Study of Acalabrutinib and Tafasitamab in MZL Patients
Study Details
Study Description
Brief Summary
This is a multicenter open label phase II trial in patients with previously treated Marginal Zone Lymphomas.
The aim of the study is to evaluate the efficacy and the safety of tafasitamab in combination with acalabrutinib.
Twenty-four patients are expected to be enrolled and treated every 28 days with acalabrutinib and tafasitamab for 24 cycles.
The study consists of two parts, which are performed sequentially. The first part is a safety run-in to evaluate the safety data once 6 patients (representing the 25% of the total cohort) have completed the first cycle of treatment. An Independent Data Monitoring Committee (IDMC) will provide an independent assessment of this evaluation.
The second part starts after the outcome of this evaluation and will include the remaining 18 patients. The 6 patients of the safety run-in phase will be considered for the final evaluation of the study.
Between 11 - 13 weeks, patients showing partial or complete response (PR, CR) will continue treatment, while patients showing stable disease (SD) will discontinue it. However, patients in SD who benefit from therapy may continue to be treated, after agreement between the Investigator and the Sponsor.
Patients who complete the 24 cycles of treatment will enter the follow-up phase up to 3 years from patient's last study treatment dose (about 5 years from treatment start).
Patients who discontinue treatment before cycle 24 for any reason will be followed for up to 3 years (every 6 months for the first year and yearly for the second and third year) from the patient's last study treatment dose.
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Condition or Disease | Intervention/Treatment | Phase |
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Phase 2 |
Detailed Description
Marginal zone B cell lymphomas (MZLs) comprise three distinct entities: extranodal MZL (EMZL) of mucosa-associated lymphoid tissue type (MALT) lymphoma, splenic MZL (SMZL) and nodal MZL (NMZL).
Together they represent approximately 5%-15% of all non-Hodgkin lymphomas.
MZL are in general indolent lymphomas with relatively low risk of transformation. The available treatment options can lead to responses but disease recurrence is often observed. For patients with MZL and recurrent disease following initial treatment, currently there is no established standard therapy and new treatment options and treatment combinations are needed.
The proposed trial will evaluate the safety and efficacy of the anti-CD19 monoclonal antibody tafasitamab in combination with the BTK inhibitor acalabrutinib. The B-lymphocyte, lineage specific surface antigen CD19 is broadly and homogeneously expressed in MZLs. This makes CD19 an attractive target for the treatment of MZL patients, in particular those who failed a previous rituximab-containing regimen.
On the other hand, genetic and immunogenetic data point to B-cell receptor signalling as a key oncogenic pathway of MZLs. The activity of single agent ibrutinib in MZLs is an in vivo proof that MZLs are addicted of BTK-driven signalling and that the BCR pathway is a vulnerability of these lymphomas.
The safety profile of the anti CD19 monoclonal antibody tafasitamab and of the BTK inhibitor acalabrutinib indicate the possibility that their combination can be developed without major overlapping side effects.
The proposed trial is a prospective multicenter trial combining tafasitamab and acalabrutinib in patients with MZL (including EMZL, SMZL and NMZL) with disease refractory to or in first or greater relapse after prior systemic therapy.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Tafasitamab and Acalabrutinib Acalabrutinib will be administered continuously at the dose of 100 mg BID (equivalent to a total daily dose of 200 mg), from day 1 to day 28 of each cycle for 24 cycles. Tafasitamab will be administered 12 mg/kg iv on days 1, 8, 15 and 22 for the first 3 cycles. Then patients will continue treatment until cycle 24 with tafasitamab 12mg/kg iv on day 1 |
Drug: Tafasitamab
200 mg powder for reconstitution with 5 ml water for injection
Other Names:
Drug: Acalabrutinib
100 mg hard gelatin capsules
Other Names:
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Outcome Measures
Primary Outcome Measures
- Complete Response (CR) Rate as best response to treatment [Between 11 - 13 weeks after treatment start, at the end of cycles 6, 12, 18, 24 (each cycle is 28 days)]
defined according to the international Revised Response Criteria for Malignant Lymphoma (Cheson et al 2014). For patients with SMZL, response is defined according to Matutes et al. 2008 and for patients with gastric lymphomas, histological response is evaluated according to GELA scoring system (Copie-Bergman et al 2003).
Secondary Outcome Measures
- Number of treatment emergent adverse events (AE) [From the time of informed consent signature until 28 days after treatment discontinuation or until resolution of all treatment-related AEs, whichever occurs later.]
Analysis of type and severity of Adverse Events according to CTCAE v5.0 and relationship to study treatment
- Overall Response Rate (ORR) [Between 11 - 13 weeks after treatment start, at the end of cycles 6, 12, 18, 24 (each cycle is 28 days)]
ORR will be defined as sum of PR plus CR defined according to the revised response criteria for malignant lymphomas (Cheson et al 2014), to the GELA Histological Grading System for gastric EMZL and the Matutes criteria for SMZL.
- Progression Free Survival (PFS) [From the date of treatment start to the date of progression or the date of death for any cause until 3 years from last treatment dose]
PFS will be computed from the first IMP dose to date of disease progression or date of death for any reason or censored at the date of the last follow-up visit, whichever occurs earlier
- Duration of response (DoR) [From the date of the first documented response to the date of disease progression or relapse or death until 3 years from last treatment dose]
DOR will be define as the time between the first documented response to therapy and subsequent disease progression or relapse or death according to the international Revised Response Criteria for Malignant Lymphoma (Cheson et al 2014).
- Overall Survival (OS) [From the date of treatment start to the date of death for any cause until 3 years from last treatment dose]
Overall survival (OS) will be computed from the first IMP dose to the date of death for any reason or censored at the date of the last contact, whichever occurs earlier
Eligibility Criteria
Criteria
Inclusion Criteria:
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Ability to understand and willingness to sign a written informed consent
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Histologically confirmed diagnosis of MZL.
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Disease refractory to or in first or greater relapse after prior systemic therapy.
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In need of treatment disease satisfying the following criteria:
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EMZL: symptomatic lymphoma or with other treatment indications (overt progression, deep invasion, bulky disease, impending organ damage, patient preference), symptomatic disseminated disease, contraindications to RT, failure after antibiotics or after local therapy,
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SMZL: presence of progressive or symptomatic splenomegaly and/ or any progressive cytopaenias,
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NMZL: B symptoms, deterioration of peripheral blood counts due to lymphoma infiltration of the bone marrow, rapid enlargement of lymph nodes or compression of vital organs by bulky disease.
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Measurable or non-measurable lesions where the response is nevertheless evaluable by non-imaging means (e.g., gastric or bone marrow infiltrations).
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Ann Arbor Stage I-IV.
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ECOG performance status of 0, 1 or 2.
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Age ≥ 18 years.
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Absolute neutrophil count (ANC) ≥ 1.000/mm3 and platelets ≥ 100.000/mm3, unless these abnormalities are related to bone marrow infiltration or to hypersplenism.
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Adequate hepatic function, renal function and coagulation parameters
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Women with childbearing potential who are using highly effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and for at least 3 months after the last IMP dose.
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Men who agree not to father a child during trial treatment and for at least 3 months after the last IMP dose.
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Patient able and willing to swallow trial drugs as whole capsule
Exclusion Criteria:
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Patients with a prior malignancy and treated with curative intention, unless all treatments of that malignancy were completed at least 2 years before registration and the patient has no evidence of disease at registration. Less than 2 years is acceptable for malignancies with low-risk of recurrence and/or no late recurrence.
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Major surgery and any systemic anti-cancer treatment within 3 weeks prior to registration.
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Prior exposure to a BTK inhibitor or CD19-targeted therapy.
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Steroid therapy for anti-neoplastic intent.
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Severe or uncontrolled cardiovascular disease
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History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to registration and known bleeding disorders
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Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML).
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Concomitant diseases that require anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists and patients treated with dual anti-platelet therapy. Patients being treated with factor Xa inhibitors (e.g. rivaroxaban, apixaban, edoxaban), direct thrombin inhibitors (e.g. dabigatran) LMWH, or single anti-platelets agents (e.g. aspirin, clopidogrel) can be included, but must be properly informed about the potential risk of bleeding.
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Malabsorption syndrome or other condition that precludes enteral route of administration.
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Active human immunodeficiency virus (HIV) or active chronic hepatitis C or hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous (iv) antimicrobial treatment.
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Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune. thrombocytopenia) requiring steroid therapy with > 20 mg daily of prednisone dose or equivalent.
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Known hypersensitivity to trial drugs or to any component of the trial drugs.
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Concomitant treatment with strong CYP3A inducers or inhibitors
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Treatment with proton pump inhibitors. Subjects receiving proton pump inhibitors who switch to antacids are eligible for enrollment to this study.
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Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with trial participation or IMPs administration or may interfere with the interpretation of trial results and/or would make the patient inappropriate for enrolment into this trial.
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Concurrent participation in another therapeutic clinical trial
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | University of Wien | Wien | Austria | 1190 | |
2 | ASST Spedali Civili di Brescia | Brescia | Italy | ||
3 | Fondazione IRCCS - Istituto Nazionale dei Tumori | Milano | Italy | ||
4 | Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico | Milano | Italy | ||
5 | Ospedale Maggiore della Carità | Novara | Italy | ||
6 | AUSL Ravenna U.O. Ematologia | Ravenna | Italy | 48121 | |
7 | Azienda Ospedaliera - IRCCS - Arcispedale Santa Maria Nuova | Reggio Emilia | Italy | ||
8 | A.O.U. Città della Salute e della Scienza di Torino - Ospedale Molinette | Torino | Italy | ||
9 | Ospedale di Circolo e Fondazione Macchi - ASST Sette Laghi | Varese | Italy | ||
10 | Oncology Institute of Southern Switzerland | Bellinzona | Switzerland | 6500 |
Sponsors and Collaborators
- International Extranodal Lymphoma Study Group (IELSG)
Investigators
- Study Chair: Anastasios Stathis, MD, Oncology Institute of Southern Switzerland - Bellinzona, Switzerland
- Study Chair: Davide Rossi, MD, Oncology Institute of Southern Switzerland - Bellinzona, CH
- Study Chair: Emanuele Zucca, MD, Oncology Institute of Southern Switzerland - Bellinzona, CH
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IELSG49
- 2019-004396-38