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The purpose of the study is to evaluate the safety and to define the Maximal Tolerated Dose (MTD) or the Maximal Administered Dose (MAD) of oral azacitidine as a single agent and in combination with carboplatin (CBDCA) or paclitaxel protein bound particles (ABI-007,ABX) in subjects with relapsed or refractory solid tumors.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm A: CC-486 plus Carboplatin | Experimental | CC-486 will be administered orally at doses between 100-300 mg daily for either 14 or 21 days depending on tolerability. Carboplatin will be given by intravenous (IV) infusion once every 21 Days at a dosage of AUC x 4. |
|
| Arm B: CC-486 plus ABI-007 | Experimental | CC-486 will be administered orally at doses between 100-300 mg daily for either 14 or 21 days depending on tolerability ABI-007 will be administered by intravenous (IV) infusion on two of every three weeks at a dosage of 100 mg/m^2 |
|
| Arm C: CC-486 | Experimental | CC-486 will be administered orally at doses between 100-300 mg daily for either 14 or 21 days depending on tolerability |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CC-486 | Drug | CC-486 will be administered orally at doses between 100-300 mg daily for either 14 or 21 days depending on tolerability |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants with adverse events | An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity. | Up to 3 years |
| Measure | Description | Time Frame |
|---|---|---|
| Cmax | Maximum observed concentration in plasma (Cmax) | Up to 30 days |
| AUC | Area under the concentration-time curve (AUC) | Up to 30 days |
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Inclusion Criteria:
Men and women, 18 years or older at the time of signing the Informed Consent Document (ICD).
Understand and voluntarily sign an ICD prior to any study-related assessments or procedures are conducted.
Able to adhere to the study visit schedule and other protocol requirements.
With histological or cytological confirmation of advanced unresectable solid tumors, including those who have progressed on (or not been able to tolerate) standard anticancer therapy, or for whom no other effective therapy exists, or for who declines standard therapy.
Consent to screening tumor biopsy (for accessible tumors when appropriate [optional in Part 1, mandatory in Part 2]).
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.
The following laboratory values:
Females of child-bearing potential {defined as a sexually mature women who
has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or,
has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months} must
Male subjects with female partner of childbearing potential must agree to the use of a physician-approved contraceptive method throughout the course of the study to avoid fathering a child during the course of the study and for 6 months following the last dose of oral azacitidine.
The criteria below are in addition to or supersede the Part 1 inclusion criteria above:
With histological or cytological confirmation of relapsed or refractory advanced unresectable solid tumors as listed below for each Arm, including those who have progressed on or were unable to tolerate standard anti-cancer therapy.
Subjects with documented liver metastases must have serum albumin ≥ 3 g/dL;
Sites of disease (primary or metastatic) that are, in the opinion of the investigator, accessible for biopsy without undue risk to the subject
Consent to tumor biopsy at screening (prior to the first dose of CC-486) and at Cycle 1 Day 15.
Measurable disease according to RECIST v1.1.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gordan Bray, M.D., Ph.D | Celgene | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Scottsdale Healthcare Research Institute | Scottsdale | Arizona | 85258 | United States | ||
| University of California, San Francisco |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | LoRusso P, et al. A Phase Ib study of CC-486 (Oral Azacitidine) as a priming agent for carboplatin or NAB-paclitaxel in subjects with relapsed and refractory solid tumors . Presented at 25th AACR-NCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics, October 19-23, 2013, Boston, MA. Abstract No. A120. |
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|
| Carboplatin | Drug | Carboplatin will be given by intravenous (IV) infusion once every 21 Days at a dosage of AUC x 4. |
|
|
| ABI-007 | Drug | ABI-007 will be administered by intravenous (IV) infusion on two of every three weeks at a dosage of 100 mg/m^2 |
|
|
| Tmax | Time to maximum concentration (tmax); | Up to 30 days |
| T1/2 | Terminal half-life (t1/2) | Up to 30 days |
| CL/F | Apparent total body clearance (CL/F) | Up to 30 days |
| Vz/F | Apparent volume of distribution (Vz/F). | Up to 30 days |
| DNA Methylation | Change from baseline (Cycle 1 Day 1 pre-dose) in DNA methylation (global and gene-specific assays) in whole blood and tumor tissue (as available in Part 1) | Up to 30 days |
| DNMT1 protein levels | Reduction from baseline (Cycle 1 Day 1 predose) in DNMT1 protein levels in tumor tissue (as available in Part 1) | Up to 30 days |
| Tumor Response Rate | Response and progression were evaluated using the RECIST 1.1 criteria. Treatment response includes both complete response and partial response.
| Up to 3 years |
| Progression Free Survival | Progression-free survival is defined as the time from first dose of study drug to the start of disease progression or patient death, whichever occurs first. | Up to 3 years |
| Duration of Response | Duration of response is defined as progression-free survival in responders, i.e. as the time between the start of a complete response (CR) or partial response (PR) and the start of progressive disease (PD) or patient death from any cause, whichever occurred first | Up to 3 years |
| San Francisco |
| California |
| 94115 |
| United States |
| Indiana University Cancer Center | Indianapolis | Indiana | 46202 | United States |
| Karmanos Cancer Institute | Detroit | Michigan | 48201-2014 | United States |
| Greenville Hospital | Greenville | South Carolina | 29605 | United States |
| Sarah Cannon Research Institute | Nashville | Tennessee | 37205 | United States |
| South Texas Accelerated Research Therapeutics | San Antonio | Texas | 78229 | United States |
| Centre Georges Francois Leclerc | Dijon | 21079 | France |
| Institut Curie | Paris | 75005 | France |
| The Netherlands Cancer Instiute Antoni Van Leeuwenhoekziekenhuis | Amsterdam | 1066 CX | Netherlands |
| Erasmus Medical Center | Rotterdam | 3015 CN | Netherlands |
| Hospital General Universitario Gregorio Maranon | Madrid | 28007 | Spain |
| Hospital Universitario 12 de Octubre | Madrid | 28041 | Spain |
| ID | Term |
|---|---|
| D001749 | Urinary Bladder Neoplasms |
| D002295 | Carcinoma, Transitional Cell |
| D010051 | Ovarian Neoplasms |
| D005185 | Fallopian Tube Neoplasms |
| D010534 | Peritoneal Neoplasms |
| D002289 | Carcinoma, Non-Small-Cell Lung |
| D021441 | Carcinoma, Pancreatic Ductal |
| D014412 | Tumor Virus Infections |
| D012008 | Recurrence |
| ID | Term |
|---|---|
| D014571 | Urologic Neoplasms |
| D014565 | Urogenital Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D001745 | Urinary Bladder Diseases |
| D014570 | Urologic Diseases |
| D052801 | Male Urogenital Diseases |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D004701 | Endocrine Gland Neoplasms |
| D010049 | Ovarian Diseases |
| D000291 | Adnexal Diseases |
| D005831 | Genital Diseases, Female |
| D005833 | Genital Neoplasms, Female |
| D000091662 | Genital Diseases |
| D004700 | Endocrine System Diseases |
| D006058 | Gonadal Disorders |
| D005184 | Fallopian Tube Diseases |
| D000008 | Abdominal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D004066 | Digestive System Diseases |
| D010532 | Peritoneal Diseases |
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D008175 | Lung Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
| D013899 | Thoracic Neoplasms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D044584 | Carcinoma, Ductal |
| D000230 | Adenocarcinoma |
| D018299 | Neoplasms, Ductal, Lobular, and Medullary |
| D010190 | Pancreatic Neoplasms |
| D010182 | Pancreatic Diseases |
| D014777 | Virus Diseases |
| D007239 | Infections |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C000709231 | cc-486 |
| D001374 | Azacitidine |
| D016190 | Carboplatin |
| D000068196 | Albumin-Bound Paclitaxel |
| C520255 | 130-nm albumin-bound paclitaxel |
| ID | Term |
|---|---|
| D001372 | Aza Compounds |
| D009930 | Organic Chemicals |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
| D056831 | Coordination Complexes |
| D017239 | Paclitaxel |
| D043823 | Taxoids |
| D043822 | Cyclodecanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D004224 | Diterpenes |
| D013729 | Terpenes |
| D000418 | Albumins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
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