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

This is a Phase 1b/2 study to investigate the safety and effectiveness of the investigational
drug, cirmtuzumab, when given in combination with ibrutinib in patients with B-cell lymphoid
malignancies. The Phase 1b will be conducted in two parts (Part 1 and Part 2). Part 1 is a
dose-finding evaluation of the sequential administration of cirmtuzumab monotherapy followed
by cirmtuzumab and ibrutinib combination therapy in chronic lymphocytic leukemia/small
lymphocytic leukemia (CLL/SLL) or or previously treated mantle cell lymphoma (MCL) subjects
who have not received prior Bruton tyrosine kinase (BTK) inhibitor therapy. Up to 48 subjects
will be enrolled in Part 1 to determine the recommended dosing regimen (RDR). In Part 2, up
to 18 subjects will be enrolled to further evaluate the safety and pharmacology of the
cirmtuzumab and ibrutinib combination given at the RDR determined in Part 1 of the study. In
the Phase 2 (Part 3) portion of the study, approximately 90 subjects with CLL will be
randomized to either Arm 1 (cirmtuzumab and ibrutinib) at the RDR or Arm 2 (ibrutinib alone)
to evaluate the clinical activity and safety of the two arms.

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 prior
therapy.

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

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

7. 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]).

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 before
the start of study therapy.

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

11. Adequate bone marrow function:

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

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

3. Hemoglobin ≥8.0 g/dL (Grade ≤2) 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).

12. Adequate hepatic profile:

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

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

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

13. Adequate renal function:

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

2. Measured creatinine clearance >45 mL/minute (as assessed with a 24-hour urine
collection)

14. Adequate coagulation profile:

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

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

15. Negative viral serology:

1. Negative human immunodeficiency virus (HIV) antibody.

2. 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.

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

16. For female subjects of childbearing potential, a negative urine or serum pregnancy
test prior to the start of study therapy.

17. 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 [beta HCG]); or is menopausal (age
≥50 years with amenorrhea for ≥6 months).

18. 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.

19. 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.

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

21. 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.

Exclusion Criteria:

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

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

3. Presence of another cancer with disease manifestations or therapy that could adversely
affect 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, arterial
thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of
study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New
York Heart Association Class 3 or 4 congestive heart failure; or uncontrolled Grade ≥3
hypertension (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg)
despite antihypertensive therapy.

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

6. Gastrointestinal disease (eg, gastric or intestinal bypass surgery, pancreatic enzyme
insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic
diarrheal illness, bowel obstruction) that might interfere with drug absorption or
with 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 upper
respiratory tract infections) at the time of start of study therapy. Note: Subjects
with localized fungal infections of skin or nails are not precluded from
participation.

9. In subjects with prior hematopoietic progenitor cell transplantation, evidence of
ongoing 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 7
days 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 QT
interval (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 to
interfere with a subject's ability to provide informed consent, adversely affect the
subject's ability to cooperate and participate in the study, or compromise the
interpretation of study results.