Lapatinib and Bortezomib in Patients With Advanced Malignancies
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Advanced Solid Tumors |
Drug: Lapatinib and bortezomib |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Phase I Study of the HER1, HER2 Dual Kinase Inhibitor, Lapatinib Plus the Proteosomal Inhibitor Bortezomib in Patients With Advanced Malignancies |
- Maximum tolerated dose [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]The highest dose at which </= 1 out of 6 subjects has a dose-limiting toxicity
- toxicity [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]Adverse events seen during the trial graded using CTCAE version 4
- Response rate [ Time Frame: 18 months ] [ Designated as safety issue: No ]complete response and partial response measured by RECIST 1.1
- Disease control rate [ Time Frame: 2 months ] [ Designated as safety issue: No ]stable disease after two cycles+ partial response + complete response as determined by RECIST 1.1 criteria
- Pharmacodynamics [ Time Frame: pre-treatment, after 1 week of therapy and adter 3 weeks of therapy ] [ Designated as safety issue: No ]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
| Estimated Enrollment: | 40 |
| Study Start Date: | September 2011 |
| Estimated Study Completion Date: | December 2015 |
| Estimated Primary Completion Date: | March 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Bortezomib plus lapatinib
Combination treatment with lapatinib and bortezomib
|
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. Other Name: Velcade
|
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| Contact: Rose Hardesty, RN | 202-687-2111 | RK286@georgetown.edu |
| Contact: Ion Cotarla | 202-687-4510 | IC34@georgetown.edu |
| United States, District of Columbia | |
| Georgetown Lombardi Comprehensive Cancer Center | Recruiting |
| Washington, District of Columbia, United States, 20007 | |
| Contact: Rose Hardesty, RN 202-687-2111 rk286@georgetown.edu | |
| Contact: Ion Cotarla 202-687-4510 IC34@georgetown.edu | |
| Principal Investigator: Michael Pishvaian, MD PhD | |
| Principal Investigator: | Michael Pishvaian, MD PhD | Georgetown University |
More Information
No publications provided
| Responsible Party: | Georgetown University |
| ClinicalTrials.gov Identifier: | NCT01497626 History of Changes |
| Other Study ID Numbers: | 2010-533, XO5371, 8LAP114999 |
| Study First Received: | December 20, 2011 |
| Last Updated: | March 11, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Georgetown University:
|
Advanced cancer Solid tumor |
Additional relevant MeSH terms:
|
Bortezomib Lapatinib Antineoplastic Agents Therapeutic Uses Pharmacologic Actions |
Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Protein Kinase Inhibitors |
ClinicalTrials.gov processed this record on May 19, 2013