Clinical Trials /

Venetoclax Plus R-ICE Chemotherapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

NCT03064867

Description:

The purpose of this study is to determine the correct dose and safety of adding a new cancer drug, venetoclax, to a standard combination of chemotherapy drugs as a second treatment for relapsed/refractory DLBCL. In this study, venetoclax will be added to RICE (rituximab, ifosfamide, carboplatin, etoposide), a common set to cancer drugs used as a second line treatment for relapsed/refractory DLBCL. Venetoclax, is a new targeted anti-cancer drug, which works by mimicking a particular protein produced by the tumor and interrupting its normal processes, ultimately causing the tumor cells to die. Adding venetoclax to the standard RICE regimen is believed to increase the chance of getting cancer into remission. Venetoclax is experimental because it is not approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory DLBCL. Venetoclax has been FDA approved for use in patients with chronic lymphocytic leukemia (CLL).

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax Plus R-ICE Chemotherapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma
  • Official Title: Phase I Trial of Venetoclax in Combination With R-ICE (V+RICE) Chemotherapy for Relapsed/Refractory Diffuse Large B-cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: CASE2415
  • NCT ID: NCT03064867

Conditions

  • Diffuse Large B-cell-lymphoma

Interventions

DrugSynonymsArms
VenetoclaxVenetoclax + RICE
RICEVenetoclax + RICE

Purpose

The purpose of this study is to determine the correct dose and safety of adding a new cancer drug, venetoclax, to a standard combination of chemotherapy drugs as a second treatment for relapsed/refractory DLBCL. In this study, venetoclax will be added to RICE (rituximab, ifosfamide, carboplatin, etoposide), a common set to cancer drugs used as a second line treatment for relapsed/refractory DLBCL. Venetoclax, is a new targeted anti-cancer drug, which works by mimicking a particular protein produced by the tumor and interrupting its normal processes, ultimately causing the tumor cells to die. Adding venetoclax to the standard RICE regimen is believed to increase the chance of getting cancer into remission. Venetoclax is experimental because it is not approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory DLBCL. Venetoclax has been FDA approved for use in patients with chronic lymphocytic leukemia (CLL).

Detailed Description

      Primary Objective:

      Establishment of safety of V+RICE in order to identify the recommended Phase II dose (RPD2)

      Secondary Objectives:

        1. Determine the overall response rate (ORR) of V+RICE relative to historical controls of
           RICE alone in r/r DLBCL.

        2. Determine the percent of patients who proceed to autologous stem cell transplantation
           after V+RICE relative to historical controls.

        3. Describe the progression-free survival (PFS) and overall survival (OS) for patients
           treated with V + RICE who do and do not proceed to auto-Stem Cell Transplant, relative
           to historical controls.

        4. Measure total number of peripheral blood stem cells collected in patients treated with
           V + RICE who proceed to stem cell mobilization/harvesting, compared to historical
           controls.
    

Trial Arms

NameTypeDescriptionInterventions
Venetoclax + RICEExperimentalVenetoclax with rituximab, ifosfamide, carboplatin, and etoposide
  • Venetoclax
  • RICE

Eligibility Criteria

        Inclusion Criteria:

          -  Histological confirmation of relapsed/refractory diffuse large B-cell lymphoma after
             prior rituximab and anthracycline-containing systemic treatment regimen such as
             R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone),
             R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate,
             cyclophosphamide, doxorubicin hydrochloride), R-HyperCVAD (rituximab,
             cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone) etc.

          -  Subjects must have received no more than 2 prior systemic therapies for lymphoma.
             Prior therapy with systemic rituximab monotherapy or conventional chemotherapy (i.e.
             bendamustine, CVP (Cyclophosphamide, Vincristine Sulfate, Prednisone) or other) ±
             rituximab for indolent non-Hodgkin's lymphoma (NHL) ± maintenance/extended-use
             rituximab will count as 1 line of systemic therapy.

          -  Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2

          -  Subjects must have normal organ and marrow function as defined below:

               -  Hemoglobin ≥ 8.0 g/dl

               -  Absolute neutrophil count ≥ 1,000/mcL

               -  Platelet count ≥ 75,000/mcL

               -  Total bilirubin ≤ 1.5 X the upper limit of normal (ULN) unless a known history
                  of impaired bilirubin conjugation such as Gilbert's, for whom the maximum will
                  be 2.5 ULN.

               -  Aspartate transaminase (AST) (SGOT) ≤ 2.5 X institutional ULN

               -  Alanine transaminase (ALT) (SGPT) ≤ 2.5 X institutional ULN

               -  International normalized ratio (INR) > 1.5 ×ULN

               -  Patients must have a calculated serum creatinine clearance > 50 mL/min using
                  Cockcroft-Gault calculation or based on 24-hour urine collection performed
                  within 7 days prior to treatment.

          -  Specific guidelines will be followed regarding inclusion of relapsed/refractory DLBCL
             based on Hepatitis B serological testing as follow:

               -  HBsAg negative, HBcAb negative, HBsAb positive patients are eligible.

               -  Patients who test positive for HBsAg are ineligible

               -  Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status)
                  should have a HBV DNA testing performed and protocol eligibility determined as
                  follow:

                    -  If HBV DNA is positive, the subject is ineligible.

                    -  If HBV DNA is negative, the subject may be included but must undergo HBV
                       DNA PCR testing monthly x 3 months beginning from the start of treatment

          -  Subjects must have the ability to understand and the willingness to sign a written
             informed consent document.

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
             per year during the treatment period and for at least 30 days after the last dose of
             venetoclax or 18 months after the last dose of rituximab, whichever is longer.

        A woman is considered to be of childbearing potential if she is postmenarcheal, has not
        reached a postmenopausal state (< 12 continuous months of amenorrhea with no identified
        cause other than menopause), and has not undergone surgical sterilization (removal of
        ovaries and/or uterus).

          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive measures, and agreement to refrain from donating sperm, as defined
             below:

        With female partners of childbearing potential, men must remain abstinent or use a condom
        plus an additional contraceptive method that together result in a failure rate of < 1% per
        year during the treatment period and for at least 6 months after the last dose of
        rituximab. Men must refrain from donating sperm during this same period.

        With pregnant female partners, men must remain abstinent or use a condom during the
        treatment period and for at least 6 months after the last dose of rituximab to avoid
        exposing the embryo.

        Exclusion Criteria:

          -  Prior treatment toxicities have not resolved to < Grade 2 according to NCI CTCAE
             Version 4.0 (except clinically insignificant toxicities such as alopecia).

          -  Subjects receiving any other investigational agents.

          -  Patients with active tumor lysis syndrome (TLS) either from laboratory or clinical
             changes.

          -  Patients with active central nervous system (CNS) disease defined as symptomatic
             meningeal lymphoma or known CNS parenchymal lymphoma.

          -  History of severe allergic reactions attributed to compounds of similar chemical or
             biologic composition to rituximab or other agents used in this study.

          -  Subjects with uncontrolled intercurrent illness .

          -  HIV-positive subjects on combination antiretroviral therapy are ineligible because of
             the potential for pharmacokinetic interactions with Venetoclax. In addition, these
             subjects are at increased risk of lethal infections when treated with marrow
             suppressive therapy. Appropriate studies will be undertaken in subjects receiving
             combination antiretroviral therapy when indicated. HIV testing prior to enrollment is
             not required for screening but strongly encouraged for patients with no documented
             prior HIV assessment.

          -  Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface
             antigen (HBsAg), or hepatitis C (HCV) antibody.

               -  Patients who are positive for HCV antibody must be negative for HCV by
                  polymerase chain reaction (PCR) to be eligible for study participation

               -  Patients with occult or prior HBV infection (defined as positive total hepatitis
                  B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is
                  undetectable. These patients must be willing to undergo monthly DNA testing.

          -  Women who are pregnant or lactating

          -  Malabsorption syndrome or other condition that precludes enteral route of
             administration

          -  Chemotherapy or radiation within 3 weeks of the first scheduled study treatment.

          -  Less than 2-year disease free from another primary malignancy (other than squamous or
             basal cell carcinoma of the skin, "in-situ" carcinoma of the cervix or breast,
             superficial bladder carcinoma, or previously treated localized prostate cancer with
             normal prostate specific antigen (PSA) levels). Patients who have had completed all
             anti-cancer treatment for another primary malignancy more than 2 years prior to
             screening are eligible if they are not considered to have a "currently active"
             malignancy based on having less than a 30% risk of relapse.

          -  Major surgery, other than diagnostic surgery, within 2 weeks.

          -  Medical condition requiring chronic use of high dose systemic corticosteroids (i.e.,
             doses of prednisone higher than 10 mg/day or equivalent). Brief (<15 days) treatment
             with glucocorticoids (prednisone 100 mg by mouth daily, or equivalent) is acceptable.

          -  Known allergy to both xanthine oxidase inhibitors and rasburicase.

          -  Use of warfarin is prohibited. Anticoagulation with low-molecular weight heparin
             (i.e. enoxaparin) or direct thrombin inhibitors is permitted.

          -  The following concomitant medications are not allowed from 7 days prior to the first
             dose of study drug and during venetoclax administration: Strong CYP3A4 inhibitors
             including but not limited to fluconazole, ketoconazole, and clarithromycin or strong
             CYP3A4 inducers included but not limited to rifampin, carbamazepine.

          -  Receipt of live-virus vaccines within 28 days prior to the initiation of study
             treatment or need for live-virus vaccines at any time during study treatment.

          -  Concomitant medications that fall into the categories below could potentially lead to
             adverse reactions and should be considered cautionary.

               -  Moderate/Weak CYP3A inducers such as efavirenz and oxcarbazepine

               -  CYP2C8 substrates such as thiazolidinediones (glitazones) and select statins
                  (because of expected inhibition of the metabolism of CYP2C8 substrates) by
                  venetoclax

               -  CYP2C9 substrates such as tolbutamide (because of expected inhibition of the
                  metabolism of CYP2C9 substrates by venetoclax. It is recommended to exclude
                  CYP2C9 substrates with a narrow therapeutic index such as phenytoin.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase II Dose
Time Frame:Up to 12 weeks
Safety Issue:
Description:A maximum of 18 patients can theoretically participate in the initial dose escalation with Retinoic and Lithium, based on 4 dose levels with a maximum of 6 patients at each dose level. At a true dose limiting toxicity rate of 20%, the chance of escalating to the next dose level is 71% and of establishing the lower dose level as maximum tolerated dose is 29%.

Secondary Outcome Measures

Measure:Overall Response Rate
Time Frame:Up to 12 weeks
Safety Issue:
Description:number of patients with complete response or partial response as document in a positron emission tomography/ computerized tomography (PET/CT) scan and defined by the Revised Response Criteria for Malignant Lymphoma
Measure:Proportion of Patients Proceeding to Autologous Stem Cell Transplant
Time Frame:Up to 12 weeks
Safety Issue:
Description:the number of patients with Autologous Stem Cell Transplant divided by the total number of patients
Measure:Progression Free Survival
Time Frame:Up to 12 weeks
Safety Issue:
Description:Average time disease did not progress as based on the Revised Response Criteria for Malignant Lymphoma up to 12 weeks
Measure:Overall Survival
Time Frame:Up to 12 weeks
Safety Issue:
Description:Average time participants are alive from starting treatment to death or 12 weeks, whichever comes first
Measure:Number of Peripheral Blood Stem Cells Collected
Time Frame:Up to 12 weeks
Safety Issue:
Description:Estimated through measurement of CD34+ cells/kg
Measure:Median Number of cluster of differentiation 34 (CD34+) Cells/kg
Time Frame:Up to 12 weeks
Safety Issue:
Description:Median value of CD34+ in cells/kg collected from patients

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Paolo Caimi, MD

Trial Keywords

  • venetoclax
  • rituximab
  • ifosfamide
  • carboplatin
  • etoposide

Last Updated

February 22, 2017