A Phase 1, Open-label Trial of Oral Azacitidine (CC-486) Plus RCHOP in Subjects With Large B-Cell Lymphoma or Follicular Lymphoma or Transformed Lymphoma

NCT02343536 | Completed Phase 1 DMC

• 1 other identifier: CC-486-DLBCL-001
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 7

Brief Summary

The goal of the study is to identify a dose and schedule of CC-486 that can be safely administered with R-CHOP. To evaluate the safety and maximum tolerated dose (MTD) or the maximal administered dose (MAD) of CC-486 in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in subjects with high risk (IPI 2 or more) previously untreated DLBCL or Grade 3B FL. Also, to determine pharmacokinetics (PK) of CC-486 when administered alone and in combination with R-CHOP and to explore preliminary efficacy of CC-486 plus R-CHOP by 2007 International Working Group (IWG) criteria.

Conditions

Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular

Keywords

Phase 1; Oral Azacitidine (CC-486); R-CHOP; Diffuse Large B-cell Lymphoma; Grade 3B Follicular Lymphoma; Follicular Lymphoma; Transformed Lymphoma

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD)

  The dose level corresponding to the target Dose Limiting Toxicity (DLT) probability of 0.20.

  1 year

• Maximal Administered Dose (MAD)

  The highest recorded dose administered to a subject if the MTD is not reached

  1 Year

• Adverse Event (AE)

  Number of participants with adverse events

  2 Years

Secondary Outcomes (9)

• Pharmacokinetics- Cmax

  2 Years

• Pharmacokinetics - AUC

  2 Years

• Pharmacokinetics - Tmax

  2 Years

• Pharmacokinetics - t1/2

  2 Years

• Pharmacokinetics CL/F

  2 Years

Study Arms (2)

Oral Azacitidine (CC-486) and R-CHOP

EXPERIMENTAL

Will examine four escalating dose-levels of CC- 486 (100 mg, 150 mg, 200 mg and 300 mg).

Drug: Oral Azacitidine; Drug: Rituximab; Drug: cyclophosphamide; Drug: Vincristine; Drug: Prednisone

R-CHOP

ACTIVE COMPARATOR

R-CHOP, (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) \* rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on Day 1; while prednisone is administered Days 1-5

Drug: Rituximab; Drug: cyclophosphamide; Drug: Vincristine; Drug: Prednisone

Interventions

Oral Azacitidine DRUG

Also known as: CC-486

Oral Azacitidine (CC-486) and R-CHOP

Rituximab DRUG

Oral Azacitidine (CC-486) and R-CHOP; R-CHOP

cyclophosphamide DRUG

Oral Azacitidine (CC-486) and R-CHOP; R-CHOP

Vincristine DRUG

Oral Azacitidine (CC-486) and R-CHOP; R-CHOP

Prednisone DRUG

Oral Azacitidine (CC-486) and R-CHOP; R-CHOP

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• A formalin fixed paraffin embedded lymph node or tumor biopsy specimen must be submitted during the Screening Period. The specimen must have been acquired by a surgical or core needle biopsy (≥ 2 cores at baseline); material from a fine needle aspiration is not acceptable.
• Fresh core biopsy, frozen, must be performed before start of therapy and submitted for storage. This is optional only for the subjects who have a biopsy-accessible site and consent to the procedure. In case no prior fixed formalin paraffin embedded (FFPE) biopsy is available, this specimen can also be used for diagnostic confirmation.
• No prior anti-lymphoma therapy. However, for subjects with bulky disease,systemic symptoms, compressive disease, or rapidly progressing adenopathies, pre-phase treatment with 1 mg/kg/day prednisone, or equivalent, for a maximum of 7 days is permitted prior to Cycle 1 Day -6 at the discretion of the Investigator. In exceptional cases, if clinically indicated, a higher dose of steroids and/or a slightly longer duration is allowed for the purpose of urgent symptom management, and the subjects is considered eligible. A washout period does not apply. However the fresh core biopsy mentioned above should be performed before starting prednisone.
• 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 ICD.
• Understand and voluntarily sign an ICD (Informed Consent Document) 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, defined as a sexually mature woman who: 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or, 2) 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), may participate providing they agree to the following conditions:
• Either commit to true abstinence\* from heterosexual contact (which must be reviewed on a monthly basis) or agree to the use of a physician-approved contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intrauterine device; barrier contraceptive with spermicide; or vasectomized partner) without interruption, while on CC-486 (including dose interruptions); and for 3 months following the last dose of IP; and
• Agree to have a medically supervised serum pregnancy test with sensitivity of at least 25 mIU/mL obtained at Screening. A serum pregnancy test is to be performed within 72 hours prior to Day 1 of starting study therapy on Cycle 1 Day -6, and within 72 hours prior to Day 1 of every subsequent cycle, and at the Treatment Discontinuation Visit. The subject may not receive IP until the Investigator has verified that the result of the pregnancy test is negative.
• Male subjects 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).

You may not qualify if:

• Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
• Any condition including the presence of laboratory abnormalities, which places the subject 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 (e.g., Crohnis disease, ulcerative colitis),celiac disease (i.e., sprue), 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 subject to an increased risk of gastrointestinal toxicity.
• Seropositive for or active viral infection with hepatitis B virus (HBV):
• Hepatitis B surface antigen (HBsAg) positive
• HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral DNA
• Subjects who are HBsAg negative, anti-HBs positive, and/or anti-HBc positive, but viral DNA negative are not eligible
• Subjects who are seropositive because of HBV vaccination are eligible (HBV surface antibody positive, HBV core antibody negative, and HBV surface antigen negative)
• Prior history of malignancies, other than diffuse large B-cell lymphoma, unless the subject has been free of the disease for ≥ 5 years from the signing of the ICD. Exceptions to the ≥ 5 year time limit include history of the following:
• Basal cell carcinoma of the skin
• Squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast

Sponsors & Collaborators

• Celgene: lead

Study Sites (7)

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02117, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Weill Cornell Medicine

New York, New York, 10065, United States

Location

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

Related Publications (1)

• Martin P, Bartlett NL, Chavez JC, Reagan JL, Smith SM, LaCasce AS, Jones J, Drew J, Wu C, Mulvey E, Revuelta MV, Cerchietti L, Leonard JP. Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL. Blood. 2022 Feb 24;139(8):1147-1159. doi: 10.1182/blood.2021011679.

  PMID: 34428285 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular

Interventions

Azacitidine; cc-486; Rituximab; Cyclophosphamide; Vincristine; Prednisone

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Lei Zhang, MD

  Celgene

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: January 16, 2015
• First Posted: January 22, 2015
• Study Start: April 29, 2015
• Primary Completion: January 29, 2020
• Study Completion: January 29, 2020
• Last Updated: August 28, 2020

Record last verified: 2020-08

Locations

US (7)