Clinical Trials /

Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma

NCT03010358

Description:

This phase I/II trial studies the side effect and best dose of entospletinib when giving together with obinutuzumab and to see how well they work in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or non-Hodgkin lymphoma that has come back. Entospletinib may stop the growth of cancer cells by blocking some of the enzymes need for cell growth. Monoclonal antibodies, such as obinutuzumab, may interfere with the ability of cancer cells to grow and spread. Giving entospletinib and obinutuzumab together may work better in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or non-Hodgkin lymphoma.

Related Conditions:
  • B-Cell Prolymphocytic Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Follicular Lymphoma
  • Hairy Cell Leukemia
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Richter Syndrome
  • Small Lymphocytic Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma
  • Official Title: A Phase I/II Study of Syk Inhibitor Entospletinib (GS-9973) in Combination With Obinutuzumab in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and B-Cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: STUDY00016140
  • SECONDARY ID: NCI-2016-02029
  • SECONDARY ID: STUDY00016140
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT03010358

Conditions

  • Anemia
  • B-Cell Prolymphocytic Leukemia
  • Fatigue
  • Fever
  • Grade 1 Follicular Lymphoma
  • Grade 2 Follicular Lymphoma
  • Grade 3a Follicular Lymphoma
  • Hairy Cell Leukemia
  • Lymphadenopathy
  • Lymphocytosis
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Night Sweats
  • Recurrent Chronic Lymphocytic Leukemia
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Small Lymphocytic Lymphoma
  • Richter Syndrome
  • Splenomegaly
  • Thrombocytopenia
  • Weight Loss

Interventions

DrugSynonymsArms
EntospletinibENTO, GS 9973, GS-9973Treatment (entospletinib, obinutuzumab)
ObinutuzumabAnti-CD20 Monoclonal Antibody R7159, GA-101, GA101, Gazyva, huMAB(CD20), R7159, RO 5072759Treatment (entospletinib, obinutuzumab)

Purpose

This phase I/II trial studies the side effect and best dose of entospletinib when giving together with obinutuzumab and to see how well they work in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or non-Hodgkin lymphoma that has come back. Entospletinib may stop the growth of cancer cells by blocking some of the enzymes need for cell growth. Monoclonal antibodies, such as obinutuzumab, may interfere with the ability of cancer cells to grow and spread. Giving entospletinib and obinutuzumab together may work better in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or non-Hodgkin lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of entospletinib administered in combination with
      obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia/small
      lymphocytic lymphoma (CLL/SLL) and non-Hodgkin lymphoma (NHL), and identify the dose for
      phase 2 expansion. (Phase I) II. To evaluate the efficacy of entospletinib in combination
      with obinutuzumab in patients with relapsed or refractory CLL/SLL, as measured by complete
      response (CR) rate. (Phase II)

      SECONDARY OBJECTIVES:

      I. Objective response rate (ORR, defined as complete remission, complete response with
      incomplete marrow recovery, partial remission and nodular partial response). (Phase II) II.
      Event free survival defined as the interval between the date of first study treatment and the
      date of objective signs of disease recurrence, subsequent anti-leukemic therapy, or death,
      whichever is first reported. (Phase II) III. Safety and tolerability of entospletinib in
      combination with obinutuzumab by adverse events (AEs). (Phase II)

      TERTIARY OBJECTIVES:

      I. Peripheral blood B-cell depletion and recovery. II. Preliminary assessment of the
      predictive value of minimal residual disease (MRD).

      III. Pharmacodynamics effects of in vivo administration of entospletinib on NFkappaB
      activation and expression of anti-apoptotic proteins in CLL cells.

      IV. Association of established biomarkers (chromosomal abnormalities, immunoglobulin heavy
      chain [IGHV] mutational status, p53 mutational status) with response (ORR and event-free
      survival [EFS]) to entospletinib (ENTO) in combination with obinutuzumab in patients with
      relapsed/refractory CLL.

      OUTLINE: This is a phase I, dose-escalation study of entospletinib followed by a phase II
      study.

      Patients receive entospletinib orally (PO) either once a day (QD) or twice a day (BID) on
      days -7 to -1 (run-in phase) depending on the assigned dose level. Patients also receive
      obinutuzumab intravenously (IV) on days 1, 2, 8, and 15 of the first course and on day 1 of
      all subsequent courses. Treatment with obinutuzumab repeats every 28 days for up to 6 courses
      and daily treatment with entospletinib continues every 28 days for up to 12 courses in the
      absence of disease progression or unexpected toxicity. Patients who do not receive MRD may
      continue receive entospletinib beyond 12 courses with approval from the treating physician
      and sponsor-investigator in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 12 months
      then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (entospletinib, obinutuzumab)ExperimentalPatients receive entospletinib PO either QD or BID on days -7 to -1 (run-in phase) depending on the assigned dose level. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of the first course, and on day 1 of subsequent courses. Treatment with obinutuzumab repeats every 28 days for up to 6 courses and daily treatment with entospletinib continues every 28 days for up to 12 courses in the absence of disease progression or unexpected toxicity. Patients who do not receive MRD may continue receive entospletinib beyond 12 courses with approval from the treating physician and sponsor-investigator in the absence of disease progression or unacceptable toxicity.
  • Entospletinib
  • Obinutuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Phase I portion of the study: Histologically or flow cytometry confirmed diagnosis of
             B-CLL/SLL according to National Cancer Institute (NCI)-Working Group (WG) 1996
             guidelines

          -  Phase I portion of the study: The following types of NHL as documented by medical
             records and with histology based on criteria established by the World Health
             Organization (WHO):

               -  Mantle cell lymphoma (MCL)

               -  Follicular lymphoma (FL) - grades 1-3a

               -  Lymphoplasmacytic lymphoma (LPL)

               -  Marginal zone lymphoma (MZL)

               -  CLL in Richter's transformation

               -  B-cell prolymphocytic leukemia

          -  Phase I portion of the study: Patients with histologically confirmed classical hairy
             cell leukemia (HCL)

          -  Phase II portion of the study - histologically or flow cytometry confirmed diagnosis
             of BCLL/SLL according to NCI-WG 1996 guidelines; patients who lack CD23 expression on
             their leukemia cells should be examined for (and found NOT to have) either t(11;14) or
             cyclin D1 overexpression, to rule out mantle cell lymphoma

          -  Patients underwent >= 1 prior chemotherapy-based or immunotherapy-based regimen or
             targeted therapy (e.g., inhibitors of BTK, PI3K etc.) administered for >= 2 cycles,
             and have had either documented disease progression or no response (stable disease) to
             the most recent treatment regimen

          -  Patients with CLL/SLL must demonstrate active disease meeting at least 1 of the
             International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for
             requiring treatment:

               -  A minimum of any one of the following constitutional symptoms:

                    -  Unintentional weight loss > 10% within the previous 6 months prior to
                       screening

                    -  Extreme fatigue (unable to work or perform usual activities)

                    -  Fevers of greater than 100.5 Fahrenheit (F) for >= 2 weeks without evidence
                       of infection

                    -  Night sweats without evidence of infection

               -  Evidence of progressive marrow failure as manifested by the development of, or
                  worsening of anemia or thrombocytopenia

               -  Massive (i.e., > 6 cm below the left costal margin), progressive or symptomatic
                  splenomegaly

               -  Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive
                  lymphadenopathy

               -  Progressive lymphocytosis with an increase of > 50% over a 2-month period, or an
                  anticipated doubling time of less than 6 months

               -  Autoimmune anemia or thrombocytopenia that is poorly responsive to
                  corticosteroids

          -  Patients with HCL must be intolerant of or not candidates for purine analog-based
             therapy, or failed to achieve response (CR or partial response [PR]) or relapsed
             within 2 years of such therapy, AND meet the standard treatment initiation criteria
             (absolute neutrophil count [ANC] =< 1000/uL, hemoglobin [Hgb] =< 10 g/dL, platelet
             count =< 100,000/uL); patients with indolent lymphoma (FL, LPL, MZL) and patients with
             B-cell prolymphocytic leukemia must have an indication for treatment in the opinion of
             the investigator; patients with MCL and patients with CLL in Richter's transformation
             should have previously received or not be candidates for high dose
             chemotherapy/autologous stem cell transplant

          -  For diseases other than CLL, LPL, and HCL, presence of radiographically measurable
             lymphadenopathy or extra-nodal lymphoid malignancy (defined as the presence of >= 1
             lesion that measures >= 2.0 cm in the longest dimension [LD] and >= 1.0 cm in the
             longest perpendicular dimension [LPD] as assessed by computed tomography [CT] or
             magnetic resonance imaging [MRI]); for LPL, measureable disease will be defined as
             serum monoclonal IgM > 0.5 g/dL or meeting at least 1 of the recommendations from the
             Second International Workshop on LPL for requiring treatment

          -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Direct bilirubin =< 2 X institutional upper limit of normal (ULN) (unless due to known
             Gilbert's syndrome or compensated hemolysis directly attributable to CLL)

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) less than 2.5 X
             institutional ULN

          -  Estimated creatinine clearance (CrCL) using the Cockcroft-Gault equation >= 50 mL/min

          -  Platelets >= 50,000/mm^3 independent of transfusion support, with no active bleeding

          -  Absolute neutrophil count (ANC) >= 1000/mm^3, unless due to disease involvement in the
             bone marrow

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

        Exclusion Criteria:

          -  Prior therapeutic intervention with any of the following:

               -  Therapeutic anticancer antibodies within 4 weeks (rituximab), except within 6
                  months for obinutuzumab or a similar investigational type II monoclonal antibody;

               -  Radio- or toxin-immunoconjugates within 10 weeks;

               -  Inhibitors of BTK (ibrutinib), PI-3K (idelalisib), BH3-mimetic venetoclax,
                  lenalidomide and other "targeted" therapy (including but not limited to
                  investigational BTK and PI-3K inhibitors, etc.) - within 6 half-lives (i.e., 36
                  hours for ibrutinib)

               -  All other chemotherapy, radiation therapy within 3 weeks prior to initiation of
                  therapy

               -  SYK inhibitors at any time

          -  Inadequate recovery from adverse events related to prior therapy to grade =< 1
             (excluding grade 2 alopecia and neuropathy)

          -  Chronic use of corticosteroids in excess of prednisone 30 mg/day or its equivalent

          -  Stem cell transplant recipients must have no evidence of and not receive treatment for
             graft-versus-host disease

          -  Concomitant use or use in the prior two weeks of moderate or strong CYP3A and CYP2C9
             inducers or strong CYP2C9 inhibitors, including nutraceutical preparations, e.g.,
             grapefruit juice and St John's wort

          -  History prior malignancy except:

               -  Malignancy treated with curative intent and no known active disease present for
                  >= 2 years prior to initiation of therapy on current study

               -  Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ)
                  without evidence of disease

               -  Adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without
                  evidence of disease

               -  Asymptomatic prostate cancer managed with "watch and wait" strategy

               -  Myelodysplastic syndrome which is clinically well controlled and no evidence of
                  the cytogenetic abnormalities characteristic of myelodysplasia on the bone marrow
                  at screening

          -  Uncontrolled immune hemolysis or thrombocytopenia (positive direct antiglobulin test
             in absence of hemolysis or history of immune-mediated cytopenias are not exclusions)

          -  History of human immunodeficiency virus (HIV) infection or active hepatitis B or C

          -  Major surgery (requiring general anesthesia) within 2 weeks prior to initiation of
             therapy

          -  Inability to swallow and retain an oral medication; patients with clinically
             significant medical condition of malabsorption, inflammatory bowel disease, chronic
             conditions which manifest with diarrhea, refractory nausea, vomiting or any other
             condition that will interfere significantly with drug absorption are excluded;
             patients must also have adequate venous access

          -  Need for ongoing therapy with proton pump inhibitors; H2 antagonists are allowed

          -  Active uncontrolled infection

          -  Women who are pregnant or lactating

          -  Fertile men or women of childbearing potential unless 1) permanently sterile or 2)
             using a highly effective measure of contraception such as condoms in males and
             consistent and correct use of one of the following in females: intrauterine device,
             tubal sterilization, Essure micro-insert system, vasectomy in the male partner;
             effective contraception is required for males during treatment with study drug and to
             continue for 3 months after the last dose of either entospletinib or obinutuzumab,
             whichever is later; for women, effective contraception is required to continue for >=
             12 months after the last dose of obinutuzumab or for 30 days after the last dose of
             entospletinib, whichever is later; for men, effective contraception is required to
             continue for 3 months after the last dose of obinutuzumab treatment

               -  Definition of childbearing potential: for this study, a female subject is
                  considered of childbearing potential until becoming post-menopausal unless
                  permanently sterile or with medically documented ovarian failure; women are
                  considered to be in a postmenopausal state when >= 54 years of age with cessation
                  of previously occurring menses for >= 12 months without an alternative cause;
                  women of any age with amenorrhea of >= 12 months may also be considered
                  post-menopausal if their follicle stimulating hormone (FSH) level is in the
                  post-menopausal range and they are not using hormonal contraception or hormonal
                  replacement therapy; permanent sterilization in females includes hysterectomy,
                  bilateral oophorectomy, or bilateral salpingectomy in a female subject of any
                  age; permanent sterilization in males include bilateral orchiectomy or medical
                  documentation of alternative explanation

          -  Any condition for which participation in the study is judged by the Investigator to be
             detrimental to the patient with inter-current illness or psychiatric/social situations
             that would jeopardize compliance with study requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) and/or a recommended phase II dose as measured by the incidence of dose limiting toxicities assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:All adverse events will be tabulated and summarized by major organ category, grade, anticipation, and drug attribution. Severe adverse event specific incidence and exact 95% confidence interval will be provided where appropriate.

Secondary Outcome Measures

Measure:Objective response rate (ORR) (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:Will be summarized with 95% confidence intervals.
Measure:Event free survival (Phase II)
Time Frame:The interval between the date of first study treatment and the date of objective signs of disease recurrence, subsequent anti leukemic therapy, or death, whichever is first reported, assessed up to 5 years
Safety Issue:
Description:Will be summarized descriptively using the Kaplan-Meier estimate.
Measure:Incidence of adverse events assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Time Frame:Up to 5 years
Safety Issue:
Description:Will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All adverse events (AEs) will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (version 4.03).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

Last Updated

September 28, 2018