * 1  1/15 (6.67%)  1
Dry skin * 1  1/15 (6.67%)  1
Erythema multiforme * 1  1/15 (6.67%)  1
Pain of skin * 1  1/15 (6.67%)  1
Skin ulceration * 1  1/15 (6.67%)  1
Vascular disorders   
Hot flashes * 1  2/15 (13.33%)  2
Hypotension * 1  1/15 (6.67%)  1
Thromboembolic event * 1  1/15 (6.67%)  1
1
Term from vocabulary, CTCAE (4.0)
*
Indicates events were collected by non-systematic assessment
[Not Specified]
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Hatem Soliman
Organization: H. Lee Moffitt Cancer Center and Research Institute
Phone: 813-745-4933
EMail: hatem.soliman@moffitt.org
Layout table for additonal information
Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT02139358     History of Changes
Other Study ID Numbers: MCC-17656
ML28939 ( Other Identifier: Genentech )
First Submitted: May 13, 2014
First Posted: May 15, 2014
Results First Submitted: June 25, 2018
Results First Posted: July 20, 2018
Last Update Posted: September 10, 2019