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

Phase 1

Completed

• Conditions: Mantle Cell Lymphoma; Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
• Interventions: Drug: TGR-1202; Drug: Ibrutinib

• Registration Number: NCT02268851
• Lead Sponsor: Dana-Farber Cancer Institute

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

Study Timeline

• Study First Submitted: 2014-10-16
• Study First Submitted QC: 2014-10-16
• Study First Posted: 2014-10-20
• Study Start: 2014-11
• Primary Completion: 2018-05
• Results First Submitted: 2020-05-12
• Results First Submitted QC: 2020-06-10
• Results First Posted: 2020-06-23
• Study Completion: 2022-10
• Status Verified: 2024-09
• Last Update Submitted: 2024-09-11
• Last Update Posted: 2024-11-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 45

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
CLL	TGR-1202	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.
MCL	TGR-1202	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.
CLL	Ibrutinib	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.
MCL	Ibrutinib	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.

Primary Outcome Measures

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

Name	Time	Method
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	The overall response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) by Lugano Criteria ( Cheson et al,.24) for MCL.
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	nPR will only be evaluated in CLL patients, defined as percentage of patients achieved nodal PR. As per Cheson et al., 2012, patients who achieve a radiographic PR but continue to have a lymphocytosis with \>5,000 B-lymphocytes per μL are considered to have a nodular partial response, also known as PR with lymphocytosis, due to the fact that they appear to derive a similar clinical benefit from BCR inhibitors as patients who achieve a traditional PR.
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.	Progression-free survival based on the Kaplan-Meier method is defined as the duration between randomization and documented disease progression (PD) or death, or is censored at time of last dsease assessment.
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.	Duration of Overall Response (DOR), estimated using the Kaplan Meier method, is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) per 2008 IWCLL Criteria, until the first date that recurrent or progressive disease is objectively documented. Patients without progressive disease are censored at the date of last disease assessment.

Trial Locations

Locations (5)

Pacific Cancer Care; 🇺🇸 Monterey, California, United States

St. Francis Hospital and Cancer Center; 🇺🇸 Hartford, Connecticut, United States

Beth Israel Deaconness Medical Center; 🇺🇸 Boston, Massachusetts, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Eastern Maine Medical Center/ Northern Light Cancer Care; 🇺🇸 Brewer, Maine, United States