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

  • STATUS
    Recruiting
  • participants needed
    156
  • sponsor
    Oncternal Therapeutics, Inc
Updated on 8 November 2020
platelet count
cancer
anemia
monoclonal antibodies
leukemia
thrombocytopenia
hepatitis b surface antigen
progressive disease
neutrophil count
tumor cells
monoclonal protein
renal function tests
beta human chorionic gonadotrophin
ibrutinib
lymphadenopathy

Summary

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. Cirmtuzumab is a monoclonal antibody that attaches to a protein (called ROR1) that is found on hematologic tumor cells. ROR1 has been shown to play a role in cell signaling that cause leukemia 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 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 MCL 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.

Details
Condition Mantle cell lymphoma, Chronic Lymphocytic Leukemia
Treatment Ibrutinib, Cirmtuzumab followed by Cirmtuzumab plus ibrutinib, Cirmtuzumab plus ibrutinib
Clinical Study IdentifierNCT03420183
SponsorOncternal Therapeutics, Inc
Last Modified on8 November 2020

Eligibility

Yes No Not Sure

Inclusion Criteria

Men and women of age 18 years
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
Histological diagnosis of CLL/SLL or MCL as documented in medical records
MCL has been previously treated and has relapsed after or progressed during prior therapy
No history of prior BTK-inhibitor-containing therapy
A medically appropriate candidate for ibrutinib treatment (based on the judgement of the clinical investigator)
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])
Current medical need for therapy due to disease-related symptoms, lymphadenopathy, organomegaly, extranodal organ involvement, or progressive disease
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
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])
Adequate bone marrow function
Absolute neutrophil count (ANC) 1.0 10^9/L (Grade 2)
Platelet count 50 10^9/L (Grade 2)
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)
\. Adequate hepatic profile
Serum alanine aminotransferase (ALT) 3 upper limit of normal (ULN) (Grade 1)
Serum aspartate aminotransferase (AST) 3 ULN (Grade 1)
Serum bilirubin 1.5 ULN (Grade 1)
Adequate renal function
Estimated creatinine clearance (eClCR) >45 mL/min (with eCLCR to be calculated by the Cockcroft-Gault formula, or
Measured creatinine clearance >45 mL/minute (as assessed with a 24-hour urine collection)
Adequate coagulation profile
Prothrombin time (PT) 1.5 ULN (Grade 1)
Activated partial thromboplastin time (aPTT) 1.5 ULN (Grade 1)
Negative viral serology
Negative human immunodeficiency virus (HIV) antibody
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
Negative hepatitis C virus (HCV) antibody or negative HCV ribonucleic acid (RNA) by quantitative PCR
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 [beta HCG]); or is menopausal (age 50 years with amenorrhea for 6 months)
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
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
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
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

Known histological transformation to an aggressive lymphoma (ie, Richter transformation). Note: Biopsy documentation of the absence or presence of transformation is not required
Known central nervous system malignancy. Note: Central nervous system imaging is only required in subjects with suspected central nervous system malignancy
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
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
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)
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 a 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
In subjects with prior hematopoietic progenitor cell transplantation, evidence of ongoing graft-versus-host disease (GVHD)
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
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)
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
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