PHASE 1 TRIAL OF CUDC-907, A NOVEL, ORAL DUAL INHIBITOR OF HDAC AND PI3K: UPDATED ASSESSMENT OF PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA, INCLUDING DOUBLE EXPRESSOR LYMPHOMA
(Abstract release date: 05/19/16)
EHA Library. Younes A. 06/11/16; 135236; S480
Dr. Anas Younes
Contributions
Contributions
Abstract
Abstract: S480
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:45 - 17:00
Location: Hall A1
Background
Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is an aggressive form of non-Hodgkin lymphoma with significant heterogeneity in terms of gene expression, prognosis and response to treatment. Certain histone modifications and HDAC expression patterns have been implicated in the pathobiology of DLBCL and other cancers. Aberrant PTEN/PI3K/AKT signaling is also frequently observed in a variety of human cancers including DLBCL, where loss of PTEN and/or activating mutations in PI3K have been shown to inhibit apoptosis and promote tumor cell proliferation. Synergistic anti-tumor effects achieved with HDAC and PI3K inhibitor combinations in DLBCL xenograft models have provided a strong rationale for testing a highly potent dual HDAC and PI3K inhibitor, CUDC-907. Significant anti-tumor effects have been observed across a wide range of DLBCL models exposed to CUDC-907, including the U2932 ABC DLBCL model that harbors BCL2 amplification and over-expresses cMYC and BCL6, and the double hit WSU-DLCL-2 GCB DLBCL model that harbors MYC and BCL2 translocations. These disease mechanisms and preclinical data have led to testing of CUDC-907 in an ongoing Phase 1 trial in patients with various hematologic cancers.
Aims
This study is evaluating the effect of CUDC-907 on treatment-related toxicity and efficacy in patients with relapsed or refractory (RR) lymphoma and multiple myeloma (MM).
Methods
Seventy-five heavily pre-treated patients with RR lymphoma or MM have received CUDC-907 in 21-day cycles according to once daily (QD), intermittent (BIW or TIW), or five days on/two days off (5/2) dosing schedules. CUDC-907 was escalated in 30 mg increments such that patients received 30-60 mg QD, 60-150 mg intermittently, or 60 mg 5/2. Dose expansion investigating the 60 mg 5/2 dose and schedule as monotherapy and in combination with rituximab is ongoing. To date, a total of 29 patients have been treated with the 5/2 dosing schedule, including 4 patients who were assigned to concomitant standard of care dosing of rituximab on day 1 of the first 6 cycles of treatment.
Results
The most common treatment-related adverse events (AEs) were Grade 1-2 diarrhea (56%; 4% Grade ≥3), fatigue (33%; 4% Grade ≥3), nausea (29%), thrombocytopenia (27%; 17% Grade ≥3), and neutropenia (12%; 9% Grade ≥3), with dose limiting toxicities of hyperglycemia (QD and BIW schedules) and diarrhea (QD and TIW schedules). Side effects were reversible and manageable. The AE profile for patients who received CUDC-907 on the 60 mg 5/2 dosing schedule, including those who received concomitant rituximab, was commensurate with that of the overall safety population.Among 20 response-evaluable patients with RR DLBCL, 9 (45%) achieved objective responses (3 CRs and 6 PRs); lasting a median of 2.6 months (range: <1-14+). Three response evaluable patients were found to overexpress MYC (≥40%) and BCL2 (≥70%) by IHC, meeting criteria applied to “double-expressor” (DE) DLBCL. Two of these patients attained objective responses: 1 CR (followed by autologous stem cell transplant) and 1 PR (lasting 4 months). The third patient has experienced lengthy disease stabilization (5.7+ months). Interestingly, all 3 CRs observed on this study occurred in patients with MYC gene copy number gain, including the patient who also had DE DLBCL.
Conclusion
Signals emerging from preclinical and clinical studies suggest that patients with DLBCL, including those with MYC-altered and therefore particularly aggressive disease, may derive benefit from treatment with CUDC-907. A Phase 2 trial examining CUDC-907 60 mg 5/2 as monotherapy and in combination with rituximab in RR MYC-altered DLBCL is currently ongoing. Patients are being enrolled based on locally reported MYC status, defined as gene translocation or copy number gain by FISH and/or protein expression ≥40% by IHC. Tumoral tissue will be assessed centrally to confirm MYC status of enrolled patients. Other genetic aberrations, such as BCL2 and BCL6, will also be evaluated for correlation with clinical outcomes (NCT02674750).
Session topic: Diffuse large B-cell lymphoma
Keyword(s): BCL2, DLBCL, MYC, Relapsed lymphoma
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:45 - 17:00
Location: Hall A1
Background
Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is an aggressive form of non-Hodgkin lymphoma with significant heterogeneity in terms of gene expression, prognosis and response to treatment. Certain histone modifications and HDAC expression patterns have been implicated in the pathobiology of DLBCL and other cancers. Aberrant PTEN/PI3K/AKT signaling is also frequently observed in a variety of human cancers including DLBCL, where loss of PTEN and/or activating mutations in PI3K have been shown to inhibit apoptosis and promote tumor cell proliferation. Synergistic anti-tumor effects achieved with HDAC and PI3K inhibitor combinations in DLBCL xenograft models have provided a strong rationale for testing a highly potent dual HDAC and PI3K inhibitor, CUDC-907. Significant anti-tumor effects have been observed across a wide range of DLBCL models exposed to CUDC-907, including the U2932 ABC DLBCL model that harbors BCL2 amplification and over-expresses cMYC and BCL6, and the double hit WSU-DLCL-2 GCB DLBCL model that harbors MYC and BCL2 translocations. These disease mechanisms and preclinical data have led to testing of CUDC-907 in an ongoing Phase 1 trial in patients with various hematologic cancers.
Aims
This study is evaluating the effect of CUDC-907 on treatment-related toxicity and efficacy in patients with relapsed or refractory (RR) lymphoma and multiple myeloma (MM).
Methods
Seventy-five heavily pre-treated patients with RR lymphoma or MM have received CUDC-907 in 21-day cycles according to once daily (QD), intermittent (BIW or TIW), or five days on/two days off (5/2) dosing schedules. CUDC-907 was escalated in 30 mg increments such that patients received 30-60 mg QD, 60-150 mg intermittently, or 60 mg 5/2. Dose expansion investigating the 60 mg 5/2 dose and schedule as monotherapy and in combination with rituximab is ongoing. To date, a total of 29 patients have been treated with the 5/2 dosing schedule, including 4 patients who were assigned to concomitant standard of care dosing of rituximab on day 1 of the first 6 cycles of treatment.
Results
The most common treatment-related adverse events (AEs) were Grade 1-2 diarrhea (56%; 4% Grade ≥3), fatigue (33%; 4% Grade ≥3), nausea (29%), thrombocytopenia (27%; 17% Grade ≥3), and neutropenia (12%; 9% Grade ≥3), with dose limiting toxicities of hyperglycemia (QD and BIW schedules) and diarrhea (QD and TIW schedules). Side effects were reversible and manageable. The AE profile for patients who received CUDC-907 on the 60 mg 5/2 dosing schedule, including those who received concomitant rituximab, was commensurate with that of the overall safety population.Among 20 response-evaluable patients with RR DLBCL, 9 (45%) achieved objective responses (3 CRs and 6 PRs); lasting a median of 2.6 months (range: <1-14+). Three response evaluable patients were found to overexpress MYC (≥40%) and BCL2 (≥70%) by IHC, meeting criteria applied to “double-expressor” (DE) DLBCL. Two of these patients attained objective responses: 1 CR (followed by autologous stem cell transplant) and 1 PR (lasting 4 months). The third patient has experienced lengthy disease stabilization (5.7+ months). Interestingly, all 3 CRs observed on this study occurred in patients with MYC gene copy number gain, including the patient who also had DE DLBCL.
Conclusion
Signals emerging from preclinical and clinical studies suggest that patients with DLBCL, including those with MYC-altered and therefore particularly aggressive disease, may derive benefit from treatment with CUDC-907. A Phase 2 trial examining CUDC-907 60 mg 5/2 as monotherapy and in combination with rituximab in RR MYC-altered DLBCL is currently ongoing. Patients are being enrolled based on locally reported MYC status, defined as gene translocation or copy number gain by FISH and/or protein expression ≥40% by IHC. Tumoral tissue will be assessed centrally to confirm MYC status of enrolled patients. Other genetic aberrations, such as BCL2 and BCL6, will also be evaluated for correlation with clinical outcomes (NCT02674750).
Session topic: Diffuse large B-cell lymphoma
Keyword(s): BCL2, DLBCL, MYC, Relapsed lymphoma
Abstract: S480
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:45 - 17:00
Location: Hall A1
Background
Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is an aggressive form of non-Hodgkin lymphoma with significant heterogeneity in terms of gene expression, prognosis and response to treatment. Certain histone modifications and HDAC expression patterns have been implicated in the pathobiology of DLBCL and other cancers. Aberrant PTEN/PI3K/AKT signaling is also frequently observed in a variety of human cancers including DLBCL, where loss of PTEN and/or activating mutations in PI3K have been shown to inhibit apoptosis and promote tumor cell proliferation. Synergistic anti-tumor effects achieved with HDAC and PI3K inhibitor combinations in DLBCL xenograft models have provided a strong rationale for testing a highly potent dual HDAC and PI3K inhibitor, CUDC-907. Significant anti-tumor effects have been observed across a wide range of DLBCL models exposed to CUDC-907, including the U2932 ABC DLBCL model that harbors BCL2 amplification and over-expresses cMYC and BCL6, and the double hit WSU-DLCL-2 GCB DLBCL model that harbors MYC and BCL2 translocations. These disease mechanisms and preclinical data have led to testing of CUDC-907 in an ongoing Phase 1 trial in patients with various hematologic cancers.
Aims
This study is evaluating the effect of CUDC-907 on treatment-related toxicity and efficacy in patients with relapsed or refractory (RR) lymphoma and multiple myeloma (MM).
Methods
Seventy-five heavily pre-treated patients with RR lymphoma or MM have received CUDC-907 in 21-day cycles according to once daily (QD), intermittent (BIW or TIW), or five days on/two days off (5/2) dosing schedules. CUDC-907 was escalated in 30 mg increments such that patients received 30-60 mg QD, 60-150 mg intermittently, or 60 mg 5/2. Dose expansion investigating the 60 mg 5/2 dose and schedule as monotherapy and in combination with rituximab is ongoing. To date, a total of 29 patients have been treated with the 5/2 dosing schedule, including 4 patients who were assigned to concomitant standard of care dosing of rituximab on day 1 of the first 6 cycles of treatment.
Results
The most common treatment-related adverse events (AEs) were Grade 1-2 diarrhea (56%; 4% Grade ≥3), fatigue (33%; 4% Grade ≥3), nausea (29%), thrombocytopenia (27%; 17% Grade ≥3), and neutropenia (12%; 9% Grade ≥3), with dose limiting toxicities of hyperglycemia (QD and BIW schedules) and diarrhea (QD and TIW schedules). Side effects were reversible and manageable. The AE profile for patients who received CUDC-907 on the 60 mg 5/2 dosing schedule, including those who received concomitant rituximab, was commensurate with that of the overall safety population.Among 20 response-evaluable patients with RR DLBCL, 9 (45%) achieved objective responses (3 CRs and 6 PRs); lasting a median of 2.6 months (range: <1-14+). Three response evaluable patients were found to overexpress MYC (≥40%) and BCL2 (≥70%) by IHC, meeting criteria applied to “double-expressor” (DE) DLBCL. Two of these patients attained objective responses: 1 CR (followed by autologous stem cell transplant) and 1 PR (lasting 4 months). The third patient has experienced lengthy disease stabilization (5.7+ months). Interestingly, all 3 CRs observed on this study occurred in patients with MYC gene copy number gain, including the patient who also had DE DLBCL.
Conclusion
Signals emerging from preclinical and clinical studies suggest that patients with DLBCL, including those with MYC-altered and therefore particularly aggressive disease, may derive benefit from treatment with CUDC-907. A Phase 2 trial examining CUDC-907 60 mg 5/2 as monotherapy and in combination with rituximab in RR MYC-altered DLBCL is currently ongoing. Patients are being enrolled based on locally reported MYC status, defined as gene translocation or copy number gain by FISH and/or protein expression ≥40% by IHC. Tumoral tissue will be assessed centrally to confirm MYC status of enrolled patients. Other genetic aberrations, such as BCL2 and BCL6, will also be evaluated for correlation with clinical outcomes (NCT02674750).
Session topic: Diffuse large B-cell lymphoma
Keyword(s): BCL2, DLBCL, MYC, Relapsed lymphoma
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:45 - 17:00
Location: Hall A1
Background
Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is an aggressive form of non-Hodgkin lymphoma with significant heterogeneity in terms of gene expression, prognosis and response to treatment. Certain histone modifications and HDAC expression patterns have been implicated in the pathobiology of DLBCL and other cancers. Aberrant PTEN/PI3K/AKT signaling is also frequently observed in a variety of human cancers including DLBCL, where loss of PTEN and/or activating mutations in PI3K have been shown to inhibit apoptosis and promote tumor cell proliferation. Synergistic anti-tumor effects achieved with HDAC and PI3K inhibitor combinations in DLBCL xenograft models have provided a strong rationale for testing a highly potent dual HDAC and PI3K inhibitor, CUDC-907. Significant anti-tumor effects have been observed across a wide range of DLBCL models exposed to CUDC-907, including the U2932 ABC DLBCL model that harbors BCL2 amplification and over-expresses cMYC and BCL6, and the double hit WSU-DLCL-2 GCB DLBCL model that harbors MYC and BCL2 translocations. These disease mechanisms and preclinical data have led to testing of CUDC-907 in an ongoing Phase 1 trial in patients with various hematologic cancers.
Aims
This study is evaluating the effect of CUDC-907 on treatment-related toxicity and efficacy in patients with relapsed or refractory (RR) lymphoma and multiple myeloma (MM).
Methods
Seventy-five heavily pre-treated patients with RR lymphoma or MM have received CUDC-907 in 21-day cycles according to once daily (QD), intermittent (BIW or TIW), or five days on/two days off (5/2) dosing schedules. CUDC-907 was escalated in 30 mg increments such that patients received 30-60 mg QD, 60-150 mg intermittently, or 60 mg 5/2. Dose expansion investigating the 60 mg 5/2 dose and schedule as monotherapy and in combination with rituximab is ongoing. To date, a total of 29 patients have been treated with the 5/2 dosing schedule, including 4 patients who were assigned to concomitant standard of care dosing of rituximab on day 1 of the first 6 cycles of treatment.
Results
The most common treatment-related adverse events (AEs) were Grade 1-2 diarrhea (56%; 4% Grade ≥3), fatigue (33%; 4% Grade ≥3), nausea (29%), thrombocytopenia (27%; 17% Grade ≥3), and neutropenia (12%; 9% Grade ≥3), with dose limiting toxicities of hyperglycemia (QD and BIW schedules) and diarrhea (QD and TIW schedules). Side effects were reversible and manageable. The AE profile for patients who received CUDC-907 on the 60 mg 5/2 dosing schedule, including those who received concomitant rituximab, was commensurate with that of the overall safety population.Among 20 response-evaluable patients with RR DLBCL, 9 (45%) achieved objective responses (3 CRs and 6 PRs); lasting a median of 2.6 months (range: <1-14+). Three response evaluable patients were found to overexpress MYC (≥40%) and BCL2 (≥70%) by IHC, meeting criteria applied to “double-expressor” (DE) DLBCL. Two of these patients attained objective responses: 1 CR (followed by autologous stem cell transplant) and 1 PR (lasting 4 months). The third patient has experienced lengthy disease stabilization (5.7+ months). Interestingly, all 3 CRs observed on this study occurred in patients with MYC gene copy number gain, including the patient who also had DE DLBCL.
Conclusion
Signals emerging from preclinical and clinical studies suggest that patients with DLBCL, including those with MYC-altered and therefore particularly aggressive disease, may derive benefit from treatment with CUDC-907. A Phase 2 trial examining CUDC-907 60 mg 5/2 as monotherapy and in combination with rituximab in RR MYC-altered DLBCL is currently ongoing. Patients are being enrolled based on locally reported MYC status, defined as gene translocation or copy number gain by FISH and/or protein expression ≥40% by IHC. Tumoral tissue will be assessed centrally to confirm MYC status of enrolled patients. Other genetic aberrations, such as BCL2 and BCL6, will also be evaluated for correlation with clinical outcomes (NCT02674750).
Session topic: Diffuse large B-cell lymphoma
Keyword(s): BCL2, DLBCL, MYC, Relapsed lymphoma
{{ help_message }}
{{filter}}