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

  • STATUS
    Recruiting
  • End date
    Jun 30, 2027
  • participants needed
    160
  • sponsor
    University of California, San Diego
Updated on 8 September 2021
platelet count
cancer
hematologic malignancy
anemia
chronic lymphocytic leukemia
lymphoma
monoclonal antibodies
leukemia
gilbert's syndrome
thrombocytopenia
hepatitis b surface antigen
progressive disease
neutrophil count
tumor cells
blood transfusion
autograft
monoclonal protein
renal function tests
beta human chorionic gonadotrophin
ibrutinib
btk inhibitor
lymphadenopathy
acalabrutinib
pi3k inhibitor
lymphoma cells

Summary

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.

Description

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.

Details
Condition Lymphoma, Mantle cell lymphoma, Chronic Lymphocytic Leukemia, Lymphocytic Leukemia, Chronic, Non-Hodgkin's Lymphoma, leukemia chronic lymphocytic, chronic lymphocytic leukemia (cll), small lymphocytic lymphoma, b-cell small lymphocytic lymphoma
Treatment Ibrutinib, cirmtuzumab, Cirmtuzumab plus ibrutinib, Cirmtuzumab (2-16 kg/mg) plus Ibrutinib, Cirmtuzumab (300mg) plus Ibrutinib, Cirmtuzumab (600 mg) plus ibrutinib, Cirmtuzumab (RDR) plus ibrutinib, Ibrutinib alone, Cirmtuzumab + Ibrutinib (Arm A, B, C and D)
Clinical Study IdentifierNCT03088878
SponsorUniversity of California, San Diego
Last Modified on8 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

)Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
)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 nave 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
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
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
)Presence of radiographically measurable lymphadenopathy or extranodal
lymphoid malignancy (defined as the presence of 1 non-biopsied, non-irradiated
lesion that measures >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
)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
Negative human immunodeficiency virus (HIV) antibody
of the previous drug) before the start of study therapy. (Exception: Patients
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
enrolled in Parts 4A- 4D may continue BTKi monotherapy until Day 0/study
Negative hepatitis C virus (HCV) antibody or negative HCV ribonucleic acid (RNA) by quantitative PCR
start.) 10)All acute toxic effects of any prior antitumor therapy resolved to
For female subjects of childbearing potential, a negative urine or serum pregnancy test prior to the start of study therapy
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 [HCG]); or is menopausal (age 50 years with amenorrhea for 6 months)
Grade 1 before the start of study therapy (with the exceptions of alopecia, or
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
neurotoxicity [Grade 1 or 2 permitted], or selected laboratory parameters
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
[Grade 1 or Grade 2 permitted with exceptions as noted below])
)Adequate bone marrow function
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
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
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)
)Adequate coagulation profile
Prothrombin time (PT) 1.5 ULN. b) Activated partial thromboplastin time (aPTT) 1.5 ULN. 15)Negative viral serology
)Willingness and ability of the subject to comply with scheduled visits
drug administration plan, protocol-specified laboratory tests, other study
procedures, and study restrictions
)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

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
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
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
Contraindication for ibrutinib use because of bleeding diathesis
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
Pregnancy or breastfeeding
Major surgery within 4 weeks before the start of study therapy
Prior solid organ transplantation
Prior anti-ROR1 therapy within 12 weeks prior to the start of study therapy
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
Concurrent participation in another therapeutic or imaging clinical trial
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
Known histological transformation to an aggressive lymphoma (ie, Richter transformation)
Known central nervous system malignancy
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
In patients with prior hematopoietic progenitor cell transplantation, evidence of ongoing graft-versus-host disease (GVHD)
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