Clinical Trials /

Obinutuzumab in Combination With Ibrutinib in Treating Patients With Relapsed Mantle Cell Lymphoma

NCT02736617

Description:

This phase II trial studies how well obinutuzumab works in combination with ibrutinib in treating patients with mantle cell lymphoma that has returned (relapsed) or that does not respond to treatment (refractory). Obinutuzumab binds to a protein called cluster of differentiation (CD)20, which is found on B cells and some types of leukemia and lymphoma cells and help the immune system kill cancer cells. Ibrutinib blocks a protein called Bruton's tyrosine kinase (BTK), which may help keep cancer cells from growing. Giving obinutuzumab in combination with ibrutinib may kill more cancer cells.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Obinutuzumab in Combination With Ibrutinib in Treating Patients With Relapsed Mantle Cell Lymphoma
  • Official Title: A Phase II Study of Obinutuzumab (GA-101) in Combination With Ibrutinib (I) for the Treatment of Relapsed Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: STUDY00015255
  • SECONDARY ID: NCI-2016-00398
  • SECONDARY ID: STUDY00015255
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT02736617

Conditions

  • Recurrent Mantle Cell Lymphoma
  • Refractory Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Treatment (obinutuzumab and ibrutinib)
ObinutuzumabAnti-CD20 Monoclonal Antibody R7159, GA-101, GA101, Gazyva, huMAB(CD20), R7159, RO 5072759Treatment (obinutuzumab and ibrutinib)

Purpose

This phase II trial studies how well obinutuzumab works in combination with ibrutinib in treating patients with mantle cell lymphoma that has returned (relapsed) or that does not respond to treatment (refractory). Obinutuzumab binds to a protein called cluster of differentiation (CD)20, which is found on B cells and some types of leukemia and lymphoma cells and help the immune system kill cancer cells. Ibrutinib blocks a protein called Bruton's tyrosine kinase (BTK), which may help keep cancer cells from growing. Giving obinutuzumab in combination with ibrutinib may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Best overall response of complete response/partial response (CR/PR).

      SECONDARY OBJECTIVES:

      I. Toxicity defined as any adverse event (AE) grade 3 and higher. II. Progression free
      survival.

      TERTIARY OBJECTIVES:

      I. Gene expression profiling using Lymph5Cx test. II. Sequencing using the ion torrent
      platform (76 gene panel for known mutations in lymphoma).

      III. Sequencing of BTK to evaluate for BTK mutations. IV. Minimal residual disease testing
      (MRD by flow cytometry and targeted sequencing post treatment).

      OUTLINE:

      Patients receive obinutuzumab intravenously (IV) over 30 minutes on days 1, 8, 15 (course 1)
      and day 1 (courses 2-6). Patients also receive ibrutinib orally (PO) once daily (QD)
      beginning on day 1 (course 1). Treatment repeats every 28 days for 6 courses in the absence
      of disease progression or unacceptable toxicity. Patients achieving partial response (PR)
      continue to receive obinutuzumab IV every 2 months and ibrutinib PO QD for up to 2 years in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6 months for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (obinutuzumab and ibrutinib)ExperimentalPatients receive obinutuzumab IV on days 1, 8, 15 and ibrutinib PO QD of first treatment course. Patients then receive obinutuzumab IV on day 1 and ibrutinib PO QD from 2-6 treatment courses. Patients who have PR continue to receive obinutuzumab IV every 2 months and ibrutinib PO QD for 2 years in the absence of disease progression or unacceptable toxicity.
  • Ibrutinib
  • Obinutuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must have a diagnosis of relapsed or refractory mantle cell lymphoma as
             follows:

               -  Diagnosis of mantle cell lymphoma (MCL) must include morphology and expression of
                  either cyclin D1 in association with other relevant markers (eg, CD19, CD20, CD5)
                  or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ
                  hybridization (FISH), or polymerase chain reaction (PCR)

               -  Relapsed or refractory disease is defined as no response or progressive disease
                  to prior treatment if the prior treatment comprised any of the following:

                    -  1 regimen containing an anti-CD20 antibody administered for >= 2 doses,
                       and/or

                    -  >= 1 regimen containing 1 cytotoxic agent (e.g., bendamustine, chlorambucil,
                       cyclophosphamide, cytarabine, doxorubicin) administered for 2 cycles

          -  At least 1 measurable site of disease according to Revised Response Criteria for
             Malignant Lymphoma (Cheson Criteria); the site of disease must be greater than 1.5 cm
             in the long axis regardless of short axis measurement or greater than 1.0 cm in the
             short axis regardless of long axis measurement, and clearly measurable in 2
             perpendicular dimensions

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Absolute neutrophil count (ANC) >= 1.0 K/cu mm; for subjects with ANC < 1.0 K/cu mm
             due to significant marrow involvement by MCL, ANC must be > .5 K/cu mm

          -  Platelets (plt) >= 50 K/cu mm; for subjects with plt < 50 K/cu mm due to significant
             marrow involvement by MCL, plt must be > 25 K/cu mm

          -  Total bilirubin =< 2.5 X institutional limits

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 X institutional upper limit of normal

          -  Creatinine < or = 2

          -  Women of childbearing potential and men who are sexually active must be practicing a
             highly effective method of birth control during and after the study consistent with
             local regulations regarding the use of birth control methods for subjects
             participating in clinical trials; men must agree to not donate sperm during and after
             the study; for females, these restrictions apply for 12 months after last dose of
             obinutuzumab, or 1 month after the last dose of ibrutinib, whichever is later; for
             males, these restrictions apply for 12 months after the last dose of obinutuzumab or 3
             months after the last dose of ibrutinib, whichever is later

          -  Women of childbearing potential must have a negative serum (beta-human chorionic
             gonadotropin [beta-hCG]) or urine pregnancy test at screening; women who are pregnant
             or breastfeeding are ineligible for this study

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Major surgery within 4 weeks of drug administration

          -  Known central nervous system lymphoma

          -  Diagnosed or treated for malignancy other than MCL, except:

               -  Malignancy treated with curative intent and with no known active disease present
                  for >= 2 years before randomization

               -  Adequately treated non-melanoma skin cancer or melanoma in situ without evidence
                  of disease

               -  Adequately treated cervical carcinoma in situ without evidence of disease

               -  Asymptomatic prostate cancer managed with "active surveillance"

          -  History of stroke or intracranial hemorrhage within 6 months prior to randomization

          -  Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg,
             phenprocoumon)

          -  Vaccinated with live, attenuated vaccines within 4 weeks of randomization

          -  Requires treatment with strong cytochrome P450 3A (CYP3A) inhibitors

          -  Subjects who have had standard cytotoxic chemotherapy or radiotherapy within 4 weeks
             prior to entering the study or those whose adverse events due to agents administered
             more than 4 weeks earlier have not recovered to =< grade 1; this excludes alopecia and
             hematologic adverse events

          -  Subjects who have received investigational or approved oral or "targeted" agents (such
             as spleen tyrosine kinase [SYK], phosphatidylinositol 3 kinase [PI3K], B-cell chronic
             lymphocytic leukemia [CLL]/lymphoma 2 [bcl-2], BTK inhibitors) or lenalidomide within
             1 week prior to entering the study or those whose adverse events due to agents
             administered more than 1 week earlier have not recovered to =< grade 1; this excludes
             hematologic adverse events

          -  Subjects who have received monoclonal antibodies (such as Rituxan) within 1 week prior
             to entering the study or those whose adverse events due to agents administered more
             than 1 week earlier have not recovered to =< grade 1; this excludes hematologic
             adverse events

          -  Subjects who are actively receiving any other investigational agents

          -  History of severe allergic reactions attributed to compounds of similar chemical or
             biologic composition as obinutuzumab or ibrutinib or other agents used in the study

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant or lactating women are excluded from this study

          -  Known history of human immunodeficiency virus (HIV) or active hepatitis C

          -  Virus or active hepatitis B virus infection; patients who are hepatitis B core
             antibody (Hep B cAb) positive may be eligible as long as there is no evidence of
             active infection with negative hepatitis B (Hep B) by polymerase chain reaction (PCR);
             in this case, Hep B PCR must be monitored monthly

          -  Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics

          -  Any life-threatening illness, medical condition, or organ system dysfunction which, in
             the investigator's opinion, could compromise the subject's safety, interfere with the
             absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue
             risk

          -  Patients previously treated with ibrutinib > 14 days are ineligible; if patient has
             been treated with ibrutinib for < 14 days, it must be discontinued 1 week (7 days)
             weeks prior to study initiation

          -  Active graft versus (vs.) host disease (gvhd)

          -  Ongoing glucocorticoids (prednisone > 10 mg daily, or equivalent); higher doses (> 10
             mg daily) are permitted for up to 5 days to help control disease related symptoms
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best overall response of CR/PR, measured from the start of treatment until disease progression/recurrence
Time Frame:Up to 5 years
Safety Issue:
Description:A point and interval estimate (95% confidence interval) will be provided.

Secondary Outcome Measures

Measure:Incidence of toxicity, defined as any adverse event grade 3 or higher, classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Progression free survival (PFS)
Time Frame:Time from the first day of combined study treatment (obinutuzumab plus ibrutinib -day 16 of course 1) to disease progression or death within 30 days of the last study drug administration, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:Kaplan-Meier method will be used to estimate PFS.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

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