Clinical Trials /

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

NCT03283202

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Safety and Efficacy of CC-122 Combined With RCHOP for Newly-diagnosed DLBCL With Poor Risk Factors
  • Official Title: A Phase 1/2 Study of CC-122 in Combination With R-CHOP for Previously Untreated Poor-Risk (IPI >=3) Diffuse Large B-Cell Lymphoma and Transformed Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: CC-122-DLBCL-002
  • SECONDARY ID: U1111-1201-1994
  • SECONDARY ID: 2016-003778-42
  • NCT ID: NCT03283202

Conditions

  • Diffuse B-Cell Lymphoma

Interventions

DrugSynonymsArms
CC-122CC-122 plus R-CHOP-21
RituximabRituxan, MabTheraCC-122 plus R-CHOP-21
Cyclophosphamide 750mg/m2 by IV infusionCC-122 plus R-CHOP-21
VincristineOncovin, VincasarCC-122 plus R-CHOP-21
PrednisonePrednisoloneCC-122 plus R-CHOP-21

Purpose

This is Phase 1/2 study of 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 CC-122 with R-CHOP could help in controlling DLBCL in this patient population.

Detailed Description

      This research study is for patients who have been newly diagnosed with diffuse large B-cell
      lymphoma DLBCL and are receiving treatment for the first time.

      This study will be conducted in two phases. Phase 1 will test the safety of increasing dose
      levels of CC-122 when given in combination with R-CHOP-21 therapy to identify an appropriate
      dose and schedule for further evaluation in Phase 2. Phase 2 will evaluate the rate of
      complete response when adding CC-122 to the R-CHOP-21 regimen in first-line treatment of
      patients with poor risk DLBCL.

      This study is separated into three periods: the Screening period, the Treatment period and
      the Follow-up period. Before the patient can receive the drug the doctor will perform test to
      find out whether he/she can participate in the study. This is done during the Screening
      period. If the patient and the treating physician determine that the patient is eligible to
      participate in the study, the patient will be registered in the study and receive CC-122
      combined with R-CHOP.

      In the Treatment period the patient will receive treatment for up to 6 treatment cycles. Each
      treatment cycle is 21 days long. The full length of the treatment period will be
      approximately 4 months.

      The follow-up period begins when the patient has completed treatment or is discontinued for
      any reason. During the follow-up period the patient will have fewer exams, test and visits.
      The first follow-up visit will be 28 days after treatment is completed or discontinued. After
      that, the follow-up visits will be every 3 months during the first year, then every 6 months
      until the study is closed.
    

Trial Arms

NameTypeDescriptionInterventions
CC-122 plus R-CHOP-21ExperimentalCC-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)
  • CC-122
  • Rituximab
  • Cyclophosphamide 750mg/m2 by IV infusion
  • Vincristine
  • Prednisone

Eligibility Criteria

        Inclusion Criteria:

          1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).

          2. Subject has documented, histologically locally confirmed, previously untreated CD20+
             DLBCL (NOS) per World Health Organization (WHO) classifications (Swerdlow, 2008).

          3. Subject is considered an appropriate candidate (per Investigator assessment) for
             induction therapy with 6 cycles of R-CHOP-21 immunochemotherapy.

          4. 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.

          5. Subject has poor-risk disease defined as International Prognostic Index (IPI) score ≥
             3 (high-intermediate or high-risk classification).

          6. 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.

          7. 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.

        8. 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.

          1. 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.

          2. 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.

          3. 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.

          4. Serum total bilirubin ≤ 2.0 mg/dL (34 μmol/L). In the case of Gilbert's syndrome, or
             documented liver or pancreatic involvement by lymphoma, serum total bilirubin must be
             ≤ 5.0 mg/dL (86 μmol/L).

          5. Calculated creatinine clearance (CrCl) of ≥ 50 mL/min by the Cockcroft-Gault formula.

        9. Subject must understand and voluntarily sign an Informed Consent Form (ICF) prior to any
        study-specific assessments/procedures being conducted.

        10. Subject is willing and able to adhere to the study visit schedule and other protocol
        requirements.

        11. Sufficient tissue from diagnostic tumor/ lymph node biopsy (from within 2 months prior
        to ICF signature) must be available for translational research purposes or subject is
        willing to undergo core needle or incisional/ excisional biopsy during Screening.

        12. Females of childbearing potential (FCBP)1 must:

          1. Agree to use two reliable forms of contraception simultaneously or to practice
             complete abstinence (True abstinence is acceptable when this is in line with the
             preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar,
             ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable
             methods of contraception.) from heterosexual contact during the following time periods
             related to this study: 1) for at least 28 days before starting CC-122; 2) while taking
             CC-122; 3) during dose interruptions; and 4) for at least 28 days after the last dose
             of CC-122 as specified in the Pregnancy Prevention and Risk Management Plan (PPRMP)

          2. Have a negative result confirmed for a medically supervised urine (or serum) pregnancy
             test (with a sensitivity of at least 25 mIU/mL) 10-14 days prior to the first dose of
             IP. A second pregnancy test performed within 24 hours prior to the first dose of IP
             must also be confirmed to be negative prior to IP administration.

        13. Avoid conceiving for at least 12 months after the last dose of rituximab, or according
        to the local rituximab Prescribing Information or Summary of Product characteristics
        (SmPC); at least 28 days after the last dose of any other study drug.

          1. Agree to ongoing pregnancy testing during the course of the study as outlined in the
             PPRMP.

        14. Male subjects must:

          1. Practice complete abstinence (True abstinence is acceptable when this is in line with
             the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar,
             ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable
             methods of contraception.) or agree to use a condom during sexual contact with a
             pregnant female or a FCBP for at least 12 months after the last dose of rituximab.

          2. Agree to not donate semen or sperm for at least 12 months following the last dose of
             rituximab.

        15. All subjects must:

          1. Understand that CC-122 could have a potential teratogenic risk.

          2. Agree to abstain from donating blood while taking IP and for at least 28 days
             following discontinuation of IP.

          3. Agree not to share IP with another person

          4. Be counseled about pregnancy precautions and risks of fetal exposure and agree to
             requirements of the Pregnancy Prevention and Risk Management Plan (PPRMP)

        16. Subject is able to swallow pills.

        Exclusion Criteria:

        1. Subject is seropositive for or has active viral infection with hepatitis B virus (HBV):

          1. HBV surface antigen (HBsAg) positive

          2. 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).

        2. Subject is known to be seropositive for, or have an active infection with, hepatitis C
        virus (HCV).

        3. Subject is known to be seropositive for, or have an active infection with, human
        immunodeficiency virus (HIV).

        4. Subject has any neuropathy > Grade 1. 5. Subject has impaired cardiac function or
        clinically significant cardiac diseases, including any of the following:

          1. Left ventricular ejection fraction (LVEF) < 45% as determined by multi-gated
             acquisition scan (MUGA) or echocardiogram (ECHO).

          2. Complete left bundle branch or bifascicular block.

          3. Congenital long QT syndrome

          4. Persistent or clinically meaningful ventricular arrhythmias.

          5. QTcF > 460 msec on Screening electrocardiogram (ECG)

          6. Unstable angina pectoris or myocardial infarction ≤ 3 months prior to starting
             treatment in the study.

          7. 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.

        6. 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.

        7. Subject has any significant medical condition, laboratory abnormality, or psychiatric
        illness that would prevent the subject from participating in the study.

        8. Subject has any condition including the presence of laboratory abnormalities, which
        places the subject at unacceptable risk if he/she were to participate in the study.

        9. Subject has any condition that confounds the ability to interpret data from the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose/Maximum Administered Dose (MTD/MAD) (Phase 1)
Time Frame:Through 6 cycles of treatment (approximately 18 weeks or 4 months)
Safety Issue:
Description:Frequency of dose-limiting toxicities (DLTs) associated with the addition of CC-122 to R-CHOP-21 therapy

Secondary Outcome Measures

Measure:Overall Response Rate (ORR); Percentage of participants who achieve a PR or CR according to the Lugano criteria.
Time Frame:6 to 8 weeks after completion of treatment
Safety Issue:
Description:ORR is defined as the rate of the responses (including CR; see definition above for CR and PR; PR is defined as ≥ 50% decrease in sum of perpendicular diameters (SPD) of up to 6 target measurable nodes and extranodal sites. When a lesion is too small to measure on CT, assign 5 mm × 5 mm as the default value; When no longer visible, 0 × 0 mm; for a node > 5 mm × 5 mm, but smaller than normal, use actual measurement for calculation; Absent/normal, regressed, but no increase in non measurable lesions; spleen must have regressed > 50% in length beyond normal and no new lesions.
Measure:ORR by Predictive Gene Signature
Time Frame:6 to 8 weeks after completion of treatment
Safety Issue:
Description:ORR by Predictive Gene Signature is defined as the correlation between baseline gene expression signatures and clinical response to study treatment
Measure:Progression-free Survival (PFS)
Time Frame:From enrollment up to 24 months after last subject is enrolled
Safety Issue:
Description:PFS is defined as the time from enrollment to disease progression or death from any cause
Measure:Event-free Survival (EFS)
Time Frame:At 12 and 24 months after enrollment
Safety Issue:
Description:EFS is defined as the percentage of participants without event (relapse or progression, unplanned re-treatment of lymphoma after initial immunochemotherapy, or death from any cause)
Measure:Overall Survival (OS)
Time Frame:Up to 24 months after enrollment
Safety Issue:
Description:OS is defined as the time from enrollment until death from any cause
Measure:Adverse Events (AEs)
Time Frame:From enrollment until at least 28 days after completion of study treatment
Safety Issue:
Description:An 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 (ie, any clinically significant adverse change in the frequency or intensity of a pre- existing condition) should be considered an AE.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

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

Last Updated

November 29, 2017