Study of Safety and Efficacy of Avadomide (CC-122) Combined With RCHOP for Newly-diagnosed DLBCL With Poor Risk Factors

NCT03283202 | Completed Phase 1 DMC FDA Drug

• 3 other identifiers: CC-122-DLBCL-002U1111-1201-19942016-003778-42
• Study Type: interventional
• Target: 35
• Locations: 4 countries
• Sites: 15

Brief Summary

This is Phase 1/2 study of avadomide (CC-122) in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, for first-line treatment of patients with Diffuse B-Cell Large B-Cell Lymphoma (DLBCL) that has poor risk factors. Approximately 40% of patients diagnosed with DLBCL are not cured with R-CHOP alone and would need additional treatment for DLBCL in the future. The addition of the experimental drug avadomide (CC-122) with R-CHOP could help in controlling DLBCL in this patient population.

Conditions

Diffuse B-Cell Lymphoma

Keywords

Diffuse B-Cell Lymphoma; R-CHOP-21; International Prognostic Index (IPI)

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose/Maximum Administered Dose (MTD/MAD) (Phase 1)

  Frequency of dose-limiting toxicities (DLTs) associated with the addition of avadomide (CC-122) to R-CHOP-21 therapy

  Through 6 cycles of treatment (approximately 18 weeks or 4 months)

• Complete Response Rate (CRR); Percentage of participants experiencing positron emission tomography (PET)-negative complete response (CR) (Phase 2)

  CR is defined as target nodes/nodal masses regress to ≤ 1.5 cm in LDi; no extralymphatic sites of disease; no measurable lesions, no organ enlargement and normal morphology on bone marrow (BM) exam; immunohistochemically (IHC) negative

  6 to 8 weeks after completion of treatment

Secondary Outcomes (6)

• Overall Response Rate (ORR); Percentage of participants who achieve a PR or CR according to the Lugano criteria.

  6 to 8 weeks after completion of treatment

• ORR by Predictive Gene Signature

  6 to 8 weeks after completion of treatment

• Progression-free Survival (PFS)

  From enrollment up to 24 months after last subject is enrolled

• Event-free Survival (EFS)

  At 12 and 24 months after enrollment

• Overall Survival (OS)

  Up to 24 months after enrollment

Study Arms (1)

Avadomide (CC-122) plus R-CHOP-21

EXPERIMENTAL

Avadomide (CC-122) by mouth (PO) at varying dose levels (Ph 1) on Days 1 through 5 and Days 8 through 12 plus Rituxan 375 mg/m2 by intravenous (IV) infusion, cyclophosphamide 750mg/m2 by IV infusion, doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 (max is 2.0 mg) IV and 100 mg PO prednisone/prednisolone on Days 1 through 5 of each 21-day treatment cycles for up to 6 total treatment cycles (approximately 18 weeks or 4 months)

Drug: Avadomide (CC-122); Drug: Rituximab; Drug: Cyclophosphamide 750mg/m2 by IV infusion; Drug: Vincristine; Drug: Prednisone

Interventions

Avadomide (CC-122) DRUG

Avadomide (CC-122) by mouth at the assigned dose in Ph 1 starting on Day 1 for 5 consecutive days per week, followed by 2 days without avadomide (CC-122) administration (5/7) for the first two weeks of a 21-day treatment cycle. If the highest proposed dose level to be explored in Phase 1 is applied, the dosing regimen will be 5/7 days for all 3 weeks of each 21-day treatment cycle.

Avadomide (CC-122) plus R-CHOP-21

Rituximab DRUG

Rituxan 375 mg/m2 on Day 1 by intravenous (IV) infusion of a 21-day treatment cycle for up to a total of 6 cycles

Also known as: Rituxan, MabThera

Avadomide (CC-122) plus R-CHOP-21

Cyclophosphamide 750mg/m2 by IV infusion DRUG

Cyclophosphamide 750mg/m2 on Day 1 by IV infusion of a 21-day treatment cycle for up to a total of 6 cycles

Avadomide (CC-122) plus R-CHOP-21

Vincristine DRUG

Vincristine 1.4 mg/m2 (maximum of 2.0 mg total) on Day 1 by IV bolus on Day 1 of a 21-day treatment cycle for up to a total of 6 cycles

Also known as: Oncovin, Vincasar

Avadomide (CC-122) plus R-CHOP-21

Prednisone DRUG

Prednisone 100 mg PO on Days 1 through 5 of each 21-day treatment or 100mg IV on Day 1 is also acceptable for up to a total of 6 cycles

Also known as: Prednisolone

Avadomide (CC-122) plus R-CHOP-21

Eligibility Criteria

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

You may qualify if:

• \. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
• \. Subject has documented, histologically locally confirmed, previously untreated CD20+ DLBCL (NOS) and the following histologies; refer to the World Health Organization (WHO) 2016 classification (Appendix G):
• DLBCL associated with chronic inflammation
• Epstein-Barr virus positive (EBV+) of the elderly
• T-cell/histiocyte-rich DLBCL 3. Subject is considered an appropriate candidate (per Investigator assessment) for induction therapy with 6 cycles of R-CHOP-21 immunochemotherapy.
• \. Subject has a performance status (PS) of 0-2 according to the Eastern Cooperative Oncology Group (ECOG) scale. Subjects with ECOG PS of 3 may be included if decreased PS is secondary to DLBCL only, and not to comorbidities.
• \. Subject has poor-risk disease defined as International Prognostic Index (IPI) score ≥ 3 (high-intermediate or high-risk classification) and has an age-adjusted IPI defined as ≤ 60 age-adjusted IPI score of 2 with elevated LDH are eligible.
• \. Subject has measurable disease on cross-sectional imaging by computed tomography (CT) with at least one (post-biopsy) measurable lesion ≥ 2.0 cm in its longest dimension.
• \. Subject must appropriately be able to complete Screening assessments before beginning treatment for DLBCL, in the judgement of the Investigator.
• For subjects with bulky disease, B-symptoms, compressive disease, elevated bilirubin due to lymphoma, rapidly progressing adenopathies, or worsening performance status, pre-phase treatment with up to 100 mg/day prednisone, or equivalent, for a maximum of 10 days is permitted prior to beginning the treatment period, at the discretion of the Investigator. A washout period is not required, however, the Screening positron emission tomography (PET), CT, tumor biopsy (if needed), and bone marrow biopsy (if needed) should be completed before initiating corticosteroids.
• \. Subject's central laboratory values must fulfill the following requirements during Screening: Blood product transfusions and hematopoietic growth factors may not be used to meet eligibility criteria. Screening samples should not be collected within 14 days after subject receives a blood product transfusion or growth factors.
• If treatment needs to be urgently started and screening central laboratory results are not available then local laboratory results may be used to confirm eligibility. In these cases, the Celgene medical monitor must be consulted prior to beginning treatment. The investigator must still ensure that samples for the central laboratory are drawn before investigational product is administered and sent to the central laboratory.
• \. Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 (1.5 x 109/L) unless secondary to extensive bone marrow involvement by lymphoma (ie, ≥ 50%) as demonstrated by unilateral bone marrow core biopsy performed during Screening or within 3 months prior to signing the ICF. In the case of documented extensive bone marrow involvement an ANC ≥ 1,000 cells/mm3 (1.0 x 109/L) is required.
• \. Platelet count ≥ 100,000/mm3 (100 x 109/L) unless secondary to extensive bone marrow involvement by lymphoma (ie, ≥ 50%) as demonstrated by unilateral bone marrow core biopsy performed during Screening or within 3 months prior to signing the ICF. In the case of documented extensive bone marrow involvement, a platelet count of ≥ 75,000/ mm3 (75 x 109/L) is required.
• \. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≤ 3.0 x upper limit of normal (ULN). In the case of documented liver involvement by lymphoma, ALT/SGPT and AST/SGOT must be ≤ 5.0 x ULN.

You may not qualify if:

• \. Subject is seropositive for or has active viral infection with hepatitis B virus (HBV):
• HBV surface antigen (HBsAg) positive
• HBV surface antigen (HBsAg) negative, HBV surface ant ibody (ant i-HBs) posit ive and/or HBV core antibody (ant i-HBc) positive, and detectable viral DNA Subjects who are seropositive because of prior HBV vaccination are eligible (anti- HBs positive, anti-HBc negative, and HBsAg negative).
• \. Subject is known to be seropositive for, or have an active infection with, hepatitis C virus (HCV).
• \. Subject is known to be seropositive for, or have an active infection with, human immunodeficiency virus (HIV).
• \. Subject has any neuropathy \> Grade 1. 5. Subject has impaired cardiac function or clinically significant cardiac diseases, including any of the following:
• Left ventricular ejection fraction (LVEF) \< 45% as determined by multi-gated acquisition scan (MUGA) or echocardiogram (ECHO).
• Complete left bundle branch or bifascicular block.
• Persistent or clinically meaningful ventricular arrhythmias.
• Unstable angina pectoris or myocardial infarction ≤ 3 months prior to starting treatment in the study.
• Troponin-T value \> 0.4 ng/mL or B-type natriuretic protein (BNP) \> 300 pg/mL by central laboratory assessment Subjects with baseline troponin-T \> ULN or BNP \> 100 pg/mL are eligible but must have a cardiologist evaluation prior to enrollment in the trial for baseline assessment and optimization of cardioprotective therapy.
• If troponin-T is not usually tested by local laboratory then troponin-I may be used to confirm subject meets the Screening eligibility criteria. The central laboratory sample must still be collected prior to first dose and sent to central laboratory. Elevated cut-off value for troponin I will depend on the assay used at the site. If baseline troponin I \>ULN, the subject must have a cardiologist consultation prior to enrollment and optimization of cardioprotective therapy.
• In case of discrepancy between both troponin-I and troponin-T test, the troponin-T test will be repeated.
• Subject has confirmed central nervous system (CNS) involvement by DLBCL. Subjects at risk for CNS involvement per Investigator assessment must receive prophylaxis. For subjects at risk, or with any neurological symptoms, testing for CNS involvement is required at Screening.
• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.

Sponsors & Collaborators

• Celgene: lead

Study Sites (15)

George Washington University

Washington D.C., District of Columbia, 20037, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

UZ Gent

Ghent, 9000, Belgium

Location

University Hospital Gasthuisberg

Lueven, B-3000, Belgium

Location

Tom Baker Cancer Center

Calgary, Alberta, T2N 4N2, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Hospital Germans Trias I Pujol

Badalona, 8916, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 8035, Spain

Location

Hospital de San Pedro de Alcantara

Cáceres, 10003, Spain

Location

Hospital Universitario Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Clinico Universitario de Salamanca

Salamanca, 37007, Spain

Location

Hospital Universitario Virgen Del Rocio

Seville, 41013, Spain

Location

MeSH Terms

Interventions

3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; Rituximab; Cyclophosphamide; Vincristine; Prednisone; Prednisolone

Intervention Hierarchy (Ancestors)

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; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienetriols

Study Officials

• Richard Delarue, MD

  Celgene

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2017
• First Posted: September 14, 2017
• Study Start: October 4, 2017
• Primary Completion: July 30, 2019
• Study Completion: December 16, 2020
• Last Updated: April 29, 2021

Record last verified: 2021-04

Locations

BE (2); ES (7); US (3); CA (3)