Clinical Trial 18165

Cancer Type: Malignant Hematology
Interventions:Adriamycin (doxorubicin); CC-486 (Azacitidine (Oral)); Rituxan (rituximab); Vincristine; cyclophosphamide; cytoxan (cyclophosphamide); doxorubicin; prednisone; rituximab

Study Type: Treatment
Phase of Study: Phase I
Investigators:

  • Julio Chavez

Overview

Study Title

A Phase 1, Open-Label, Multicenter Trial of Oral Azacitidine (CC-486) Plus R-Chop in Subjects with IPI 2 or More Previously Untreated Diffuse Large B-Cell Lymphoma or Grade 3B Follicular Lymphoma, or Transformed Lymphoma

Summary

The purpose of this study is to look at the safety of oral azacitidine when combined with R- CHOP (drugs normally used in treating Diffuse large B-cell lymphoma or Grade 3B follicular lymphoma). The other purposes of this study are to understand how the human body takes in and removes oral azacitidine when given with R-CHOP, if the Diffuse large B-cell lymphoma or Grade 3B follicular lymphoma tumor size decreases, and to look into the effects the drug can have on the human body.

Objective

Primary Objective: The primary objective of the study is to evaluate the safety and to determine the MTD or the maximal administered dose (MAD) of CC-486 in combination with R-CHOP in subjects with IPI>=2 or previously untreated DLBCL, Grade 3B FL, or transformed lymphoma. The MAD is the highest recorded dose administered to a subject if the MTD is not reached (Le Tourneau, 2010). Secondary Objectives: The secondary objectives of the study are: To determine pharmacokinetics (PK) of CC-486 when administered alone and in combination with R-CHOP. To explore preliminary efficacy of CC-486 plus R-CHOP by 2007 International Working Group (IWG) criteria. Exploratory Objectives: The exploratory objectives of the study are, by means of a biomarker program: To evaluate the pharmacodynamic effects of CC-486: - Confirm that low doses of CC-486 can reduce global DNA methylation (enhanced reduced representation bisulfite [ERRBS]) without DNA damage (phospho 2AX). - Explore/confirm MOA hypothesis based on reversal of hypermethylation of genes controlling the « SWING » phenotype restoring sensitivity to cytotoxic agents (MassArray). To evaluate potential predictive/correlative biomarkers for DLBCL subgroups that are considered important. To explore cytidine deaminase (CDA) activity and polymorphisms.

Inclusion Criteria

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  • Histologically confirmed previously untreated DLBCL or Grade 3B FL, [double-positive for BCL2 and c-MYC] or transformed lymphoma. Transformed lymphoma from FL or marginal zone lymphoma, but not chronic lymphocytic leukemia (CLL) [Richter Transformation] are allowed as long as no prior anti-lymphoma therapy of any kind has been administered.
  • International Prognostic Index score ≥ 2 or DLBCL with double-positive for BCL2 and c-MYC by IHC (immunohistochemistry) or FISH (fluorescent in situ hybridization) based on local pathology lab assessment.
  • Measurable disease on cross section imaging by CT (computed tomography) that is at least 1.5 cm in the longest diameter and measurable in two perpendicular dimensions as defined by IWG (International Working Group) response criteria for NHL (non-Hodgkin Lymphoma).
  • Ann Arbor stage II to IV.
  • Men and women 18 years of age to 80 years of age of any ethnic origin or race at the time of signing the Informed Consent Document (ICD).
  • Understand and voluntarily sign an ICD prior to any study related assessments/procedures are conducted.
  • Able to adhere to the study visit schedule and other protocol requirements.
  • Performance status ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) scale.
  • Negative serum pregnancy test within 72 hours before starting study treatment on Cycle 1 Day -6 for females of childbearing potential (FCBP). A female of child-bearing potential may participate providing they agree to the contraception and pregnancy conditions.
  • Males with a female partner of childbearing potential must either commit to true abstinence* or agree to the use of a physician-approved contraceptive method throughout the course of the study and avoid fathering a child during the course of the study and for 3 months following the last dose of the IP (Investigational Product).

  • Exclusion Criteria

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  • Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study.
  • Any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study.
  • Any condition that confounds the ability to interpret data from the study.
  • Any condition causing an inability to swallow tablets.
  • History of inflammatory bowel disease, prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with absorption, distribution, metabolism, or excretion of the IP and/or predispose the participant to an increased risk of gastrointestinal toxicity.
  • Hematologic and Non-hematologic exclusion criteria before start of therapy.
  • Seropositive for or active viral infection with hepatitis B virus (HBV): Potential participants who are seropositive because of HBV vaccination may be eligible.
  • Prior history of malignancies, other than diffuse large B-cell lymphoma, unless free of the disease for ≥ 5 years from the signing of the ICD. Exceptions to the ≥ 5 year time limit: Basal cell carcinoma of the skin; Squamous cell carcinoma of the skin; Carcinoma in situ of the cervix; Carcinoma in situ of the breast; Incidental histological finding of prostate cancer (TNM stage of T1a or T1b).
  • Known seropositive for or active infection with hepatitis C virus (HCV).
  • Known seropositive for or active viral infection with human immunodeficiency virus (HIV).
  • Known or suspected hypersensitivity to azacitidine or mannitol or any other ingredient used in the manufacture of oral azacitidine.
  • Contraindication to any drug in the chemotherapy regimen, and specifically: LVEF 480 msec (using the Fridericia formula); Neuropathy uropathy europathy Nemediastinal DLBCL.
  • Primary mediastinal DLBCL.
  • Active uncontrolled systemic fungal, bacterial, or viral infection.
  • Significant active cardiac disease within the previous 6 months from the signing of the ICD.
  • Women who are pregnant or breast feeding.