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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03088878
Recruitment Status : Active, not recruiting
First Posted : March 23, 2017
Last Update Posted : April 12, 2022
Sponsor:
Collaborators:
California Institute for Regenerative Medicine (CIRM)
University of California, San Diego
Information provided by (Responsible Party):
Oncternal Therapeutics, Inc

Brief 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.

Condition or disease Intervention/treatment Phase
B-cell Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Mantle Cell Lymphoma Drug: Cirmtuzumab (2-16 kg/mg) plus Ibrutinib Drug: Cirmtuzumab (300mg) plus Ibrutinib Drug: Cirmtuzumab (600 mg) plus ibrutinib Drug: Cirmtuzumab (RDR) plus ibrutinib Drug: Cirmtuzumab plus ibrutinib Drug: Ibrutinib alone Drug: Cirmtuzumab + Ibrutinib (Arm A, B, C and D) Phase 1 Phase 2

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of the ROR1-Targeting Monoclonal Antibody, Cirmtuzumab (UC-961), and the Bruton Tyrosine Kinase Inhibitor, Ibrutinib, in Patients With B-Cell Lymphoid Malignancies
Actual Study Start Date : January 3, 2018
Estimated Primary Completion Date : June 30, 2025
Estimated Study Completion Date : June 30, 2027


Arm Intervention/treatment
Experimental: Part 1
Cirmtuzumab followed by Cirmtuzumab plus ibrutinib
Drug: Cirmtuzumab (2-16 kg/mg) plus Ibrutinib
Participants will receive escalating doses of cirmtuzumab (2-16 mg/kg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 or 560 mg) orally once daily, starting at week 4.
Other Names:
  • UC-961
  • Imbruvica

Drug: Cirmtuzumab (300mg) plus Ibrutinib
Participants will receive cirmtuzumab (300 mg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily.
Other Names:
  • UC-961
  • Imbruvica

Drug: Cirmtuzumab (600 mg) plus ibrutinib
Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily.
Other Names:
  • UC-961
  • Imbruvica

Experimental: Part 2
Cirmtuzumab plus ibrutinib
Drug: Cirmtuzumab (RDR) plus ibrutinib
Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter, plus ibrutinib (420 or 560 mg) orally once daily
Other Names:
  • UC-961
  • Imbruvica

Experimental: Part 3 - Arm A
Cirmtuzumab plus ibrutinib
Drug: Cirmtuzumab plus ibrutinib
Arm A: Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily.
Other Names:
  • UC-961
  • Imbruvica

Active Comparator: Part 3 - Arm B
Ibrutinib only
Drug: Ibrutinib alone
Arm B: Participants will receive ibrutinib (420 mg) orally once daily
Other Name: Imbruvica

Active Comparator: Part 4
Cirmtuzumab plus ibrutinib
Drug: Cirmtuzumab + Ibrutinib (Arm A, B, C and D)
Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter, plus ibrutinib (560 mg) orally once daily.
Other Names:
  • UC-961
  • Imbruvica




Primary Outcome Measures :
  1. Part 1:To determine the Recommended dosing regimen (RDR) of cirmtuzumab within the tested dose range in combination of ibrutinib [ Time Frame: From first dose of study drug to completion of study drug treatment and have been followed for > 12 weeks ]
  2. Part 2: To determine the Recommended dosing regimen (RDR) of cirmtuzumab in combination with ibrutinib [ Time Frame: From first dose of study drug to completion of study drug treatment and have been followed for > 12 weeks ]
  3. Part 1-2: Treatment-emergent adverse events (TEAEs) as assessed by CTCAE v4.03 [ Time Frame: From first dose of study drug to 30 days after the last dose of study drug or 72 weeks after accrual of the final subject ]
    Defined as type, frequency, severity, timing of onset, duration, and relationship to study drugs of any treatment-emergent adverse events (TEAEs); SAEs; or AEs leading to interruption, modification, or discontinuation of study treatment

  4. Part 3: To evaluate Complete Response Rate [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Defined as the proportion of subjects that achieve CR or CRi for those with CLL/SLL; and the achievement of a CR for those with MCL

  5. Part 4: To evaluate Overall Response [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Defined as achievement of complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), or partial response with lymphocytosis (PR-L) for those with CLL/SLL; and the achievement of a CR or PR for those with MCL


Secondary Outcome Measures :
  1. Part 3-4: Treatment-emergent adverse events (TEAEs) as assessed by CTCAE v4.03 [ Time Frame: From first dose of study drug to 30 days after the last dose of study drug or 72 weeks after accrual of the final subject ]
    Defined as type, frequency, severity, timing of onset, duration, and relationship to study drugs of any treatment-emergent adverse events (TEAEs); SAEs; or AEs leading to interruption, modification, or discontinuation of study treatment

  2. Part 1-2: Area under the serum concentration-time curve [AUC] [ Time Frame: From first dose of study drug to 30 days after the last dose of study drug ]
    To determine the pharmacokinetic profile of cirmtuzumab alone and in combination with ibrutinib

  3. Part 1-4: Changes in ROR1 cell surface expression and receptor occupancy [ Time Frame: From first dose of study drug to completion of study drug treatment and have been followed for > 12 weeks ]
    To determine the effects of cirmtuzumab and cirmtuzumab + ibrutinib on exploratory biomarkers

  4. Part 1-4: Changes in titers and neutralizing capacity of circulating cirmtuzumab-reactive antibodies [ Time Frame: From randomization to 30 days after the last dose of study drug or 72 weeks after accrual of the final subject ]
    To determine the changes in titers and neutralizing capacity of circulating cirmtuzumab-reactive antibodies (as assessed using immunoassay methods)

  5. Part 1-3:To evaluate Overall Response (OR) [ Time Frame: From randomization to 30 days after the last dose of study drug or 72 weeks after accrual of the final subject ]
    Defined as achievement of complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), or partial response with lymphocytosis (PR-L) for those with CLL/SLL; and the achievement of a CR or PR for those with MCL

  6. Parts 1, 2, 4:To evaluate Complete Response (CR) [ Time Frame: From randomization to 30 days after the last dose of study drug or 72 weeks after accrual of the final subject ]
    Defined as achievement of CR or CRi for those with CLL/SLL; and the achievement of a CR for those with MCL

  7. Parts 1-4:To evaluate percent change in tumor dimensions [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Defined as the best (most negative) percent change from baseline in the sum of the products of the diameters (SPD) of index lesions

  8. Parts 1-4: To evaluate Time to Response (TTR) [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Defined as the interval from the start of study therapy to the first documentation of an objective response

  9. Part 1-4:To evaluate Duration of Response (DOR) [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Defined as the interval from the first documentation of objective response to the earlier of the first documentation of disease progression or death from any cause

  10. Part 1-4: To evaluate Progression-free Survival (PFS) [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause

  11. Part 1-4: To evaluate Time to Progression (TTP) [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Defined as the time from the start of study therapy until objective tumor progression; TTP does not include deaths

  12. Part 1-4: To evaluate Time to Treatment Failure (TTF) [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Defined as the interval from start of study therapy to the earliest of the first documentation of disease progression, the permanent cessation of study drug due to an AE, or death from any cause

  13. Part 1-4:To evaluate Time to Next Treatment (TNT) [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Defined as the interval from start of study therapy to the earliest of the start of a new regimen for CLL/SLL or for MCL due to study treatment failure

  14. Part 1-4: To evaluate Overall Survival (OS) [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Defined as the interval from the start of study therapy to death from any cause



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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.

    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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03088878


Locations
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United States, California
City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
Duarte, California, United States, 91010
UCSD Moores Cancer Center
La Jolla, California, United States, 92093
UC Davis Comprehensive Cancer Center
Sacramento, California, United States, 95817
United States, Connecticut
Yale Cancer Center
New Haven, Connecticut, United States, 06510
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, Louisiana
Louisiana State University Health New Orleans (NCI Community Oncology Research Program)
New Orleans, Louisiana, United States, 70112
United States, New Jersey
Hackensack Meridian Health, John Theurer Cancer Center
Hackensack, New Jersey, United States, 07601
United States, New York
Northwell Health
New Hyde Park, New York, United States, 11042
Manhattan Hematology Oncology Research Foundation, Inc.
New York, New York, United States, 10016
Columbia University Medical Center
New York, New York, United States, 10032
United States, Ohio
The Christ Hospital Lindner Research Center
Cincinnati, Ohio, United States, 45219
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Oncternal Therapeutics, Inc
California Institute for Regenerative Medicine (CIRM)
University of California, San Diego
Investigators
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Principal Investigator: Michael Choi, MD University of California, San Diego
  Study Documents (Full-Text)

Documents provided by Oncternal Therapeutics, Inc:
Study Protocol  [PDF] March 15, 2021

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Oncternal Therapeutics, Inc
ClinicalTrials.gov Identifier: NCT03088878    
Obsolete Identifiers: NCT03420183
Other Study ID Numbers: 170127
First Posted: March 23, 2017    Key Record Dates
Last Update Posted: April 12, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Oncternal Therapeutics, Inc:
Chronic lymphocytic leukemia
Small lymphocytic lymphoma
Mantle cell lymphoma
Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1)
Bruton Tyrosine Kinase (BTK)
Ibrutinib
Additional relevant MeSH terms:
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Lymphoma
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia
Leukemia, B-Cell
Lymphoma, Non-Hodgkin