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Trial record 4 of 5 for:    cirmtuzumab

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

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ClinicalTrials.gov Identifier: NCT03088878
Recruitment Status : Recruiting
First Posted : March 23, 2017
Last Update Posted : July 8, 2020
Sponsor:
Collaborators:
California Institute for Regenerative Medicine (CIRM)
Oncternal Therapeutics, Inc
Information provided by (Responsible Party):
Michael Choi, University of California, San Diego

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 Drug: Ibrutinib Drug: Cirmtuzumab plus ibrutinib 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 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/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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 156 participants
Allocation: Randomized
Intervention Model: Single Group 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 : October 1, 2020
Estimated Study Completion Date : December 1, 2022


Arm Intervention/treatment
Experimental: Phase 1b - Dose Finding
Cirmutuzumab followed by Cirmtuzumab plus ibrutinib
Drug: Cirmtuzumab
Administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter
Other Name: UC-961

Drug: Cirmtuzumab plus ibrutinib
  • Cirmtuzumab: Administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter
  • Ibrutinib: Self-administered orally once daily
Other Names:
  • UC-961
  • Imbruvica

Experimental: Phase 1b - Dose Expansion
Cirmtuzumab plus ibrutinib
Drug: Cirmtuzumab plus ibrutinib
  • Cirmtuzumab: Administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter
  • Ibrutinib: Self-administered orally once daily
Other Names:
  • UC-961
  • Imbruvica

Experimental: Phase 2 - Cirmtuzumab plus ibrutinib
Phase 2 safety and efficacy evaluation
Drug: Cirmtuzumab plus ibrutinib
  • Cirmtuzumab: Administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter
  • Ibrutinib: Self-administered orally once daily
Other Names:
  • UC-961
  • Imbruvica

Active Comparator: Phase 2 - Ibrutinib
Phase 2 safety and efficacy evaluation
Drug: Ibrutinib
Self-administered orally once daily
Other Name: Imbruvica




Primary Outcome Measures :
  1. Phase 1b: Recommended dosing regimen (RDR) of cirmtuzumab [ Time Frame: From baseline to 52 weeks ]
    Evaluation of cirmtuzumab dose-pharmacodynamic and pharmacokinetic-pharmacodynamic relationships, and safety

  2. Phase 2: Complete Response (CR) rate [ Time Frame: From randomization to end of follow-up or 72 weeks after accrual of the final subject ]
    Proportion of subjects achieving a CR in accordance with pre-established response criteria for lymphoma (Cheson 2007; Cheson 2014)


Secondary Outcome Measures :
  1. Phase 1b & 2: Safety Profile [ 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 ]
    Type, frequency, severity, timing of onset, duration, and relationship to study drugs of any treatment-emergent adverse events (TEAEs); laboratory abnormalities; vital sign/oxygen saturation abnormalities; adverse electrocardiogram (ECG) findings; SAEs; or AEs leading to interruption, modification, or discontinuation of study treatment assessed by CTCAE v.4.03

  2. Phase 1b: Pharmacokinetics [ Time Frame: From randomization to 30 days after the last dose of study drug ]
    Cirmtuzumab serum concentrations measured using a validated immunoassay and derived pharmacokinetic parameters.

  3. Phase 1b & 2: Duration of Response [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    The interval from the first documentation of objective response to the earlier of the first documentation of disease progression or death from any cause

  4. Phase 1b & 2: Progression Free Survival [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    The interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause

  5. Phase 1b & 2: Time to Treatment Failure [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    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 adverse event, or death from any cause

  6. Phase 1b & 2: Overall Survival [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    The interval from the start of study therapy to death from any cause

  7. Phase 1b: Pharmacodynamics [ Time Frame: From randomization to discontinuation of study treatment ]
    Changes in pharmacodynamic markers relating to drug mechanism, immune profile, and disease manifestations including ROR1 cell surface expression and receptor occupancy, Rac1 and/or RhoA activation, ALC in peripheral blood, cancer stem cell parameters, plasma concentrations of chemokines and cytokines.

  8. Phase 1b & 2: Immunogenicity [ Time Frame: From randomization to 30 days after the last dose of study drug or 72 weeks after accrual of the final subject ]
    Changes in titers and neutralizing capacity of circulating cirmtuzumab-reactive antibodies using immunoassay methods.

  9. Phase 1b & 2: Overall response (OR) [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Achievement of complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), or partial 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

  10. Phase 1b & 2: Complete response (CR) [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    Achievement of CR or CRi for those with CLL/SLL; and the achievement of a CR for those with MCL

  11. Phase 1b & 2: Minimal residual disease (MRD) response [ Time Frame: From randomization to end of treatment or 72 weeks after accrual of the final subject ]
    achievement of <1 x10-4 malignant cells/total cells in peripheral blood and/or bone marrow (as assessed by flow cytometry or comparably sensitive methods)

  12. Phase 1b & 2: Percent change in tumor dimensions [ Time Frame: From randomization to end of treatment or 72 weeks after accrual of the final subject ]
    The best (most negative) percent change from baseline in the sum of the products of the diameters (SPD) of index lesions

  13. Phase 1b & 2: Time to response (TTR) [ Time Frame: From randomization to end of follow up or 72 weeks after accrual of the final subject ]
    the interval from the start of study therapy to the first documentation of an objective response



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:

  • 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
  • A medically appropriate candidate for ibrutinib treatment (based on the judgement of the clinical investigator)
  • Minimal prior BTK-inhibitor therapy (<6 weeks) discontinued for reasons other than progressive disease or toxicity.

    a) Relapsed MCL patients who previously were treated with ibrutinib who were responding (PR or CR), who then went on to consolidation hyperCVAD/autotransplant are also eligible

  • 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 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]).
  • 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.

  • 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:

    1. Serum alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN).
    2. Serum aspartate aminotransferase (AST) ≤3 × ULN.
    3. Serum bilirubin ≤1.5 × ULN unless elevated due to Gilbert syndrome.
  • Adequate renal function:

    a) Estimated creatinine clearance (eClCR) >45 mL/minute (with eClCR to be calculated by the Cockcroft-Gault formula), or b) Measured creatinine clearance >45 mL/minute (as assessed with a 24-hour urine collection).

    2. Adequate coagulation profile:

    1. Prothrombin time (PT) ≤1.5 × ULN.
    2. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN.
  • 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.
  • 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 [βHCG]); 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, 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 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.
  • 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 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 or 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.

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


Contacts
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Contact: Alpha Stem Cell Clinic 844-317-STEM (7836) alphastemcellclinic@ucsd.edu

Locations
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United States, California
City of Hope (City of Hope National Medical Center, City of Hope Medical Center) Recruiting
Duarte, California, United States, 91010
Contact: Elaina Corbett    626-218-0047    ecorbett@coh.org   
Principal Investigator: Tanya Siddiqi, MD         
UCSD Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Alpha Stem Cell Clinic    844-317-7836    alphastemcellclinic@ucsd.edu   
Principal Investigator: Michael Choi, MD         
UC Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Christina Romo, BS    916-734-1455    cromo@ucdavis.edu   
Principal Investigator: Joseph Tuscano, MD         
United States, Connecticut
Yale Cancer Center Recruiting
New Haven, Connecticut, United States, 06510
Contact: Laura Leary    203-800-1969      
Principal Investigator: Iris Isufi, MD         
United States, Louisiana
Lousiana State University Health New Orleans (NCI Community Oncology Research Program) Recruiting
New Orleans, Louisiana, United States, 70112
Contact: Dina Brackman, BSA, BA    504-210-2669    dbrack@lsuhsc.edu   
Principal Investigator: Sukanthini Subbiah, MD         
United States, New Jersey
Hackensack Meridian Health, John Theurer Cancer Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Kara A Yannotti, MSN    551-996-5168    Kara.Yannotti@hackensackmeridian.org   
Principal Investigator: Lori Leslie, MD         
United States, New York
Northwell Health Recruiting
New Hyde Park, New York, United States, 11042
Contact: Dina MarkPadula    718-470-4745    Dpadula1@northwell.edu   
Principal Investigator: Jacqueline Barrientos, MD, MS         
Manhattan Hematology Oncology Research Foundation, Inc. Recruiting
New York, New York, United States, 10016
Contact: Phenoia Browne    212-689-6791 ext 228      
Principal Investigator: Alec Goldenberg, MD         
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Hanna Weissbrot    212-304-5558    hw2432@cumc.columbia.edu   
Principal Investigator: Nicole Lamanna, MD         
United States, Ohio
The Christ Hospital Lindner Research Center Recruiting
Cincinnati, Ohio, United States, 45219
Contact: Marsha Zartman    513-585-2165      
Principal Investigator: Gina Chung, MD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Sheri Allred    713-745-0554    slallred@mdanderson.org   
Principal Investigator: William Wierda, MD, PhD         
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Mayra Linares    713-792-2171    malinares@mdanderson.org   
Principal Investigator: Hun Lee, MD         
Sponsors and Collaborators
University of California, San Diego
California Institute for Regenerative Medicine (CIRM)
Oncternal Therapeutics, Inc
Investigators
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Principal Investigator: Michael Choi, MD University of California, San Diego
Publications:
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Responsible Party: Michael Choi, Assistant Clinical Professor, Department of Medicine, University of California, San Diego
ClinicalTrials.gov Identifier: NCT03088878    
Obsolete Identifiers: NCT03420183
Other Study ID Numbers: 170127
First Posted: March 23, 2017    Key Record Dates
Last Update Posted: July 8, 2020
Last Verified: July 2020
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 Michael Choi, University of California, San Diego:
Chronic lymphocytic leukemia
Small lymphocytic lymphoma
Mantle cell lymphoma
Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1)
Bruton Tyrosine Kinase (BTK)
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