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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

Tracking Information
First Submitted Date  ICMJE March 2, 2017
First Posted Date  ICMJE March 23, 2017
Last Update Posted Date July 8, 2020
Actual Study Start Date  ICMJE January 3, 2018
Estimated Primary Completion Date October 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 6, 2020)
  • 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
  • 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)
Original Primary Outcome Measures  ICMJE
 (submitted: March 22, 2017)
  • Phase 1b: Recommended dosing regimen (RDR) [ Time Frame: From baseline to 52 weeks ]
    Evaluation of cirmtuzumab dose-pharmacodynamic and pharmacokinetic-pharmacodynamic relationships, and safety
  • Phase 2: Complete Response (CR) rate [ Time Frame: From randomization to discontinuation of treatment of all study subjects 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)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 6, 2020)
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • 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
  • 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
  • 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)
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: March 22, 2017)
  • Phase 1b: Treatment Related Adverse Events [ Time Frame: From baseline to 52 weeks ]
    Number of participants with adverse events and clinical laboratory abnormalities assessed by CTCAE v.4.03
  • Phase 2: Cirmtuzumab Plasma Concentration [ Time Frame: From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject ]
    Concentrations measured using a validated immunoassay
  • Phase 2: ROR1 Cell Surface Expression [ Time Frame: From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject ]
    Changes in ROR1 cell surface expression on malignant cells in peripheral blood and bone marrow.
  • Phase 2: Duration of Response [ Time Frame: From randomization to discontinuation of treatment of all study subjects 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
  • Phase 2: Progression Free Survival [ Time Frame: From randomization to discontinuation of treatment of all study subjects 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
  • Phase 2: Time to Treatment Failure [ Time Frame: From randomization to discontinuation of treatment of all study subjects 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
  • Phase 2: Overall Survival [ Time Frame: From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject ]
    The interval from the start of study therapy to death from any cause
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Cirmtuzumab and Ibrutinib in Patients With B-Cell Lymphoid Malignancies
Official Title  ICMJE 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
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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • B-cell Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
  • Mantle Cell Lymphoma
Intervention  ICMJE
  • Drug: Cirmtuzumab
    Administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter
    Other Name: UC-961
  • Drug: Ibrutinib
    Self-administered orally once daily
    Other Name: Imbruvica
  • 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
Study Arms  ICMJE
  • Experimental: Phase 1b - Dose Finding
    Cirmutuzumab followed by Cirmtuzumab plus ibrutinib
    Interventions:
    • Drug: Cirmtuzumab
    • Drug: Cirmtuzumab plus ibrutinib
  • Experimental: Phase 1b - Dose Expansion
    Cirmtuzumab plus ibrutinib
    Intervention: Drug: Cirmtuzumab plus ibrutinib
  • Experimental: Phase 2 - Cirmtuzumab plus ibrutinib
    Phase 2 safety and efficacy evaluation
    Intervention: Drug: Cirmtuzumab plus ibrutinib
  • Active Comparator: Phase 2 - Ibrutinib
    Phase 2 safety and efficacy evaluation
    Intervention: Drug: Ibrutinib
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 22, 2017)
156
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2022
Estimated Primary Completion Date October 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Alpha Stem Cell Clinic 844-317-STEM (7836) alphastemcellclinic@ucsd.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03088878
Other Study ID Numbers  ICMJE 170127
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Michael Choi, University of California, San Diego
Study Sponsor  ICMJE University of California, San Diego
Collaborators  ICMJE
  • California Institute for Regenerative Medicine (CIRM)
  • Oncternal Therapeutics, Inc
Investigators  ICMJE
Principal Investigator: Michael Choi, MD University of California, San Diego
PRS Account University of California, San Diego
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP