Category: Clinical Trials

Updated Efficacy Results of Ibrutinib Compared with Ofatumumab in Relapsed CLL (RESONATE Trial), with Analysis of Genetic and Prognostic Subgroups

Picture3By Dr. Richard Furman, MD

The role of various prognostic factors in CLL/SLL is not yet fully understood, including the implications of new genetic markers associated with high risk. Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor that is approved for the treatment of CLL patients who have received at least 1 prior therapy, and for patients with 17p deletion CLL. In results presented before the 56th annual meeting of the American Society of Hematology, updated efficacy results from the phase 3 RESONATE (PCYC-1112) study comparing ibrutinib to ofatumumab were reported.

In the phase III study 391 randomized patients received 420 mg daily of ibrutinib or ofatumumab daily, until disease progression or unacceptable toxicity for up to 24 weeks. During an interim analysis at the median follow up of 9.4 months, patients in the ofatumumab arm were provided access to the ibrutinib arm.

Comparatively, progression free survival (PFS) was significantly longer for ibrutinib compared to ofatumumab. Overall survival (OS) was significantly better for ibrutinib compared to ofatumumab, with 18-month OS rates of 85% and 78% respectively. Higher number of prior therapies (≥3) and 11q deletion were associated with significantly lower 12-month PFS rate for ofatumumab, but not for ibrutinib. The overall response rate (ORR) for ibrutinib versus ofatumumab was 90% to 25%. Compared to ofatumumab, ibrutinib improved 12-month PFS and ORR regardless of baseline genetics, complex cytogenetics, or number of prior therapies. No significant difference in 12-month PFS was observed in ibrutinib treated patients with or without del(17p) or for those who developed lymphocytosis compared to those without lymphocytosis. Median treatment duration was longer for ibrutinib versus ofatumumab and was 16 to 5 months respectively.

In this one on one comparison ibrutinib significantly outperformed ofatumumab in PFS, OS, and ORR in patients with CLL/SLL with at least one prior therapy. These results are consistent with previously published findings, and provide further evidence for the clinical utility  of ibrutinib in patients with CLL.

ASH 2014 – WCMC Related Abstracts

It has been another productive year for research in the Lymphoma Program at Weill Cornell Medical College. Listed below are the abstracts we were involved in whole or in part to be presented at this year’s 56th Annual Meeting of the American Society of Hematology (ASH).

Look to this space for future updates about developments at ASH 2014.

Anaplastic Large Cell Lymphoma
781 – Convergent Mutations and New Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma
1679 – Identification of a New Subclass of ALK Negative Anaplastic Large Cell Lymphoma Expressing Aberrant Levels of ERBB4 Transcripts

CLL/SLL
327 – Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial
330 – Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG®) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors
1990 – Pattern of Use of Anticoagulation and/or Antiplatelet Agents in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Single-Agent Ibrutinib Therapy
3316 – Extracellular Nicotinamide Phosphoribosyltransferase (NAMPT) Shapes the CLL Microenvironment Promoting Macrophage M2 Polarization Via a Non-Enzymatic Mechanism
3331 – Updated Efficacy Including Genetic and Clinical Subgroup Analysis and Overall Safety in the Phase 3 RESONATETM Trial of Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
4615 – Cancer-Associated Mutations in SF3B1 Exhibit Neomorphic Splicing Activity and Block Erythroid Differentiation
3343 – Long-Term Follow-up of a Phase 1 Trial of Idelalisib (ZYDELIG®) in Combination with Bendamustine (B), Bendamustine/Rituximab (BR), Fludarabine (F), Chlorambucil (Chl), or Chlorambucil/Rituximab (ChlR) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

DLBCL
59 – Demethylase Activity of Aid during Germinal Center B Cell Maturation Could Contribute to Lymphomagenesis
143 – Akt Activation Confers an Inferior Survival in Patients with Activated B-Cell Subtype of Diffuse Large B-Cell Lymphoma: A Report from the International DLBCL Rituximab-CHOP Consortium Program
567 – BCL6 Mediates a Stress Tolerance Phenotype through Its BTB Domain
864 – Strand-Specific Total RNA Sequencing Establishes the Complete Transcriptome and Alternative Splicing Repertoire in Diffuse Large B Cell Lymphoma
928 – A Virtual B Cell Lymphoma Model to Predict Effective Combination Therapy
1620 – NF-κB Subunit c-Rel Cooperates with Myc and Mutated p53 to Confer Significantly Worse Survival in Patients with Diffuse Large B-Cell Lymphoma: A Report from the International DLBCL Rituximab-CHOP Consortium Program
1692 – Genetic Mechanisms of Immune Escape in Diffuse Large B Cell Lymphoma
1764 – Hsp90 at the Hub of Metabolic Homeostasis in Malignant B Cells
2032 – Whole-Genome Epigenomic Analysis in Multiple Myeloma Reveals DNA Hypermethylation of B-Cell Specific Enhancers
2963 – Mirna-181a expression Lead to Longer Animal Survival and Slower Tumor-Growth Rate in Diffuse Large B-Cell Lymphoma Xenograft Models
3021 – Characterization of DLBCL-Derived Exosomes and Investigation of Their Biological Properties
3091 – Unexpected and Serious Toxicity Observed with Combined Idelalisib, Lenalidomide and Rituximab in Relapsed/Refractory B Cell Lymphomas: Alliance A051201 and A051202
3547 – EBV Microrna Mir-BHRF1-2 Targets PRDM1/Blimp1: Potential Role in EBV Lymphomagenesis
4417 – A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Non-Leukemic Hematologic Malignancies

Hodgkin Lymphoma
501 – Results of a Phase II Trial of Brentuximab Vedotin As First Line Salvage Therapy in Relapsed/Refractory HL Prior to AHCT
4400 – Circulating Memory T Cells Isolated from Hodgkin Lymphoma Patients Display Evidence of Exhaustion and Chronic Activation

Mantle Cell Lymphoma
625 – Sustained Remission with the Combination Biologic Doublet of Lenalidomide Plus Rituximab As Initial Treatment for Mantle Cell Lymphoma: A Multi-Center Phase II Study Report
2250 – Acquired in Vitro Resistance to Ibrutinib Is Associated with Transcriptional Re-Programming and Sustained Survival Signaling in Waldenströms Macroglobulinemia and Mantle Cell Lymphoma, Independent of BTK Cys481Mutation
3047 – Poor Overall Survival of Patients with Ibrutinib-Resistant Mantle Cell Lymphoma
4453 – Single-Agent Ibrutinib Demonstrates Safety and Durability of Response at 2 Years Follow-up in Patients with Relapsed or Refractory Mantle Cell Lymphoma: Updated Results of an International, Multicenter, Open-Label Phase 2 Study
4461 – Safety Results from the United States Cohort of the Ibrutinib Early Access Treatment Protocol (EAP: MCL4001) in Patients with Relapsed or Refractory Mantle Cell Lymphoma
4471 – Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy

Marginal Zone Lymphoma
705 – The Coding Genome of Nodal Marginal Zone Lymphoma Reveals Recurrent Molecular Alterations of PTPRD and Other Jak/Stat Signaling Genes

Non-Hodgkin Lymphoma
60 – Protein Arginine Methyltransferase 5 Directly Targets and Epigenetically Silences microRNAs miR33b and miR96 to Support Constitutive Cyclin D1 Activity in Non-Hodgkin’s Lymphoma
3063 – Durable Responses Following Treatment with the PI3K-Delta Inhibitor Idelalisib in Combination with Rituximab, Bendamustine, or Both, in Recurrent Indolent Non-Hodgkin Lymphoma: Phase I/II Results

T-cell Lymphoma
510 – Integrin αvβ3 Transduces Survival and Angiogenic Signals to T Cell Lymphomas and Is a Therapeutic Target
810 – Transcription Regulation Targeting in Peripheral T Cell Lymphomas Induces Apoptosis and Sensitization to BCL2 Inhibitors

Waldenstrom’s Macroglobulinemia
1689 – The Selective Bcl-2 Inhibitor ABT-199 Synergizes with BTK or Proteasome Inhibitors to Induce Potent Cell Death in Preclinical Models of Bortezomib or Ibrutinib-Resistant Waldenströms Macroglobulinemia
2250 – Acquired in Vitro Resistance to Ibrutinib Is Associated with Transcriptional Re-Programming and Sustained Survival Signaling in Waldenströms Macroglobulinemia and Mantle Cell Lymphoma, Independent of BTK Cys481Mutation
3115 – Therapeutic Sensitivity of CD20- Waldenströms Macroglobulinemia Cells Is Determined By Underlying Genomic and Epigenetic Events
3116 – Targeted Disruption of USP14 and UCHL5 with the Novel Deubiquitinase Enzyme (DUB) Inhibitor, VLX1570, Induces Immense Proteotoxicity and Cell Death in Malignant Plasma Cells
3551 – Methylation Patterns in Waldenströms Macroglobulinemia Cells That Are Inherently Resistant or Have Acquired Resistance to Bortezomib, Converge on the TP63 and Cepba Family of Transcription Factors

New Clinical Trial: A Phase 1 Open Label Study of ACP-196 in Patients with Waldenstrom’s Macroglobulinemia

The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men and women with diffuse large B-cell lymphoma. The study sponsor is Acerta Pharma BV, and the principal investigator at Weill Cornell is Dr. Richard Furman. For more information about the study, please call Amelyn Rodgriguez, RN at (212) 746-1362 or e-mail Amelyn at amr2017@med.cornell.edu.

Key Eligibility

  • Men and women age 18 and older with a confirmed diagnosis of Waldenstrom’s Macroglobulinemia
  • Previously treated with at least one prior therapy
  • Cannot have received prior therapy with a BTK inhibitor
  • Must be disease free from a former malignancy for at least two years
  • Detailed eligibility reviewed when you contact the study team. 

Study Details

This clinical trial is for men and woman with a form of cancer called Waldenstrom’s Macroglobulinemia (WM) who have relapsed or not responded to at least one prior therapy. Inhibition of Bruton’s tyrosine kinase (BTK) has been established as an effective means for treating WM.  ACP-196 is an oral, novel inhibitor of BTK with increased specificity for the target and fewer drug interactions than other BTK inhibitors being studied.  Subjects will receive different doses ACP-196 (depending upon when they enter the trial) in order to determine the side effects and effective dose of ACP-196.

Treatment Plans

Subjects will be assigned to one of two treatment groups:

Cohort 1: ACP-196 100 mg twice a day (BID) for 28 days
Cohort 2: ACP-196 200 mg once a day (QD) for 28 days