Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Digestive System Diseases

Skin and Connective Tissue Diseases

Rare Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Prostatic Neoplasms

Stomach Neoplasms

Breast Neoplasms

Carcinoma, Hepatocellular

Uterine Cervical Neoplasms

Stomach Cancer

Antineoplastic Agents

All Drugs and Chemicals

Fluorouracil

Eniluracil

Enzyme Inhibitors

ADH300004

Howard Burris, III, MD

5 fluorouracil (5 FU), one of the most actively investigated anti-cancer drugs, is rapidly inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD). ADH300004 blocks DPD. This study will test the safety and effects of oral ADH300004 14 hours prior to oral 5 FU in subjects with refractory solid tumors.

A Study of 5 Fluorouracil and the Anti-Tumor Activity of ADH300004 and 5 Fluorouracil in Subjects With Incurable Solid Tumors

A 2-Part Phase 1 Study Evaluating the Safety and Anti-Tumor Activity of ADH300004 (Eniluracil) Administered With 5-Fluorouracil (5-FU), and the Pharmacokinetics of 5-FU Given as: 5.0 mg ADH300004 With Escalating Doses of 5-FU Administered Orally 3 Weeks Out of 4 in Subjects With Refractory Solid Tumors (Part 1); or 5.0 mg ADH300004 With 5 FU Administered Orally as a Split Dose for 3 Weeks Out of 4 in Subjects With Hepatocellular Carcinoma, Non-Small Cell Lung Carcinoma, Gastric Cancer, Cervical Cancer, Prostate Cancer, or Breast Cancer (Part 2) (Adherex Protocol Number AHX-03-104)

Adherex Technologies, Inc.

Clinical Study Manager

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

Vascular Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Lymphoproliferative Disorders

Paraproteinemias

Hematologic Diseases

Hemorrhagic Disorders

Neoplasms by Histologic Type

Blood Protein Disorders

Immunoproliferative Disorders

Analgesics

Anti-Inflammatory Agents

Coagulants

Antirheumatic Agents

Bortezomib

Hemostatics

Anti-Inflammatory Agents, Non-Steroidal

Vorinostat

Analgesics, Non-Narcotic

Histone Deacetylase Inhibitors

Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1-14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1-14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

Four 100 mg capsules vorinostat taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.

1.3 mg/m2 of bortezomib by IV push, on Days 1, 4, 8, and 11 of each 21-day treatment cycle.

bortezomib

Four placebo capsules taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.

placebo to vorinostat

Medical Director

Study of the efficacy and safety of bortezomib administered in combination with vorinostat in patients with relapsed or refractory multiple myeloma. Histone deacetylases (HDAC) facilitate gene transcription by modulating the uncoiling of chromatin. HDAC function is dysregulated in hematologic and solid malignancies, and this dysregulation may result in over-expression of oncogenes. Thus, inhibition of HDACs may result in anti-cancer effects. HDAC inhibitors, like vorinostat, represent a new class of antitumor agents that have the ability to induce antiproliferative effects including cyto-differentiation, cell cycle growth arrest or apoptosis in various cancer cell lines. Several studies have investigated the in vitro antimyeloma activity of vorinostat in combination with bortezomib and have demonstrated that vorinostat may act synergistically with bortezomib to modulate tumor cell growth. Mitsiades et al have shown that vorinostat enhances the sensitivity of bortezomib. Pei et al found that exposure of human multiple myeloma cell lines \& patient-derived multiple myeloma cells to bortezomib and vorinostat resulted in synergistic interactions as a result of: (1) Interruption of NF-kB \& related signaling pathways (JNK, XIAP, Mcl-1, etc.) (2) Inhibition of Hsp90 (3)Induction of ER stress signal and (4) acetylation of Dynein/disruption of aggresome function/formation, salvage for ubiquitinated proteins. In addition a marked increase in mitochondrial injury, caspase activation, and apoptosis was also observed. Bortezomib is indicated for the treatment of patients with multiple myeloma. Two Phase I dose-ranging studies of a regimen combining vorinostat and bortezomib among patients with relapsed as well asend-stage, refractory multiple myeloma have been conducted. These studies enrolled a total of 57 patients. In these studies, administration of vorinostat with standard doses of bortezomib resulted in responses in 20/45 (44%) evaluable patients (Weber et al 2007, Badros et al 2007). The purpose of the present study is to definitively evaluate the clinical activity of vorinostat in combination with bortezomib inpatients with multiple myeloma.

Study of Vorinostat (MK-0683) or Placebo, in Combination With Bortezomib in Participants With Multiple Myeloma (MK-0683-088 AMN)

An International, Multicenter, Randomized, Double-Blind Study of Vorinostat (MK-0683) or Placebo in Combination With Bortezomib in Patients With Multiple Myeloma

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Progression-free survival was measured from the start of the treatment to the time when the criteria for progression was met or death due to any cause (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.

An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. Grades come from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Per protocol, clinical and laboratory AEs are presented as a combined total for each grade.

Overall survival was measured from the start of the treatment to death due to any cause. Overall Survival is represented as the number of deaths per 100-person- months and was computed by dividing the number of participants with an event of death that occurred during the study follow-up period by the total duration of follow-up (in 100 months) for all the participants in each cohort since participants had different lengths of follow-up.

Time to progression was measured from the start of the treatment to the time when the criteria for progression was met or death due to myeloma (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.

Objective response rate was measured as the proportion of patients who achieved a confirmed partial response or better during the course of the study. Response to study therapy was assessed using EBMT Criteria and confirmed by Independent Adjudication Review.

Merck Sharp & Dohme LLC

Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.

Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

Vorinostat + Bortezomib

Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

Placebo + Bortezomib

Total

Age, Continuous

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Senior Vice President, Global Clinical Development

Cox model stratified by myeloma stage at enrollment, history of a bone marrow transplant, and number of prior treatment regimens, with a single treatment covariate.

The analysis population includes all randomized participants.

Progression-Free Survival (PFS)

Grade 3

Grade 4

Grade 5

The analysis population includes all randomized participants who received ≥1 dose of study medication.

Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs)

Overall Survival

Time to Progression

Objective Response Rate

Overall Study

Symptoms and General Pathology

Recurrence

Neoplasms, Glandular and Epithelial

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Jacqueline Whang-Peng, MD

5-fluorouracil (5-FU), one of the most actively investigated anti-cancer drugs, is rapidly inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD). ADH300004 blocks DPD. This study will test the safety and effects of oral ADH300004 14 hours prior to oral 5-FU in subjects with locally advanced, recurrent, or metastatic hepatocellular carcinoma.

A Study of ADH300004 and 5-Fluorouracil in Locally Advanced, Recurrent, or Metastatic Hepatocellular Carcinoma

A Phase 1/2 Study in Subjects With Locally Advanced, Recurrent, or Metastatic Hepatocellular Carcinoma, Evaluating the Safety, and Anti-Tumor Activity of ADH300004 (Eniluracil) With Escalating Doses of 5 Fluorouracil Administered Orally Once Weekly for 3 Weeks Out of Every 4 (Adherex Protocol Number AHX-03-103)

Capecitabine

Carboplatin

Docetaxel

Tubulin Modulators

Antimitotic Agents

Antimetabolites

ADH -1 and carboplatin

ADH -1 and docetaxel

ADH -1 and capecitabine

N-cadherin, a protein involved in blood vessel cell binding, is increased as cancer progresses, and is on the surface of many tumor cells. ADH-1 blocks N-cadherin. This study will test the safety and effects of the combination ADH-1 and carboplatin or ADH-1 and docetaxel or ADH-1 and capecitabine in subjects with specific incurable, solid tumors with a protein biomarker called N-cadherin.

A Study of ADH 1 in Combination With Carboplatin, or Docetaxel or Capecitabine

A Phase 1, Multicenter, Dose-Escalation Study to Investigate the Safety and Tolerability of ADH-1 in Combination With 1) Carboplatin or 2) Docetaxel or 3) Capecitabine in Subjects With N-Cadherin Positive, Advanced Solid Tumors (Adherex Protocol Number AHX-01-006)

US Oncology Research

Melanoma

Melphalan

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunosuppressive Agents

Immunologic Factors

ADH-1

By Isolated Limb Infusion (ILI), Lower Extremity: 7.5 mg/L (Limb Volume), Day 1 or Upper Extremity: 10 mg/L (Limb Volume), Day 1

melphalan

Doug Tyler, MD

N-cadherin, a protein involved in blood vessel cell binding and on the surface of many tumor cells, is increased as cancer progresses. ADH-1 blocks N-cadherin. This study will test the safety and effects of the combination ADH-1 with Normothermic Isolated Limb Infusion of Melphalan in subjects with locally advanced malignant melanoma.

A Study of ADH-1 in Combination With Normothermic Isolated Limb Infusion of Melphalan

An Open-Label, Multicenter, Phase 1/2 Dose Escalation Study to Evaluate Safety, Tolerability and Anti-tumor Activity of Systemic ADH-1 in Combination With Normothermic Isolated Limb Infusion of Melphalan in Subjects With Locally Advanced In-Transit Malignant Melanoma (Adherex Protocol Number AHX-01-007).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of 5 Fluorouracil and the Anti-Tumor Activity of ADH300004 and 5 Fluorouracil in Subjects With Incurable Solid Tumors	NCT00264472	Neoplasms	ADH300004	18 Years -	Adherex Technologies, Inc.
Study of Vorinostat (MK-0683) or Placebo, in Combination With Bortezomib in Participants With Multiple Myeloma (MK-0683-088 AMN)	NCT00773747	Multiple Myelom...	Vorinostat bortezomib placebo to vori...	18 Years -	Merck Sharp & Dohme LLC
A Study of ADH300004 and 5-Fluorouracil in Locally Advanced, Recurrent, or Metastatic Hepatocellular Carcinoma	NCT00319683	Hepatocellular ...	ADH300004	18 Years -	Adherex Technologies, Inc.
A Study of 5 Fluorouracil and the Anti-Tumor Activity of ADH300004 and 5 Fluorouracil in Subjects With Incurable Solid Tumors	NCT00264472	Neoplasms	ADH300004	18 Years -	Adherex Technologies, Inc.
A Study of ADH 1 in Combination With Carboplatin, or Docetaxel or Capecitabine	NCT00390676	Neoplasms	ADH -1 and carb... ADH -1 and doce... ADH -1 and cape...	18 Years -	Adherex Technologies, Inc.
A Study of ADH-1 in Combination With Normothermic Isolated Limb Infusion of Melphalan	NCT00421811	Neoplasms	ADH-1 melphalan	18 Years -	Adherex Technologies, Inc.

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