New Clinical Trial: A Phase 1/2 Proof of Concept Study of the Combination of ACP-196 & ACP-319 in Subjects with B-cell Malignancies

The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men and women with previously treated B-cell malignancies. The study sponsor is Acerta Pharmaceuticals, and the principal investigator at Weill Cornell is Richard Furman M.D.. 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.
  • Diagnosis of non-GCB DLBCL, MCL, FL, WM, or CLL/SLL.
  • At least one prior therapy meeting the criteria for relevant disease type.
  • Detailed eligibility reviewed when you contact the study team.

Study Summary

This clinical trial is for men and women with previously treated B-cell malignancies.

In recent years, clinical trials with small molecule inhibitors of Btk and PI3K-delta have produced high response rates with few drug-related toxicities in subjects with B-cell malignancies. Specifically, ibrutinib and idelalisib have shown very encouraging results and each have gained FDA approval in specific patient populations, however, some subjects develop progressive disease or resistance after a period of time on these treatments. This study aims to assess the clinical potential and safety of a dual inhibition approach by combining ACP-196, a second generation Btk inhibitor, with ACP-319, a second generation PI3K inhibitor. The study will provide more information about whether this targeted combination therapy can benefit subjects with B-cell malignancies over single agent therapies or traditional chemotherapy combinations without an increase in toxicity.

Subjects will receive ACP-196 and ACP-319 continuously throughout the study as long as they are responding to therapy and not experiencing unacceptable side effects. Both ACP-196 and ACP-319 are administered orally twice daily. After discontinuing treatment, subjects will remain in long-term follow-up until they receive their next therapy.

FDA Approves Ibrutinib for the Treatment of Patients with Waldenstrom’s Macroglobulinemia

Earlier today the FDA announced the expanded approval of ibrutinib in the treatment of patients with Waldenstrom’s Macroglobulinemia. Ibrutinib had previously received a “breakthrough therapy” designation for this use.

“The FDA based its approval of Imbruvica for WM on a clinical study of 63 previously treated participants. All study participants received a daily 420 milligram orally administered dose of the medication until disease progression or side effects became intolerable. Results showed 62 percent of participants had their cancer shrink after treatment (overall response rate). At the time of the study, the duration of response ranged from 2.8 months to approximately 18.8 months.”

This is the fourth lymphoma related indication that ibrutinib has received approval to treat. Previously the drug received approval for the treatment of patients with  mantle cell lymphoma who received one prior therapy, patients with previously treated chronic lymphocytic leukemia (CLL), and treatment of CLL patients who carry a deletion in chromosome 17. Currently, further studies with ibrutinib for patients with Waldenstrom’s are ongoing at Weill Cornell. 

Finally, we would like to recognize all the patients with WM that have participated in these trials at WCMC and elsewhere for making FDA approval of this groundbreaking drug a reality.

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