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Recurrent Diffuse Large B-Cell LymphomaPhase 2NCT02874404

TGR-1202 and Ibrutinib in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

A Phase 2 study testing Ibrutinib, Laboratory Biomarker Analysis and PI3K-delta Inhibitor TGR-1202 in people with Recurrent Diffuse Large B-Cell Lymphoma and Refractory Diffuse Large B-Cell Lymphoma, run by University of Nebraska at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This phase IIa trial studies the side effects and how well TGR-1202 and ibrutinib work in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement or does not respond to treatment. Read more about this study

Who is it for?
Ages 19 years and older
What is being tested?
Ibrutinib, Laboratory Biomarker Analysis and PI3K-delta Inhibitor TGR-1202
Could I receive a placebo?
No, everyone receives an active treatment
How many people
13 participants
Where
1 siteUnited States
Study dates
7 Oct 2016to 1 Jul 2019
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 19 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically confirmed diffuse large B-cell lymphoma (DLBCL) or transformed DLBCL
  • Hematoxylin and eosin (H\&E) stain and immunohistochemistry (IHC) slides or a representative formalin-fixed, paraffin-embedded (FFPE) tissue block along with the pathology report from initial diagnosis, (as well as, an optional 8 unstained slides of 4 micron thickness to store for future IHC and DNA specified research use), should be sent to be reviewed, and the diagnosis confirmed by University of Nebraska Medical Center (UNMC) (retrospective diagnostic review: treatment may commence prior to the UNMC review); please NOTE: the diagnostic H\&E slide and IHC slides will be returned after review; only the optional 8 unstained slides will be retained and stored for future unspecified research use
  • Patients with relapsed or refractory DLBCL that has relapsed post-transplant or that has been determined to be ineligible or unsuitable for transplant; patients must have to have received at least one prior systemic therapy
  • Patients must have measurable (>= 1.5 cm) or evaluable disease; baseline measurements and evaluations must be obtained within 6 weeks of registration to the study; abnormal PET scans will not constitute evaluable disease, unless verified by CT scan or other appropriate imaging; measurable disease must have at least one objective measurable disease parameter; a clearly defined, bi-dimensionally measurable defect or mass measuring at least 1.5 cm in diameter on a CT scan will constitute measurable disease; proof of lymphoma in the liver is required by a confirmation biopsy; skin lesions can be used as measurable disease provided bi-dimensional measurements are possible
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
  • By automated or manual review, whichever is greatest
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  • Platelets >= 100 x 10^9/L:
  • Unless due to bone marrow infiltration then eligible if platelets > 50 x 10^9/L)
  • Total bilirubin =< 1.5 x upper normal limit if documented hepatic involvement with lymphoma, or =< 5 x upper normal limit if history of Gilbert's disease
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) if no liver involvement or =< 5 x the ULN if documented liver involvement
  • Creatinine =< 2.0 mg/dL OR calculated creatinine clearance >= 50 mL/min (as calculated by the Cockcroft-Gault method)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or expected survival duration of > 2 months
  • Ability to swallow and retain oral medication
  • Women must not be pregnant or breast-feeding
  • All female patients of child-bearing potential must have a negative serum pregnancy test within 2 weeks prior to treatment to rule out pregnancy
  • Pregnancy testing is not required for post-menopausal or surgically sterilized women
  • Male and female patients of reproductive potential must agree to follow accepted birth control measures throughout the study period and for 30 days after the last dose of either study drug for females and 3 months after the last dose of study drug for males
  • Patient must be able to adhere to the study visit schedule and other protocol requirements
  • Patient must be aware of the neoplastic nature of his/her disease and willingly sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study
  • No serious disease or condition that, in the opinion of the investigator, would compromise the patient's ability to participate in the study

Who cannot join

  • Currently receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, and surgery and/or tumor embolization) or any investigational drug within 7 days of cycle 1/day 1, 14 days of cycle 1/day 1 for limited palliative radiation, and/or five half-live of an oral therapy
  • Corticosteroid therapy started at least 7 days prior to initiation of treatment (prednisone =< 10 mg daily or equivalent) is allowed as clinically warranted); topical or inhaled corticosteroids are permitted
  • Major surgery or a wound that has not fully healed within 4 weeks of enrollment
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment
  • Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon)
  • Vaccinated with live, attenuated vaccines within 4 weeks of enrollment
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  • Autologous hematologic stem cell transplant within 3 months of study entry
  • Allogeneic hematologic stem cell transplant within 12 months of study entry
  • Active graft versus-host disease and must not be on immunosuppression
  • Wide field radiotherapy within 28 days of cycle 1/day 1 or active side effects of such therapy
  • Active hepatitis B (hepatitis B virus [HBV]) or C (hepatitis C virus [HCV]) infection (negative serology required excluding those with are seropositive due to prior vaccination) and/or known history of human immunodeficiency virus (HIV)
  • Primary central nervous system involvement only
  • Require treatment with strong cytochrome P450 family 3 subfamily A (CYP3A) inhibitors
  • Known history of drug-induced liver injury, alcoholic liver disease, primary biliary cirrhosis, ongoing extra-hepatic obstruction caused by stones, cirrhosis of the liver or portal hypertension
  • Any life-threatening illness, severe and/or uncontrolled medical condition, or organ system dysfunction, laboratory abnormality, psychiatric illness or other condition which, in the Investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, put the study outcomes at undue risk or affect their participation in the study such as
  • Symptomatic, or history of documented congestive heart failure New York Heart Association (NYHA) functional classification III-IV (NYHA)
  • Corrected QT interval using Fridericia's formula (QTcF) > 470 msec (unless related to pacemaker) on echocardiogram (EKG) within 7 days of initiation of treatment
  • Angina not well-controlled by medication
  • Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting within 6 months prior to enrollment
  • Prior malignancies within the past 1 year with exception of adequately treated basal cell, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer of Gleason grade 6 or less with stable prostate specific antigen (PSA) levels
  • Women who are pregnant or breastfeeding; women who agree to stop breastfeeding would be eligible
  • Known hypersensitivity to either study drug (TGR-1202 or ibrutinib)

Trial locations and contacts

1 site in 1 country.

United States1 site
  • University of Nebraska Medical Center

    Omaha, Nebraska, 68198

Other trials in United States

About this study

Official title: A Single-Center Phase IIa Study Evaluating the Safety and Tolerability of TGR-1202 and Ibrutinib in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Trial of the Lymphoma Precision Medicine Laboratory

This phase IIa trial studies the side effects and how well TGR-1202 and ibrutinib work in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement or does not respond to treatment. TGR-1202 and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the safety and tolerability of PI3K delta inhibitor TGR-1202 (TGR-1202) and ibrutinib in relapsed and refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL).

SECONDARY OBJECTIVES:

  1. To determine the overall response rate (ORR) defined as the sum of complete responses (CR) and partial responses (PR).

II. To determine the event-free survival (EFS), time to response (TTR), and duration of response (DOR) in patients with rel/ref DLBCL.

TERTIARY OBJECTIVES:

  1. To evaluate molecular profiling of patient samples (optional lymph node biopsies) obtained at days 0 (pre-treatment; core biopsy), day 8 (fine needle aspiration) and end of treatment (progressive disease or end of study treatment-1 year; core biopsy).

II. To evaluate the baseline characteristics and dynamic shifts in mutational Landscape, transcriptional signatures and intracellular signaling cascades in primary tumor cells.

III. To define the mutational status of 384 genes that mutated in DLBCL, including cluster of differentiation (CD)79B, caspase recruitment domain family member 11 (CARD11), and myeloid differentiation primary response 88 (MYD88).

IV. To evaluate signatures of B-cell receptor signaling and the back-up pathway of oxidative phosphorylation.

  1. To measure the basal and induced level of activation of components within parallel signaling pathways downstream of the B-cell receptor.

VI. To monitor changes in T-cell characteristics in response to exposure to TGR-1202 and ibrutinib.

VII. To perform quantitative response evaluation by peripheral blood cell-free deoxyribonucleic acid (DNA) sequencing at enrollment, day 8, 1 month, at every response assessment time point compared to standard radiographic response evaluation by positron emission tomography (PET)/ computed tomography (CT) or CT and end of treatment (progressive disease or end of study treatment-1 year).

VIII. To evaluate the genetic profiling for drug resistance mutations. IX. To evaluate DLBCL subtype analysis by immunohistochemistry compared to Nanostring assessment.

OUTLINE: Patients are assigned to 1 of 3 groups.

GROUP A: Patients receive PI3K delta inhibitor TGR-1202 orally (PO) once daily (QD) on days 1-28 and ibrutinib PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

GROUP B: Patients receive ibrutinib PO QD on days 1-28 and PI3K delta inhibitor TGR-1202 PO QD and days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

GROUP C: Patients then receive PI3K delta inhibitor TGR-1202 PO QD and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and after 1 year.

Being tested
Ibrutinib, Laboratory Biomarker Analysis, PI3K-delta Inhibitor TGR-1202
Medical subject headings
Lymphoma, Large B-Cell, Diffuse

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IbrutinibDrug

    Also called BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative markers

  • PI3K-delta Inhibitor TGR-1202Drug

    Also called RP5264, TGR-1202

    Given PO

Study groups in NCT02874404
Study groupRoleWhat they receive
Group A (PI3K delta inhibitor TGR-1202, ibrutinib)ExperimentalPatients receive PI3K delta inhibitor TGR-1202 PO QD on days 1-28 and ibrutinib PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Drug: PI3K-delta Inhibitor TGR-1202
Group B (Ibrutinib, PI3K delta inhibitor TGR-1202)ExperimentalPatients receive ibrutinib PO QD on days 1-28 and PI3K delta inhibitor TGR-1202 PO QD and days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Drug: PI3K-delta Inhibitor TGR-1202
Group C (PI3K delta inhibitor TGR-1202, ibrutinib)ExperimentalPatients then receive PI3K delta inhibitor TGR-1202 PO QD and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Drug: PI3K-delta Inhibitor TGR-1202

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Participants With Adverse Events

    Notable serious or recurrent adverse events (SAEs or AEs) of interest occurring across all cycles regardless of attribution assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

    Measured: Up to 112 days (course 4)

Secondary outcomes (2)
  1. Overall Response Rate (ORR)

    ORR is defined as number of patients achieving a best response of complete response or partial response at any disease assessment time point. Response is based on PET/CT (Deauville 3 or less) or CT alone if CR is achieved by PET/CT. Response criteria, modified from the Lugano response criteria. DLBCL is considered FDG avid.

    Complete response:

    Complete disappearance of all detectable clinical evidence of disease and definitely disease-related symptoms if present before therapy.

    Criteria for Partial Response (PR):

    Regression of measurable disease and no new sites

    Measured: Up to 4 years

  2. Estimated Progression-free Survival (PFS) at 6 Months

    PFS is defined as the time between study registration and documented progression or death if no progression was observed.

    Measured: Time between study registration and documented progression or death if no progression was observed, assessed up to 4 years (6 Month estimate shown)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Aug 2016 (estimated)
  2. Study start7 Oct 2016
  3. Primary completion1 Jul 2019
  4. Study completion1 Jul 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
13 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02874404
Sponsor's protocol ID
0345-16-FB
Other IDs
NCI-2016-01082, P30CA036727
Status last verified
Sep 2023
First submitted
17 Aug 2016
Last updated
5 Oct 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ibrutinib, Laboratory Biomarker Analysis and PI3K-delta Inhibitor TGR-1202 in people with Recurrent Diffuse Large B-Cell Lymphoma and Refractory Diffuse Large B-Cell Lymphoma, run by University of Nebraska at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Feb 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Participants With Adverse Events (time frame: Up to 112 days (course 4)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Oct 2023.

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