Summary

This phase Ib/II trial studies the side effects and best dose of cirmtuzumab when given together with ibrutinib and to see how well they work in treating patients with B-cell lymphoid malignancies. Immunotherapy with cirmtuzumab, may induce changes in body’s immune system and may interfere with the ability of tumor cells to grow and spread. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving ibrutinib with or without cirmtuzumab may work better in treating patients with B-cell lymphoid malignancies.

Objectives

PRIMARY OBJECTIVES:
I. To determine the recommended dosing regimen (RDR) of cirmtuzumab when given alone and in combination with ibrutinib in subjects with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL). (Part 1 [cirmtuzumab ? cirmtuzumab + ibrutinib])
II. To further characterize the safety and pharmacology of cirmtuzumab/ibrutinib when administered using the RDR. (Part 2 [cirmtuzumab + ibrutinib])
III. To evaluate the complete response (CR) rate associated with cirmtuzumab/ibrutinib when administered using the RDR. (Part 3 [cirmtuzumab + ibrutinib versus ibrutinib])

SECONDARY OBJECTIVES:
I. To determine the drug administration, safety, and supportive care profiles of cirmtuzumab and the combination of cirmtuzumab/ibrutinib.
II. To evaluate the pharmacokinetic profile of cirmtuzumab alone and in combination with ibrutinib.
III. To assess the effects of cirmtuzumab and cirmtuzumab/ibrutinib on pharmacodynamic markers relating to drug mechanism, immune profile, and disease manifestations.
IV. To characterize the immunogenicity of cirmtuzumab.
V. To characterize the antitumor activity of cirmtuzumab monotherapy and cirmtuzumab/ibrutinib combination therapy.

OUTLINE: This is a phase Ib, dose-escalation study of cirmtuzumab followed by a phase II study. Patients are randomized to 1 of 2 arms.

ARM I: Patients receive cirmtuzumab intravenously (IV) over 30-90 minutes every 2 weeks for 3 doses (weeks 0, 2, and 4) and then every 4 weeks on weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. Patients also receive ibrutinib orally (PO) once daily (QD) starting week 0. Treatment continues in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days, and then every 3 or 6 months for up to 5 years.

Eligibility

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
2. Histological diagnosis of CLL/SLL or MCL as documented in medical records.
3. MCL has been previously treated and has relapsed after or progressed during prior therapy.
4. A medically appropriate candidate for ibrutinib treatment (based on the judgement of the clinical investigator).
5. No history of prior BTK-inhibitor-containing therapy.
6. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of >= 1 non-biopsied, non-irradiated lesion that measures >= 2.0 cm in the longest dimension [LD] and >= 1.0 cm in the longest perpendicular dimension [LPD] as assessed by computed tomography [CT] or magnetic resonance imaging [MRI]).
7. Current medical need for therapy due to disease-related symptoms, lymphadenopathy, organomegaly, extranodal organ involvement, or progressive disease.
8. Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer >= 1 week before the start of study therapy.
9. All acute toxic effects of any prior antitumor therapy resolved to grade =< 1 before the start of study therapy (with the exceptions of alopecia, or neurotoxicity [grade 1 or 2 permitted], or selected laboratory parameters [grade 1 or grade 2 permitted with exceptions as noted below]).
10. Absolute neutrophil count (ANC) >= 1.0 x 10^9/L.
11. Platelet count >= 50 x 10^9/L.
12. Hemoglobin >= 8.0 g/dL maintained for >= 1 week from any prior transfusion. * Note: grade >= 3 neutropenia, thrombocytopenia, or anemia is permitted if the abnormality is related to bone marrow involvement with hematological malignancy (as documented by bone marrow biopsy/aspirate obtained since the last prior therapy).
13. Serum alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN).
14. Serum aspartate aminotransferase (AST) =< 3 x ULN.
15. Serum bilirubin =< 1.5 x ULN unless elevated due to Gilbert syndrome.
16. Estimated creatinine clearance (eClCR) > 45 mL/minute (with eClCR to be calculated by the Cockcroft-Gault formula), or
17. Measured creatinine clearance > 45 mL/minute (as assessed with a 24-hour urine collection).
18. Prothrombin time (PT) =<1.5 x ULN.
19. Activated partial thromboplastin time (aPTT) =< 1.5 x ULN.
20. Negative human immunodeficiency virus (HIV) antibody.
21. Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc) antibody or undetectable hepatitis B (HBV) deoxyribonucleic acid (DNA) by quantitative polymerase chain reaction (PCR) testing.
22. Negative hepatitis C virus (HCV) antibody or negative HCV RNA by quantitative PCR.
23. For female subjects of childbearing potential, a negative urine or serum pregnancy test prior to the start of study therapy.
24. For female subjects of childbearing potential, willingness to use an effective method of contraception from the start of the screening period until >= 3 months after the last dose of cirmtuzumab and >= 1 month after the last dose of ibrutinib, whichever is later. Note: a female subject is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone [FSH] levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin [betaHCG]); or is menopausal (age >= 50 years with amenorrhea for >= 6 months).
25. For male subjects who can father a child and are having intercourse with females of childbearing potential who are not using adequate contraception, willingness to use an effective method of contraception from the start of study therapy until >= 3 months after the last dose of cirmtuzumab and >= 1 month after the last dose of ibrutinib, whichever is later and to refrain from sperm donation from the start of study therapy until >= 3 months after administration of the final dose of either of the study drugs. Note: a male subject is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy.
26. In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current disease status, medical condition, and the potential benefits and risks of alternative treatments for the subject’s cancer.
27. Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions.
28. Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation.