CC-486 (Oral Azacitidine) Bioequivalence Study in Patients With Solid Tumor or Hematologic Malignancies

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified August 2014 by Celgene Corporation
Sponsor:
Information provided by (Responsible Party):
Celgene Corporation
ClinicalTrials.gov Identifier:
NCT02223052
First received: August 20, 2014
Last updated: NA
Last verified: August 2014
History: No changes posted
  Purpose

This is a Phase 1, open-label, multicenter, randomized, 2-period crossover study consisting of 2 phases: Pharmacokinetics and Extension.

The study will enroll approximately 60 subjects with hematologic or solid tumor malignancies, excluding gastrointestinal tumors and tumors that have originated or metastasized to the liver. Approximately 8 sites in the US will participate in this study.


Condition Intervention Phase
Hematological Neoplasms
Non-Hodgkin's Lymphoma
Hodgkin's Lymphoma
Lymphoma
Multiple Myeloma
Acute Myeloid Leukemia
Leukemia
Myelodysplastic Syndromes
Neoplasms
Melanoma
Breast Cancer
Metastatic Breast Cancer
Non-Small Cell Lung Cancer
Small Cell Lung Cancer
Renal Cell Carcinoma
Glioblastoma Multiforme
Osteosarcoma
Sarcoma
Thyroid Cancer
Genitourinary
Drug: CC-486
Drug: Vidaza
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Open-label, Multicenter, Randomized, 2-period, Crossover Study to Evaluate the Bioequivalence of CC-486 (Oral Azacitidine) Tablets in Adult Cancer Subjects.

Resource links provided by NLM:


Further study details as provided by Celgene Corporation:

Primary Outcome Measures:
  • PK- Cmax [ Time Frame: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose ] [ Designated as safety issue: No ]
    The observed maximum concentration

  • PK-Tmax [ Time Frame: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose ] [ Designated as safety issue: No ]
    The observed time to first maximum concentration

  • PK-AUC-t [ Time Frame: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose ] [ Designated as safety issue: No ]
    Area under the concentration-time curve from time zero to the last quantifiable time point calculated by the linear trapezoidal rule

  • PK-AUC-infinity [ Time Frame: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose ] [ Designated as safety issue: No ]
    Area under the concentration time-curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity. It will be calculated as AUC∞ = [AUCt + Ct/λz]. Ct is the last quantifiable concentration

  • PK- λz (Terminal Rate) [ Time Frame: Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.3.5, 4, 6, and 8 hours post-dose ] [ Designated as safety issue: No ]
    Terminal phase rate constant, determined by linear regression of the terminal points of the log-linear concentration-time curve

  • Terminal Half-Life (t½) [ Time Frame: Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose ] [ Designated as safety issue: No ]
    Terminal phase half-life, calculated according to the following equation: t½ = 0.693/λz

  • Apparent total clearance (CL/F) [ Time Frame: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose ] [ Designated as safety issue: No ]
    Apparent total clearance, calculated as Dose/AUC∞

  • Apparent volume of distribution (Vd/F) [ Time Frame: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose ] [ Designated as safety issue: No ]
    Apparent volume of distribution, calculated according to the equation: Vd/F = (CL/F) / λz


Secondary Outcome Measures:
  • Incidence of treatment-emergent adverse events [ Time Frame: Up to 10 days after the last dose of CC-486 in the PK phase and up to 28 days after the last dose of Vidaza in the extension phase ] [ Designated as safety issue: Yes ]
    Adverse Event (AE) is defined as 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 of a pre-existing condition) should be considered an AE.


Estimated Enrollment: 60
Study Start Date: October 2014
Estimated Study Completion Date: April 2016
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CC-486 Arm 1 (Oral Azacitidine) Dosing Sequence 1
Two 150-mg tablets of CC-486 under fasting condition on PK Dosing Day 1, followed by 300mg tablet of CC-486 on PK dosing Day 2; If PI chooses to treat the patient in the extension phase with azacitidine, Vidaza (Azacitidine for Injection) 75mg/m^2 intravenously (IV) or subcutaneously (SC) daily x 7 days every 4 weeks for ≤ 6 (four-week) cycles will be administered
Drug: CC-486
Arm 1: Two 150-mg tablets of CC-486 on Day 1 and 1 x 300 mg CC-486 on Day 2 Arm 2: 1 x 300mg tablet of CC 486 on Day 1 and 2 x 150mg CC-486 on Day 2
Other Name: Oral Azacitdine
Drug: Vidaza
75mg/m^2 IV or SC daily x 7 days every 4 weeks for ≤ 6 (four-week) cycles
Other Names:
  • Azacitidine for Injection
  • AZA
Experimental: CC-486 Arm 2 (Oral Azacitidine) Dosing Sequence 2
One 300mg tablet of oral CC-486 under fasting condition on PK dosing Day 1, followed by 2 x 150mg CC-486 tablets on PK dosing Day 2; If PI chooses to treat the patient in the extension phase with azacitidine, Vidaza (Azacitidine for Injection) 75mg/m2 intravenously (IV) or subcutaneously (SC) daily x 7 days every 4 weeks for ≤ 6 (four-week) cycles will be administered.
Drug: CC-486
Arm 1: Two 150-mg tablets of CC-486 on Day 1 and 1 x 300 mg CC-486 on Day 2 Arm 2: 1 x 300mg tablet of CC 486 on Day 1 and 2 x 150mg CC-486 on Day 2
Other Name: Oral Azacitdine
Drug: Vidaza
75mg/m^2 IV or SC daily x 7 days every 4 weeks for ≤ 6 (four-week) cycles
Other Names:
  • Azacitidine for Injection
  • AZA

Detailed Description:

Currently, the 150 mg tablet formulation (F8) of CC-486 is being provided to subjects in two large Phase 3 randomized placebo-controlled studies in lower-risk MDS and AML maintenance. This CC-486-CAGEN-001 study is designed to assess the bioequivalence of CC-486 when administered once daily as one 300 mg tablet (F9) relative to two 150 mg tablets (F8) in adult cancer subjects with hematologic malignancies or various tumor types excluding gastrointestinal tumors and tumors that have originated or metastasized to the liver.

Following confirmation of eligibility during screening, subjects will be randomized to one of two dosing sequences in the pharmacokinetics (PK) phase and will have blood samples taken prior to dosing and at several time points during the 8 hours following dosing. Safety information will be collected in this phase and the PK parameters describing the levels of investigational product (IP) in circulation will be used to assess bioequivalence of the two formulations.

In the extension phase of the study, Vidaza® (Azacitidine for Injection) will be provided for ≤ 6 cycles as an opportunity for subjects who currently have limited treatment options or have failed previous therapies. It is up to the discretion of the investigator to treat the subject with Vidaza® for the diagnosed malignancy at study entry in this phase. Only safety information will be collected in this phase.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must satisfy the following criteria to be enrolled in the study:

    1. Age ≥ 18 years of age at the time of signing the informed consent document.
    2. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
    3. Documented diagnosis of any of the following:

      1. Myelodysplastic Syndrome (MDS) according to the World Heatlh Organization (WHO) 2008 classification
      2. Acute myeloid leukemia (AML)
      3. Multiple myeloma (MM), limited to those patients for whom standard curative or palliative treatments do not exist or are no longer effective
      4. Non-Hodgkin's lymphoma (NHL), limited to those patients for whom standard curative or palliative treatment do not exist or are no longer effective,
      5. Hodgkin's lymphoma (HL), limited to those patients for whom standard curative or palliative treatment do not exist or are no longer effective
      6. Metastatic or inoperable solid tumors* (except gastrointestinal tumors or tumors that originated or metastasized to the liver) for which no standard treatment exists, or have progressed or recurred following prior therapy.

        • Subjects must not be eligible for therapy of higher curative potential where an alternative treatment has been shown to prolong survival in an analogous population.
    4. Patients with a history of treated brain metastases should be clinically stable for ≥ 4 weeks prior to signing the informed consent. Glucocorticoid therapy for central nervous system (CNS) edema is permitted if ≤ 20 mg of prednisolone (or equivalent).
    5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
    6. Have a life expectancy of ≥ 3 months.
    7. Have stable renal function without dialysis for at least 2 months prior to Investigational Product (IP) administration defined by:

      1. Serum creatinine < 2.5 x the upper limit of normal (ULN)
      2. An average calculated creatinine clearance > 30 mL/min/1.73 m^2
    8. Have organ and marrow function at the screening and pre-dose visits as defined by:

      1. Hemoglobin ≥ 8 g/dL
      2. Absolute neutrophil count (ANC) ≥ 0.75 x 10^3/uL without treatment with a myeloid growth factor within 3 days prior to first dose of IP
      3. Platelets ≥ 30 x 10^3/uL
      4. Total bilirubin ≤ 1.5 x Upper Limits of Normal (ULN)
      5. Aspartate aminotransferase (AST) ≤ 2 x ULN
      6. Alanine aminotransferase (ALT) ≤ 2 x ULN
    9. Have a 12-lead Electrocardiogram (ECG) that is not clinically significant at screening, as determined by the investigator
    10. Females of childbearing potential (FCBP) may participate, providing the subject meets the following conditions:

      • Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) or agree to practice true abstinence* throughout the study, and for 3 months following the last dose of IP; and
      • Negative serum pregnancy test at screening (sensitivity of at least 25 mIU/mL); and
      • Negative serum or urine pregnancy test (investigator's discretion; sensitivity of at least 25 mIU/mL) within 72 hours prior to starting IP in the extension phase (note that the screening serum pregnancy test can be used as the test prior to starting IP in the pharmacokinetics phase if it is performed within the 72-hour timeframe)
    11. Male subjects must:

      a. Practice true abstinence* or agree to the use of at least two physician-approved contraceptive methods throughout the course of the study and should avoid fathering a child during the course of the study for at least 3 months following the last dose of IP.

      * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the patient. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception].

    12. Able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

  1. Women who are pregnant or nursing (lactating).
  2. Gastrointestinal tumors, tumors that have originated or metastasized to the liver, or other tumors known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
  3. Had chemotherapy or radiotherapy within 4 weeks prior to the first day of Investigational Product (IP) administration.
  4. Have been treated with an investigational agent within 4 weeks prior to the first day of IP administration.
  5. Have ongoing clinically significant adverse event(s) due to prior treatments administered as determined by the investigator.
  6. Significant active cardiac disease within the previous 6 months, including:

    • New York Heart Association (NYHA) class IV congestive heart failure
    • Unstable angina or angina requiring surgical or medical intervention; and/or
    • Myocardial infarction
  7. Have known or suspected hypersensitivity to azacitidine or any other ingredient used in the manufacturing of Azacitidine.
  8. Have known active viral infection with human immunodeficiency virus (HIV) or active hepatitis B (HBV) or C (HCV)
  9. History of inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis), celiac disease, prior gastrectomy, gastric bypass, upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.
  10. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
  11. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
  12. Any condition that confounds the ability to interpret data from the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02223052

Contacts
Contact: Lynn O'Connell, MPT 732-652-6146 loconnell@celgene.com
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

Locations
United States, South Carolina
Greenville Hospital System Not yet recruiting
Greenfield, South Carolina, United States, 29605
Sponsors and Collaborators
Celgene Corporation
Investigators
Study Director: CL Beach, PharmD Celgene Corporation
  More Information

No publications provided

Responsible Party: Celgene Corporation
ClinicalTrials.gov Identifier: NCT02223052     History of Changes
Other Study ID Numbers: CC-486-CAGEN-001
Study First Received: August 20, 2014
Last Updated: August 20, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Celgene Corporation:
CC-486
Oral Azacitidine
Soli Tumor Malignancy
Hematological Malignancy
Leukemia
Lymphoma
Multiple Myeloma
Acute Myeloid Leukemia
Myelodysplastic Syndromes
Neoplasms
Melanoma
Breast Cancer
Metastatic Breast Cancer
Non-Small Cell Lung Cancer
Small Cell Lung Cancer
Renal Cell Carcinoma
Glioblastoma Multiforme
Brain Cancer
Kindney Cancer
Lung cancer
Blood Cancer
Thyroid Cancer
Bone Cancer
Bone Metastasis
Testicular Cancer
Prostate Cancer
Bladder Cancer
Ovarian Cancer
Skin Cancer
Cancer general

Additional relevant MeSH terms:
Breast Neoplasms
Carcinoma
Carcinoma, Non-Small-Cell Lung
Carcinoma, Renal Cell
Glioblastoma
Hematologic Neoplasms
Hodgkin Disease
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Lung Neoplasms
Lymphoma
Lymphoma, Non-Hodgkin
Melanoma
Multiple Myeloma
Myelodysplastic Syndromes
Neoplasms
Neoplasms, Plasma Cell
Osteosarcoma
Preleukemia
Small Cell Lung Carcinoma
Syndrome
Thyroid Neoplasms
Adenocarcinoma
Astrocytoma
Blood Protein Disorders
Bone Marrow Diseases
Breast Diseases
Bronchial Neoplasms
Carcinoma, Bronchogenic

ClinicalTrials.gov processed this record on October 30, 2014