Neoplasms

All Conditions

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Symptoms and General Pathology

Infections

Rare Diseases

Carcinoma

Nasopharyngeal Neoplasms

Recurrence

Head and Neck Neoplasms

Epstein-Barr Virus Infections

Virus Diseases

Nasopharyngeal Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Nasopharyngeal Diseases

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Antineoplastic Agents

All Drugs and Chemicals

Azacitidine

Cc-486

Antimetabolites

Enzyme Inhibitors

CC-486 will be administered orally every day on Days 1-14 of a 21 day cycle at a dose of 300 mg. The first 6 participants of Asian-Pacific ethnicity will receive a starting dose of 200 mg. If there are no safety concerns, the 300 mg dose will be administered to all subsequent participants of Asian-Pacific ethnicity.

CC-486

Abderahim (Rahim) Fandi, MD, PhD

The purpose of this study is to evaluate the safety and efficacy of CC-486 in previously treated patients with locally advanced or metastatic nasopharyngeal carcinoma having failed one to two previous regimens, including platinum-based chemotherapy. Participants will be enrolled according to a Simon two-stage design; if the predefined activity is met (\>4 responses \[complete response; partial response {CR/PR}\] out of the first 17 evaluable participants based on independent radiological assessment), then the study will continue to enroll an additional 34 participants. If 4 or less responses out of 17 are observed, then the study enrollment will be stopped.

Safety and Efficacy of CC-486 in Previously Treated Patients With Locally Advanced or Metastatic Nasopharyngeal Carcinoma

A Phase 2, Multicenter, International, Single Arm Study To Assess The Safety And Efficacy Of Single Agent Cc-486 (Oral Azacitidine) In Previously Treated Subjects With Locally Advanced Or Metastatic Nasopharyngeal Carcinoma

Overall response rate was defined as the combined incidence of Complete Response (CR) or Partial Response (PR), confirmed no less than 4 weeks after the criteria for response were first met, based on independent radiology assessment according to RECIST 1.1 criteria.

Complete response was defined as the disappearance of all target lesions and non-target lesions; Partial response is at least a 30% decrease from baseline in the sum of diameters of target lesions with no progression of non-target lesions and no new lesions or disappearance of target lesions with persistence of one or more non-target lesions from baseline.

PFS was defined as the time from the date of start of the study treatment to the date of disease progression or death (any cause) on or prior to the data cut-off date for the statistical analysis, whichever occurred earlier, based on an independent radiology assessment of response using RECIST v1.1 criteria. Progressive disease was defined as at least a 20% increase in the sum of diameters of target or non-target lesions from nadir or appearance of a new lesion.

Overall survival was the time from the first dose of study drug to patient death from any cause. Participants who did not die were censored at the last known time the patient was alive date or the clinical data cutoff date, whichever was earlier.

Disease Control Rate (DCR) was defined as the percentage of participants with a CR, PR, confirmed ≥ 4 weeks after the criteria for response were first met, or stable disease for ≥ 16 weeks from the first treatment, based on independent radiology assessment using RECIST 1.1 criteria. A complete response was defined as the disappearance of all target lesions and non-target lesions; a partial response is at least a 30% decrease from baseline in the sum of diameters of target lesions with no progression of non-target lesions and no new lesions or disappearance of target lesions with persistence of one or more non-target lesions from baseline. Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease

Treatment-emergent adverse events (TEAEs) were defined as any adverse event (AE) or serious adverse event (SAE) that occurred or worsened on or after the day of the first dose of the investigational product (IP) through 28 days after the last dose of IP. In addition, any SAE with an onset date more than 28 day after the last dose of IP that was assessed by the investigator as related to IP was considered a TEAE. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and based on the following scale: Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death.

Area under the plasma concentration-time curve from Time 0 to the time of the last quantifiable concentration, calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing.

Area under the plasma concentration-time curve from Time 0 extrapolated to infinity, calculated as \[AUCt + Ct/ λz\]. Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If AUC %Extrap was ≥25%, AUC inf was not reported.

Maximum observed plasma concentration, obtained directly from the observed concentration versus time data.

Time to Cmax, obtained directly from the observed concentration versus time data.

Terminal phase half-life in plasma, calculated as \[(ln 2)/λz\]. t1/2 was only calculated when a reliable estimate for λz could be obtained.

Apparent volume of distribution, calculated as \[(CL/F)/λz\].

Celgene

Asian-Pacific island participants received CC-486 200 mg tablets by mouth (PO) on days 1-14 of each 21-day cycle until radiologic disease progression, unacceptable toxicity, adverse event, a new anticancer therapy is begun, withdrawal of consent, subject refusal, physician decision, or death. If well tolerated, and there were no safety concerns, subsequent participants of Asian-Pacific Island ethnicity were administered CC-486 300-mg PO daily for 14 days of a 21-day cycle.

CC-486 200 mg

Participants received CC-486 300 mg tablets by mouth on days 1-14 of each 21-day cycle until radiologic disease progression, unacceptable toxicity, adverse event (AE), a new anticancer therapy is begun, withdrawal of consent, subject refusal, physician decision, or death.

CC-486 300 mg

Total

Age, Continuous

Sex: Female, Male

Asian

White

Race/Ethnicity, Customized

Hispanic

Non-Hispanic or Latino

0 = Fully Active

1 = Restrictive but ambulatory

2 = Ambulatory but unable to work

3 = Limited Self-Care

ECOG performance status is used by doctors and researchers to assess how a subject's disease is progressing, assess how the disease affects the daily living activities of the subject and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, No self-care (Least Favorable Activity)

Eastern Cooperative Oncology Group (ECOG) Performance Status

Time From Initial Diagnosis to First Dose

Undifferentiated Nasopharyngeal Carcinoma

Poorly Differentiated Nasopharyngeal Carcinoma

Other

The 3 types of NPC, based on how the cancer cells look under the microscope include:

1. Undifferentiated Nasopharyngeal Carcinoma
2. Poorly Differentiated Nasopharyngeal Carcinoma
3. Other

Nasopharyngeal Cancer (NPC) Diagnosis Types

The Safety Population included all participants who received at least

1 dose of investigational product (IP)

Participants with Prior Anti-Cancer Therapies

Enrolled Population: The Enrolled Population included all participants who were enrolled to the study.

The review of the efficacy data from the trial participants did not support proceeding to Stage 2 as the protocol-defined criteria of \> 4 responders (a best response of CR or PR) in Stage 1 was not reached and study enrollment was stopped.

Anne McClain, Senior Manager, Clinical Trial Disclosure

The Efficacy Evaluable Population included all enrolled participants who met eligibility criteria and either received 2 cycles of CC-486 at any dose and discontinued treatment for progressive disease or received 4 cycles of CC-486 and had a baseline and at least 2 post-screening tumor assessments.

Percentage of Participants Who Achieved a Complete or Partial Response According to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Based on an Independent Radiology Assessment (IRA)

Kaplan Meier Estimate of Progression-Free Survival (PFS) Based on an Independent Radiology Assessment According to RECIST 1.1 Criteria

Kaplan Meier Estimate of Overall Survival

Efficacy Evaluable Population = enrolled participants who met eligibility criteria and either received 2 cycles of IP at any dose and discontinued treatment for progressive disease or received 4 cycles of IP and had at least 2 post-screening tumor exams.

Percentage of Participants With Stable Disease for ≥ 16 Weeks From the Date of the First Treatment, or CR or PR According to RECIST 1.1 Criteria and Based on an Independent Radiology Assessment

Any TEAE

Any TEAE Related to IP

Any Serious TEAE

Any Serious TEAE Related to IP

Any CTCAE Grade 3 or 4 TEAE

Any CTCAE Grade 3 or 4 TEAE Related to IP

Any TEAE Leading to Death

Any TEAE Leading to Dose Reduction

Any TEAE Leading to Drug Interruption

Any TEAE Leading to IP Discontinuation

The Safety Population included all participants who received at least 1 dose of IP.

Number of Participants With Treatment Emergent Adverse Events

Cycle 1 Day 1

Cycle 1 Day 14

The PK population includes participants with evaluable CC-486 plasma PK profiles.

Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration Of CC-486 (AUC-t)

Area Under the Plasma Concentration -Time Curve From 0 Extrapolated to Infinity (AUC-inf, AUC0-∞) Of CC-486

The PK population includes participants with evaluable CC-486 plasma PK profiles

Maximum Observed Concentration (Cmax) Of CC-486

Time to Reach Maximum Concentration (Tmax) Of CC-486

Terminal Half-Life (t1/2) of CC-486

Apparent Total Clearance (CL/F) Of CC-486

Apparent Volume of Distribution (Vz/F) Of CC-486

Treatment Period

Follow-Up Survival Period

Blood and Lymph Conditions

Immune System Diseases

Syndrome

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Graft vs Host Disease

Preleukemia

Myelodysplastic Syndromes

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Homologous Wasting Disease

Acute Graft Versus Host Disease

Decitabine

5-aza SC or IV 32mg/m2 - 75mg/m2 (based on dose escalation)

The planned initial dose of 5-aza is 32mg/m2 (Level 0) administered either subcutaneously or intravenously for days 1 through 5 of a 28-day cycle, which will be initiated between day+30 and day+100 after HCT. Patients who tolerate this dose based on hematologic parameters and with no SAEs for two consecutive cycles will be eligible for a dose escalation to 50mg/m2 (Level +1). Patients who tolerate this dose based on the same criteria as above for two consecutive cycles will be eligible for a dose escalation to 75mg/m² (Level +2). Patients will continue at dose Level +2 for the remainder of the study provided there are no toxicities that require dose reduction. Patients requiring a dose reduction are not eligible for re-escalation.

5-azacytidine (5-aza) maintenance therapy after transplant

Annie Im, MD

Despite improvements in outcomes after Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS), the risk of relapse remains high and is the most common cause of mortality after HCT. Moreover, treatment options for relapse after HCT are limited. Strategies to reduce relapse with maintenance therapy in patients who are at high risk are needed to improve survival. 5-aza is a hypomethylating agent that has shown immune modulating properties that may enhance the graft-versus-leukemia (GVL) effect, including upregulation of tumor-associated antigen and costimulatory molecule expression. Moreover, 5-aza has properties that suggest protection against graft-versus-host disease (GVHD) as well. Preliminary data shows that it is well tolerated and effective in clinical use for the treatment of AML or MDS relapse after HCT, as well as for maintenance therapy. This study will evaluate the use of 5-aza for maintenance after HCT in patients with AML or MDS with risk factors that are associated with a high risk for relapse.

Phase II study of 5-aza maintenance after allogeneic Hematopoietic Cell Transplantation (HCT) for high-risk Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Early studies indicate 5-aza is a hypomethylating agent that has shown immune modulating properties that may enhance the graft-versus-leukemia (GVL) effect, including upregulation of tumor-associated antigen and costimulatory molecule expression. 5-aza also has properties that suggest protection against graft-versus-host disease (GVHD). The primary objective is to evaluate relapse rate at one year. Secondary objectives will include the incidence of both acute and chronic GVHD as well as relapse-free survival, overall survival and toxicity. Correlatives will be performed to evaluate the effect of 5-aza maintenance on the immune system.

Subjects must be transplant candidates with MDS or high risk characteristics of AML. Subjects are consented, screened, then transplanted. Those showing complete response and no active GVHD after transplant can proceed to maintenance with 5-aza. Bone marrow biopsies are performed for response assessment after transplant as well as every three cycles (1 cycle=28 days) while on treatment. Dosing starts at 32mg/m2 and can be increased every 2 cycles without a serious adverse event (SAE), or reduced per toxicity for up to 12 cycles.

Phase II Study of 5-azacytidine Maintenance After Transplant for AML or MDS

Phase II Study of 5-azacytidine Maintenance After Allogeneic Hematopoietic Cell Transplantation for High-risk Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Study will evaluate the effect of 5-aza maintenance on the immune system using T-cell phenotype subsets and receptor expression, cytokine levels including tumor necrosis factor alpha (TNFα) and Interferon-y (IFNγ) (proinflammatory), and interleukin 7 (IL-7) and interleukin 15 (IL-15) (homeostatic) and association of correlative measures with relapse and incidence of GVHD.

Study will evaluate the relapse rate associated with 5-azacytidine (5-aza) as maintenance therapy after HCT in patients with high-risk AML or MDS.

University of Pittsburgh

Principal Investigator

Panobinostat

Histone Deacetylase Inhibitors

LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 15 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 20 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 30 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 40 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 40 mg/day three times a week on nonconsecutive days for the first 2 weeks in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 will be given in the dose and in the schedule that was found to work in the Phase I portion which was Level 5B.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589

Geoffrey Uy, M.D.

This study is designed to evaluate the combination of LBH589 and decitabine in patients age ≥ 60 years with high risk Myelodysplastic Syndrome (IPSS Int-2 or High) or Acute Myeloid Leukemia.

To address the need for less toxic, more effective treatments for older patients with advanced MDS and AML, the purpose of this Phase 1-2 single institution study is to evaluate the safety and efficacy of LBH 589 and decitabine administered in combination.

Decitabine is an epigenetic modifier of gene expression that has been shown to be well-tolerated in this population at the dose schedule proposed in this study, with reasonable efficacy. Although its precise mechanism of action is incompletely understood, it is postulated to work by reactivating the expression of key tumor suppressor genes silenced in tumor cells by reversing a pattern of hypermethylation of promotor elements.

LBH389 is likewise an epigenetic modifier that inhibits the deacetylation of both histones and non-histone proteins, including HSP90 and p53. Although clinical experience with LBH589 in AML is limited, aberrant histone deacetylase activity has been previously shown to play a significant role in the pathogenesis of AML. The addition of LBH589 to a decitabine regimen of previously established efficacy and tolerability will allow us to evaluate the hypothesis that two epigenetic modifiers that are believed to work through distinct mechanisms of action may act together to improve the responses of patients treated with decitabine alone, without significant additional toxicity.

LBH589 Plus Decitabine for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)

A Phase I/II Study of LBH589 Plus Decitabine for Patients Age ≥ 60 Years With High Risk MDS or AML

* Morphologic complete remission (CR). A CR designation requires that the patient achieve the morphologic leukemia-free state with less than 5% blasts in an aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. There should be no blasts with Auer rods or persistence of extramedullary disease. Patients must also have an absolute neutrophil count of more than 1,000/μLand platelets of 100,000/μL.
* Cytogenetic complete remission (CRc). A CRc will be defined by the achievement of a CR with reversion to a normal karyotype in a minimum of 20 metaphases analyzed by cytogenetics.
* Morphologic complete remission with incomplete blood count recovery (CRi): Achievement of all of the criteria for CR except for residual neutropenia (\< 1,000/μL) or thrombocytopenia (\< 100,000/μL).

Cytogenetic complete remission (CRc). A CRc will be defined by the achievement of a CR with reversion to a normal karyotype in a minimum of 20 metaphases analyzed by cytogenetics.

-The FACT-Leu consists of a 27-item compilation of general questions divided into four primary quality of life domains: physical well-being, social/family well being, emotional well-being, and functional well-being along with a 17 item subscale developed specifically for patients with leukemia.

Time to response is defined as the date of the first dose of study drug to the date that all criteria for CR or CRi are fulfilled.

Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0.

Defined as the first date that all criteria for CR, CRi or HI are fulfilled to the date of treatment failure, relapse from CR, or death due to any cause.

Event-free survival is defined as the interval from the date of first dose of study drug to date of treatment failure, relapse from CR, or death due to any cause.

Overall survival is defined as the date of first dose of study drug to the date of death from any cause.

Morphologic complete remission with incomplete blood count recovery (CRi): Achievement of all of the criteria for CR except for residual neutropenia (\< 1,000/μL) or thrombocytopenia (\< 100,000/μL).

-Hematologic improvement (HI). Includes the following categories:

* Erythroid response: Hemoglobin increase by ≥ 1.5 g/dL over baseline in which the pretreatment hemoglobin is \< 11 g/dL or reduction of RBC transfusions of at least 4 RBC transfusions / 8 wk compared with the pretreatment transfusion number in the previous 8 weeks.
* Platelet response. Absolute increase of \> 30 x 10\^9/L for patients starting with 20 x 10\^9/L or increase from \< 20 x 10\^9/L to \> 20 x 109/L and by at least 100%
* Neutrophil response. At least 100% increase and an absolute increase \> 0.5 x 109/L for patients with pretreatment neutrophils \< 1.0 x 109/L)

Washington University School of Medicine

LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 1

LBH589 15 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 2

LBH589 20 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 3

LBH589 30 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 4

LBH589 40 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 5

LBH589 40 mg/day three times a week on nonconsecutive days for the first 2 weeks in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 5B

LBH589 will be given in the dose and in the schedule that was found to work in the Phase I portion which was dose from Level 5B.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Phase II

United States

Region of Enrollment

Phase I (Includes Levels 1-5)

After enrolling all Phase I patients in Dose Levels 1-5b, the maximum tolerated dose was not determined. The Phase II portion of the study used the 5b dose level.

Phase I: Maximum Tolerated Dose (MTD) of LBH589 When Given in Combination With Decitabine

* Level 1:LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.
* Level 2:LBH589 15 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.
* Level 3: LBH589 20 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.
* Level 4:LBH589 30 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.
* Level 5:LBH589 40 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.
* Level 5B/Phase II:LBH589 will be given in the dose and in the schedule that was found to work in the Phase I portion which was dose from Level 5B. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

Level 1-Phase II (All Patients Enrolled)

Phase II: Overall Rate of Morphologic Complete Remission (CR) + Cytogenetic Complete Remission (CRc) + Morphologic Complete Remission With Incomplete Blood Count Recovery (CRi)

Rate of Cytogenetic Complete Remission (CRc)

Data was not collected for this outcome measure.

Changes in Quality of Life Scores as Measured by the Function Assessment of Cancer Therapy-Leukemia (FACT-Leu) Version 4

Number of participants analyzed are participants that met the criteria for CR or CRi.

Time to Response

Fatigue

Febrile neutropenia

Diarrhea

Nausea

Safety and Tolerability of Regimen as Measured by the Rate of the Most Common Adverse Events Experienced

Number of participants analyzed include those participants who met the criteria for CR, CRi, or HI.

Remission Duration

Data was not collected for this outcome measure. Progression is very hard to define for MDS and AML and including it as a pre-specified secondary outcome measure in the protocol was an oversight.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy of CC-486 in Previously Treated Patients With Locally Advanced or Metastatic Nasopharyngeal Carcinoma	NCT02269943	Nasopharyngeal ...	CC-486	18 Years -	Celgene
Phase II Study of 5-azacytidine Maintenance After Transplant for AML or MDS	NCT02204020	Acute Myeloid L... Myelodysplastic...	5-azacytidine (...	18 Years -	University of Pittsburgh
Safety and Efficacy of CC-486 in Previously Treated Patients With Locally Advanced or Metastatic Nasopharyngeal Carcinoma	NCT02269943	Nasopharyngeal ...	CC-486	18 Years -	Celgene
LBH589 Plus Decitabine for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)	NCT00691938	Leukemia, Myelo... Myelodysplastic...	LBH589 Decitabine	60 Years -	Washington University School of Medicine
LBH589 Plus Decitabine for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)	NCT00691938	Leukemia, Myelo... Myelodysplastic...	LBH589 Decitabine	60 Years -	Washington University School of Medicine

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