Antitumor activity of the novel BTK inhibitor TG-1701 is associated with disruption of Ikaros signaling in patients with B-cell non-Hodgkin lymphoma

8070 Background: Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL) after failure of other therapies. Based on the high objective response rate observed in patients with systemic ALCL, a type of non-Hodgkin lymphoma that is characterized by homogeneous CD30 expression, a study was initiated in other non-Hodgkin lymphomas that express the CD30 target. Methods: A phase 2 open-label single-arm study is underway in patients with relapsed or refractory CD30-positive non-Hodgkin lymphoma, excluding ALCL (NCT01421667). Brentuximab vedotin is administered IV at 1.8 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint is objective response rate assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Tumor specimens are assessed by central lab in order to characterize the relationship of CD30 expression with antitumor activity. Results: Ten patients (age range 28–83; 5 M, 5 F) have enrolled to date. Diagnoses include diffuse large B-cell lymphoma (DLBCL, n=2), EBV-positive DLBCL of the elderly (n=3), primary mediastinal B-cell lymphoma (n=2), peripheral T-cell lymphoma NOS (n=2), and angioimmunoblastic T-cell lymphoma (AITL). Patients had received 1–6 prior chemotherapy regimens; 3 patients had prior stem cell transplants. Of 6 patients who have completed the cycle 2 response assessment, 2 attained complete remission, 1 with DLBCL (90% CD30+) and 1 with AITL (8% CD30+), 1 had stable disease, and 3 had progressive disease. Treatment-related serious adverse events observed to date were rash, febrile neutropenia, and mastoiditis. Conclusions: Preliminary results suggest that brentuximab vedotin may have antitumor activity in patients with relapsed or refractory CD30-expressing non-Hodgkin lymphomas, in addition to the efficacy previously observed in systemic ALCL. Updated study results will be presented.

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A phase 1 adaptive dose-escalation study to evaluate the tolerability, safety, pharmacokinetics, and antitumor activity of ADCT-402 in patients with relapsed or refractory B-cell lineage non Hodgkin lymphoma (B-NHL).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.tps7580 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. TPS7580-TPS7580 ◽

Cited By ~ 1

Author(s):

Ki Y. Chung ◽

Mehdi Hamadani ◽

Brad S. Kahl ◽

Leonard T. Heffner ◽

Paolo Fabrizio Caimi ◽

...

Keyword(s):

Antitumor Activity ◽

B Cell ◽

Hodgkin Lymphoma ◽

Dose Escalation ◽

Phase 1 ◽

Cell Lineage ◽

Dose Escalation Study ◽

Non Hodgkin Lymphoma

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Abstract 1744: ACP-196: A second generation Btk inhibitor demonstrates biologic activity in a canine model of B-cell non-Hodgkin lymphoma

10.1158/1538-7445.am2014-1744 ◽

2014 ◽

Cited By ~ 5

Author(s):

Heather L. Gardner* ◽

Bonnie K. Harrington* ◽

Raquel Izumi ◽

Ahmed Hamdy ◽

Allard Kaptein ◽

...

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

Second Generation ◽

Canine Model ◽

Non Hodgkin Lymphoma ◽

Biologic Activity ◽

Btk Inhibitor

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Effects of the Btk Inhibitor Ibrutinib on Monocyte Responses to Antibodies

Blood ◽

10.1182/blood.v126.23.1017.1017 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1017-1017

Author(s):

Li Ren ◽

Amanda Campbell ◽

Shalini Gautam ◽

Huiqing Fang ◽

Kavin Fatehchand ◽

...

Keyword(s):

B Cell ◽

Actin Polymerization ◽

Cytokine Production ◽

Kinase Inhibitor ◽

Antibody Therapy ◽

Lymphocytic Leukemia ◽

Calcium Flux ◽

The Novel ◽

Non Hodgkin Lymphoma ◽

Btk Inhibitor

Abstract The novel and irreversible tyrosine kinase inhibitor, Ibrutinib, has shown significant activities across a variety of B-cell tumors such as Chronic Lymphocytic Leukemia (CLL) and B-cell Non-Hodgkin lymphoma, either alone or in combination with antibody therapy. Fcγ receptors (FcγR) on effector immune cells such as macrophages play an important role in tumor-specific antibody-mediated immune responses. Here we tested the effect of Ibrutinib on FcγR-mediated activities in monocytes. Our results indicated that Ibrutinib does not affect monocyte FcγR-mediated phagocytosis even at concentrations higher than those achieved physiologically, but suppresses FcγR-mediated cytokine production. This phenomenon was also seen in macrophages from Xid mice, in which there is a decrease in FcγR-mediated cytokine production but not phagocytosis. One major signaling event downstream of Btk that is blocked by Ibrutinib is calcium flux. Thus, we next tested whether phagocytosis was independent of calcium flux in order to help explain the lack of effect that Ibrutinib had on monocyte phagocytic ability. Results showed that intracellular calcium flux is required for FcγR-mediated cytokine production but not for phagocytosis. In order to verify this finding, we then measured the activation of the GTPase Rac, which is responsible for actin polymerization needed for phagocytosis. Results showed that Ibrutinib did not inhibit Rac activation, nor did inhibition of calcium flux by BAPTA-AM. We next asked whether the effect of Ibrutinib on cytokine production could be reversed by IFNγ priming since NK cells produce significant levels of IFNγ in response to antibody therapy. Treatment of monocytes with IFNγ prior to Ibrutinib treatment resulted in a lack of inhibition of cytokine production, suggesting that IFNγ signaling can overcome Ibrutinib effects. We are currently in the process of examining the mechanisms by which IFNγ can protect from Ibrutinib effects on monocytes. These results suggest that combing Ibrutinib with monoclonal antibodies can enhance B-CLL killing while not affecting macrophage effector function. Disclosures Byrd: Acerta Pharma BV: Research Funding.

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Safety and pharmacokinetics of polatuzumab vedotin in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma: a phase 1 dose-escalation study

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa169 ◽

2020 ◽

Vol 51 (1) ◽

pp. 70-77

Author(s):

Tomohiro Kinoshita ◽

Kiyohiko Hatake ◽

Kazuhito Yamamoto ◽

Yusuke Higuchi ◽

Satsuki Murakami ◽

...

Keyword(s):

Antitumor Activity ◽

B Cell ◽

Disease Progression ◽

Hodgkin Lymphoma ◽

Dose Escalation ◽

Phase 1 ◽

B Cell Lymphoma ◽

Japanese Patients ◽

Dose Escalation Study ◽

Non Hodgkin Lymphoma

Abstract Objective A phase 1 dose-escalation study of polatuzumab vedotin (pola) was conducted to assess safety, pharmacokinetics and preliminary antitumor activity of pola in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Methods Patients received pola (1.0 or 1.8 mg/kg) intravenously every 21 days until disease progression or intolerance. Intra-patient dose escalation was prohibited. Tolerability was determined by the standard 3 + 3 rule. Blood sampling was performed to characterize pharmacokinetics. Antitumor activity was evaluated through computed tomography and bone marrow sampling. Results Four patients received pola 1.0 mg/kg; three received 1.8 mg/kg. Patients had follicular lymphoma (n = 4) or diffuse large B-cell lymphoma (n = 3), median age of 62 years, received a median of 3 prior therapies; six were female. Pola was well tolerated in both cohorts, with no dose-limiting toxicities observed. The most common adverse event was peripheral sensory neuropathy (n = 4). Grade 3 adverse events were cholecystitis and neutrophil count decreased (one each; both 1.0 mg/kg), and syncope and cataract (one each; both 1.8 mg/kg). The plasma half-life of antibody-conjugate monomethyl auristatin E was 4.43–7.98 days, and systemic exposure of unconjugated monomethyl auristatin E was limited in both cohorts. Four patients achieved objective responses (three complete, one partial) without disease progression during the study. Conclusions This phase 1 dose-escalation study demonstrated that pola has an acceptable safety profile and offers encouraging antitumor activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Pola 1.8 mg/kg, the recommended phase 2 dose, was tolerable in Japanese patients.

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