Clinical trial NCT02222688: UC-961 (Cirmtuzumab) in Relapsed or Refractory Chronic Lymphocytic Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia
Keywords: cancer
CLL
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
First posted: 2014-08-21
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) or Biologically Active Dose of Cirmtuzumab
timeFrame: 1 year
measure: Rate of Dose Limiting Toxicities (DLTs)
timeFrame: 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 outcomes:
measure: Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs.
timeFrame: From the start of investigational treatment to completion of follow-up, an average of 33 weeks
measure: Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria
timeFrame: From baseline visit to response assessment visit at 56 days after final cirmtuzumab infusion, an average of 52 days
measure: Progression Free Survival as Determined by iwCLL Criteria
timeFrame: From start of treatment until objective tumor progression or death
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UCSD Moores Cancer Center
state: California
Study officials:
affiliation: University of California Medical Center
name: Catriona Jamieson, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Calilfornia Medical Center
name: Michael Choi, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Choi MY, Widhopf GF 2nd, Ghia EM, Kidwell RL, Hasan MK, Yu J, Rassenti LZ, Chen L, Chen Y, Pittman E, Pu M, Messer K, Prussak CE, Castro JE, Jamieson C, Kipps TJ. Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia. Cell Stem Cell. 2018 Jun 1;22(6):951-959.e3. doi: 10.1016/j.stem.2018.05.018.