A Modular Phase I/II Open-label Dose Escalation and Dose Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of AZD5492, a T Cell-engaging Antibody Targeting CD20 in Subjects With Relapsed or Refractory B-Cell Malignancies (TITANium)
Study Identifier:
D9960C00001
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
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Recruiting
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Study Summary
This is a Phase I/II study designed to evaluate if experimental T cell engaging antibody targeting CD20 AZD5492 is safe, tolerable and efficacious in participants with Relapsed or Refractory B-Cell Malignancies.
To evaluate the safety and tolerability of AZD5492 as monotherapy or in combination with other anticancer drugs in subjects with R/RB cell malignancies
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
I/II
Sex
Female & Male
Age
18+ years
Study Drug
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Study Status
Indicates the current recruitment status or the expanded access status
Recruiting
Requirements information
Inclusion criteria
- ≥18 years of age;
- Histologically documented CD20+ mature B-cell neoplasm
- Large B-cell lymphoma
- Follicular lymphoma
- Mantle cell lymphoma
- Chronic lymphocytic leukemia
- Small lymphocytic lymphoma
- Relapsed, progressive and/or refractory disease following at least 2 prior lines of therapy;
- ECOG performance status of ≤ 2 (< 2 in EU countries).
- The above is a summary, other inclusion criteria details may apply.
- 1 When signing the informed consent form, subjects must be ≥18 years old (or the legal age of informed consent in the jurisdiction where the research is conducted).
- 2 Eastern Cooperative Oncology Group performance status score ≤ 2
- 3 Be able to provide a tumor biopsy sample obtained prior to AZD5492 treatment (except for subjects with CLL who should provide a bone marrow sample). Note: It is not necessary to receive a tumor sample prior to study entry.
- 4 Normal organ and bone marrow function
- 5 Male or female contraceptive measures should comply with local regulations on contraceptive methods for clinical research subjects.
- 6 Ability to sign the informed consent form (as described in Appendix A), including compliance with the requirements and restrictions outlined in the ICF and this protocol
- 7 CD20+ mature B-cell neoplasms confirmed by histological examination according to the WHO classification (Swerdlow et al 2016), specifically: - Large B-cell lymphoma: o DLBCL (not otherwise specified) o Grade 3b FL o High-grade B-cell lymphoma with rearrangement of MYC and BCL2 and/or BCL6 o High-grade B-cell lymphoma (not otherwise specified) o Primary mediastinal large B-cell lymphoma - Follicular lymphoma (grades 1 to 3a) - Mantle cell lymphoma - Chronic lymphocytic leukemia - Small lymphocytic lymphoma
- 8 Subjects must: - For LBCL, FL, or MCL: have at least one measurable FDG-PET avid lesion based on PET and CT/MRI scans (Appendix G). - For SLL: have at least one measurable lesion based on CT/MRI scans. Note: Measurable lesions are defined as: * For lymph node lesions: >1.5 cm in long diameter * For extranodal lesions: >1 cm in long diameter
- 9 Disease relapse, progression, and/or refractory after at least 2 prior lines of therapy: - FL or LBCL subjects must have received prior anti-CD20 targeted therapy (e.g., rituximab). - MCL subjects must have received prior anti-CD20 targeted therapy (e.g., rituximab) and BTKi. - CLL or SLL subjects must have received prior BCL2i and at least one BTKi in any line of therapy.
- 10 CLL or SLL subjects must meet the treatment requirements of the iwCLL 2018 treatment initiation criteria to meet at least one of the following: - Evidence of progressive bone marrow failure, as evidenced by the development or worsening of anemia (e.g., hemoglobin <10 g/dL) and/or thrombocytopenia (e.g., platelets ≤100×109/L). - Splenomegaly (i.e., spleen margin ≥6 cm below the left costal margin), progressive or symptomatic splenomegaly (>13 cm). - Massive lymphadenopathy (i.e., long diameter ≥10 cm) or progressive or symptomatic lymphadenopathy. - Progressive lymphocytosis, with an increase in lymphocytes >50% within 2 months, or a lymphocyte doubling time <6 months. Other causes of lymphocytosis other than CLL/SLL (e.g., infection, steroid administration) should be excluded. - Autoimmune complications, including anemia or thrombocytopenia that is inadequately responsive to corticosteroids. - Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine). - Disease-related symptoms defined as any of the following: * Unintentional weight loss ≥10% in the past 6 months * Fever ≥100.5°F or 38.0°C for ≥2 weeks without other evidence of infection * Night sweats for ≥1 month without evidence of infection
- 11 FL subjects must require initiation of treatment based on investigator assessment of symptoms and/or disease burden.
- Age 21B years.
- Eastern Cooperative Oncology Group performance status S2_
- Histologically documented CD20+ mature a-cell neoplasm according to the World Health Organization classification5, specifically:
- BCC: Diffuse LBCL not otherwise specified, Grade 3b FL, high-grade a-ce I lymphoma with MYC and BCL2 and/or BCL6 rearrangements,
- high-grade B-ce I lymphoma not Otherwise specified, primary mediastinal LBCC
- FL (Grade I to 3a).
- MCL.
- - CLUSLL.
- For LBCL, MCL and FL, at least one measurable fluorodeoxyglucose-positron emission tomography (FDG-PET) avid lesion based on PET and computed
- tomography/magnetic resonance imaging.
- Active CLUSLL disease requiring therapy (International Workshop of CLL 201 8 criteria6).
- Relapsed, progressive and/or refractory disease following at least 2 prior lines of therapy:
- — Patients with FL or LBCL must have received an anti-CD20 targeted therapy.
- — Patients with MCL must have received an anti-CD20 targeted therapy and a Bruton 's tyrosine kinase inhibitor (BTKi).
- Patients with CLL Or SLL must have been exposed to a BCL2 inhibitor and at least one BTKi in any line of therapy.
- Adequate organ and bone marrow function.
- Eligible patients are aged ≥18 years with histologically documented CD20+ mature B-cell neoplasm, specifically large B-cell lymphoma (LBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL), with ≥1 measurable lesion (except for CLL) and relapsed or refractory disease after ≥2 prior lines of therapy.
Exclusion criteria
- Any neoplasm histology not specified in the IC section;
- Active CNS involvement in lymphoma;
- CNS pathology including but not limited to any history of seizure disorder/epilepsy;
- Prior allogeneic HSCT within 180 days, prior autologous HSCT within 90 days, or cell therapy within 90 days of start of therapy;
- History of Grade ≥ 3 CRS or Grade ≥ 3 ICANS;
- Active and uncontrolled infections;
- Unresolved AEs ≥2 Grade due to prior anticancer therapies, with some exceptions
- The above is a summary, other exclusion criteria details may apply.
- 1Active CNS involvement due to lymphoma, leptomeningeal disease, or spinal cord compression. Subjects with a history of and previously treated for CNS lymphoma were eligible if they had no evidence of CNS involvement by CSF cytology and/or brain MRI at study entry.
- 2CNS pathology, including: - History of symptomatic or treatment-requiring CNS disease in the past year, such as CNS vasculitis, severe brain injury, dementia, Parkinson's disease, neurodegenerative disease, cerebellar disease, severe uncontrolled psychiatric illness, psychosis, autoimmune disease with CNS involvement. - Occurrence of paresis, aphasia, or stroke within 3 months prior to signing the informed consent. - History of epilepsy/seizure disorder. Subjects receiving stable doses of anti-epileptic drugs or not receiving anti-epileptic drugs may be included if there is no seizure activity in the past year. - History of progressive multifocal leukoencephalopathy (PML).
- 3Subjects with a history of hemophagocytic lymphohistiocytosis/macrophage activation syndrome.
- 4Anti-HCV Ab is positive unless HCV PCR is undetectable at screening.
- 5Serological tests indicate active hepatitis B: - HBsAg positive subjects will be excluded. - HBc IgG Ab positive subjects will be excluded if HBV PCR is positive. Subjects may be enrolled if HBV PCR is negative and repeat (or serial) HBV PCR tests are performed during the study (see relevant SoA).
- 6Active HIV infection. HIV-infected subjects who are receiving effective antiretroviral therapy and have an undetectable viral load for more than 6 months prior to enrollment are eligible to participate in this study after confirmation by the sponsor.
- 7Any medical or psychiatric condition of the subject that, in the assessment of the investigator or medical monitor, places the subject at unacceptably high risk of toxicity, may interfere with the success or safety of treatment, or may interfere with the evaluation of the investigational product or the interpretation of the subject's safety or study results. Examples include severe mental illness and drug or alcohol abuse.
- 8A history of QT prolongation associated with other drugs may require discontinuation of the drug.
- 9Suffering from congenital long QT syndrome.
- 10Symptomatic or treatment-requiring arrhythmias (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), symptomatic or uncontrolled atrial fibrillation, or a history of asymptomatic sustained ventricular tachycardia. Subjects whose atrial fibrillation is controlled with medication may participate in the study.
- 11Major cardiac abnormalities, including but not limited to: uncontrolled angina or life-threatening unstable arrhythmias, history of myocardial infarction ≤12 weeks before screening, ≥3 New York Heart Association congestive heart failure, severe heart failure, or persistent QTc interval prolongation (≥480 ms, QTcF).
- 12Non-hematologic AEs of grade ≥ 2 (NCI CTCAE v5.0) due to unresolved prior anticancer therapy, excluding the following: - Alopecia - Fatigue - Grade 2 peripheral neuropathy - Endocrine disorders controllable by replacement hormonal therapy - Stable vitiligo
- 13Other invasive malignancies within 2 years prior to screening, except for the following: (a) Malignancies that have been treated with curative intent and have no evidence of active disease within 2 years prior to screening, and are considered by the treating physician to have a low risk of recurrence. (b) Adequately treated lentigo maligna melanoma with no current evidence of disease, or adequately controlled non-melanoma skin cancer.
- 14Any severe and uncontrolled medical condition requiring treatment (e.g., uncontrolled hypertension, bleeding diathesis, liver failure, clinically significant liver disease [including cirrhosis or hepatitis], unstable respiratory or cardiac disease, active infection [bacterial, viral, fungal or other infection], any major infection requiring hospitalization or treatment with intravenous or oral antimicrobial agents within 14 days prior to Study Day 1, clinically active ILD or evidence of active non-infectious pneumonia, or history of non-infectious pneumonia/ILD) that the investigator believes makes the subject unsuitable for study participation or poses a safety risk to the subject's participation in the study. Please note that a history of COVID-19 infection may be a risk factor, but if recovered and the subject is vaccinated, the subject may be allowed to participate.
- 15Active or documented autoimmune or inflammatory disease (including but not limited to: inflammatory bowel disease [e.g., colitis or Crohn's disease], myasthenia gravis, myositis, autoimmune hepatitis, diverticulitis, systemic lupus erythematosus, Sarcoidosis syndrome or Wegener syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, antiphospholipid syndrome-related vascular thrombosis, Sjogren's syndrome, Guillain-Barre syndrome, vasculitis, glomerulonephritis, etc.) The following are exceptions to this criterion: (a) Vitiligo or alopecia (b) Hypothyroidism that is stable on hormone replacement therapy (e.g., after Hashimoto's thyroiditis). (c) Type 1 diabetes mellitus that can be controlled with insulin. (d) Any subject with a chronic skin disease that does not require systemic therapy. (e) Subjects with no active disease in the past 5 years may be enrolled, but only after consultation with the study physician. (f) Celiac disease that can be controlled with diet alone.
- 16Receipt of a live attenuated vaccine within 28 days prior to the first dose of study treatment.
- 17Subjects with known hypersensitivity to AZD5492 or any of the excipients of this product.
- 18Personnel involved in the design and/or conduct of the study (applicable to AstraZeneca staff and/or site staff).
- 19Subjects who are judged by the investigator to be unlikely to comply with the study procedures, regulations, and requirements are not allowed to participate in this study.
- 20Patients in this study had previously received AZD5492 treatment.
- twenty oneCurrently pregnant (confirmed by a positive pregnancy test), or breastfeeding, or planning to become pregnant (females) or give birth (males) during the study period.
- twenty twoDiagnosis of post-transplant lymphoproliferative disorder, Ritcher transformation, Burkitt lymphoma, or Burkitt-like lymphoma
- Diagnosis of post-transplant lymphoprolferative disease, Richter's transformation, Burkitts lymphoma, or Burkitt-like lymphoma.
- Active central nervous system involvement by lymphoma, leptomeningeal disease or spinal cord compression.
- History of Grade 23 CRS or Grade 23 ICANS.
- History of hemophagocytic lymphohistiocytosis/macrophage activation syndrome,
- History Of seizure disorder/epilepsy.
- Unresolved non-hematological Grade 22 adverse events (AEs) due to prior anticancer therapy except for alopecia, fatigue, Grade 2 peripheral neuropathy, endocrine disorders that are controlled with replacement hormone therapy, and stable vitiligo,
- Received any anti-CD20 monoclonal antibody within 28 days prior to the first dose Of study treatment.
- Prior allogeneic hematopoietic Stem cell transplantation (HSCT) within 180 days, prior autologous HSCT within 90 days, or cell therapy within 90 days of start Of study treatment.
- Active and uncontrolled infections.
- Patients with history of Grade ≥3 CRS or ICANS, post-transplant lymphoproliferative disease, Ritcher’s transformation, Burkitt’s lymphoma or Burkitt-like lymphoma are excluded.
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (FJD)
Madrid, Spain, 28040
Investigator
Daniel Morillo Giles
Status
Recruiting
Condition(s) Treated at Site
Hematological Cancer