Clinical Trials /

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

NCT03088878

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Mantle Cell Lymphoma
  • Small Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Cirmtuzumab and Ibrutinib in Patients With B-Cell Lymphoid Malignancies
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 170127
  • NCT ID: NCT03088878
  • NCT ALIAS: NCT03420183

Conditions

  • B-cell Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
Cirmtuzumab plus IbrutinibUC-961, ImbruvicaPart 1
Cirmtuzumab plus IbrutinibUC-961, ImbruvicaPart 1
Cirmtuzumab plus ibrutinibUC-961, ImbruvicaPart 1
IbrutinibImbruvicaPart 3 - Arm B
Cirmtuzumab plus ibrutinibUC-961, ImbruvicaPart 1

Purpose

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1ExperimentalCirmutuzumab followed by Cirmtuzumab plus ibrutinib
  • Cirmtuzumab plus Ibrutinib
  • Cirmtuzumab plus Ibrutinib
  • Cirmtuzumab plus ibrutinib
  • Cirmtuzumab plus ibrutinib
Part 2ExperimentalCirmtuzumab plus ibrutinib
  • Cirmtuzumab plus Ibrutinib
  • Cirmtuzumab plus Ibrutinib
  • Cirmtuzumab plus ibrutinib
  • Cirmtuzumab plus ibrutinib
Part 3 - Arm AExperimentalCirmtuzumab plus ibrutinib
  • Cirmtuzumab plus Ibrutinib
  • Cirmtuzumab plus Ibrutinib
  • Cirmtuzumab plus ibrutinib
  • Cirmtuzumab plus ibrutinib
Part 3 - Arm BActive ComparatorIbrutinib only
  • Ibrutinib
Part 4Active ComparatorCirmtuzumab plus ibrutinib
  • Cirmtuzumab plus Ibrutinib
  • Cirmtuzumab plus Ibrutinib
  • Cirmtuzumab plus ibrutinib
  • Cirmtuzumab plus ibrutinib

Eligibility 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"
             measuresv>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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description:To determine the pharmacokinetic profile of cirmtuzumab alone and in combination with ibrutinib
Measure: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
Safety Issue:
Description:To determine the effects of cirmtuzumab and cirmtuzumab + ibrutinib on exploratory biomarkers
Measure: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
Safety Issue:
Description:To determine the changes in titers and neutralizing capacity of circulating cirmtuzumab-reactive antibodies (as assessed using immunoassay methods)
Measure: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
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description:Defined as achievement of CR or CRi for those with CLL/SLL; and the achievement of a CR for those with MCL
Measure: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
Safety Issue:
Description:Defined as the best (most negative) percent change from baseline in the sum of the products of the diameters (SPD) of index lesions
Measure: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
Safety Issue:
Description:Defined as the interval from the start of study therapy to the first documentation of an objective response
Measure: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
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description:Defined as the time from the start of study therapy until objective tumor progression; TTP does not include deaths
Measure: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
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description:Defined as the interval from the start of study therapy to death from any cause

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Diego

Trial Keywords

  • Chronic lymphocytic leukemia
  • Small lymphocytic lymphoma
  • Mantle cell lymphoma
  • Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1)
  • Bruton Tyrosine Kinase (BTK)
  • Ibrutinib

Last Updated

August 5, 2021