IRB Study Number 24-395
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
Characterize the safety and tolerability of loncastuximab tesirine in combination with polatuzumab vedotin, glofitamab, or mosunetuzumab, and to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) for the combinations
Secondary Objectives
Evaluate the anti-cancer effect of the combination of loncastuximab tesirine with polatuzumab vedotin, glofitamab, or mosunetuzumab
Characterize the pharmacokinetics (PK) of loncastuximab tesirine in combination with polatuzumab vedotin, glofitamab, or mosunetuzumab
Evaluate the immunogenicity of loncastuximab tesirine, glofitamab, and mosunetuzumab
Inclusion Criteria
Male or female patient aged 18 years or older.
Pathologic diagnosis of relapsed (disease that has recurred following a response) or refractory (disease that failed to respond to prior therapy) B-NHL (2016 World Health Organization classification) who have failed, or been intolerant to any approved therapy and had received at least two systemic treatment regimens in dose-escalation part; and at least one systemic treatment regimen in dose-expansion part.
DLBCL (including transformed diseases, but for Arms E and F, including transformed FL only)
HGBCL
FL
MZL
For Arm C only:
MCL
BL
Life expectancy of at least 24 weeks according to Investigator’s judgement
Need of systemic treatment for any of the listed indications as assessed by the investigator, including indolent B-NHLs (e.g., FL and MZL)
Measurable disease as defined by the 2014 Lugano Classification (Appendix 2)
Availability of formalin-fixed paraffin-embedded tumor tissue block (or minimum 10 freshly cut unstained slides if block is not available); if not available, Sponsor approval is required. Note: Any biopsy since initial diagnosis is acceptable, but if several samples are available, the most recent sample is preferred. For the arms including glofitamab or mosunetuzumab, a biopsy collected after the last prior CD20 directed therapy should be submitted, if available.
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
Adequate organ function as defined by screening laboratory values within the following parameters:
Absolute neutrophil count (ANC) ≥1.5 × 103/μL (off growth factors at least 72 hours)
Platelet count ≥75 × 103/μL without transfusion in the past 7 days
Hemoglobin ≥9 g/dL, transfusion allowed
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and GGT ≤2.5 × the upper limit of normal (ULN)
Total bilirubin ≤1.5 × ULN (patients with known Gilbert’s syndrome may have a total bilirubin up to ≤3 × ULN)
Calculated creatinine clearance ≥60 mL/min by the Cockcroft and Gault equation Note: A laboratory assessment may be repeated a maximum of two times during the Screening Period to confirm eligibility.
- Women of childbearing potential (WOCBP)* must agree to use a highly effective** method of contraception from the time of giving informed consent until at least 10 months after the last dose of loncastuximab tesirine. Men with female partners who are of childbearing potential must agree to use a condom when sexually active or practice total abstinence from the time of the first dose until at least 7 months after the last dose of loncastuximab tesirine. Men must refrain from donating sperm during this same period. For the arm that includes glofitamab, WOCBP must agree to use contraceptive methods that result in a failure of <1% per year or remain abstinent (refrain from heterosexual intercourse) during the treatment period and for at least 18 months after pretreatment with obinutuzumab. For the arm that includes mosunetuzumab, WOCBP must agree to use contraceptive methods that result in a failure of <1% per year or remain abstinent (refrain from heterosexual intercourse) during the treatment period and for at least 3 months after the final dose of mosunetuzumab and tocilizumab (if applicable). * WOCBP are defined as sexually mature women who have not undergone bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or who have not been postmenopausal (i.e., who have not menstruated at all) for at least one year. A postmenopausal 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 postmenopausal 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. ** Highly effective forms of birth control are methods that achieve a failure rate of less than 1% per year when used consistently and correctly. Highly effective forms of birth control include: hormonal contraceptives with inhibition of ovulation (oral, injectable, patch, intrauterine devices), male partner sterilization, or total abstinence from heterosexual intercourse, when this is the preferred and usual lifestyle of the patient. Note: The double-barrier method (e.g., synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), periodic abstinence (such as calendar, symptothermal, post ovulation), withdrawal (coitus interruptus), lactational amenorrhea method, and spermicideonly are not acceptable as highly effective methods of contraception.
Exclusion Criteria
Known history of hypersensitivity resulting in treatment discontinuation to, or positive serum human anti-drug antibody (ADA) to a CD19 antibody
Previous therapy with loncastuximab tesirine
Previous treatment with polatuzumab vedotin, glofitamab, or mosunetuzumab (applied to relevant arm and/or cohort of the specific drug administered)
Patients who received previous treatment of polatuzumab vedotin containing regimen will be excluded from Arm C
Patients who received previous treatment of glofitamab containing regimen will be excluded from Arm E
Patients who received previous treatment of mosunetuzumab containing regimen will be excluded from Arm F
Allogeneic or autologous stem cell transplant within 60 days prior to start of study drug (Cycle 1 Day 1 [C1D1])
Active acute graft-versus-host disease
Post-transplant lymphoproliferative disorder
Human immunodeficiency virus (HIV) seropositive with any of the following:
a. CD4+ T-cell (CD4+) counts <350 cells/μL
b. Acquired immunodeficiency syndrome-defining opportunistic infection within 12 months prior to screening
c. Not on anti-retroviral therapy, or on anti-retroviral therapy for <4 weeks at the time of screening
d. HIV viral load ≥400 copies/mL
Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy or with detectable HBV viral load
Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load
History of confirmed progressive multifocal leukoencephalopathy
History of Stevens-Johnson syndrome, toxic epidermal necrolysis, or macrophage activation syndrome (MAS)/HLH
Lymphoma with active central nervous system (CNS) involvement at the time of screening, including leptomeningeal disease
Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath)
Breastfeeding or pregnant
Significant medical comorbidities, including but not limited to uncontrolled hypertension (blood pressure [BP] ≥160/100 mmHg repeatedly), unstable angina, congestive heart failure (greater than New York Heart Association class II, or objective class C or D heart disease), venous or arterial thromboembolism, electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial infarction within 6 months prior to screening, uncontrolled atrial or ventricular cardiac arrhythmia, poorly controlled diabetes, or severe chronic pulmonary disease
Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy, within 14 days prior to start of study drugs (C1D1), except shorter if approved by the Sponsor
Use of any other experimental medication within 14 days or five half-lives prior C1D1
Live vaccine within 4 weeks prior to C1D1
Failure to recover to Grade ≤1 (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) from acute non-hematologic toxicity (Grade ≤2 alopecia) due to previous therapy prior to screening
Congenital long QT syndrome or a corrected Fridericia correction of the QT measure (QTcF) interval of >480 ms at screening (unless secondary to pacemaker or bundle branch block)
Active second primary malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor’s medical monitor and Investigator agree and document should not be exclusionary
Any other significant medical illness, abnormality, or condition that would, in the Investigator’s judgment, make the patient inappropriate for study participation or put the patient at risk
Extra Exclusion Criteria for Arms E (includes glofitamab) and F (includes mosunetuzumab) Note: as applicable, the arm-specific exclusion criteria may supersede the general ones, such as stem cell transplant.
Prior allogeneic stem cell transplant and solid organ transplant
Autologous stem cell transplant within 100 days prior to C1D1
History of CNS lymphoma or leptomeningeal infiltration
Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease Note: patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past two years and have no residual neurologic deficits, as judged by the investigator, are allowed.
Known active infection, reactivation of a latent infection, whether bacterial, viral (including, but not limited to severe pneumonia, COVID-19, Epstein-Barr virus [EBV], cytomegalovirus [CMV]), fungal, mycobacterial (e.g., tuberculosis), or other pathogens (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within four weeks prior to C1D1 Note: Patients receiving prophylactic antibiotics (e.g. to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study. Exclusion of patients with mycobacterial infections on the basis of chest X-ray, computed tomography (CT), or a positive Quantiferon or Mantoux test.
Active or history of autoimmune disease or immune deficiency, including but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
Rash must cover <10% of body surface area.
Disease is well controlled at baseline and requires only low-potent topical corticosteroids.
No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potent oral corticosteroids within the previous 12 months.
Prior treatment with anti-cancer/lymphoma targeted therapies (e.g., tyrosine kinase inhibitors, systemic immunotherapeutic/immunostimulating agents, including, but not limited to, CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), anti-programmed cell death protein 1 (PD1), and anti-programmed death-ligand 1 (PDL1) therapeutic antibodies, radio-immunoconjugates, ADCs, immune/cytokines and monoclonal antibodies) or treatment with systemic immunosuppressive medication (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to C1D1, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
Prior treatment with CAR T-cell therapy within 30 days prior to C1D1
Toxicities from prior anti-cancer therapy including immunotherapy that did not resolve to ≤ Grade 1 with the exception of alopecia, endocrinopathy managed with replacement therapy and stable vitiligo
Any history of immune-related Grade ≥3 AE with the exception of endocrinopathy managed with replacement therapy
Ongoing corticosteroid use >25 mg/day of prednisone or equivalent within 4 weeks prior and during study treatment
Patients who received corticosteroid treatment with ≤25 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 week duration prior to Day -7 of Cycle 1.
Patients may have received a brief (<7 days) course of systemic steroids (< /=100 mg prednisone equivalent per day) prior to initiation of study therapy for control of lymphoma-related symptoms.
- Administration of a live attenuated vaccine within 4 weeks prior to the first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after last dose of study treatment Notes: Influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccine (e.g., Flumist®) at any time during the study treatment period and after the last dose until B-cell recovery to the normal ranges. Investigators should review the vaccination status of potential study patients being considered for this study and follow local disease control and prevention guidelines for adult vaccination with any other non-live vaccines intended to prevent infectious disease prior to study entry.
Extra Exclusion Criteria for Arm E (includes glofitamab) Only
- Known history of hypersensitivity to obinutuzumab
