A Study of Cirmtuzumab and Ibrutinib in Patients With B-Cell Lymphoid Malignancies

Inclusion Criteria:

1. Men and women of age ≥18 years.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

3. Histological diagnosis of CLL/SLL or MCL as documented in medical records.

4. MCL has been previously treated and has relapsed after or progressed during priortherapy.

5. No history of prior BTK-inhibitor-containing therapy.

6. A medically appropriate candidate for ibrutinib treatment (based on the judgement ofthe clinical investigator).

7. Presence of radiographically measurable lymphadenopathy or extranodal lymphoidmalignancy (defined as the presence of ≥1 non-biopsied, non-irradiated lesion thatmeasures ≥2.0 cm in the longest dimension [LD] and ≥1.0 cm in the longestperpendicular dimension [LPD] as assessed by computed tomography [CT] or magneticresonance imaging [MRI]).

8. Current medical need for therapy due to disease-related symptoms, lymphadenopathy,organomegaly, extranodal organ involvement, or progressive disease.

9. Completion of all previous therapy (including surgery, radiotherapy, chemotherapy,immunotherapy, or investigational therapy) for the treatment of cancer ≥1 week beforethe start of study therapy.

10. All acute toxic effects of any prior antitumor therapy resolved to ≤Grade 1 before thestart of study therapy (with the exception of alopecia [Grade 1 or 2 permitted], orneurotoxicity [Grade 1 or 2 permitted], or selected laboratory parameters [Grade 1 orGrade 2 permitted with exceptions as noted below]).

11. Adequate bone marrow function:

12. Absolute neutrophil count (ANC) ≥1.0 × 10^9/L (Grade ≤2).

13. Platelet count ≥50 × 10^9/L (Grade ≤2).

14. Hemoglobin ≥8.0 g/dL (Grade ≤2) maintained for ≥1 week from any priortransfusion. Note: Grade ≥3 neutropenia, thrombocytopenia, or anemia is permitted if theabnormality is related to bone marrow involvement with hematological malignancy (asdocumented by bone marrow biopsy/aspirate obtained since the last prior therapy).

15. Adequate hepatic profile:

16. Serum alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN) (Grade ≤1).

17. Serum aspartate aminotransferase (AST) ≤3 × ULN (Grade ≤1).

18. Serum bilirubin ≤1.5 × ULN (Grade ≤ 1).

19. Adequate renal function:

20. Estimated creatinine clearance (eClCR) >45 mL/min (with eCLCR to be calculated bythe Cockcroft-Gault formula, or

21. Measured creatinine clearance >45 mL/minute (as assessed with a 24-hour urinecollection)

22. Adequate coagulation profile:

23. Prothrombin time (PT) ≤1.5 × ULN (Grade ≤1).

24. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN (Grade ≤1).

25. Negative viral serology:

26. Negative human immunodeficiency virus (HIV) antibody.

27. Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc)antibody or undetectable hepatitis B (HBV) deoxyribonucleic acid (DNA) byquantitative polymerase chain reaction (PCR) testing.

28. Negative hepatitis C virus (HCV) antibody or negative HCV ribonucleic acid (RNA)by quantitative PCR.

29. For female subjects of childbearing potential, a negative urine or serum pregnancytest prior to the start of study therapy.

30. For female subjects of childbearing potential, willingness to use an effective methodof contraception from the start of the screening period until ≥3 months after the lastdose 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 hashad a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medicallydocumented ovarian failure (with serum estradiol and follicle-stimulating hormone [FSH] levels within the institutional laboratory postmenopausal range and a negativeserum or urine beta human chorionic gonadotropin [beta HCG]); or is menopausal (age ≥50 years with amenorrhea for ≥6 months).

31. For male subjects who can father a child and are having intercourse with females ofchildbearing potential who are not using adequate contraception, willingness to use aneffective method of contraception from the start of study therapy until ≥3 monthsafter 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 therapyuntil ≥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 abilateral vasectomy with documented aspermia or a bilateral orchiectomy.

32. In the judgment of the investigator, participation in the protocol offers anacceptable benefit-to-risk ratio when considering current disease status, medicalcondition, and the potential benefits and risks of alternative treatments for thesubject's cancer.

33. Willingness and ability of the subject to comply with scheduled visits, drugadministration plan, protocol-specified laboratory tests, other study procedures (including all bone marrow biopsy/aspirations and radiographic studies), and studyrestrictions.

34. Evidence of a personally signed informed consent indicating that the subject is awareof the neoplastic nature of the disease and has been informed of the procedures to befollowed, the experimental nature of the therapy, alternatives, potential risks anddiscomforts, potential benefits, and other pertinent aspects of study participation.

Exclusion Criteria:

1. Known histological transformation to an aggressive lymphoma (ie, Richtertransformation). Note: Biopsy documentation of the absence or presence oftransformation is not required.

2. Known central nervous system malignancy. Note: Central nervous system imaging is onlyrequired in subjects with suspected central nervous system malignancy.

3. Presence of another cancer with disease manifestations or therapy that could adverselyaffect subject safety or longevity, create the potential for drug-drug interactions,or compromise the interpetation of study results.

4. Significant cardiovascular disease (eg, myocardial infarction, arterialthromboembolism, cerebrovascular thromboembolism) within 3 months prior to start ofstudy therapy; angina requiring therapy; symptomatic peripheral vascular disease; NewYork Heart Association Class 3 or 4 congestive heart failure; or uncontrolled Grade ≥3hypertension (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg)despite antihypertensive therapy.

5. Significant screening ECG abnormalities, including unstable cardiac arrhythmiarequiring medication, atrial fibrillation/flutter, left bundle branch block, 2nd-degree atrioventricular (AV) block type II, 3rd degree AV block, Grade ≥2bradycardia, or corrected QT (QTc) >450 msec (for men) or >470 msec (for women).

6. Gastrointestinal disease (eg, gastric or intestinal bypass surgery, pancreatic enzymeinsufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronicdiarrheal illness, bowel obstruction) that might interfere with drug absorption orwith interpretation of gastrointestinal AEs.

7. Contraindication for ibrutinib use because of a bleeding diathesis.

8. Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upperrespiratory tract infections) at the time of start of study therapy. Note: Subjectswith localized fungal infections of skin or nails are not precluded fromparticipation.

9. In subjects with prior hematopoietic progenitor cell transplantation, evidence ofongoing graft-versus-host disease (GVHD).

10. Pregnancy or breastfeeding.

11. Major surgery within 4 weeks before the start of study therapy.

12. Prior solid organ transplantation.

13. Prior anti-ROR1 therapy within 12 weeks prior to the start of study therapy.

14. Use of a moderate or strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 within 7days prior to the expected start of ibrutinib therapy.

16. Use within 7 days prior to the start of study therapy of a drug known to prolong the QTinterval (study parts 1 and 2 only).

17. Concurrent participation in another therapeutic or imaging clinical trial.

18. Any illness, medical condition, organ system dysfunction, or social situation,including mental illness or substance abuse, deemed by the investigator to be likely tointerfere with a subject's ability to provide informed consent, adversely affect thesubject's ability to cooperate and participate in the study, or compromise theinterpretation of study results.