A Phase I/II Open Label, Single Center, Study of the Combination of ALX148, Rituximab and Lenalidomide in Patients With Indolent and Aggressive B-Cell Non-Hodgkin Lymphoma

  • STATUS
    Recruiting
  • End date
    Mar 10, 2026
  • participants needed
    52
  • sponsor
    M.D. Anderson Cancer Center
Updated on 14 October 2022

Summary

This phase I/II trial finds out the best dose, possible benefits and/or side effects of ALX148 in combination with rituximab and lenalidomide in treating patients with indolent and aggressive B-cell non-Hodgkin lymphoma. Immunotherapy with ALX148, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody that binds to a protein called CD20 found on B-cells, and may kill cancer cells. Giving ALX148 in combination with rituximab and lenalidomide may help to control the disease.

Description

PRIMARY OBJECTIVES:

I. To evaluate safety and tolerability, and to determine the recommended phase II dose (RP2D) and schedule of CD47 antagonist ALX148 (ALX148) in combination with rituximab and lenalidomide in patients with relapsed or refractory B-non-Hodgkin lymphomas (NHLs) (both indolent and aggressive histology) in phase I.

II. To evaluate the efficacy of the combination of ALX148, rituximab and lenalidomide at the RP2D (determined in phase I) in patients with previously untreated and high tumor burden indolent B-NHL in phase II.

SECONDARY OBJECTIVE:

I. To evaluate other toxicity and efficacy measures of the combination of ALX148, rituximab and lenalidomide.

EXPLORATORY OBJECTIVE:

I. To determine the pharmacodynamic effects and investigate biomarkers of response and resistance.

OUTLINE: This is a phase I, dose-escalation study of ALX148 followed by a phase II study.

Patients receive ALX148 intravenously (IV) over 1 hour once on days 1, 8, 15 and 22, or days 1 and 15, or day 1 depending on dose level. Patients also receive rituximab IV over 4-6 hours on days 1, 8, 15 and 22 of cycle 1, then on day 1 of cycles 2-6, and lenalidomide orally (PO) daily once (QD) on days 1-21 of cycles 1-6. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 7 and 30 days, then up to 3 years.

Details
Condition Aggressive B-Cell Non-Hodgkin Lymphoma, Ann Arbor Stage III Grade 2 Follicular Lymphoma, Ann Arbor Stage III Grade 3 Follicular Lymphoma, Ann Arbor Stage III Marginal Zone Lymphoma, Ann Arbor Stage IV Grade 1 Follicular Lymphoma, Ann Arbor Stage IV Grade 2 Follicular Lymphoma, Ann Arbor Stage IV Grade 3 Follicular Lymphoma, Ann Arbor Stage IV Marginal Zone Lymphoma, Composite Lymphoma, Indolent B-Cell Non-Hodgkin Lymphoma, Refractory Aggressive B-Cell Non-Hodgkin Lymphoma, Refractory Follicular Lymphoma, Refractory Grade 3b Follicular Lymphoma, Refractory High Grade B-Cell Lymphoma, Refractory Mantle Cell Lymphoma, Refractory Marginal Zone Lymphoma, Refractory Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Refractory Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma, Refractory Transformed Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma, Richter Syndrome
Treatment Rituximab, Lenalidomide, CD47 Antagonist ALX148
Clinical Study IdentifierNCT05025800
SponsorM.D. Anderson Cancer Center
Last Modified on14 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Phase I: histologically confirmed B-cell NHL, including marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, large B-cell lymphoma (including transformed marginal zone lymphoma [MZL], transformed follicular lymphoma [FL], Richter syndrome with absolute lymphocyte count [ALC] < 5,000 10^9/L, FL grade 3B, high grade B-cell lymphoma and primary mediastinal B-cell lymphoma), and composite lymphoma (concomitant indolent and aggressive B-NHL)
Phase I: have failed at least one line of systemic therapy and not be eligible for known standard of care curative treatment option; patients with mantle cell lymphoma and aggressive B-cell lymphoma will need to have received 2 prior lines of systemic therapy
Phase II: histologically confirmed follicular lymphoma, grade 1, 2, or 3a or marginal zone lymphoma
Phase II: have had no prior systemic treatment for lymphoma
Phase II: high tumor burden disease, defined by meeting 1 or more of the following Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria
Bulky disease defined as: a nodal or extranodal (except spleen) mass > 7 cm in its greater diameter or, involvement of at least 3 nodal or extranodal sites (each with a diameter greater than > 3 cm)
Presence of at least one of the following B symptoms: fever (> 38 Celsius [C]) of unclear etiology, night sweats, weight loss greater than 10% within the prior 6 months
Symptomatic splenomegaly
Impending organ compression or involvement
Any one of the following cytopenias due to lymphoma: hemoglobin < 10 g/dL (6.25 mmol/L), platelets < 100 x 10^9/L , or absolute neutrophil count (ANC) < 1.5 x 10^9 /L
Pleural or peritoneal serous effusion (irrespective of cell content)
Lactate dehydrogenase [LDH] > upper limit of normal (ULN) or beta 2 microglobulin > ULN
Phase II: stage III or IV disease
Bi-dimensionally measurable disease, with at least one nodal lesion >= 1.5 cm or one extra-nodal lesion >= 1 cm in longest diameter by computed tomography (CT), positron emission tomography (PET)/CT, and/or magnetic resonance imaging (MRI)
Must be >= 18 years of age
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Absolute neutrophil count (ANC) >= 1,000/mm^3, independent of growth factor support (within 28 days prior to signing informed consent)
Platelet counts >= 75,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement with lymphoma, independent of transfusion support for >= 14 days in either situation (within 28 days prior to signing informed consent)
Hemoglobin > 8 g/dL, independent of transfusion support for >= 14 days (within 28 days prior to signing informed consent)
Serum aspartate transaminase (AST) and alanine transaminase (ALT) < 2 x upper limit of normal (ULN)
Creatinine clearance > 30 ml/min calculated by modified Cockcroft-Gault formula
Total bilirubin < 1.5 x ULN unless bilirubin is due to Gilbert's syndrome, documented liver involvement with lymphoma, or of non-hepatic origin, in which case bilirubin should not exceed 3 g/dL
Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial thromboplastin time (PTT) < 1.5 x ULN
Must be able to adhere to the study visit schedule and other protocol requirements
Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study (females of childbearing potential: must either completely abstain from heterosexual sexual conduct or must use 2 methods of reliable contraception, 1 highly effective [intrauterine device, birth control pills, hormonal patches, injections, vaginal rings, or implants] and at least 1 additional method [condom, diaphragm, cervical cap] of birth control). Reliable contraceptive methods must be started at least 4 weeks before lenalidomide, and continued for at least 4 weeks after last dose of lenalidomide. Males who are sexually active must be practicing complete abstinence or agree to a condom during sexual contact with a pregnant female or female of child bearing potential. Men must agree to not donate sperm during the study and 28 days after the last dose of lenalidomide. For females, these restrictions apply at least 4 weeks before study treatment, during the period of therapy and for 120 days after the last dose of study drug. For males, these restrictions apply during the period of therapy and for 28 days after the last dose of study drug
Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study
Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program
Sign (or their legally-acceptable representatives must sign) an informed consent
All study participants must be registered into the mandatory Revlimid REMS program, and be willing and able to comply with the requirements of the REMS program
document indicating that they understand the purpose of and procedures
required for the study, including biomarkers, and are willing to participate
in the study

Exclusion Criteria

Known active central nervous system lymphoma or leptomeningeal disease, except subjects with a history of central nervous system lymphoma treated and in remission > 6 months
Burkitt lymphoma
Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia
Any prior history of other malignancy besides B-NHL, unless the patient has been free of disease for >= 3 years and felt to be at low risk for recurrence by the treating physician, except
Adequately treated localized skin cancer without evidence of disease
Adequately treated cervical carcinoma in situ without evidence of disease
Known history of human immunodeficiency virus (HIV), or active hepatitis C virus, or active hepatitis B virus infection, or any uncontrolled active significant infection, including suspected or confirmed JC virus infection and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)
Patients with inactive hepatitis B infection must adhere to hepatitis B reactivation prophylaxis unless contraindicated. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded. Subjects with a history of hepatitis C who received antiviral treatment are eligible as long as PCR is negative
Any life-threatening illness, medical condition, or organ system dysfunction which, in
Known anaphylaxis or immunoglobulin (Ig)E-mediated hypersensitivity to murine proteins or to any component of ALX148, lenalidomide and/or rituximab
the investigator's opinion, could compromise the subject's safety, interfere
Requires chronic treatment with strong CYP3A inhibitors, for a list of strong CYP3A inhibitors. If patients have been on a strong CYP3A inhibitor in the past, they will not be eligible if the CYP3A inhibitor was administered within 7 days of the first dose of study drug
with the absorption or metabolism of lenalidomide capsules, or put the study
Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study
outcomes at undue risk
Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree block
Active bleeding or known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia
History of immunodeficiency (with the exception of hypogammaglobulinemia) or
History of stroke or intracranial hemorrhage within 6 months prior to study entry
concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus
Vaccinated with live, attenuated vaccines within 4 weeks of study entry
etc., or chronic administration glucocorticoid equivalent of > 10 mg/day of
Lactating or pregnant subjects
prednisone) within 28 days of the first dose of study drug
Administration of any investigational agent within 28 days of first dose of study drug
Patients who have undergone major surgery within 28 days or minor surgery within 3 days of first dose of study drug
Patients taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 10 mg/day prednisone (over these 4 weeks)
Life expectancy < 6 months
Neuropathy > grade 1
Prior exposure to lenalidomide or to a CD47/SIRP alpha antagonist/inhibitor, independently from indication
Patient who received chimeric antigen receptor (CAR) T-cell therapy within 1 month, autologous stem cell transplant within 3 months, allogeneic stem cell transplant within 6 months
Patients who have difficulty with or are unable to swallow oral medication, or have disease significantly affecting gastrointestinal function that would limit absorption of oral medication
Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP)
History of hemolytic transfusion reaction secondary to allo-antibodies
Patients who have an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
Patients who have a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
Known history of symptomatic deep vein thrombosis or pulmonary embolism
Known history of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) or drug rash with eosinophilia and systemic symptoms (DRESS)
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