UC-961 (Cirmtuzumab) in Relapsed or Refractory Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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The purpose of the study is to investigate the safety of the investigational agent, cirmtuzumab. Cirmtuzumab is a monoclonal antibody drug designed to attach to a protein, called ROR1, on the surface of chronic lymphocytic leukemia (CLL) cells to block cell growth and survival. ROR1 is rarely expressed on healthy cells so the idea is to preferentially get rid of the cancer cells. Although there is evidence in laboratory animals that cirmtuzumab can decrease the number of CLL cells, the investigators do not know if this will work in humans. This drug will be given to humans for the first time in this study. Therefore, the goal of this study is to see if cirmtuzumab is safe and tolerated in study participants.

Detailed Description
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This is a first in human, open-label single institution, Phase I dose escalation study of in patients with relapsed or refractory CLL. Treatment cycle (14 days) will consist of cirmtuzumab administered intravenously on a bi-weekly (every two weeks) schedule for a total of 4 doses. Eight dose cohorts (of 3 to 6 patients in size) plus an expansion cohort of 6 patients are planned. In the first 4 dose cohorts, there is intra-patient dose escalation to monitor for acute toxicities, such as tumor lysis syndrome. A cycle may be repeated every 14 days if the patient has at least stable disease by clinical examination (or interim response assessment) and has again met hematologic, renal, and hepatic laboratory parameters as defined in the eligibility section, and is without ongoing Grade 3 non-hematologic or Grade 4 hematologic toxicities attributable to cirmtuzumab. The total duration of study drug administration is 4 cycles. Each cycle consists of clinical and laboratory evaluation on Day 1 and safety assessments on Days 3 and 8.

Official Title
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A Phase I Clinical Trial to Determine the Safety and Tolerability of UC-961 (Cirmtuzumab), an Anti-ROR1 Monoclonal Antibody, for the Treatment of Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Who Are Ineligible for Chemotherapy

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: cirmtuzumab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Clinical and phenotypic verification of B cell CLL and measurable disease. Immunophenotyping of the leukemic cells must demonstrate a monoclonal B cell population with immunophenotype consistent with CLL. Relapsed or refractory disease, defined by failure to achieve a partial response within 6 months of initiation of therapy, or a 50% increase of baseline disease measurements after achieving a clinical response. Not amenable to approved therapies. Prior Therapy: Must have progressed after purine-analog or alkylator based therapy, or be considered inappropriate for chemo-immunotherapy due to one of the following: Del 17p, which is associated with poor response to chemo-immunotherapy, or Age greater than 70, or Age greater than 65 with one of the following: Grade ≥ 3 neutropenia, anemia, or thrombocytopenia attributable to cumulative myelotoxicity from prior administration of cytotoxic agents (as documented by bone marrow biopsy obtained since last prior therapy), or Clinically apparent autoimmune cytopenia which may be exacerbated by fludarabine therapy, or Estimated creatinine clearance (eCCr) <70 mL/min (as determined by the Cockcroft-Gault method), or Eastern Cooperative Oncology Group (ECOG) performance status greater than 0. Has recovered from the toxic effects of prior therapy to their clinical baseline. Women of childbearing potential must agree not to become pregnant for the duration of the study. Both men and women must agree to use a barrier method of contraception for the duration of the study and until 10 weeks after the final dose of cirmtuzumab. Subjects must have at least one of the following indications for treatment: Symptomatic or progressive splenomegaly; Symptomatic lymph nodes, nodal clusters, or progressive lymphadenopathy; Progressive anemia (hemoglobin ≤ 11 g/dL); Progressive thrombocytopenia (platelets ≤ 100 x 10^9/L); Weight loss > 10% body weight over the preceding 6 month period; Fatigue attributable to CLL; Fever or night sweats for > 2 weeks without evidence of infection; Progressive lymphocytosis with an increase of > 50% over a 2-month period or an anticipated doubling time of less than 12 months. Subjects must have an ECOG performance status of 0-2. Adequate hematologic function Adequate renal function Adequate hepatic function Adequate coagulation tests EXCLUSION CRITERIA: Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Patients who are currently receiving another investigational agent are excluded. Patients who have had chemotherapy (e.g., purine analogues, alkylating agents), immunotherapy, radiation therapy, or participation in any investigational drug treatment within 4 weeks of initiation of UC-961 or at any time during the study. Patients who have had prior (within 8 weeks of initiation of UC-961) or concurrent antibody therapy directed against CLL (i.e., Rituxan® and Campath®). Current infection requiring parenteral antibiotics. Active infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV). Concurrent malignancy or prior malignancy within the previous 3 years (other than completely resected carcinoma in situ, prostate cancer, or localized non-melanoma skin cancer). Known central nervous system (CNS) involvement by malignancy. Untreated autoimmunity such as autoimmune hemolytic anemia, or immune thrombocytopenia. Uncompensated hypothyroidism (defined as thyroid-stimulating hormone (TSH) greater than 2x upper limit of normal not treated with replacement hormone). Presence of more than 55% pro-lymphocytes in peripheral blood. Patients with Richter's transformation are not excluded. Insufficient recovery from surgical-related trauma or wound healing. Impaired cardiac function including any of the following: Myocardial infarction within 6 months of starting study drug; A past medical history of clinically significant ECG abnormalities, including QTc 481 milliseconds or greater; Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cirmtuzumab 0.015 - 0.03 mg/kg<br>Cohort 1: Cirmtuzumab 0.015 mg/kg for two 14-day cycles followed by cirmtuzumab 0.03 mg/kg for two 14-day cycles via intravenous (IV) infusion | Drug: cirmtuzumab<br> <br> * Other names: UC-961;|
| Experimental: Cirmtuzumab 0.06 - 0.12 - 0.24 mg/kg<br>Cohort 2: Cirmtuzumab 0.06 mg/kg for one 14-day cycle, followed by cirmtuzumab 0.12 mg/kg for one 14-day cycle, followed by 0.24 mg/kg for two 14-day cycles via IV infusion | Drug: cirmtuzumab<br> <br> * Other names: UC-961;|
| Experimental: Cirmtuzumab 0.5 - 1.0 mg/kg<br>Cohort 3: Cirmtuzumab 0.5 mg/kg for one 14-day cycle, followed by cirmtuzumab 1.0 mg/kg for three 14-day cycles via IV infusion | Drug: cirmtuzumab<br> <br> * Other names: UC-961;|
| Experimental: Cirmtuzumab 2.0 - 4.0 mg/kg<br>Cohort 4: Cirmtuzumab 2.0 mg/kg for two 14-day cycles, followed by cirmtuzumab 4.0 mg/kg for two 14-day cycles via IV infusion | Drug: cirmtuzumab<br> <br> * Other names: UC-961;|
| Experimental: Cirmtuzumab 8 mg/kg<br>Cohort 5: Cirmtuzumab 8 mg/kg for four 14-day cycles via IV infusion | Drug: cirmtuzumab<br> <br> * Other names: UC-961;|
| Experimental: Cirmtuzumab 16 mg/kg<br>Cohort 6: Cirmtuzumab 16 mg/kg for four 14-day cycles (or maximum 2000 mg) via IV infusion | Drug: cirmtuzumab<br> <br> * Other names: UC-961;|
| Experimental: Cirmtuzumab 20 mg/kg<br>Cohort 7: Cirmtuzumab 20 mg/kg for four 14-day cycles (or maximum 2000 mg) | Drug: cirmtuzumab<br> <br> * Other names: UC-961;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) or Biologically Active Dose of Cirmtuzumab | The MTD is defined as the highest dose studied at which no more than one in six patients experience a dose-limiting toxicity (DLT) during the DLT observation period. The biologically active dose will be determined at a dose below or equal to the MTD upon review of the the study data; the final determination will also consider any cumulative or delayed toxicity. | 1 year | 
| Rate of Dose Limiting Toxicities (DLTs) | The occurrence of any of the following adverse events considered to be possibly, probably, or definitely related to cirmtuzumab within the DLT observation period (56 days from the first infusion for cohorts with intrapatient dose escalation, and 28 days of the start investigational treatment for cohorts without intrapatient dose escalation): Grade 3 or greater non-hematologic toxicity with the exception of Grade 3 infusion reaction. Grade 4 neutropenia lasting more than 5 days despite appropriate medical management. Grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding or any requirement for platelets transfusion. Grade 3 or greater febrile neutropenia (temperature ≥ 38.5ºC). Grade 4 anemia unexplained by underlying disease. Any AE requiring a dose delay of greater than 14 days. Patients with baseline cytopenias or starting blood counts in the grade 2 range are evaluable for hematologic DLT. | The DLT observation period is 56 days from the start of the first infusion for the intra-patient dosing cohorts and 28 days after the start of the first infusion for subsequent dosing cohorts | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs. | Treatment emergent adverse events (description, timing, CTCAE grade, severity, seriousness, and relatedness) | From the start of investigational treatment to completion of follow-up, an average of 33 weeks | 
| Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Clinical response [stable disease (SD) or progressive disease (PD)] defined by iwCLL criteria including clinical, hematological, and bone marrow features for a period of at least 2 months from completion of therapy | From baseline visit to response assessment visit at 56 days after final cirmtuzumab infusion, an average of 52 days | 
| Progression Free Survival as Determined by iwCLL Criteria | The duration of time from the start of study treatment until objective tumor progression or death | From start of treatment until objective tumor progression or death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, CLL