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 : Completed
First Posted : January 5, 2017
Last Update Posted : May 4, 2021
|Condition or disease||Intervention/treatment||Phase|
|Anemia B-Cell Prolymphocytic Leukemia Grade 1 Follicular Lymphoma Grade 2 Follicular Lymphoma Grade 3a Follicular Lymphoma Hairy Cell Leukemia Lymphoplasmacytic Lymphoma Mantle Cell Lymphoma Marginal Zone Lymphoma Recurrent Chronic Lymphocytic Leukemia Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia Refractory Small Lymphocytic Lymphoma Richter Syndrome||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. Pharmacodynamics effects of in vivo administration of entospletinib on NFkappaB activation and expression of anti-apoptotic proteins in CLL cells.
III. 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 cycle and on day 1 of all 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.
After completion of study treatment, patients are followed up every 3 months for 12 months then every 6 months thereafter. In the event of study closure, patients who are receiving study drug at the time of closure will complete an abbreviated End of Treatment (EOT) visit. No additional follow up will occur.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||24 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|
|Actual Primary Completion Date :||April 29, 2021|
|Actual Study Completion Date :||April 29, 2021|
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 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.
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
- Maximum tolerated dose (MTD) and/or a recommended phase II dose (Phase I) [ Time Frame: Up to 28 days ]Will be measured by the incidence of dose limiting toxicities assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 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.
- Complete response (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.
- Objective response rate (ORR) (Phase II) [ Time Frame: Up to 5 years ]Will be summarized with 95% confidence intervals.
- Event free survival (EFS) (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. EFS will be censored if entospletinib is discontinued for other reasons (such as drug is no longer available).
- Incidence of adverse events [ Time Frame: Up to 5 years ]Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 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, Medical Dictionary for Regulatory Activities (MedDRA) preferred term, and severity grade using NCI CTCAE (version 4.03).
- 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 chronic lymphocytic leukemia (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.
- Biomarkers (chromosomal abnormalities, IGHV mutational status, p53 mutational status) [ Time Frame: Up to 5 years ]Will be assessed by IgH somatic hypermutation assay version 2.0. Will associate with response (ORR and EFS) to entospletinib (ENTO) in combination with obinutuzumab in patients with relapsed/refractory CLL.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03010358
|United States, Oregon|
|OHSU Knight Cancer Institute|
|Portland, Oregon, United States, 97239|
|Principal Investigator:||Craig Okada, M.D.||OHSU Knight Cancer Institute|