This is 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. Cirmtuzumab is a monoclonal antibody that attaches to a protein (called ROR 1)
that is found on hematologic tumor cells. ROR1 has been shown to play a role in cell
signaling that cause leukemia and lymphoma cells to grow and survive. ROR1 is rarely found on
healthy cells.
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 previously treated mantle cell lymphoma (MCL) subjects are
BTKI naiive or have received a prior Bruton tyrosine kinase (BTK) inhibitor therapy, unless
they demonstrated primary or acquired resistance to BTKi. Up to 48 subjects will be enrolled
in Part 1 to determine the recommended dosing regimen (RDR). In Part 2, up to 50 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 31 subjects with CLL/SLL who may have received
minimal prior BTK inhibitor therapy 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. Parts 4A, B and C, will enroll up to 6 MCL patients into each exploratory
treatment arm and Part D will enroll up to 16 MCL patients. In Part 4, cirmtuzumab and
ibrutinib will be evaluated in patients with MCL that initially responded, were sensitive to
BTKi therapy (defined as having measurable tumor regression) but then had progressive disease
(Cheson 2014) while receiving continuous therapy with BTKi containing regimens for at least 6
months with ibrutinib (4A), acalabrutinib (4B), or zanubrutinib (4C). Part 4D will evaluate
the ability of cirmtuzumab and ibrutinib to improve clinical responses in MCL patients who
are currently receiving ibrutinib monotherapy or an ibrutinib-containing regimen and have
received at least 6 months of ongoing treatment but have only achieved SD or PR. Patients
will be enrolled to receive cirmtuzumab and ibrutinib to investigate if the addition of
cirmtuzumab could result in improving responses from stable disease (SD) to partial response
(PR) or complete response (CR) or from PR to CR.
Inclusion Criteria:
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(pathology reports and slides
or blocks should be available for review or additional testing) 4)MCL has been previously
treated and has relapsed after or progressed during prior therapy. CLL/SLL may have been
previously treated or are treatment naïve but now require therapy 5)A medically appropriate
candidate for ibrutinib treatment (based on the judgement of the clinical investigator)
6)Patients who have received prior BTK inhibitor therapy are eligible, unless they
demonstrated primary or acquired resistance to a BTK inhibitor or experienced a serious or
severe adverse event attributed to BTK inhibitor therapy.
The following exceptions apply:
1. For Parts 4A, B, C, patients with MCL who initially responded/were sensitive to BTKi
therapy (defined as having measurable tumor regression) but then had progressive
disease while receiving continuous therapy with BTKi containing regimens (ibrutinib,
acalabrutinib, or zanubrutinib) for at least 6 months may be eligible.
2. For Part 4D, patients with MCL who are currently receiving ibrutinib monotherapy or an
ibrutinib-containing regimen and have received at least 6 months of ongoing treatment
but have only achieved SD or PR may be eligible.
7)Presence of radiographically measurable lymphadenopathy or extranodal lymphoid
malignancy (defined as the presence of ≥1 non-biopsied, non-irradiated lesion that"
measuresv>1.5 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 any Bcl-2 or PI3K inhibitor therapy,
surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for
the treatment of cancer ≥1 week (or ≥3 half-lives of the previous drug) before the
start of study therapy. (Exception: Patients enrolled in Parts 4A- 4D may continue
BTKi monotherapy until Day 0/study start.) 10)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]).
11)Adequate bone marrow function:
a) Absolute neutrophil count (ANC) ≥1.0 × 109/L. b) Platelet count ≥50 × 109/L. b)
Hemoglobin ≥8.0 g/dL maintained for ≥1 week from any prior transfusion. 12) Adequate
hepatic profile:
a) Serum alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN). b) Serum
aspartate aminotransferase (AST) ≤3 × ULN. c) Serum bilirubin ≤1.5 × ULN unless elevated
due to Gilbert syndrome. 13) Adequate renal function:
a) Estimated creatinine clearance (eClCR) >30 mL/minute (with eClCR to be calculated by the
Cockcroft-Gault formula), or b) Measured creatinine clearance >30 mL/minute (as assessed
with a 24-hour urine collection).
14)Adequate coagulation profile:
a) Prothrombin time (PT) ≤1.5 × ULN. b) Activated partial thromboplastin time (aPTT) ≤1.5 ×
ULN. 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 [βHCG]); 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, 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).
2. Known 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 interpretation 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, or Grade ≥2
bradycardia.
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 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 patients 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.
15. Concurrent participation in another therapeutic or imaging clinical trial.
16. 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.
