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

NCT03420183

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. Cirmtuzumab is a monoclonal antibody that attaches to a protein (called ROR1) that is found on hematologic tumor cells. ROR1 has been shown to play a role in cell signaling that cause leukemia 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, and the Bruton Tyrosine Kinase Inhibitor, Ibrutinib, in Patients With B-Cell Lymphoid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: CIRM-0001
  • NCT ID: NCT03420183

Conditions

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

Interventions

DrugSynonymsArms
Cirmtuzumab followed by Cirmtuzumab plus ibrutinibUC-961, ImbruvicaPhase 1b-Dose Finding
Cirmtuzumab plus ibrutinibUC-961, ImbruvicaPhase 1b-Dose Expansion
IbrutinibImbruvicaPhase 2-Ibrutinib

Purpose

This is a Phase 1b/2 study to investigate the safety and effectiveness of the investigational drug, cirmtuzumab, when given in combination with ibrutinib in patients with B-cell lymphoid malignancies. Cirmtuzumab is a monoclonal antibody that attaches to a protein (called ROR1) that is found on hematologic tumor cells. ROR1 has been shown to play a role in cell signaling that cause leukemia 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 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1b-Dose FindingExperimentalCirmtuzumab followed by Cirmtuzumab plus ibrutinib
  • Cirmtuzumab followed by Cirmtuzumab plus ibrutinib
Phase 1b-Dose ExpansionExperimentalCirmtuzumab plus ibrutinib
  • Cirmtuzumab plus ibrutinib
Phase 2-Cirmtuzumab plus ibrutinibExperimentalPhase 2 safety and efficacy evaluation
  • Cirmtuzumab plus ibrutinib
Phase 2-IbrutinibActive ComparatorPhase 2 safety and efficacy evaluation
  • Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

          1. Men and women of age ≥18 years.

          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.

          4. MCL has been previously treated and has relapsed after or progressed during prior
             therapy.

          5. No history of prior BTK-inhibitor-containing therapy.

          6. A medically appropriate candidate for ibrutinib treatment (based on the judgement of
             the clinical investigator).

          7. 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]).

          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 surgery, radiotherapy, chemotherapy,
             immunotherapy, or investigational therapy) for the treatment of cancer ≥1 week before
             the start of study therapy.

         10. All acute toxic effects of any prior antitumor therapy resolved to ≤Grade 1 before the
             start of study therapy (with the exception of alopecia [Grade 1 or 2 permitted], or
             neurotoxicity [Grade 1 or 2 permitted], or selected laboratory parameters [Grade 1 or
             Grade 2 permitted with exceptions as noted below]).

         11. Adequate bone marrow function:

               1. Absolute neutrophil count (ANC) ≥1.0 × 10^9/L (Grade ≤2).

               2. Platelet count ≥50 × 10^9/L (Grade ≤2).

               3. Hemoglobin ≥8.0 g/dL (Grade ≤2) maintained for ≥1 week from any prior
                  transfusion.

             Note: Grade ≥3 neutropenia, thrombocytopenia, or anemia is permitted if the
             abnormality is related to bone marrow involvement with hematological malignancy (as
             documented by bone marrow biopsy/aspirate obtained since the last prior therapy).

         12. Adequate hepatic profile:

               1. Serum alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN) (Grade ≤1).

               2. Serum aspartate aminotransferase (AST) ≤3 × ULN (Grade ≤1).

               3. Serum bilirubin ≤1.5 × ULN (Grade ≤ 1).

         13. Adequate renal function:

               1. Estimated creatinine clearance (eClCR) >45 mL/min (with eCLCR to be calculated by
                  the Cockcroft-Gault formula, or

               2. Measured creatinine clearance >45 mL/minute (as assessed with a 24-hour urine
                  collection)

         14. Adequate coagulation profile:

               1. Prothrombin time (PT) ≤1.5 × ULN (Grade ≤1).

               2. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN (Grade ≤1).

         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 [beta HCG]); 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
             (including all bone marrow biopsy/aspirations and radiographic studies), 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). Note: Biopsy documentation of the absence or presence of
             transformation is not required.

          2. Known central nervous system malignancy. Note: Central nervous system imaging is only
             required in subjects with suspected 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 interpetation 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, Grade ≥2
             bradycardia, or corrected QT (QTc) >450 msec (for men) or >470 msec (for women).

          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 a 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 subjects 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.

        16) Use within 7 days prior to the start of study therapy of a drug known to prolong the QT
        interval (study parts 1 and 2 only).

        17) Concurrent participation in another therapeutic or imaging clinical trial.

        18) 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:Phase 1b: Recommended dosing regimen (RDR)
Time Frame:From baseline to 52 weeks
Safety Issue:
Description:Evaluation of cirmtuzumab dose-pharmacodynamic and pharmacokinetic-pharmacodynamic relationships, safety

Secondary Outcome Measures

Measure:Phase 1b: Treatment Related Adverse Events
Time Frame:From baseline to 52 weeks
Safety Issue:
Description:Number of participants with adverse events and clinical laboratory abnormalities assessed by CTCAE v4.03
Measure:Phase 2: Cirmtuzumab Serum Concentration
Time Frame:From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject
Safety Issue:
Description:Concentrations measured using a validated immunoassay
Measure: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
Safety Issue:
Description:Changes in ROR1 cell surface expression on malignant cells in peripheral blood and bone marrow.
Measure: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
Safety Issue:
Description: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: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
Safety Issue:
Description:The interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause
Measure: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
Safety Issue:
Description:The interval from the start of study therapy to the earlier of the first documentation of disease progression, the permanent cessation of study drug due to an adverse event, or death from any cause
Measure: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
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:Oncternal Therapeutics, Inc

Trial Keywords

  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
  • Mantle cell lymphoma
  • Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1)
  • Bruton Tyrosine Kinase (BTK)
  • Leukemia, lymphoid
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia
  • Lymphoma
  • Lymphoma, mantle cell
  • Neoplasms by histologic type
  • Neoplasms
  • Lymphoproliferative Disorders
  • Lymphatic Diseases
  • Immunoproliferative Disorders
  • Immune System Diseases
  • Lymphoma, Non-Hodgkin

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