Tolerability of the Combination of Lapatinib and Trastuzumab in Adults Age 60 or Older With HER2 Positive Locally Advanced or Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT01273610
• Recruitment Status: Active, not recruiting
• First Posted: January 10, 2011
• Last Update Posted: June 22, 2021
• Sponsor: City of Hope Medical Center
• Collaborators: GlaxoSmithKline; Novartis
• Information provided by (Responsible Party): City of Hope Medical Center

Study Description

Brief Summary:

This phase II trial studies the side effects and how well lapatinib ditosylate and trastuzumab work in treating older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or to other parts of the body (metastatic). Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor to grow and spread. Others find tumor cells and help kill them or tumor cancer-killing substances to them. Giving lapatinib ditosylate together with trastuzumab may kill more tumor cells.

Condition or disease	Intervention/treatment	Phase
Breast Neoplasms; HER2/Neu Positive; Geriatric Health Services	Drug: Lapatinib; Drug: Trastuzumab; Other: laboratory biomarker analysis; Other: pharmacological study	Phase 2

Detailed Description:

PRIMARY OBJECTIVES: I. To estimate the safety and tolerability of the combination of trastuzumab and lapatinib (lapatinib ditosylate) in adults age 60 or older with locally advanced or metastatic breast cancer. SECONDARY OBJECTIVES: I. To describe the full toxicity profile including all grades; to estimate the rate of all grades of cardiac toxicity; to estimate the rate of all grades of diarrhea, nausea, and vomiting. II. To describe the pharmacokinetic parameters of lapatinib in older adults. III. To estimate objective response rate and clinical benefit rate as defined by modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria. IV. To estimate median progression-free and overall survival. V. To explore factors other than chronological age that can affect toxicity rates as identified using a cancer-specific geriatric assessment. VI. To estimate rates of adherence to lapatinib in older adults.

OUTLINE: Patients receive lapatinib ditosylate orally (PO) once daily (QD) and trastuzumab intravenously (IV) over 30-90 minutes once weekly OR once every 3 weeks. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days and then periodically thereafter.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Tolerability of the Combination of Lapatinib and Trastuzumab in Adults Age 60 or Older With HER2 Positive Locally Advanced or Metastatic Breast Cancer
• Actual Study Start Date: April 20, 2011
• Actual Primary Completion Date: February 22, 2018
• Estimated Study Completion Date: February 22, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Lapatinib and trastuzumab; Patients receive lapatinib ditosylate PO QD and trastuzumab IV once weekly OR once every 3 weeks. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: Lapatinib; 250 mg tablets; Other Names: Tykerb; Tyverb; GSK572016; GW-572016; GW2016; Drug: Trastuzumab; Intravenous injection; Other Name: Herceptin; Other: laboratory biomarker analysis; Other Name: Correlative studies; Other: pharmacological study; Other Name: Correlative studies

Outcome Measures

Primary Outcome Measures :

1. Grade 3 or higher non-hematological toxicities and symptomatic congestive heart failure (as defined by NCI CTCAE v.4.0) [ Time Frame: Until 30 days after last dose of treatment ]
   Tables will be created to summarize the toxicities and side effects for each dose schedule by dose, course, organ and severity for all patients. All serious adverse events and other serious toxicities will be described on a patient by patient basis. Numbers of cycles received and dose reductions will be tabulated by dose. Rates and associated 95% exact Clopper and Pearson binomial confidence intervals will be estimated.

Secondary Outcome Measures :

1. All toxicities associated with the combinations as measured by NCI CTCAE v. 4.0 [ Time Frame: Until 30 days after last dose of treatment ]
   Rates and associated 95% exact Clopper and Pearson binomial confidence intervals will be estimated.
2. Dose reductions, dose interruptions, dose discontinuations [ Time Frame: While on treatment ]
   Rates and associated 95% exact Clopper and Pearson binomial confidence intervals will be estimated.
3. Tumor response (using RECIST criteria) [ Time Frame: Up to 8 years ]
   Response rate (complete response [CR] + partial response [PR]) and clinical benefit rate (CR + PR + stable disease [SD]) and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated.
4. Progression-free survival [ Time Frame: From start of treatment until documented disease progression or death ]
5. Overall survival [ Time Frame: From start of treatment until death from any cause ]
6. Pharmacokinetic parameters of lapatinib, including trough levels and area under curve (AUC) [ Time Frame: Day 15 of course 1 and days 1 and 8 of course 2 ]
   AUC will be calculated and reported using standard descriptive statistics.

Eligibility Criteria

• Ages Eligible for Study: 60 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Locally advanced or metastatic Her2/Neu positive breast cancer (defined as immunohistochemistry [IHC] 3+ or a fluorescence in situ hybridization [FISH] ratio of >= 2.0); this may be on either a primary tumor or a metastatic site, and there is no time limit from the time the specimen was obtained; locally advanced breast cancer (LABC) includes breast cancers with advanced primary tumors, i.e., large diameter (at least 5 cm) or those with skin and/or chest wall involvement, and advanced regional lymph node involvement; it also includes a rare subgroup, inflammatory breast cancer; in the 2010 American Joint Committee on Cancer and the International Union for Cancer Control (AJCC-UICC) TNM breast cancer staging system, locally advanced breast cancer (LABC) includes patients with stage III disease; this comprises:

  • Advanced primary tumors (tumors > 5 cm in greatest dimension [T3]; direct extension to the chest wall and/or to the skin [T4]: ulceration, skin nodules, and/or edema (including peau d'orange) confined to the same breast, inflammatory breast cancer [IBC, T4d])
  • Advanced regional lymph nodes (ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted or clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases [N2], ipsilateral infraclavicular [level III axillary] lymph nodes, ipsilateral internal mammary lymph node[s] with axillary lymph nodes, or ipsilateral supraclavicular lymph nodes [N3])
• Both measurable and non-measurable disease are allowed
• Life expectancy of greater than 12 weeks
• Women of child-bearing potential and sexually active men must agree to use adequate contraception prior to study entry for six months following duration of study participation
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky performance status >= 60%)
• Hemoglobin >= 10 g/dL (after transfusion if necessary)
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/aspartate aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
• Creatinine clearance >= 30 mL/min as measured using either the Cockcroft-Gault method or 24-hour creatinine clearance
• The above tests must be obtained within 14 days of study treatment
• Cardiac ejection fraction >= 50% as measured by echocardiogram or multiple gated acquisition scan (MUGA) scan
• The ability to swallow and retain oral medication
• Prior treatment with lapatinib or trastuzumab are allowed, provided that the agents have never been given in combination
• Any number of prior cancer treatments, including investigational agents, chemotherapy, hormone therapy, or targeted therapy are allowed
• All patients must have the ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

• Concurrent investigational treatment, chemotherapy, or targeted therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia)
• Unstable or symptomatic brain metastases (however, patients with stable or treated brain metastases who do not require steroids at doses above those permitted for control of symptoms may be enrolled)
• History of allergic reactions attributed to compounds of similar chemical or biological composition to lapatinib or trastuzumab; however, patients with a history of infusion reaction to trastuzumab which was controlled with premedication on subsequent infusions without a recurring infusion reaction are eligible
• Concomitant medications listed are prohibited; inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) not listed can be used with caution
• Ongoing or active infection (including human immunodeficiency virus [HIV]) or psychiatric illness/social situations that would limit compliance with study requirements
• Inability to take oral medication
• Malabsorption syndrome, (prior surgical procedures affecting absorption), or inflammatory gastrointestinal (GI) disease (e.g., Crohn's, ulcerative colitis) which in the opinion of the study coordinator is likely to limit normal absorption of the drug
• Current active hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment)

• Active cardiac disease, defined as (but not limited to):

  • History of documented congestive heart failure (CHF) or systolic dysfunction (left ventricular ejection fraction [LVEF] < 50%)
  • High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade atrio-ventricular [AV]-block, supraventricular tachycardias which are not adequately rate-controlled)
  • Angina pectoris requiring antianginal medications
  • Evidence of transmural infarction on electrocardiogram (ECG)
  • Clinically significant valvular heart disease
  • Poorly controlled hypertension (e.g. systolic > 180 mm HG or diastolic > 100 mm Hg)
  • Any other cardiac condition, which in the opinion of the treating physician would make this protocol unreasonably hazardous for the patient
• Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible

Contacts and Locations

Locations

United States, California

City of Hope Medical Center

Duarte, California, United States, 91010

City of Hope Antelope Valley

Lancaster, California, United States, 93534

South Pasadena Cancer Center

Pasadena, California, United States, 91030

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

United States, North Carolina

Lineberger Comprehensive Cancer Center, University of North Carolina

Chapel Hill, North Carolina, United States, 27599

Duke University Medical Center

Durham, North Carolina, United States, 27704

United States, Ohio

Case Western Reserve University

Cleveland, Ohio, United States, 44106

United States, Pennsylvania

Thomas Jefferson University

Philadelphia, Pennsylvania, United States, 19107

Sponsors and Collaborators

City of Hope Medical Center

GlaxoSmithKline

Novartis

Investigators

• Principal Investigator: Arti Hurria, MD; City of Hope Medical Center

More Information

Publications:

Hurria A, Gupta S, Zauderer M, Zuckerman EL, Cohen HJ, Muss H, Rodin M, Panageas KS, Holland JC, Saltz L, Kris MG, Noy A, Gomez J, Jakubowski A, Hudis C, Kornblith AB. Developing a cancer-specific geriatric assessment: a feasibility study. Cancer. 2005 Nov 1;104(9):1998-2005.

Hurria A, Lichtman SM. Pharmacokinetics of chemotherapy in the older patient. Cancer Control. 2007 Jan;14(1):32-43. Review.

Kimmick GG, Fleming R, Muss HB, Balducci L. Cancer chemotherapy in older adults. A tolerability perspective. Drugs Aging. 1997 Jan;10(1):34-49. Review.

Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol. 2004 Nov 15;22(22):4626-31.

Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. doi: 10.1200/JCO.2008.21.4437. Epub 2010 Feb 1.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT01273610
• Other Study ID Numbers: 10112; NCI-2011-00116 ( Registry Identifier: NCI CTRP )
• First Posted: January 10, 2011
• Last Update Posted: June 22, 2021
• Last Verified: June 2021

Keywords provided by City of Hope Medical Center:

Breast Neoplasms; HER2 protein, human; Geriatric Health Services; Antineoplastic Agents, Combined; Geriatric Assessment; Pharmacokinetics; Toxicity; Patient Adherence

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Trastuzumab; Lapatinib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action