IRB Study Number 19-1291
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
To assess the anti-tumor activity of single agent odronextamab as measured by the objective response rate (ORR) according to the Lugano Classification of response in malignant lymphoma (Cheson, 2014) and as assessed by independent central review in each of the following B-cell non-Hodgkin lymphoma (B-NHL) subgroups:
• In patients with follicular lymphoma (FL) grade 1-3a that has relapsed after or is refractory to at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.
• In patients with diffuse large B-cell lymphoma (DLBCL) that has relapsed after or is refractory to at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.
• In patients with mantle cell lymphoma (MCL) that has relapsed after or is refractory to a BTK inhibitor. This cohort will also include patients who have relapsed or have disease refractory to prior systemic therapy, or patients who have demonstrated intolerance to BTK inhibitor therapy, and who have progressed after other systemic therapy.
• In patients with marginal zone lymphoma (MZL) that has relapsed after or is refractory to at least 2 prior lines of systemic therapy.
• In patients with other B-NHL subtypes that have relapsed after or are refractory to at least 2 prior lines of systemic therapy.
Secondary Objectives
• To assess the anti-tumor activity of single agent odronextamab in each of 5 disease specific cohorts, as measured by:
− ORR according to the Lugano Classification and as assessed by local investigator evaluation.
− Complete response (CR) rate according to the Lugano Classification and as assessed by local investigator evaluation and independent central review.
− Progression free survival (PFS) according to Lugano Classification and as assessed by:
• Independent central review, and
• Local investigator evaluation
− Overall survival (OS)
− Duration of response (DOR) according to the Lugano Classification and as assessed by:
• Independent central review, and
• Local investigator evaluation
− Disease control rate (DCR) according to the Lugano Classification and as assessed by:
• Independent central review, and
• Local investigator evaluation
• To evaluate the safety and tolerability of odronextamab
• To assess the pharmacokinetics (PK) of odronextamab
• To assess the immunogenicity of odronextamab
• To assess the effect of odronextamab on patient reported outcomes, including healthrelated quality of life (HRQL), as measured by the validated instruments European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym), and EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L)
Inclusion Criteria
Age 18 years or greater
For the FL grade 1-3a cohort only: Central histopathologic confirmation of the FL grade 1 to 3a diagnosis must be obtained before study enrollment. Patients with FL grade 3b are ineligible for this cohort but may be included in the “Other B-NHL” cohort. Follicular lymphoma subtyping is based on the World Health Organization (WHO) classification (Swerdlow, 2017).
Disease-specific cohorts:
Patients should, in the judgment of the investigator, require systemic therapy for lymphoma at the time of study enrollment and should be deemed not appropriate for any other approved therapy with established benefit for that indication. Refractory is defined as no response (SD/PD) or relapse within ≤6 months of last treatment.
• FL grade 1-3a cohort: patients with FL grade 1-3a that has relapsed after or is refractory to at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent; patients must have failed combination lenalidomide and rituximab treatment where approved or deemed not appropriate to receive this treatment according to the investigator.
• DLBCL cohort: patients with DLBCL that has relapsed after or is refractory to at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent. Patients with de novo DLBCL or DLBCL that is transformed from a lower grade neoplasm (eg, FL or CLL) may be enrolled. Patients with DLBCL transformation from prior CLL can only be enrolled in the absence of a leukemic CLL component. For patients with transformed DLBCL, prior systemic therapies administered for the lower grade neoplasm will not be considered among the prior lines of therapy for the purpose of determining eligibility. The following subtypes based on the WHO classification (Beham-Schmid, 2017) are eligible:
− DLBCL not otherwise specified (NOS)
− Germinal center B-cell type
− Activated B-cell type
• MCL after BTK inhibitor therapy cohort: Patients with MCL who have relapsed or refractory disease to at least one prior line of systemic therapy and had prior treatment with a BTK inhibitor.
• MZL cohort: patients with MZL that has relapsed or is refractory to at least 2 prior lines of systemic therapy. As of Global Amendment 6, enrollment has resumed for patients with MZL. Please refer to Section 10.4.4.2 for more information. The following subtypes based on the WHO classification (Beham-Schmid, 2017) are eligible:
− Extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma)
− Nodal marginal zone lymphoma
− Splenic marginal zone lymphoma
• Other B-NHL cohort: patients with B-NHL other than FL grade 1-3a, DLBCL, MCL, or MZL) that has relapsed or is refractory to at least 2 prior lines of systemic therapy. The following subtypes based on the WHO classification (Beham-Schmid, 2017) are eligible:
− Primary mediastinal (thymic) large B-cell lymphoma
− T-cell/histiocyte-rich large B-cell lymphoma
− Epstein-Barr virus (EBV)+ DLBCL, NOS
− High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
− High-grade B-cell lymphoma, NOS
− B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
− Follicular lymphoma, grade 3b
Note:
▪ Patients with a current diagnosis of mixed histology B-NHL with an aggressive component (such as, concurrent FL and DLBCL) are included in Other B-NHL cohort.
▪ Patients with a current diagnosis of transformed DLBCL, that have relapsed or are refractory to at least 2 prior lines of systemic therapy administered for lower grade neoplasm which are considered as standard regimens in aggressive lymphoma, will be included in the Other B-NHL cohort.
▪ Patients with Waldenström macroglobulinemia (WM, lymphoplasmacytic lymphoma), small lymphocytic leukemia (SLL) and chronic lymphocytic leukemia (CLL), Burkitt lymphoma and Burkitt-like lymphoma with 11q aberration are excluded.
Measurable disease on cross sectional imaging (defined as at least 1 bi-dimensionally measurable nodal lesion of ≥1.5 cm or measurable non-nodal lesions of >1.0 cm in the greatest transverse diameter (GTD) regardless of the short axis diameter) documented by diagnostic imaging (computed tomography [CT], or magnetic resonance imaging [MRI]).
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
Adequate bone marrow function as documented by:
a. Platelet count ≥50 x 109/L. A patient may not have received platelet transfusion therapy within 7 days prior to first dose of odronextamab in order to meet the platelet eligibility criterion.
b. Hemoglobin ≥9.0 g/dL
c. Absolute neutrophil count (ANC) ≥1.0 x 109/L. A patient may not have received granulocyte colony stimulating factor within 2 days prior to first dose of odronextamab in order to meet the ANC eligibility criterion.
• Patients with bone marrow involvement or splenic sequestration should meet the following hematologic parameters:
− Platelet count ≥25 x 109/L. A patient may not have received platelet transfusion therapy within 3 days prior to first dose of odronextamab in order to meet the platelet eligibility criterion.
− Hemoglobin ≥7.0 g/dL
− Absolute neutrophil count (ANC) ≥ 0.5 x 109/L. A patient may not have received granulocyte colony stimulating factor within 2 days prior to first dose of odronextamab in order to meet the ANC eligibility criterion.
- Adequate hepatic function:
a. Total bilirubin 1.5 upper limit of normal (ULN) (3 ULN if attributed to lymphoma infiltration of liver)
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 ULN (5 ULN if attributed to lymphoma infiltration of liver)
c. Alkaline phosphatase (ALP) 2.5 ULN (5 ULN if attributed to lymphoma infiltration of liver)
NOTES:
Irrespective of the presence of lymphoma infiltration of the liver, a patient with an AST >2.5 ULN and/or ALT >2.5 x ULN concurrent with a total bilirubin >1.5 x ULN will be excluded.
Patients with known Gilbert syndrome will be excluded if the total bilirubin value is >4 x upper limit of normal (ULN) for the local general population.
- Serum creatinine ≤1.5 ULN, or calculated creatinine clearance by Cockcroft-Gault formula ≥50 mL/min.
NOTE: Patients with a calculated creatinine clearance <50 mL/min may be considered for enrollment if a measured creatinine clearance (based on 24-hour urine collection or other reliable method) is ≥50 mL/min.
Willingness to undergo tumor biopsy at baseline. If an investigator has determined that a baseline tumor biopsy cannot be obtained safely, the sponsor may grant an exception to the requirement for biopsy only after discussion with and approval by the medical monitor.
Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations).
Willing and able to comply with clinic visits and study-related procedures
Provide informed consent signed by study patient or legally acceptable representative
Able to understand and complete study-related questionnaires
Exclusion Criteria
Primary central nervous system (CNS) lymphoma or known involvement by non-primary CNS NHL (suspected CNS lymphoma should be evaluated by lumbar puncture, as appropriate, in addition to the mandatory head CT or MRI).
Treatment with any systemic anti-lymphoma therapy within 5 half-lives or within 28 days prior to first administration of study drug, whichever is shorter.
History of allogeneic stem cell transplantation.
Criterion removed.
Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone or anti-inflammatory equivalent within 72 hours of start of study drug.
History of neurodegenerative condition or CNS movement disorder. Patients with a history seizure within 12 months prior to study enrollment are excluded.
Vaccination within 28 days prior to first study drug administration with a vector that has replicative potential.
Another malignancy except B-NHL in the past 5 years, with the exception of nonmelanoma skin cancer that has undergone potentially curative therapy or in situ cervical carcinoma, or any other tumor that has been deemed to be effectively treated with definitive local control and with curative intent.
Evidence of significant concurrent disease or medical condition that could interfere with the conduct of the study or put the patient at significant risk, including but not limited to significant cardiovascular disease (eg, New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) and/or significant pulmonary disease (eg, obstructive pulmonary disease and history of symptomatic bronchospasm).
Cardiac ejection fraction <40% by echocardiogram or multigated acquisition (MUGA) scan.
Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first administration of study drug.
Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection; or other uncontrolled infection.
a. Patients with HIV who have controlled infection (undetectable viral load and CD4 count above 350 cells/microliter either spontaneously or on a stable antiviral regimen) are permitted.
b. Patients with hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA polymerase chain reaction [PCR] that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted.
c. Patients who are hepatitis C virus antibody positive (HCV Ab +) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.
d. Cytomegalovirus (CMV) infection as noted by detectable levels on a blood PCR assay. Patients who show detectable levels of CMV at screening will need to be treated with appropriate antiviral therapy and demonstrate at least 2 undetectable levels of CMV by PCR assay (at least 7 days apart) before being reconsidered for eligibility.
History of severe allergic reaction attributed to compounds with a similar chemical or biologic composition as that of the study drug or excipient. A severe allergic reaction is defined for this purpose as that requiring hospitalization and/or treatment with epinephrine.
Known hypersensitivity to both allopurinol and rasburicase
Member of the clinical site study team or his/her immediate family, unless prior approval granted by the sponsor.
Women of childbearing potential (WOCBP) with a positive serum β-hCG pregnancy test are ineligible for this study.
Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
Pregnant or breastfeeding women.
Women of childbearing potential* or men who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Sperm donation is prohibited during the study and for 6 months after the last dose of study drug. Highly effective contraceptive measures include:
a. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS)
c. bilateral tubal ligation
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the study participant and that the partner has obtained medical assessment of surgical success for the procedure).
e. and/or sexual abstinence†, ‡.
Women of childbearing potential are defined as women who are fertile following menarche until becoming post-menopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a post-menopausal state. The above definitions are according to Clinical Trial Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy.
† Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.
‡ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.
- Prior treatment with an anti-CD20 x anti-CD3 bispecific therapy.
