Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

NCT00978432 | Terminated Phase 2 Results

• 1 other identifier: Pro00012947
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is evaluate the response, safety and tolerability in subjects receiving the investigational drugs, RAD001 and LBH589. Subjects in Part 1 will receive one drug for four cycles followed by 4 cycles of the second drug unless they achieve complete remission. Subjects in a complete remission may receive up to 6 cycles of study drug and will not receive the next study drug until there is evidence of disease progression. Subjects in Part 2 will receive both drugs together for at least 2 cycles and up to 13 if tolerated.

Conditions

Diffuse Large B-cell Lymphoma

Keywords

NHL; DLBCL; recurrent; refractory; de novo

Outcome Measures

Primary Outcomes (2)

• Overall Response Rate

  Overall Response Rate is the number of participants with a partial and complete response assessed by the Updated Cheson criteria for lymphoma. A complete response is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy and normalization of those biochemical abnormalities. If a subject has residual lesions on CT scan and the disease was fluorodeoxyglucose (FDG) avid pre-treatment, then that subject will be considered to be in a complete response. Partial response is a greater than or equal to 50% decrease in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease

  after 2 cycles of each study drug or after 2 cycles of doublet, up to 24 weeks

• Assessment of Association Between Observed Response to RAD001 and LBH589 and the Response Predicted by Molecular Signatures Developed in Our Pre-clinical Model

  We will estimate the association of the molecular signature-predicted response to the doublet (CR+PR) with the observed response. All evaluable patients will be used in estimating response. The chi-square test with one-sided alpha of 0.10 will be used to test for the association between predicted and observed responses. Contingency tables will be used to present these associations.

  From the start of combination therapy until a maximum of 2 years after completion of therapy

Secondary Outcomes (3)

• Summary of Adverse Events (AEs)

  From the time of first dose of study drug until 4 weeks after participant has stopped study drug; up to 1 year

• Distribution of Change Across Time of mTOR and HDAC-I Inhibition From Baseline Until After the 1st 2 Cycles of Study Drug in Patients Who Received LBH and RAD.

  after 2 cycles of study therapy; up to 8 weeks

• Evaluate the Association of Observed Response to the Doublet With the Response Predicted by Molecular Signatures for Activated B Cell Like (ABC) DLBCL and for Germinal Center B Cell Like (GCB) DLBCL.

  up to 13 cycles of therapy; approximately 1 year

Study Arms (3)

Arm 1a (RAD001 followed by LBH589)

EXPERIMENTAL

Part 1a: Sequential single agent therapy with RAD001 and LBH589. Each agent will be given for four-six 28-day cycles. Subjects with less than a CR after 4 cycles of study drug should proceed to the next study drug(s) after the prescribed washout period. Subjects with a CR may receive up to 6 cycles of study drug and will not receive the next study drug(s) until there is evidence of progressive disease. There will be a 1-6 week 'washout' period between stopping and starting each agent in Part 1, unless rapid progression suggests holding therapy would not be in the patient's best interest.

Drug: RAD001; Drug: LBH589

Arm 1b (LBH589 followed by RAD001)

EXPERIMENTAL

Part 1b: Sequential single agent therapy with LBH589 and RAD001 . Each agent will be given for four-six 28-day cycles. Subjects with less than a CR after 4 cycles of study drug should proceed to the next study drug(s) after the prescribed washout period. Subjects with a CR may receive up to 6 cycles of study drug and will not receive the next study drug(s) until there is evidence of progressive disease. There will be a 1-6 week 'washout' period between stopping and starting each agent in Part 1, unless rapid progression suggests holding therapy would not be in the patient's best interest.

Drug: RAD001; Drug: LBH589

Doublet (Combination RAD001 and LBH589)

EXPERIMENTAL

Subjects will receive the doublet of RAD001 and LBH589 given in two to thirteen, 28-day cycles. Subjects will be evaluated for the disease status after completion of cycle two and then after every 4 cycles. Subjects with progressive disease will stop after 2 cycles. Subjects with stable disease or better may receive up to 13 cycles. LBH589 will start at 15mg po three days a week at least 2 days apart such as on days M/W/F or T/Th/Sat and RAD001 will start at 7.5mg po daily.

Drug: Doublet (RAD001 and LBH589)

Interventions

RAD001 DRUG

10 mg/day for Part 1 of the trial

Also known as: Everolimus

Arm 1a (RAD001 followed by LBH589); Arm 1b (LBH589 followed by RAD001)

LBH589 DRUG

40 mg on Monday, Wednesday and Friday weekly for Part 1 of the trial

Also known as: panobinostat

Arm 1a (RAD001 followed by LBH589); Arm 1b (LBH589 followed by RAD001)

Doublet (RAD001 and LBH589) DRUG

RAD001 7.5 mg by mouth daily and LBH589 15 mg by mouth on Monday/Wednesday/Friday during Part 2.

Doublet (Combination RAD001 and LBH589)

Eligibility Criteria

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

You may qualify if:

• de novo or transformed Diffuse large B cell non-Hodgkin lymphoma (DLBCL). DLBCL-like lymphomas allowed:
• Epstei-Barr virus (EBV)+ DLBCL in elderly,
• DLBCL with chronic inflammation,
• Primary cutaneous DLBCL, leg type,
• B cell lymphoma unclassifiable - between DLBCL and Burkitt lymphoma,
• B cell lymphoma unclassifiable - between large B cell lymphoma and classical Hodgkin lymphoma,
• Anaplastic lymphoma kinase (ALK)+ large B cell lymphoma,
• T cell histiocyte rich large B cell lymphoma
• Primary mediastinal B cell lymphoma
• Follicular grade 3 B cell lymphoma
• Refractory or relapsed disease to \>/= 1 prior treatment regimen: should include autologous stem cell transplant unless patient refused or ineligible.
• Age \> 18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status \<2.
• Measurable or evaluable disease by physical exam, radiographs or bone marrow involvement
• Frozen tumor or paraffin-embedded sample available.

You may not qualify if:

• Laboratory Values
• Grade 3 hyperlipidemia (Serum cholesterol \>400mg/dl or serum triglycerides \>5 x ULN)
• Serum Glucose \> 250mg/dl on \>/= 2 checks on 2 separate days
• Diabetics accepted if sugars controlled
• Unlimited prior chemotherapy regimens, however:
• No prior exposure to RAD001 or LBH589 or drugs that target mTOR (sirolimus, temsirolimus, etc) or HDAC (vorinostat)
• No valproic acid during study or 5 days preceding start of first drug
• No chemotherapy, biologics or immunotherapy \< 2 weeks before registration (6 weeks if last received bis-chloroethylnitrosourea (BCNU) or mitomycin C). Subjects must be recovered from therapy-related non-hematological toxicities to \< grade 1 or baseline if started with \> grade 1 toxicity.
• No time limit for radiation prior to registration.
• No radioimmunotherapy \< 2 months prior to registration. Subjects must be recovered from therapy-related toxicities to \< grade 1 or baseline if started with \> grade 1 toxicity.
• No prior allogeneic stem cell transplantation unless allogeneic engraftment is \<2%.
• Subjects receiving chronic, systemic treatment with corticosteroids = to \>20mg of prednisone per day.
• Subjects receiving replacement for adrenal insufficiency allowed.
• Topical or inhaled corticosteroids allowed.
• History of other primary malignancy \< 3 years ago, except inactive basal, squamous cell carcinoma of the skin or superficial melanoma only requiring excision, prostate cancer with a prostate specific antigen (PSA) stable for \>/=3 months, carcinoma in situ of cervix.

Sponsors & Collaborators

• Anne Beaven, MD: lead
• Novartis: collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Recurrence

Interventions

Everolimus; Panobinostat

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Hydroxamic Acids; Hydroxylamines; Amines; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Anne Beaven, MD
• Organization: Duke University Medical Center

anne.beaven@duke.edu

919-684-8964

Study Officials

• Anne W. Beaven, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: September 15, 2009
• First Posted: September 17, 2009
• Study Start: February 1, 2012
• Primary Completion: April 1, 2015
• Study Completion: March 1, 2016
• Last Updated: November 25, 2016
• Results First Posted: June 7, 2016

Record last verified: 2016-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)