GCC 0845:Vorinostat and Lapatinib in Advanced Solid Tumors and Advanced Breast Cancer to Evaluate Response and Biomarkers

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01118975
• Collaborator: University of Maryland Greenebaum Cancer Center (Other)
• Enrollment: 12
• Location: 1
• Arms: 2
• Duration (Months): 31
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This research is being done to find out how safe and how well the combination of lapatinib and vorinostat works against advanced cancers.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Neoplasm Metastasis	Drug: Vorinostat; Drug: Lapatinib	Phase 1/Phase 2

Detailed Description

Lapatinib is an anti-cancer drug that is approved by the Food and Drug Administration (FDA) for the treatment of metastatic HER2-positive breast cancer. HER2 is a protein involved in the growth of some cancer cells. In lab tests and small clinical studies, lapatinib is also found to kill other types of cancer that have another related protein called epidermal growth factor receptor (EGFR). For participants who have other cancers, the use of lapatinib in this study is investigational. This means the drug is not FDA approved for this use.

Vorinostat is only FDA approved for the treatment of cutaneous T cell lymphoma (a type of cancer). Vorinostat is not currently FDA approved for breast cancer or any other type of cancer. The use of vorinostat in this study is investigational.

Cancer cells can travel through the blood stream and spread to other organs. This process is called metastasis. Lab tests and small clinical trials have shown that vorinostat kills some cancer cells and prevents these cancer cells from traveling through the blood stream. These trials have shown that vorinostat improves how well lapatinib kills cancer cells.

Newer studies have also shown that a subset of cells, called "cancer stem cells," can come back, spread, and become resistant to the usual chemotherapy. In laboratory tests, we found that vorinostat and lapatinib can reduce the number of cancer stem cells. We are looking at combining vorinostat and lapatinib in the hope that we can reduce the number of cancer stem cells and cancer cells traveling through the blood stream.

There are two parts to this study.

First part- We want to learn more about the best dose of vorinostat to be given with lapatinib. We want to learn about how much vorinostat and lapatinib goes into the blood during treatment. We also want to learn the side effects (safety) of the combination of vorinostat and lapatinib. All patients will receive the FDA-approved dose of lapatinib. The first group of patients will get a slightly lower dose of vorinostat than is given normally. If the side effects are not too serious, the next group of patients will get the dose of vorinostat that is given normally.

Second part- We will find out how well the combination of vorinostat and lapatinib works in patients with HER2-positive metastatic breast cancer.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: GCC 0845: Pilot and Phase II- Vorinostat and Lapatinib in Patients With Advanced Solid Tumor Malignancies and Women With Recurrent Local-Regional or Metastatic Breast Cancer to Evaluate Response and Biomarkers of EMT and Breast Cancer Stem Cells
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pilot Phase - Vornistat 200 to 400mg + Lapatinib lapatinib 1,250 mg continuous daily and escalating doses of vorinistat (200mg run-up, 300mg, and 400mg 4 days on 3 days off)	Drug: Vorinostat; 300 mg 4 days on then 3 days off As defined in the protocol, the dose of vorinostat was increased to 400 mg 4 days on then 3 days off in the pilot phase because the adverse event threshold was not met. In the Phase II cohort, the dose of vorinistat was 400 mg 4 days on and 3 days off.; Other Names: Zolinza ; Drug: Lapatinib; 1,250 mg once daily; Other Names: Tykerb
Experimental: Phase II - Vorinistat 400mg + Lapatinib lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days	Drug: Vorinostat; 300 mg 4 days on then 3 days off As defined in the protocol, the dose of vorinostat was increased to 400 mg 4 days on then 3 days off in the pilot phase because the adverse event threshold was not met. In the Phase II cohort, the dose of vorinistat was 400 mg 4 days on and 3 days off.; Other Names: Zolinza ; Drug: Lapatinib; 1,250 mg once daily; Other Names: Tykerb

Outcome Measures

Primary Outcome Measures

1. Dose Limiting Toxicities [6 weeks]

   Safety and tolerability were assessed. Adverse events and dose limiting toxicities were recorded during an escalting dose pilot phase.

2. Clinical Benefit Rate [Radiological evaluations are performed every 12 weeks to determine disease status]

   The Clinical Benefit Rate is the number of patients with either Complete Response (CR), Partial Response (PR), or Stable Disease (SD) for ≥ 6 months

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age greater than or equal to 18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

• Consent for peripheral blood sampling for analysis of circulating tumor cells.

• Patients must have adequate organ and marrow function as defined by the protocol.

• Female patients with histologically confirmed adenocarcinoma of the breast with recurrent local-regional disease, or metastatic disease that have progressed after treatment with regimens that include an anthracycline, a taxane, or trastuzumab.

• Human Epidermal growth factor Receptor 2 (HER2) positive in the primary or secondary tumor tissue as defined by:

• Grade 3plus staining intensity (on a scale of 0 to 3) by means of Immunohistochemistry (IHC) analysis OR

• Gene amplification on fluorescence in situ hybridization (FISH) greater than or equal to 2.2.

• Patients must have measurable disease by the Response Evaluation Criteria In Solid Tumors (RECIST)criteria at the time of enrollment.

• Prior trastuzumab therapy is allowed. Trastuzumab should be stopped at least 4 weeks prior to enrollment.

Exclusion Criteria:

• Patients receiving any other investigational agents.

• Prior exposure to lapatinib, vorinostat, or other Histone deacetylase (HDAC) inhibitors. Prior valproic acid exposure is allowed providing this is a greater than or equal to 30 days wash-out period.

• History of allergic reactions or hypersensitivity to compounds of similar chemical or biologic composition to vorinostat or lapatinib.

• Patients with history of clinically significant or uncontrolled cardiac disease, as defined by the protocol, or any significant cardiac condition that in the judgment of the investigator is unsuitable.

• Significant chronic or recent (less than 30 days) acute gastrointestinal disorder with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption, or Grade 2 or greater diarrhea of any etiology at baseline).

• Prior exposure to more than 360 mg/m2 doxorubicin or liposomal doxorubicin, more than 120 mg/m2 mitoxantrone, or more than 90 mg/m2 idarubicin, or elevated baseline cardiac troponin T (more than upper limit of normal).

• Patients with active Central Nervous System (CNS) metastasis and/or carcinomatous meningitis are excluded. Patients with CNS metastasis who have completed a course of therapy would be eligible for the study provided they are clinically stable for 3 weeks prior to entry as defined as: (1) no evidence of new or enlarging CNS metastasis and (2) off steroids and/or anticonvulsants, for at least 4 weeks before an enrollment.

• Female patient that is pregnant or breastfeeding or expecting to conceive during the study. Women able to have children must have a negative pregnancy test prior to enrollment. All patients must use two effective methods of contraception (including a barrier method) during treatment and for 12 weeks after stopping treatment.

• The patient is known to be Human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C-positive (test results are not required in order to participate).

• Patients with current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirement.

• Previous or current systemic malignancy within the past 3 years other than the following: Female- breast cancer or adequately treated carcinoma in-situ of the cervix, or Female and Male- basal/squamous carcinoma of the skin.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• University of Maryland, Baltimore
• University of Maryland Greenebaum Cancer Center

Investigators

• Principal Investigator: Saranya Chumsri, MD, University of Maryland, College Park

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT01118975
• Other Study ID Numbers: HP-00040048
• First Posted: May 7, 2010
• Last Update Posted: Nov 13, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by University of Maryland, Baltimore: lapatinib ditosylate; Zolinza (vorinostat); Cancer Stem Cells
• Additional relevant MeSH terms: Breast Neoplasms; Neoplasm Metastasis; Lapatinib; Vorinostat

Study Results

Participant Flow

Arm/Group Title	Pilot Phase - Vornistat 200 to 400mg + Lapatinib	Phase II - Vorinistat 400mg + Lapatinib
Arm/Group Description	lapatinib 1,250 mg continuous daily and escalating doses of vorinistat (200mg run-up, 300mg, and 400mg 4 days on 3 days off)	lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days
Period Title: Overall Study
STARTED	9	3
COMPLETED	9	2
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Pilot Phase - Vornistat 200 to 400mg + Lapatinib	Phase II - Vorinistat 400mg + Lapatinib	Total
Arm/Group Description	lapatinib 1,250 mg continuous daily and escalating doses of vorinistat (200mg run-up, 300mg, and 400mg 4 days on 3 days off)	lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days	Total of all reporting groups
Overall Participants	9	3	12
Age, Customized (years) [Median (Full Range) ]
Median (Full Range) [years]	52	51	52
Sex: Female, Male (Count of Participants)
Female	9 100%	3 100%	12 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Dose Limiting Toxicities
Description	Safety and tolerability were assessed. Adverse events and dose limiting toxicities were recorded during an escalting dose pilot phase.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pilot Phase
Arm/Group Description	The pilot phase consisted of an escalating dose design. Three patients received lapatinib 1,250 mg daily plus 300 mg vorinistat 4 days on then 3 days off. This dose was tolerated so six more patients recieved lapatinib 1,250 mg daily plus 400 mg vorinistat 4 days on 3 days off.
Measure Participants	9
Number [Dose limiting toxicities]	0

2. Primary Outcome

Title	Clinical Benefit Rate
Description	The Clinical Benefit Rate is the number of patients with either Complete Response (CR), Partial Response (PR), or Stable Disease (SD) for ≥ 6 months
Time Frame	Radiological evaluations are performed every 12 weeks to determine disease status

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase II - Vorinistat 400mg + Lapatinib
Arm/Group Description	lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off
Measure Participants	3
Number [participants]	1 11.1%

Adverse Events

Arm/Group Title	Pilot Phase - Vornistat 200 to 400mg + Lapatinib		Phase II - Vorinistat 400mg + Lapatinib
Arm/Group Description	lapatinib 1,250 mg continuous daily and escalating doses of vorinistat (200mg run-up, 300mg, and 400mg 4 days on 3 days off)		lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days
All Cause Mortality
	Pilot Phase - Vornistat 200 to 400mg + Lapatinib		Phase II - Vorinistat 400mg + Lapatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pilot Phase - Vornistat 200 to 400mg + Lapatinib		Phase II - Vorinistat 400mg + Lapatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/9 (11.1%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Infection	1/9 (11.1%)	1	0/3 (0%)	0
Dyspnea	1/9 (11.1%)	1	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	Pilot Phase - Vornistat 200 to 400mg + Lapatinib		Phase II - Vorinistat 400mg + Lapatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		1/3 (33.3%)
Blood and lymphatic system disorders
Anemia	2/9 (22.2%)	2	0/3 (0%)	0
Bony lesion	1/9 (11.1%)	1	0/3 (0%)	0
Leukopenia	1/9 (11.1%)	1	0/3 (0%)	0
Neutropenia	1/9 (11.1%)	2	0/3 (0%)	0
Cardiac disorders
Hypertension	1/9 (11.1%)	1	0/3 (0%)	0
Prolonged QTc	1/9 (11.1%)	1	0/3 (0%)	0
Ear and labyrinth disorders
Ear ache	1/9 (11.1%)	1	0/3 (0%)	0
Endocrine disorders
Hot flashes	2/9 (22.2%)	2	0/3 (0%)	0
Eye disorders
Ocular discharge	1/9 (11.1%)	1	0/3 (0%)	0
Gastrointestinal disorders
Diarrhea	5/9 (55.6%)	9	1/3 (33.3%)	3
Nausea	4/9 (44.4%)	4	1/3 (33.3%)	2
Vomiting	0/9 (0%)	0	1/3 (33.3%)	2
Anorexia	1/9 (11.1%)	1	0/3 (0%)	0
Constipation	1/9 (11.1%)	1	0/3 (0%)	0
Dehydration	1/9 (11.1%)	1	0/3 (0%)	0
Headache	2/9 (22.2%)	3	0/3 (0%)	0
Stomatitis	1/9 (11.1%)	1	0/3 (0%)	0
General disorders
Fatigue	3/9 (33.3%)	3	1/3 (33.3%)	1
Insomnia	1/9 (11.1%)	1	0/3 (0%)	0
Migranes	1/9 (11.1%)	1	0/3 (0%)	0
Pain - back, chest or shoulder	3/9 (33.3%)	3	0/3 (0%)	0
Pain - limbs	3/9 (33.3%)	3	0/3 (0%)	0
Infections and infestations
Dental abscess	1/9 (11.1%)	2	0/3 (0%)	0
Thrush	1/9 (11.1%)	1	0/3 (0%)	0
Metabolism and nutrition disorders
Elevated chloride	1/9 (11.1%)	1	0/3 (0%)	0
Elevated creatinine	1/9 (11.1%)	1	0/3 (0%)	0
Elevated phosphorus	1/9 (11.1%)	1	0/3 (0%)	0
Elevated protein	1/9 (11.1%)	1	0/3 (0%)	0
Elevated SGPT	1/9 (11.1%)	3	0/3 (0%)	0
Elevated uric acid	1/9 (11.1%)	2	0/3 (0%)	0
Hyperbilirubinemia	1/9 (11.1%)	2	0/3 (0%)	0
Hyperglycemia	3/9 (33.3%)	3	0/3 (0%)	0
Hypokalemia	3/9 (33.3%)	5	0/3 (0%)	0
Weight loss	1/9 (11.1%)	1	0/3 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle cramps	2/9 (22.2%)	2	0/3 (0%)	0
Nervous system disorders
Dizziness	1/9 (11.1%)	3	0/3 (0%)	0
Neuropathy	2/9 (22.2%)	2	0/3 (0%)	0
Syncope	1/9 (11.1%)	1	0/3 (0%)	0
Psychiatric disorders
Depression	3/9 (33.3%)	3	0/3 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	3/9 (33.3%)	3	0/3 (0%)	0
Dyspnea	1/9 (11.1%)	1	0/3 (0%)	0
Hoarseness	1/9 (11.1%)	1	0/3 (0%)	0
Sore throat	1/9 (11.1%)	1	0/3 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	2/9 (22.2%)	2	0/3 (0%)	0
Skin Atrophy	1/9 (11.1%)	1	0/3 (0%)	0
Dry skin	1/9 (11.1%)	1	0/3 (0%)	0
Erythema	1/9 (11.1%)	1	0/3 (0%)	0
Pruritis/itching	1/9 (11.1%)	1	0/3 (0%)	0
Radiation dermatitis	1/9 (11.1%)	1	0/3 (0%)	0
Rash	3/9 (33.3%)	5	0/3 (0%)	0
Skin nodules	2/9 (22.2%)	2	0/3 (0%)	0

Limitations/Caveats

The most important limitation of this study is that the Phase II efficacy portion was terminated early by the sponsor.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.