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

NCT02268851 | Completed Phase 1 Results DMC

• 2 other identifiers: 14-396TGR-IB-105
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 5

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.

Conditions

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Mantle Cell Lymphoma

Keywords

Mantle Cell Lymphoma; Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Outcome Measures

Primary Outcomes (1)

• 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.

  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 Outcomes (4)

• Overall Response Rate (ORR)

  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

• Rate of Nodal Partial Response With Lymphocytosis (nPR)

  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

• Median Progression-Free Survival (PFS)

  Disease will be evaluated at baseline, cycle 1 day 1,8,15,22 and cycle 2 day 1,15, and cycle 3-6 on day1, and every 2 cycles until cycle 12, then every 3 cycles thereafter. In long-term follow-up, survival will be followed every 3 cycles up to 2 years.

• Median Duration of Overall Response (DOR)

  Disease response will be evaluated at baseline, cycle 1 day 1,8,15,22 and cycle 2 day 1,15, and cycle 3-6 on day1, and every 2 cycles until cycle 12, then every 3 cycles thereafter.

Study Arms (2)

CLL

EXPERIMENTAL

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; Drug: Ibrutinib

MCL

EXPERIMENTAL

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; Drug: Ibrutinib

Interventions

TGR-1202 DRUG

Capsules taken whole daily with water and with food

Also known as: RP5264, Umbralisib

CLL; MCL

Ibrutinib DRUG

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

Also known as: Imbruvica, CRA-032765, PCI-32765

CLL; MCL

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• TG Therapeutics, Inc.: collaborator
• The Leukemia and Lymphoma Society: collaborator
• Blood Cancer Research Partnership: collaborator

Study Sites (5)

Pacific Cancer Care

Monterey, California, 93940, United States

Location

St. Francis Hospital and Cancer Center

Hartford, Connecticut, 06105, United States

Location

Eastern Maine Medical Center/ Northern Light Cancer Care

Brewer, Maine, 04412, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconness Medical Center

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• 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.

  PMID: 30558987 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell

Interventions

umbralisib; ibrutinib

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma, Non-Hodgkin; Lymphoma

Results Point of Contact

• Title: Matthew Davids, MD, MMSc
• Organization: Dana-Farber Cancer Institute

matthew_davids@dfci.harvard.edu

617-632-6331

Study Officials

• Matthew Davids, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigators

Study Record Dates

• First Submitted: October 16, 2014
• First Posted: October 20, 2014
• Study Start: November 1, 2014
• Primary Completion: May 1, 2018
• Study Completion: October 1, 2022
• Last Updated: November 15, 2024
• Results First Posted: June 23, 2020

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)