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

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Primary Purpose

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

TGR-1202

Ibrutinib

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma focused on measuring Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Pacific Cancer Care
St. Francis Hospital and Cancer Center
Eastern Maine Medical Center/ Northern Light Cancer Care
Dana Farber Cancer Institute
Beth Israel Deaconness Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

CLL

MCL

Arm Description

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.

Outcomes

Primary Outcome Measures

Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) 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

Overall Response Rate

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

Rate of Nodal Response With Lymphocytosis (nPR)

Rate of Progression Free Survival

Duration of Response

Full Information

NCT ID

NCT02268851

First Posted

October 16, 2014

Last Updated

September 8, 2023

Sponsor

Dana-Farber Cancer Institute

Collaborators

TG Therapeutics, Inc., The Leukemia and Lymphoma Society, Blood Cancer Research Partnership

1. Study Identification

Unique Protocol Identification Number

NCT02268851

Brief Title

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

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 Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

November 2014 (undefined)

Primary Completion Date

May 2018 (Actual)

Study Completion Date

October 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Dana-Farber Cancer Institute

Collaborators

TG Therapeutics, Inc., The Leukemia and Lymphoma Society, Blood Cancer Research Partnership

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Mantle Cell Lymphoma

Keywords

Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

45 (Actual)

8. Arms, Groups, and Interventions

Arm Title

CLL

Arm Type

Experimental

Arm Description

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.

Arm Title

MCL

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

TGR-1202

Other Intervention Name(s)

RP5264, Umbralisib

Intervention Description

Capsules taken whole daily with water and with food

Intervention Type

Drug

Intervention Name(s)

Ibrutinib

Other Intervention Name(s)

Imbruvica, CRA-032765, PCI-32765

Intervention Description

Capsules taken whole with water- Do not consume fish oil, vitamin E, grapefruit, or Seville oranges

Primary Outcome Measure Information:

Title

Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I

Description

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.

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

Secondary Outcome Measure Information:

Title

Overall Response Rate

Description

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

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

Title

Rate of Nodal Response With Lymphocytosis (nPR)

Time Frame

2 years

Title

Rate of Progression Free Survival

Time Frame

2 Years

Title

Duration of Response

Time Frame

2 Years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

No

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Matthew Davids, MD

Organizational Affiliation

Dana-Farber Cancer Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

Pacific Cancer Care

City

Monterey

State/Province

California

ZIP/Postal Code

93940

Country

United States

Facility Name

St. Francis Hospital and Cancer Center

City

Hartford

State/Province

Connecticut

ZIP/Postal Code

06105

Country

United States

Facility Name

Eastern Maine Medical Center/ Northern Light Cancer Care

City

Brewer

State/Province

Maine

ZIP/Postal Code

04412

Country

United States

Facility Name

Dana Farber Cancer Institute

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Beth Israel Deaconness Medical Center

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

No

Citations:

PubMed Identifier

30558987

Citation

Davids MS, Kim HT, Nicotra A, Savell A, Francoeur K, Hellman JM, Bazemore J, Miskin HP, Sportelli P, Stampleman L, Maegawa R, Rueter J, Boruchov AM, Arnason JE, Jacobson CA, Jacobsen ED, Fisher DC, Brown JR; Blood Cancer Research Partnership of the Leukemia and Lymphoma Society. Umbralisib in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: a multicentre phase 1-1b study. Lancet Haematol. 2019 Jan;6(1):e38-e47. doi: 10.1016/S2352-3026(18)30196-0. Epub 2018 Dec 14.

Results Reference

derived

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Mantle Cell Lymphoma

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial