Entospletinib and Obinutuzumab in Treating Patients With Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma
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|ClinicalTrials.gov Identifier: NCT03010358|
Recruitment Status : Recruiting
First Posted : January 5, 2017
Last Update Posted : March 7, 2018
|Condition or disease||Intervention/treatment||Phase|
|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||Drug: Entospletinib Other: Laboratory Biomarker Analysis Biological: Obinutuzumab Other: Pharmacological Study||Phase 1 Phase 2|
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)
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)
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.
After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months and every 4-6 months thereafter.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||29 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||July 17, 2017|
|Estimated Primary Completion Date :||February 28, 2022|
|Estimated Study Completion Date :||February 28, 2024|
Experimental: Treatment (entospletinib, obinutuzumab)
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 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.
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
- CR defined as the proportion of subjects who achieve CR (Phase II) [ Time Frame: Up to 5 years ]The CR will be computed and presented together will the exact 95% confidence interval (CI), using the method of Clopper and Pearson. A null hypothesis of a 20% CR will be rejected if at least 7 of 17 patients achieve a CR and a treatment arm will not be considered further if this threshold is not reached.
- 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 ]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.
- 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 ]Will be summarized descriptively using the Kaplan-Meier estimate.
- Incidence of adverse events assessed by NCI CTCAE version 4.03 [ Time Frame: Up to 5 years ]Will be summarized for the safety population separately for phase 1 and phase 2 portions by dose level. All AEs will be coded by system organ class, MedDRA preferred term, and severity grade using NCI CTCAE (version 4.03).
- ORR (Phase II) [ Time Frame: Up to 5 years ]Will be summarized with 95% confidence intervals.
- Biomarkers (chromosomal abnormalities, IGHV mutational status, p53 mutational status) assessed by IgH somatic hypermutation assay version 2.0 [ Time Frame: Up to 5 years ]Will associate with response (ORR and EFS) to ENTO in combination with obinutuzumab in patients with relapsed/refractory CLL.
- Peripheral blood B-cell depletion and recovery [ Time Frame: Up to 5 years ]Will be summarized using descriptive statistics.
- Pharmacodynamics parameters of NFkappaB activation and expression of anti-apoptotic proteins in CLL cells [ Time Frame: Up to 5 years ]Pharmacokinetic parameters including peak and trough levels will be determined by noncompartmental method(s) using the pharmacokinetic profile of entospletinib and obinutuzumab.
- Predictive value of MRD assessed by flow cytometry [ Time Frame: Up to 5 years ]Will be summarized using descriptive statistics.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03010358
|United States, Arizona|
|University of Arizona Cancer Center-North Campus||Not yet recruiting|
|Tucson, Arizona, United States, 85719|
|Contact: Daniel O. Persky 520-626-2225 DPersky@uacc.arizona.edu|
|Principal Investigator: Daniel O. Persky|
|United States, North Carolina|
|Duke University Medical Center||Not yet recruiting|
|Durham, North Carolina, United States, 27710|
|Contact: Danielle M. Brander 919-684-8964 Danielle.Brander@duke.edu|
|Principal Investigator: Danielle M. Brander|
|United States, Oregon|
|OHSU Knight Cancer Institute||Recruiting|
|Portland, Oregon, United States, 97239|
|Contact: Alexey V. Danilov 503-494-8426 email@example.com|
|Principal Investigator: Alexey V. Danilov|
|Principal Investigator:||Alexey Danilov||OHSU Knight Cancer Institute|