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A Phase I/Ib Safety and Efficacy Study of the PI3K-delta Inhibitor TGR-1202 and Ibrutinib in Patients With CLL or MCL

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02268851
Recruitment Status : Active, not recruiting
First Posted : October 20, 2014
Results First Posted : June 23, 2020
Last Update Posted : March 10, 2023
Sponsor:
Collaborators:
TG Therapeutics, Inc.
The Leukemia and Lymphoma Society
Blood Cancer Research Partnership
Information provided by (Responsible Party):
Matthew S. Davids, MD, Dana-Farber Cancer Institute

Study Description
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Brief Summary:
This research study will be evaluating the safety and efficacy of a study drug called TGR-1202 in combination with a known drug ibrutinib, also known as Imbruvica, as a possible treatment for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Mantle Cell Lymphoma (MCL) that has come back or that has not responded to standard treatment.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Mantle Cell Lymphoma Drug: TGR-1202 Drug: Ibrutinib Phase 1

Detailed Description:

This research study is a Phase I and Ib combination clinical trial, which aims to both evaluate the safety of an investigational drug combination and also tries to define the appropriate dose of the investigational drug to evaluate in later clinical trials. "Investigational" means that the intervention is being studied. It also means that the FDA (U.S. Food and Drug Administration) has not approved TGR-1202 in the United States for use in MCL/CLL/SLL cancers.

TGR-1202 is a newly developed drug that may stop cancer cells from growing based on recent laboratory experiments. The results from these experiments suggest this drug may help to kill cancer cells when coupled with ibrutinib. In this research study, the safety and tolerability of TGR-1202 is being investigated to determine the highest dose that can safely be used in combination with ibrutinib. The study is also aimed to evaluate whether TGR-1202 has any effect on tumor growth (nodal response), and to determine the overall repsonse rate and duration of response in patients with CLL/SLL or MCL

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-center Phase I/Ib Study Evaluating the Efficacy and Safety of the Novel PI3k Delta Inhibitor TGR-1202 in Combination With Ibrutinib in Patients With Select B-Cell Malignancies
Study Start Date : November 2014
Actual Primary Completion Date : May 2018
Estimated Study Completion Date : October 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leukemia Lymphoma
Drug Information available for: Ibrutinib

Arms and Interventions
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Arm Intervention/treatment
Experimental: CLL

Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de-escalation.

  • Each Cycle = 28 days
  • TGR-1202 (oral): Starting on Day 1 administered daily.
  • Ibrutinib (oral): Starting on Day 1 administered daily.
 Drug: TGR-1202
Capsules taken whole daily with water and with food
Other Names:
  • RP5264
  • Umbralisib

Drug: Ibrutinib
Capsules taken whole with water- Do not consume fish oil, vitamin E, grapefruit, or Seville oranges
Other Names:
  • Imbruvica
  • CRA-032765
  • PCI-32765
Experimental: MCL

Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de-escalation.

  • Each Cycle = 28 days
  • TGR-1202 (oral): Starting on Day 1 administered daily.
  • Ibrutinib (oral): Starting on Day 1 administered daily.
 Drug: TGR-1202
Capsules taken whole daily with water and with food
Other Names:
  • RP5264
  • Umbralisib

Drug: Ibrutinib
Capsules taken whole with water- Do not consume fish oil, vitamin E, grapefruit, or Seville oranges
Other Names:
  • Imbruvica
  • CRA-032765
  • PCI-32765


Outcome Measures
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Primary Outcome Measures :
  1. Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I [ Time Frame: Participants were assessed every week or more often as needed during Cycle 1 or more often for up to 28 days to assess Dose-limiting toxicities (DLTs) during Phase I ]
    To assess the safety of TGR1202 in combination with ibrutinib relapsed or refractory CLL or MCL. DLT is based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. DLT refers to toxicities experienced at any time during the study treatment, defined as Grade 4 anemia; Grade 4 neutropenia lasting >7 days (while receiving growth factor support); Grade 4 thrombocytopenia lasting > 7 days; Grade ≥3 febrile neutropenia; and Grade ≥3 thrombocytopenia with Grade >2 hemorrhage;Grade ≥ 3 non-hematologic toxicity unresponsive to standard supportive care measure with the exception of asymptomatic Grade ≥3 lab abnormalities that resolve to ≤ Grade 1 or baseline within 7 days;treatment delay of ≥14 days due to unresolved toxicity; and non-hematologic toxicity of Grade 2 (at any time during treatment) that, in the judgment of the Investigators, Study Chair, and the Medical Monitor, is dose-limiting.


Secondary Outcome Measures :
  1. Overall Response Rate [ Time Frame: At baseline, End of Cycle 2, End of Cycle 5, End of Cycle 9, End of Cycle 14 and approximately q6 months until C26, then investigator discretion thereafter ]
    Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) by Lugano Criteria ( Cheson et al,.24) for MCL

  2. Rate of Nodal Response With Lymphocytosis (nPR) [ Time Frame: 2 years ]
  3. Rate of Progression Free Survival [ Time Frame: 2 Years ]
  4. Duration of Response [ Time Frame: 2 Years ]

Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed diagnosis of Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), or Small Lymphocytic Lymphoma (SLL)
  • Adequate organ system function ( Absolute neutrophil count, Platelets,Bilirubin, Platelets, Aspartate transferase ,Alanine aminotransferase, Creatinine Clearance)
  • Eastern Cooperative Group (ECOG) Performance status ≤ 2
  • Ability to swallow and retain oral medication
  • Female patients: must have negative serum pregnancy test at study screening/ all male partners must consent to use a medically acceptable method of contraception
  • Willingness and ability to comply with trial and follow-up procedures, and give written informed consent

Exclusion Criteria:-

  • Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization) within 3 weeks of Cycle 1/Day 1,
  • Autologous hematologic stem cell transplant within 3 months of study entry.

  • Allogeneic hematologic stem cell transplant within 12 months.

    • Post-allo patients must not have active graft versus-host disease
  • Evidence of active Hepatitis B,Hepatitis C or HIV infection.
  • Active central nervous system involvement by lymphoma
  • Requires treatment with strong CYP3A4/5 inhibitors
  • Severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study
  • QTcF >470 msec (QT interval, Fredericia calculation)
  • Angina not well-controlled by medication
  • Poorly controlled or clinically significant atherosclerotic vascular disease
  • Presence of other active cancers, or history of treatment for invasive cancer within the past 2 years.
  • Require warfarin for anticoagulation
  • Women who are pregnant or lactating
Contacts and Locations
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Information from the National Library of Medicine

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): NCT02268851


Locations
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United States, California
Pacific Cancer Care
Monterey, California, United States, 93940
United States, Connecticut
St. Francis Hospital and Cancer Center
Hartford, Connecticut, United States, 06105
United States, Maine
Eastern Maine Medical Center/ Northern Light Cancer Care
Brewer, Maine, United States, 04412
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Beth Israel Deaconness Medical Center
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Dana-Farber Cancer Institute
TG Therapeutics, Inc.
The Leukemia and Lymphoma Society
Blood Cancer Research Partnership
Investigators
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Principal Investigator: Matthew Davids, MD Dana-Farber Cancer Institute
  Study Documents (Full-Text)

Documents provided by Matthew S. Davids, MD, Dana-Farber Cancer Institute:
Study Protocol and Statistical Analysis Plan  [PDF] October 23, 2019

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Matthew S. Davids, MD, Principal Investigators, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT02268851    
Other Study ID Numbers: 14-396
TGR-IB-105 ( Other Identifier: TG Therapeutics )
First Posted: October 20, 2014    Key Record Dates
Results First Posted: June 23, 2020
Last Update Posted: March 10, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Matthew S. Davids, MD, Dana-Farber Cancer Institute:
Mantle Cell Lymphoma
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Additional relevant MeSH terms:
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Lymphoma
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
 Immunoproliferative Disorders
Immune System Diseases
Leukemia
Leukemia, B-Cell
Chronic Disease
Disease Attributes
Pathologic Processes
Lymphoma, Non-Hodgkin