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

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02139358
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 15
• Location: 1
• Arm: 1
• Actual Duration (Months): 66.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and activity of gemcitabine plus trastuzumab and pertuzumab in patients with metastatic human epidermal growth factor receptor 2 (HER2)+ breast cancer who have progressed on at least one prior line of chemotherapy plus HER2 targeted agent such as T-DM1, trastuzumab, or lapatinib.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Gemcitabine; Drug: Trastuzumab; Drug: Pertuzumab	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/IIa Trial of Gemcitabine Plus Trastuzumab and Pertuzumab in Previously Treated Metastatic HER2+ Breast Cancer
• Actual Study Start Date: Sep 5, 2014
• Actual Primary Completion Date: Apr 24, 2018
• Actual Study Completion Date: Mar 16, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Dose Escalation / Phase II Treatment Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.

Drug: 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 (1200 mg/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.; Other Names: GEMZAR® ; Drug: 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.; Other Names: Herceptin® ; Drug: Pertuzumab; Pertuzumab will be given using an 840 mg IV loading dose on C1D1, followed by 420 mg IV on subsequent cycles q 21 days.; Other Names: PERJETA®

Outcome Measures

Primary Outcome Measures

1. Phase I: Recommended Phase II Dose (RP2D) [6 Months]

   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.

2. Phase II: Objective Response Rate (ORR) [Up to 36 Months]

   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.

Secondary Outcome Measures

1. Phase II: Progression Free Survival (PFS) [Up to 12 months]

   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.

2. Overall Survival (OS) [Up to 36 months]

   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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adult males or females (aged 18 or older) with histologically confirmed, metastatic human epidermal growth factor receptor 2 (HER2)+ (by immunohistochemistry (IHC) 3+ or fluorescence in situ hydridization (FISH) ratio ≥ 2.0) breast cancer

• Have progressed on at least one prior line of chemotherapy plus HER2 directed therapy such as trastuzumab and/or pertuzumab in the metastatic setting. T-DM1 would count as a line of therapy and patients previously treated with T-DM1 are eligible.

• Have not been treated with gemcitabine in the metastatic setting

• Measurable disease per Response Evaluation in Solid Tumors (RECIST) 1.1 criteria

• Eastern Cooperative Oncology Group (ECOG) performance status 2≤

• Left Ventricular Ejection Fraction (LVEF) ≥ 50% at baseline as determined by either echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)

• Adequate bone marrow function as indicated by the following: absolute neutrophil count (ANC) >1500/µL; Platelets ≥100,000/µL; Hemoglobin >10 g/dL

• Adequate renal function, as indicated by creatinine ≤1.5x upper limit of normal (ULN)

• Adequate liver function, as indicated by bilirubin ≤1.5x ULN, aspartic transaminase (AST) or alanine transaminase (ALT) <2x ULN unless related to metastatic breast cancer to the liver (in which case AST/ALT < 5x ULN is allowed).

• Signed informed consent

• Adequate birth control in sexually active women of childbearing potential

Exclusion Criteria:

• Active uncontrolled infection or major concurrent illness which in the opinion of the investigator would render the participant unsafe to proceed with the study

• Uncontrolled central nervous system (CNS) metastases. Treated, non-progressing CNS disease (documented by brain magnetic resonance imaging [MRI]) off corticosteroids for at least 1 month potential participants are eligible.

• Women who are pregnant or lactating

• Prior chemotherapy within the last 3 weeks (last 6 weeks for nitrosureas/mitomycin)

• Prior radiation therapy within the last 4 weeks; prior radiation therapy to indicator lesion (unless objective disease recurrence or progression within the radiation portal has been documented since completion of radiation)

• Other concomitant active malignancies

• History of significant cardiac disease, cardiac risk factors or uncontrolled arrhythmias

• Ejection fraction <50% or below the lower limit of the institutional normal range, whichever is lower

• Hypersensitivity to any of the study medications

• Untreated psychiatric conditions preventing informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Genentech, Inc.

Investigators

• Principal Investigator: Hatem Soliman, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 14, 2013

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT02139358
• Other Study ID Numbers: MCC-17656; ML28939
• First Posted: May 15, 2014
• Last Update Posted: Feb 4, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Breast - Female; Metastatic; HER2+
• Additional relevant MeSH terms: Breast Neoplasms; Gemcitabine; Trastuzumab; Pertuzumab

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at Moffitt Cancer Center October 2014 through October 2016.

Arm/Group Title	Dose Escalation / Phase II Treatment
Arm/Group Description	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

Baseline Characteristics

Arm/Group Title	Dose Escalation / Phase II Treatment
Arm/Group Description	Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Overall Participants	15
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	58.2
Sex: Female, Male (Count of Participants)
Female	15 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 13.3%
Not Hispanic or Latino	12 80%
Unknown or Not Reported	1 6.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 6.7%
White	12 80%
More than one race	0 0%
Unknown or Not Reported	2 13.3%
Region of Enrollment (participants) [Number]
United States	15 100%

Outcome Measures

1. Primary Outcome

Title	Phase I: Recommended Phase II Dose (RP2D)
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

Outcome Measure Data

Analysis Population Description

All participants enrolled during Phase 1

Arm/Group Title	Dose Escalation / Phase II Treatment
Arm/Group Description	Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Measure Participants	6
Number [dose in mg/m^2]	1200

2. Primary Outcome

Title	Phase II: Objective Response Rate (ORR)
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

Outcome Measure Data

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
Arm/Group Description	Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Measure Participants	10
Complete Response	1 6.7%
Partial Response	1 6.7%
Stable Disease	8 53.3%

3. Secondary Outcome

Title	Phase II: Progression Free Survival (PFS)
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

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Dose Escalation / Phase II Treatment
Arm/Group Description	Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Measure Participants	15
Median (95% Confidence Interval) [months]	6.4883

4. Secondary Outcome

Title	Overall Survival (OS)
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

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Dose Escalation / Phase II Treatment
Arm/Group Description	Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.
Measure Participants	15
Median (95% Confidence Interval) [months]	11.3545

Adverse Events

Time Frame	3 years, 7 months
Arm/Group Title	Dose Escalation / Phase II Treatment
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 (%)	# Events
Total	2/15 (13.3%)
Serious Adverse Events
	Dose Escalation / Phase II Treatment
	Affected / at Risk (%)	# Events
Total	7/15 (46.7%)
Cardiac disorders
Cardiac arrest	1/15 (6.7%)	1
Chest pain - cardiac	1/15 (6.7%)	1
Gastrointestinal disorders
Diarrhea	1/15 (6.7%)	1
Duodenal hemorrhage	1/15 (6.7%)	1
General disorders
Fatigue	1/15 (6.7%)	1
Fever	1/15 (6.7%)	1
Sudden death NOS	1/15 (6.7%)	1
Infections and infestations
Sepsis	1/15 (6.7%)	1
Skin infection	1/15 (6.7%)	1
Investigations
Neutrophil count decreased	1/15 (6.7%)	1
Platelet count decreased	1/15 (6.7%)	1
Metabolism and nutrition disorders
Dehydration	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/15 (13.3%)	2
Pleural effusion	1/15 (6.7%)	1
Respiratory failure	1/15 (6.7%)	2
Respiratory, thoracic and mediastinal disorders - Other, Pneumonia	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Dose Escalation / Phase II Treatment
	Affected / at Risk (%)	# Events
Total	15/15 (100%)
Blood and lymphatic system disorders
Anemia	11/15 (73.3%)	39
Cardiac disorders
Sinus tachycardia	3/15 (20%)	5
Chest pain - cardiac	1/15 (6.7%)	1
Left ventricular systolic dysfunction	1/15 (6.7%)	1
Palpitations	1/15 (6.7%)	1
Ear and labyrinth disorders
Tinnitus	1/15 (6.7%)	1
Eye disorders
Blurred vision	1/15 (6.7%)	1
Dry eye	1/15 (6.7%)	1
Eye pain	1/15 (6.7%)	1
Gastrointestinal disorders
Diarrhea	10/15 (66.7%)	13
Nausea	9/15 (60%)	11
Vomiting	5/15 (33.3%)	6
Abdominal pain	2/15 (13.3%)	2
Dysphagia	2/15 (13.3%)	2
Constipation	1/15 (6.7%)	1
Dry mouth	1/15 (6.7%)	1
Duodenal hemorrhage	1/15 (6.7%)	1
Duodenal ulcer	1/15 (6.7%)	1
Dyspepsia	1/15 (6.7%)	1
Fecal incontinence	1/15 (6.7%)	1
Mucositis oral	1/15 (6.7%)	1
Oral pain	1/15 (6.7%)	1
General disorders
Fatigue	10/15 (66.7%)	12
Infusion related reaction	3/15 (20%)	3
Pain	3/15 (20%)	4
Edema limbs	2/15 (13.3%)	3
Fever	2/15 (13.3%)	2
Chills	1/15 (6.7%)	1
Malaise	1/15 (6.7%)	1
Non-cardiac chest pain	1/15 (6.7%)	1
Infections and infestations
Skin infection	2/15 (13.3%)	2
Papulopustular rash	1/15 (6.7%)	1
Sinusitis	1/15 (6.7%)	1
Tooth infection	1/15 (6.7%)	2
Upper respiratory infection	1/15 (6.7%)	1
Injury, poisoning and procedural complications
Bruising	1/15 (6.7%)	1
Fracture	1/15 (6.7%)	1
Wound dehiscence	1/15 (6.7%)	2
Investigations
Neutrophil count decreased	12/15 (80%)	47
Lymphocyte count decreased	10/15 (66.7%)	19
Platelet count decreased	9/15 (60%)	24
White blood cell decreased	9/15 (60%)	48
Alanine aminotransferase increased	6/15 (40%)	12
Aspartate aminotransferase increased	6/15 (40%)	17
Alkaline phosphatase increased	2/15 (13.3%)	3
Creatinine increased	1/15 (6.7%)	2
Ejection fraction decreased	1/15 (6.7%)	1
Electrocardiogram QT corrected interval prolonged	1/15 (6.7%)	1
Metabolism and nutrition disorders
Anorexia	6/15 (40%)	7
Hypoalbuminemia	6/15 (40%)	8
Hypocalcemia	5/15 (33.3%)	8
Hypokalemia	5/15 (33.3%)	10
Dehydration	2/15 (13.3%)	2
Hypernatremia	2/15 (13.3%)	2
Hyponatremia	2/15 (13.3%)	2
Hypophosphatemia	2/15 (13.3%)	2
Hypercalcemia	1/15 (6.7%)	1
Hypermagnesemia	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Myalgia	6/15 (40%)	7
Pain in extremity	4/15 (26.7%)	6
Bone pain	3/15 (20%)	3
Arthralgia	2/15 (13.3%)	2
Back pain	2/15 (13.3%)	3
Generalized muscle weakness	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorder - Other, Right wrist swelling	1/15 (6.7%)	1
Neck pain	1/15 (6.7%)	1
Osteoporosis	1/15 (6.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Cervical polyp	1/15 (6.7%)	1
Neoplasms benign, malignant and unspecified and polyps) - Other, Goiter with thyroid modules	1/15 (6.7%)	1
Nervous system disorders
Dizziness	4/15 (26.7%)	4
Peripheral sensory neuropathy	3/15 (20%)	3
Headache	2/15 (13.3%)	2
Somnolence	2/15 (13.3%)	2
Dysphasia	1/15 (6.7%)	1
Psychiatric disorders
Depression	1/15 (6.7%)	1
Insomnia	1/15 (6.7%)	1
Restlessness	1/15 (6.7%)	1
Renal and urinary disorders
Cystitis noninfective	1/15 (6.7%)	1
Hematuria	1/15 (6.7%)	1
Proteinuria	1/15 (6.7%)	1
Urinary frequency	1/15 (6.7%)	1
Urinary tract pain	1/15 (6.7%)	1
Reproductive system and breast disorders
Vaginal inflammation	1/15 (6.7%)	1
Vaginal pain	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	6/15 (40%)	8
Allergic rhinitis	2/15 (13.3%)	2
Epistaxis	2/15 (13.3%)	4
Nasal congestion	2/15 (13.3%)	2
Aspiration	1/15 (6.7%)	1
Cough	1/15 (6.7%)	1
Pleural effusion	1/15 (6.7%)	1
Respiratory failure	1/15 (6.7%)	1
Sore throat	1/15 (6.7%)	1
Wheezing	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Pruritus	3/15 (20%)	4
Rash acneiform	2/15 (13.3%)	2
Rash maculo-papular	2/15 (13.3%)	2
Skin and subcutaneous tissue disorders - Other, Left chest wall - Abnormal sensation	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders - Other, Rash	1/15 (6.7%)	1
Dry skin	1/15 (6.7%)	1
Erythema multiforme	1/15 (6.7%)	1
Pain of skin	1/15 (6.7%)	1
Skin ulceration	1/15 (6.7%)	1
Vascular disorders
Hot flashes	2/15 (13.3%)	2
Hypotension	1/15 (6.7%)	1
Thromboembolic event	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.