Lapatinib and Bortezomib in Patients With Advanced Malignancies

Advanced Solid Tumors Clinical Trial

Official title:

A Phase I Study of the HER1, HER2 Dual Kinase Inhibitor, Lapatinib Plus the Proteosomal Inhibitor Bortezomib in Patients With Advanced Malignancies

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01497626
• Other study ID #: 2010-533
• Secondary ID: XO53718LAP114999
• Status: Terminated
• Phase: Phase 1
• First received: December 20, 2011
• Last updated: February 15, 2016
• Start date: September 2011
• Est. completion date: December 2015

Study information

• Verified date: September 2015
• Source: Georgetown University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study is for patients with an advanced type of cancer for which no curative treatment exists.

The purpose of this study is to test the safety and efficacy of the combination of the study drugs, lapatinib and bortezomib. Lapatinib is a drug that targets two proteins important for the growth of cancer cells known as HER1 (EGFR) and HER2. By inhibiting these proteins, lapatinib can inhibit cancer cell growth and even lead to their death. Lapatinib is an oral pill given by mouth once every day. Lapatinib is approved by the FDA for patients with breast cancer.

Bortezomib is a drug that targets a part of cancer cells known as the proteosome. By inhibiting the proteosome, bortezomib can inhibit cancer cell growth and even lead to their death. Bortezomib is given intravenously, once a week, 2 out of every 3 weeks. Bortezomib is approved by the FDA for patients with multiple myeloma and mantle cell lymphoma.

This research is being done because it is not known if the combination of lapatinib and bortezomib will work better than lapatinib or bortezomib alone, although in the lab and in animal studies the combination of the two drugs was much more effective than either drug alone.

As part of this study biopsies will be taken of patients' tumors before any treatment, after starting lapatinib alone, and after receiving both lapatinib and bortezomib. Investigators want to study what markers inside tumors may relate to how well these two medications work. These biopsies are required as part of the study.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 15
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically proven malignant solid tumor with measurable disease

• Progression on, or intolerance of, or ineligibility for all standard therapies

• Biopsy accessible tumor deposits

• LVEF >/= institutional normal

• Corrected QT interval less than 500 milliseconds by EKG

• ECOG performance status 0-2

• Subjects with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or stereotactic radiosurgery at least 4 weeks prior to enrollment and have a baseline MRI that shows no evidence of active intercranial disease and have not had treatment with steroids within 1 week of enrollment.

• Adequate hepatic, bone marrow, and renal function

• Partial thromboplastin time must be </= 1.5 x upper limit of institution's normal range and INR < 1.5. Subjects on anticoagulants will be permitted to enroll as long as the INR is in the acceptable therapeutic range.

• Life expectancy > 12 weeks

• Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment and/or postmenopausal women must be amenorrheic for at least 12 months.

• Subject is capable of understanding and complying with parameters as outlines in the protocol and able to sign and date the informed consent form.

Exclusion Criteria:

• Patients with lymphomas

• CNS metastases which do not meet the criteria outlines in the inclusion criteria

• Peripheral neuropathy >/= Grade 2 at baseline or peripheral neuropathy >/= Grade 1 with neuropathic pain

• Active severe infection or known chronic infection with HIV or hepatitis B virus

• Cardiovascular disease problems including unstable angina, therapy for life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months

• Life-threatening visceral disease or other severe concurrent disease

• Women who are pregnant or breastfeeding

• Anticipated patient survival under 3 months

• Concurrent use of known CYP 3A4 inhibiting or activating medications

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Advanced Solid Tumors

Intervention

Drug:
• Lapatinib and bortezomib
Lapatinib will be taken orally continuously for 28 days of each 28-day cycle, including a run-in of lapatinib alone day -7 to day 1 of cycle 1. Bortezomib will be administered IV on days 1, 8, and 15 of each cycle. The exact doses of both drugs will be dependent on which cohort the subject is in and adverse events observed in previous cohorts.

Locations

Country	Name	City	State
United States	Georgetown Lombardi Comprehensive Cancer Center	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Georgetown University	GlaxoSmithKline, Millennium Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose	The highest dose at which	18 months	Yes
Secondary	toxicity	Adverse events seen during the trial graded using CTCAE version 4	18 months	Yes
Secondary	Response rate	complete response and partial response measured by RECIST 1.1	18 months	No
Secondary	Disease control rate	stable disease after two cycles+ partial response + complete response as determined by RECIST 1.1 criteria	2 months	No
Secondary	Pharmacodynamics	To assess changes in the following in serial tumor samples: EGFR, HER2, HER3, AKT, Actin, ERK, GSK3a-beta, IGF-1R, MEK 1/2, mTOR, p70S6, P13K, PTEN, SHC Y317, NFKB, IKB, CFK4, CDK2, cyclin D1, cyclin A, Cyclin E, p15, p16, p21, p27, beta-catenin, and ras gene mutation	pre-treatment, after 1 week of therapy and adter 3 weeks of therapy	No