Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Neoplasm Metastasis

Breast Diseases

Skin Diseases

Bone Density Conservation Agents

Antineoplastic Agents

All Drugs and Chemicals

Anticoagulants

Other Dietary Supplements

Tamoxifen

Estrogens

Citric Acid

Sodium Citrate

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Aromatase Inhibitors

Progesterone

Vorinostat

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Histone Deacetylase Inhibitors

Enzyme Inhibitors

Citrate

Vorinostat will be used to potentiate the effects of tamoxifen or overcome tamoxifen resistance. All patients will receive vorinostat at 400 mg by mouth (po) daily for 3 out of 4 weeks. Responses will be assessed after 2 cycles (8 weeks + 4 days).

suberoylanilide hydroxamic acid (SAHA, Vorinostat)

Tamoxifen will be given once daily at 20 mg. Tamoxifen will be given continuously. Responses will be assessed after 2 cycles (8 weeks + 4 days).

tamoxifen citrate (Tamoxifen)

Susan Minton, D.O.

Phase II trial to explore the efficacy of vorinostat and tamoxifen combined.

Phase II trial to explore the efficacy of vorinostat and tamoxifen combined. Tamoxifen will be given once daily, continuously. Vorinostat will be given daily for 3 out of 4 weeks (a cycle). Responses will be assessed (restaged) after 2 cycles and toxicities will be captured continuously. Eligible patients will receive treatment in consecutive 4-week cycles, until progression of disease or unacceptable toxicity. Patients will be followed for evaluation of safety for at least 30 days after the last dose of the study drug.

Tests will be obtained pre-and post vorinostat treatment and correlated with plasma levels of vorinostat at the time of tumor biopsy and vorinostat doses; the tests will consist of:

* Patient history
* Physical exam (including height and weight)
* Toxicity assessment
* Pharmacokinetic (PK) sample
* Tumor fine needle aspirate (FNA)
* Peripheral Blood Mononuclear Cells (PBMC)
* Standard labs and Chemistry Profile
* Carcinoembryonic antigen (CEA), cancer antigen (Ca) 15-3, Ca 125 (If clinically indicated)
* Pregnancy Test
* Computed tomography (CT) scans, and magnetic resonance imaging (MRI)

Documentation of response and progression will be evaluated in this study using the Response Evaluation Criteria in Solid Tumors (RECIST).

Phase II Trial of SAHA & Tamoxifen for Patients With Breast Cancer

Phase II Trial of Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat) in Combination With Tamoxifen for Patients With Advanced Breast Cancer Who Have Failed Prior Anti-hormonal Therapy.

The Objective Response Rate. Response and progression were evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST). Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria. For the purposes of this study, patients were evaluated for response every 8 weeks. In addition to a baseline scan, confirmatory scans were also obtained ≥ 4 weeks following initial documentation of objective response.

The median response duration in months. Response and progression were evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST).

Safety evaluation according to descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Merck Sharp & Dohme LLC

H. Lee Moffitt Cancer Center and Research Institute

Vorinostat and Tamoxifen as outlined in Intervention Descriptions

Vorinostat and Tamoxifen

Age, Categorical

Age, Customized

Sex: Female, Male

United States

Region of Enrollment

Number of Participants With Objective Response (OR)

Time to Progression (TTP)

Number of Participants With Serious Adverse Events (SAEs)

Overall Study

Herbal and Botanical

Amino Acids

Trastuzumab

Exemestane

Letrozole

Anastrozole

Lapatinib

Antineoplastic Agents, Immunological

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Orange

Tyrosine

In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.

In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.

In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.

Lapatinib is available as 250-mg orange tablets. Subjects randomized to the Lapatinib plus Trastuzumab arm received 1000 mg per day of Lapatinib, so wre instructed to take 4 x 250 mg tablets per day. Lapatinib was to be taken either 1 hour (or more) before a meal or 1 hour (or more) after a meal

Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab was administered on Day 1 of the start of Lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, Trastuzumab was administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab could be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg).

Subjects who were hormone receptor-positive were required to receive an aromatase inhibitor as combination treatment; however the choice of the aromatase inhibitor selected for each patient was determined by the patients' investigator. The AIs the Investigator could choose from were anastrozole, exemestane, and letrozole and dosing was per product information.

Aromatase Inhibitors (AIs)

Novartis Pharmaceuticals

This was a multicenter, open-label, Phase II study in subjects with Human epidermal growth factor receptor (HER2)-positive metastatic breast cancer who received at least 2 prior lines of anti-HER2-targeted therapies of which at least one included a Trastuzumab-containing regimen. This study was a post-approval commitment with regulatory authorities. It was designed to evaluate whether treatment with Dual blockade promoted changes to biomarkers associated with immunomodulation.

This study was designed to address the post-authorization measures as agreed with the Committee for Medicinal Products for Human Use (CHMP). Recruitment of subjects into this study was challenging, and following agreement with the European Medicines Agency (EMA) enrollment into this study was halted after the enrollment of 42 of the 225 planned subjects.

The primary endpoint of the study evaluated changes in expression of biomarkers associated with immunomodulation between a pre-treatment biopsy and the disease progression biopsy. Secondary efficacy endpoints included overall response rate, clinical benefit rate and progression-free survival (PFS), as well as safety/tolerability. All subjects received study treatment until disease progression, death, unacceptable toxicity, or subject withdrawal. In case of disease progression during the treatment period, the subject was followed-up for 30 days for safety evaluation. In case of study treatment discontinuation for any reasons other than disease progression, the subject was followed-up for safety and efficacy assessments until disease progression, new anticancer therapy, death, withdrawal of consent or end of study, whichever came first.

This study supported a better understanding of the rapidly accumulating evidence for the importance of the immune microenvironment in HER2-positive breast cancer and the observed immunomodulation in the neoadjuvant setting could be confirmed in the advanced setting and supported the putative mechanism of action of HER2 dual blockade and its potential function on the tumor microenvironment. No formal comparisons between treatment arms were undertaken.

Participants were randomized to Arms A and B but randomized to Arm C.

This was a two-cohort, three-arm, open-label Phase II study to evaluate the changes in the expression of biomarkers between pre-treatment and progression biopsy in subjects with Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Subjects were allocated to 1 of 2 cohorts depending on the molecular subtype of their biopsy.

Cohort 1 HER2 -enriched included HER2-positive subjects with a HER2-Enriched molecular subtype, and were randomized in a 1:1 ratio to receive either trastuzumab in combination with lapatinib (Arm A) or trastuzumab in combination with chemotherapy (Arm B).

Cohort 2 non-HER2-enriched, included HER2-positive subjects with luminal A, luminal B, and basal-like molecular subtypes and were to receive trastuzumab in combination with lapatinib (Arm C). Subjects with hormone receptor (ER and/or PgR)-positive MBC in this arm were required to be treated with an AI of the Investigator's choice.

Evaluation of Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer

An Open-Label, Phase II, Study to Evaluate Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer Receiving Treatment With Trastuzumab in Combination With Lapatinib or Chemotherapy (EGF117165)

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available.

For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.

PFS was defined as the time from the date of randomization (for Arm A and B) / treatment start date (for Arm C) to the date of the first documented disease progression or death due to any cause, whichever was earlier. If a subject had not progressed or died at the analysis cutoff date, PFS was censored at the time of the last adequate tumor assessment. PFS was summarized using Kaplan-Meier estimates.

Overall response rate was defined as the percentage of subjects achieving either a confirmed complete response (CR) or partial response (PR) and was calculated from the Investigator's assessment of response per RECIST 1.1 criteria. . The confirmed CR or PR was derived using the following rules: confirmed CR - at least two determinations of CR at least 4 weeks apart before disease progression; confirmed PR - at least two determinations of PR or better at least 4 weeks apart before progression.

CBR is defined as percentage of subjects with a complete response (CR), partial response (PR), or maintaining stable disease (SD) for at least 24 weeks while on study according to the investigator assessment of response per RECIST 1.1 criteria. CR and PR are confirmed responses derived using the following rules: Confirmed CR - at least 2 determinations of CR at least 4 weeks apart before disease progression. Confirmed PR - at least 2 determinations of PR or better at least 4 weeks apart before progression.

Describe if changes of biomarker expression at disease progression from baseline correlate with PFS.

Adverse Event: Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.

Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.

LAP+TRAS±AI (HER2-Enriched) - Arm A

Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.

TRAS+CHEM±AI (HER2-Enriched) • ArmB

Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.

Non-HER2-Enriched - Arm C

TRAS+CHEM±AI (HER2-Enriched) - Arm B

Non-HER2- Enriched - Arm C

Total

< 65 years

>= 65 years

Caucasian

African American

Asian

Native Hawaiian or Pacific Islander

Race/Ethnicity, Customized

Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.

Study Director

Membrane spanning 4-domains A1

POU class 2 associating factor 1

CD19+

Interleukin 6

G antigen 1

ubiquitin specific peptidase 9, Y-linked

Thy-1 cell surface antigen

Chemerin chemokine-like receptor 1

Major histocompatibility complex, class II, DR beta 4

Collectin subfamily member 12

Complement C3b/C4b receptor 1 (Knops blood group)

CD33 molecule

B-cell linker

Interleukin 12A

CD163+

C-C motif chemokine ligand 8

Chemokine (C-C motif) receptor 1

POU class 2 homeobox 2

Cyclin dependent kinase inhibitor 1A

CD27 molecule

Lymphocyte antigen 86

TNF superfamily member 8

CD34+

Integrin subunit alpha 6

C-type lectin domain containing 7A

CD180 molecule

Integrin subunit alpha M

Toll like receptor 6

Autophagy related 10

C-C motif chemokine ligand 3 like 1

Bone marrow stromal cell antigen 1

CD22+

CD37 molecule

NEG_A

Sperm auto antigenic protein 17

CD200 molecule

TNF receptor associated factor 3

Interferon alpha and beta receptor subunit 1

TNF receptor associated factor 6

Evaluable Set: Included all subjects in Arm A who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.

Fold Change in Expression Profile of Genes and/or Proteins for Arm A (LAP+TRAS±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years

C-type lectin domain containing 5A

Interferon induced transmembrane protein 1

Fibronectin 1

C-C motif chemokine ligand 7

Triggering receptor expressed on myeloid cells 1

Plasminogen activator, urokinase

Interleukin 22 receptor subunit alpha 2

Tumor necrosis factor (ligand) superfamily member 4 gene

Major histocompatibility complex, Class I-related

Cathepsin L

SPP-1 (Osteopontin)

Transforming growth factor beta 2

Hepatitis A virus cellular receptor 2

C-X-C motif chemokine ligand 5

Collagen type III alpha 1 chain

Complement C1s

IFIT1 gene

Major histocompatibility complex, class I, G

Tumour necrosis factor gene

Integrin subunit beta 1

Pro-melanin concentrating hormone

CD86+

FCGR3A SNP rs396991

TNF receptor superfamily member 10c

TNF receptor superfamily member 11b

Platelet derived growth factor C

Mannan binding lectin serine peptidase 1

Recombination activating 1

Interleukin 22

Tumor necrosis factor (ligand) superfamily member 13b gene

BMI1 proto-oncogene, polycomb ring finger

CXCL10 gene

Leukocyte immunoglobulin like receptor B1

MX1 gene

Tumor necrosis factor (ligand) superfamily member 11 gene

Cathepsin S

Interferon induced transmembrane protein 2

LYN proto-oncogene, Src family tyrosine kinase

Platelet derived growth factor receptor beta

OAS3 gene

CD58 molecule

complement C3a receptor 1

Interleukin 24 gene

Chemokine (C-X-C motif) receptor 2

Strawberry notch homolog 2

Zinc finger protein 205

Fas associated via death domain

CD3e molecule associated protein

Baculoviral IAP repeat containing 5

Interleukin 17 receptor B

Evaluable Set: Included all subjects in Arm B who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.

Fold Change in Expression Profile of Genes and /or Proteins for Arm B (TRAS+CHEM±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years

Interleukin 1 receptor, type 1 gene

Complement component 2

Evaluable Set: Included all subjects in Arm C who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.

Fold Change in Expression Profile of Genes and /or Proteins for Arm C (Non-HER2- Enriched) From Screening to Approx. 3.5 Years

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Trial of SAHA & Tamoxifen for Patients With Breast Cancer	NCT00365599	Breast Cancer	suberoylanilide... tamoxifen citra...	18 Years -	H. Lee Moffitt Cancer Center and Research Institute
Evaluation of Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer	NCT02213042	Neoplasms, Brea...	Lapatinib Trastuzumab Aromatase Inhib...	18 Years -	Novartis
Capecitabine Metronomic Chemotherapy Plus Aromatase Inhibitor for Postmenopausal Hormone Receptor Positive Breast Cancer	NCT01924078	Breast Cancer	Capecitabine aromatase Inhib...	18 Years -	Fudan University

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