NCT03010358

Brief Summary

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
24

participants targeted

Target at P25-P50 for phase_1

Timeline
Completed

Started Jul 2017

Typical duration for phase_1

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

January 3, 2017

Completed
2 days until next milestone

First Posted

Study publicly available on registry

January 5, 2017

Completed
6 months until next milestone

Study Start

First participant enrolled

July 17, 2017

Completed
3.8 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

April 29, 2021

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

April 29, 2021

Completed
2.3 years until next milestone

Results Posted

Study results publicly available

August 8, 2023

Completed
Last Updated

August 8, 2023

Status Verified

July 1, 2023

Enrollment Period

3.8 years

First QC Date

January 3, 2017

Results QC Date

April 29, 2022

Last Update Submit

July 20, 2023

Conditions

AnemiaB-Cell Prolymphocytic LeukemiaGrade 1 Follicular LymphomaGrade 2 Follicular LymphomaGrade 3a Follicular LymphomaHairy Cell LeukemiaLymphoplasmacytic LymphomaMantle Cell LymphomaMarginal Zone LymphomaRecurrent Chronic Lymphocytic LeukemiaRecurrent Small Lymphocytic LymphomaRefractory Chronic Lymphocytic LeukemiaRefractory Small Lymphocytic LymphomaRichter Syndrome

Outcome Measures

Primary Outcomes (2)

  • Maximum Tolerated Dose (MTD) of Entospletinib in Combination With Obinutuzumab

    The dose of obinutuzumab remains fixed in standard doses while the dose of entospletinib will be escalated. The starting dose of entospletinib will be 200 mg (twice-daily) and escalated to the second dose level 400 mg (twice-daily). MTD is the dose associated with a total of 6 patients treated with less than 2 dose limiting toxicities (DLT), or a total of 3 patients treated with less than 1 DLT. DLT is defined as 1) grade 3 or higher non-hematological toxicity (except grade 3 nausea, vomiting or diarrhea that was reversible within 72 hours with supportive care; grade 3 infusion-related toxicity; asymptomatic grade 3-4 laboratory abnormalities that are reversible to grade 2 or less within 72 hours; grade 3 tumor lysis syndrome or hyponatremia); 2) grade 4 neutropenia lasting \>7 days or febrile neutropenia; or 3) grade 4 thrombocytopenia/anemia or grade 3 thrombocytopenia with bleeding. The dosage follows the 3+3 traditional escalation rules.

    Up to 28 days

  • Complete Response (CR) Defined as the Percentage of Subjects Who Achieve CR

    Response for CLL/SLL measured using Modified International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 (IWCLL) guidelines. Response for hairy cell leukemia was measured using Consensus resolution: proposed criteria published in Leukemia 1987.

    Up to 45 months

Secondary Outcomes (3)

  • Objective Response Rate (ORR)

    Up to 45 months

  • Event Free Survival (EFS)

    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 45 months.

  • Number of Participants Who Experienced Adverse Events

    Up to 45 months

Other Outcomes (3)

  • Peripheral Blood B-cell Depletion and Recovery

    Up to 45 months

  • Pharmacodynamics Parameters of NFkappaB Activation and Expression of Anti-apoptotic Proteins in Chronic Lymphocytic Leukemia (CLL) Cells

    Up to 45 months

  • Biomarkers (Chromosomal Abnormalities, IGHV Mutational Status, p53 Mutational Status)

    Up to 45 months

Study Arms (1)

Treatment (entospletinib, obinutuzumab)

EXPERIMENTAL

Patients 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 cycle, and on day 1 of subsequent cycles. Treatment with obinutuzumab repeats every 28 days for up to 6 cycles and daily treatment with entospletinib continues every 28 days for up to 12 cycles in the absence of disease progression or unexpected toxicity.

Drug: EntospletinibOther: Laboratory Biomarker AnalysisBiological: ObinutuzumabOther: Pharmacological Study

Interventions

EntospletinibDRUG

Given PO

Also known as: ENTO, GS 9973, GS-9973
Treatment (entospletinib, obinutuzumab)
Laboratory Biomarker AnalysisOTHER

Correlative studies

Treatment (entospletinib, obinutuzumab)
ObinutuzumabBIOLOGICAL

Given IV

Also known as: Anti-CD20 Monoclonal Antibody R7159, GA-101, GA101, Gazyva, huMAB(CD20), R7159, RO 5072759, RO-5072759, RO5072759
Treatment (entospletinib, obinutuzumab)
Pharmacological StudyOTHER

Correlative studies

Treatment (entospletinib, obinutuzumab)

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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)
  • +16 more criteria

You may not qualify if:

  • 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
  • +10 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

OHSU Knight Cancer Institute

Portland, Oregon, 97239, United States

Location

Related Publications (3)

  • Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56. doi: 10.1182/blood-2007-06-093906. Epub 2008 Jan 23.

    PMID: 18216293BACKGROUND

  • Consensus resolution: proposed criteria for evaluation of response to treatment in hairy cell leukemia. Leukemia. 1987 Apr;1(4):405. No abstract available.

    PMID: 3669765BACKGROUND

  • Lam V, Best S, Kittai A, Orand K, Spurgeon SE, Liu T, Danilov AV. Proapoptotic and immunomodulatory effects of SYK inhibitor entospletinib in combination with obinutuzumab in patients with chronic lymphocytic leukaemia. Br J Clin Pharmacol. 2022 Feb;88(2):836-841. doi: 10.1111/bcp.14962. Epub 2021 Jul 19.

    PMID: 34196037DERIVED

MeSH Terms

Conditions

AnemiaLeukemia, Prolymphocytic, B-CellLymphoma, FollicularLeukemia, Hairy CellLymphoma, B-Cell, Marginal ZoneLymphoma, Mantle-CellLeukemia, Lymphocytic, Chronic, B-Cell

Interventions

6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amineobinutuzumab

Condition Hierarchy (Ancestors)

Hematologic DiseasesHemic and Lymphatic DiseasesLeukemia, B-CellLeukemia, LymphoidLeukemiaNeoplasms by Histologic TypeNeoplasmsLeukemia, ProlymphocyticLymphoproliferative DisordersLymphatic DiseasesImmunoproliferative DisordersImmune System DiseasesLymphoma, Non-HodgkinLymphomaLymphoma, B-CellChronic DiseaseDisease AttributesPathologic ProcessesPathological Conditions, Signs and Symptoms

Results Point of Contact

Title
Bria Thurlow
Organization
OHSU Knight Cancer Institute
thurlow@ohsu.edu
503-494-4292

Study Officials

  • Craig Okada, M.D.

    OHSU Knight Cancer Institute

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
Yes

Study Design

Study Type
interventional
Phase
phase 1
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
Adjunct Associate Professor

Study Record Dates

First Submitted

January 3, 2017

First Posted

January 5, 2017

Study Start

July 17, 2017

Primary Completion

April 29, 2021

Study Completion

April 29, 2021

Last Updated

August 8, 2023

Results First Posted

August 8, 2023

Record last verified: 2023-07

Locations

US(1)