ALX148, Rituximab and Lenalidomide for the Treatment of Indolent and Aggressive B-cell Non-Hodgkin Lymphoma

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Brief Title

ALX148, Rituximab and Lenalidomide for the Treatment of Indolent and Aggressive B-cell Non-Hodgkin Lymphoma

Official Title

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

Brief 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.
    

Detailed 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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Recommended phase II dose (RP2D) and schedule of ALX148 (Phase I)

Secondary Outcome

 Overall response rate (ORR) (CR + partial response [PR])

Condition

Aggressive B-Cell Non-Hodgkin Lymphoma

Intervention

CD47 Antagonist ALX148

Study Arms / Comparison Groups

 Treatment (ALX148, rituximab, lenalidomide)
Description:  Patients receive ALX148 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 PO QD on days 1-21 of cycles 1-6. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

52

Start Date

October 13, 2021

Completion Date

March 10, 2026

Primary Completion Date

March 10, 2026

Eligibility Criteria

        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
             document indicating that they understand the purpose of and procedures required for
             the study, including biomarkers, and are willing to participate in the study

          -  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

        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

          -  Any life-threatening illness, medical condition, or organ system dysfunction which, in
             the investigator's opinion, could compromise the subject's safety, interfere with the
             absorption or metabolism of lenalidomide capsules, or put the study outcomes at undue
             risk

          -  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

          -  History of immunodeficiency (with the exception of hypogammaglobulinemia) or
             concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc.,
             or chronic administration glucocorticoid equivalent of > 10 mg/day of prednisone)
             within 28 days of the first dose of study drug

          -  Known anaphylaxis or immunoglobulin (Ig)E-mediated hypersensitivity to murine proteins
             or to any component of ALX148, lenalidomide and/or rituximab

          -  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

          -  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

          -  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 stroke or intracranial hemorrhage within 6 months prior to study entry

          -  Vaccinated with live, attenuated vaccines within 4 weeks of study entry

          -  Lactating or pregnant subjects

          -  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)
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Paolo Strati, MD, (832) 525-8904, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT05025800

Organization ID

2021-0226

Secondary IDs

NCI-2021-08492

Responsible Party

Sponsor

Study Sponsor

M.D. Anderson Cancer Center


Study Sponsor

Paolo Strati, MD, Principal Investigator, M.D. Anderson Cancer Center


Verification Date

August 2022