Using canakinumab to prevent cancer in patients with low blood cell counts

A Randomized Double-Blind Placebo-Controlled Phase II Multi-Center Study of Inflammation Modification of Canakinumab to Prevent Leukemic Progression of Clonal Cytopenias of Unknown Significance (CCUS): IMPACT Study

This study is testing if the drug canakinumab can help prevent cancer in people with low blood cell counts and certain genetic changes.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 110 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Ohio State University Comprehensive Cancer Center (Academic / other)
• Drugs / interventions: canakinumab, chemotherapy, methotrexate, Prednisone
• Locations: 6 sites (Miami, Florida and 5 other locations)
• Trial ID: NCT05641831 on ClinicalTrials.gov

What this trial studies

This phase II trial evaluates the effectiveness of canakinumab in preventing the progression to cancer in patients diagnosed with clonal cytopenias of unknown significance (CCUS). CCUS is characterized by prolonged low blood cell counts and genetic mutations that increase the risk of developing blood cancers. The study aims to compare the time until the development of myeloid neoplasms in patients receiving canakinumab versus a control group. Secondary objectives include assessing overall response rates, survival, and the impact on blood cell recovery and inflammation.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with high-risk CCUS and clinically meaningful cytopenias.

Not a fit: Patients with other hematological malignancies or those who do not meet the specific cytopenia criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly reduce the risk of cancer development in patients with CCUS.

How similar studies have performed: While the approach of using canakinumab for this specific condition is novel, similar studies targeting inflammation in cancer prevention have shown promise.

Eligibility criteria

Inclusion Criteria:

* Patients with age \>= 18 with high-risk CCUS
* Must meet ALL the following criteria:

  * Unexplained, clinically meaningful cytopenias (greater than 4 months) in one or more of the following lineages: erythroid cells, neutrophils, platelets. Clinically meaningful cytopenia is institution specific and threshold may vary on age, sex, and race. Decision-making should depend upon lab values specific to the institution and supersede public works. Based upon published work, significant cytopenias are defined as the following (must meet criteria in at least one lineage):

    * Erythroid Cells:

      * Hemoglobin \< 11 g/dL
    * White Blood Cells:

      * Absolute Neutrophil Count \< 1800/microL and \> 500/microL
    * Platelets:

      * Platelet Count \< 150,000/microL and \> 50,000/microL
  * MDS criteria not fulfilled
  * No other evidence of hematological malignancy
  * No or only mild (\< 10%) bone marrow dysplasia
  * Blast cells \< 5% detected via morphologic examination of blood and/or bone marrow smears which can also be supported by flow cytometry and/or immunohistochemical studies
  * Any of the following:

    * Isolated somatic spliceosome mutation at any VAF (SRSF2, SF3B1, U2AF1, or ZRSR2)
    * Isolated TP53 mutation greater than 5% VAF
    * At least 1 mutation in TET2, DMNT3A, or ASXL1 at any VAF coupled with at least 1 other known myeloid pathogenic somatic mutation or known pathogenic germline mutation that predisposes to myeloid malignancy as determined by next generation sequencing and bone marrow biopsy
    * A TET2, DMNT3A, or ASXL1 greater than 10% VAF coupled with another TET2, DMNT3A, or ASXL1 greater than 10% VAF
    * The presence of two or more known myeloid pathogenic somatic or germline mutations (other than TET2, ASXL1, DMNT3A, TP53, or spliceosome mutations) greater than 10% VAF
* Ability to understand and willingness to sign the written informed consent document
* Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
* Patients with a history of hypertension or active hypertension are strongly encouraged to optimize blood pressure control
* Creatinine clearance greater than 45 ml/min using Cockcroft-Gault
* Total bilirubin =\< 1.5 x ULN
* Aspartate transaminase (AST) \< 3 x ULN
* Alanine transaminase (ALT) \< 3 x ULN

Exclusion Criteria:

* Concurrent malignancy requiring active systemic therapy
* Diagnosis of MDS or any other myeloid malignancy in the patient's lifetime
* History of Hypersensitivity to canakinumab or drug of a similar class
* Active infection requiring prompt evaluation and treatment or history of recurrent infections
* Known active or recurrent hepatic disorder including cirrhosis, hepatitis B and C (via positive or indeterminate central laboratory \[lab\] results)
* Subjects with active tuberculosis. In subjects with a history of tuberculosis but without active tuberculosis, if the results of the evaluation require treatment per local guidelines, then the treatment should be initiated before randomization (unless otherwise required by Health Authorities or Institutional Review Board (IRB) in which case curative treatment must be completed prior to screening)
* Subjects with suspected or proven immunocompromised state or infections. If the results of this screening per local treatment guidelines or clinical practice require treatment for said infection then the patient is not eligible. Suspected or proven immunocompromised states or infections include:

  * Those with any other medical condition such as active infection, treated or untreated, which in the opinion of the investigator places the subject at an unacceptable risk for participation in immunomodulatory therapy. If in the opinion of the investigator, the patient's immunocompromised state does not pose an unacceptable risk for participation, in the absence of uncontrolled infection, and the patient does not have a history of serious infections (such as tuberculosis); then the patient may participate in this study.
  * Known history of testing positive for human immunodeficiency virus (HIV) infections. For countries where HIV status is mandatory: testing positive for HIV during screening using a local test.
  * Allogeneic bone marrow or solid organ transplant (history of any or within a certain period of time?)
  * Those requiring systemic or local treatment in doses with systemic effects e.g.:

    * Prednisone \> 20 mg (or equivalent) oral or intravenous daily for \> 14 days
    * Prednisone \> 5 mg and =\< 20 mg (or equivalent) daily for \> 30 days
    * Equivalent dose of methotrexate \> 15 mg weekly
    * Note: Azathioprine is allowed. Daily glucocorticoid-replacement for conditions such as adrenal or pituitary insufficiency is allowed. Topical, inhaled or local steroid use in doses that are not considered to cause systemic effects are permitted. Steroids for pre-medication related to chemotherapy as per local standard of care are permitted.
* Live or attenuated vaccination within 3 months prior to first dose of study drug (e.g. Measles/Mumps/Rubella \[MMR\], Yellow Fever, Rotavirus, Smallpox, etc.) and after initiation of canakinumab treatment
* Use of erythropoietin stimulating agents (ESA) or growth factors within four weeks prior to the start of the study
* Pregnant or nursing women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of study treatment and for up to 130 days after last dose of study drug. Basic contraception methods include:

  * Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
  * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  * Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
  * Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal suppository
  * Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS). In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Prior to entry into this study, cisplatin-based chemotherapy, which may be toxic to the fetus, may be given. The time between the end of cisplatin-based chemotherapy and the start canakinumab/placebo treatment is variable, resulting in a variable need for continuation of highly effective contraception. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks prior to first dose of study drug. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the Informed Consent Form (ICF).

Where this trial is running

Miami, Florida and 5 other locations

• University of Miami — Miami, Florida, United States (Recruiting)
• Weill Cornell Medical College — New York, New York, United States (Recruiting)
• Memorial Sloan Kettering Cancer Center — New York, New York, United States (Recruiting)
• Ohio State University Comprehensive Cancer Center — Columbus, Ohio, United States (Recruiting)
• Vanderbilt University Medical Center — Nashville, Tennessee, United States (Recruiting)
• UT Southwestern Medical Center at Dallas — Dallas, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Uma M Borate, MD, MS — Ohio State University Comprehensive Cancer Center
• Study coordinator: The Ohio State University Comprehensive Cancer Center

Conditions Clonal Cytopenia of Undetermined Significance