Clinical Trials /

Safety And Efficacy Of TKI Cessation For CML Patients With Stable Molecular Response In A Real World Population

NCT04626024

Description:

This is a single-arm, phase II study to evaluate safety and efficacy of tyrosine kinase inhibitor (TKI) cessation for chronic myeloid leukemia (CML) patients with stable molecular response in a real world population.

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety And Efficacy Of TKI Cessation For CML Patients With Stable Molecular Response In A Real World Population
  • Official Title: Safety And Efficacy Of Tyrosine Kinase Inhibitor Cessation For Chronic Myeloid Leukemia Patients With Stable Molecular Response In A Real World Population

Clinical Trial IDs

  • ORG STUDY ID: H-48054
  • NCT ID: NCT04626024

Conditions

  • Chronic Myeloid Leukemia
  • Chronic Myeloid Leukemia, BCR/ABL-Positive, in Remission
  • Chronic Myeloid Leukemia in Remission

Interventions

DrugSynonymsArms
Imatinib Mesylate, Dasatinib, Nilotinib or Bosutinib Re-initiationGleevec, Sprycel, Tasigna, BosulifAll Subjects Enrolled (stop taking TKI)

Purpose

This is a single-arm, phase II study to evaluate safety and efficacy of tyrosine kinase inhibitor (TKI) cessation for chronic myeloid leukemia (CML) patients with stable molecular response in a real world population.

Detailed Description

      Transitioning from busulfan, hydroxyurea, IFN-α to tyrosine kinase inhibitors (TKIs) has
      dramatically altered the natural history of CML. Patients with CML appropriately managed with
      TKIs are able to benefit from near normal life expectancy. Given the age-adjusted incidence
      of 1.6 per 100,000 people combined with a reduced annual mortality of less than 2% to 3% per
      year, it is expected the prevalence in the US to increase from approximately 70,000 in 2010
      to a projected 144,000 in 2030. Thus, advancing our knowledge regarding clinical management
      is critical in order to care for this expanding population.

      However the morbidity associated with prolonged TKI exposure remains a substantial burden on
      this patient population. In addition to a relatively benign side effect profile (edema,
      muscle cramps, diarrhea, nausea, musculoskeletal pain, rash and other skin problems,
      abdominal pain, fatigue, joint pain, and headaches), patients continued to experience grade 3
      and 4 adverse events (neutropenia, thrombocytopenia, anemia, elevated liver enzymes,
      congestive heart failure, and other drug-related adverse events) more than 2 years after
      initiating therapy. For patients with high-risk CML that may benefit from faster and/or
      deeper molecular responses, or who develop intolerance or resistance to imatinib, second
      generation TKIs (dasatinib, nilotinib, and bosutinib) are available. Indeed, there is a
      structural and dose-dependent relationship between TKIs and ischemic heart disease, ischemic
      cerebrovascular events and/or peripheral artery disease accompanied with a linear increase in
      the cumulative frequency of these cardiovascular events over time. Additionally, experts
      believe the cost of CML medicines "are too high, are unsustainable, may compromise access of
      needy patients to highly effective therapy, and are harmful to the sustainability of our
      national health care systems." Given the implications on quality of life, adverse events and
      financial burden on patients, TKI therapy should be discontinued when medically appropriate.

      Thankfully, discontinuation of TKIs in CML-CP patients with RT-PCR negative for BCR-ABL1
      transcripts (Undetectable Minimal Residual Disease, UMRD) or MR has established that 38% to
      45% of patients are able to achieve TFR with persistence of UMRD and MR at 5 and 8 years,
      respectively. Subsequent studies (EURO-SKI, ENESTfreedom, ENESTop, and DADI) have
      independently validated these results, and patients who experience MR will mostly do so
      within three to six months after discontinuation.

      Furthermore, in patients with complete cytogenetic response, those who have a deeper
      molecular response (>3 log reduction in transcripts) compared to those without have an
      improved estimated 7-year event-free survival. ddPCR is a powerful tool that allows for the
      absolute quantitation of nucleic acids and provides a more precise and sensitive assay than
      real-time PCR (RT-PCR) in detecting BCR-ABL1 transcripts. There is neither a precise
      molecular mechanism to characterize MR, nor a clinically actionable assay to determine which
      patients will benefit from TKI cessation and achieve TFR. Thus, leveraging ddPCR can impact
      patient outcomes in CML-CP patients undergoing TKI treatment by potentially determining who
      is expected to achieve of TFR.

      Cancer causing mutations can affect oncogenes that normally stimulate growth, suppressor
      genes that normally inhibit growth, and repair genes that normally limit mutations. Of the
      20,000 protein coding genes in the human genome, approximately ~140 genes can promote
      tumorigenesis while the remaining passenger mutations confer no selective growth advantage.
      In CML, genomic analysis has identified variants in patients with poor outcomes. Therefore,
      mutational analysis of clinically relevant genes and genes of emerging clinical relevance
      could provide insight into which patients are at risk for relapse.

      Prior to these findings, a truly curable clinical status after CML diagnosis was previously
      attainable only with allogeneic stem cell transplantation. It is known that successful
      remission in relapsing CML patients who have undergone stem cell transplantation was
      primarily driven by an alloreactive T-cell dependent graft-versus-leukemia effect. The
      cytotoxic role of a WT-1 peptide specific TCR Vβ21 T-cell clone against K562 cells has been
      demonstrated in vitro. Taken together, these data suggest a role of immune cells and the
      subsequent maturation, generation, and homing of CML-antigen-specific T-lymphocytes - the
      hallmark of elimination during cancer immune surveillance. Massively paralleled sequencing of
      the complementarity determining region 3 by TCR-sequencing (TCR-seq) allows for a detailed
      understanding of the T-cell repertoire and is representative of clonal distribution,
      antigenic response diversity, and the degree of T-cell immunomodulation. A diverse T-cell
      repertoire capable of recognizing CML-specific antigens with concomitant clonal expansion may
      be associated with successful TFR and potentially provide additional biomarkers towards
      identifying patients with CML-CP who should be optimal candidates for TKI cessation.
    

Trial Arms

NameTypeDescriptionInterventions
All Subjects Enrolled (stop taking TKI)ExperimentalPatients with a diagnosis of Philadelphia chromosome- or BCR-ABL1-positive CML (as determined by cytogenetics, FISH, or PCR), prior evidence of a quantifiable BCR-ABL1 transcript by RT-PCR, and whom have been taking TKI for > 36 months with a current status of complete molecular remission (CMR). TKI cessation begins within 7 days of study registration. Patients undergo BCR-ABL1 test every month in 24 months.
  • Imatinib Mesylate, Dasatinib, Nilotinib or Bosutinib Re-initiation

Eligibility Criteria

        Inclusion Criteria:

          1. Patients who are 18 years or older

          2. Patients have a diagnosis of Philadelphia chromosome- or BCR-ABL1-positive CML (as
             determined by cytogenetics, FISH, or PCR).

          3. Prior evidence of a quantifiable BCR-ABL1 transcript by RT-PCR

          4. Patients who have been taking TKI for > 36 months; patient cannot have had a known
             continuous interruption of TKI therapy of greater than 14 days or for a total of 6
             weeks in the six months prior to registration.

          5. Patients must have a history of stable molecular response, defined as MR4.5 for ≥24
             months, as documented by ≥3 separate tests performed at least three months apart.

          6. Patient must have a current status of complete molecular remission (CMR), defined as
             MR4.5 (per section 5.1), to be done after signed consent.

          7. ECOG performance status < 2

          8. Patients must have normal marrow function within 30 days of registration, as defined:

               -  Absolute Neutrophil Count (ANC) ≥ 1.5 x 10E9/L

               -  Hemoglobin ≥ 9.0 g/dL

               -  Platelets ≥ 100 x 10E9/L

          9. Patients must not have any signs of extramedullary leukemia

         10. Patients must have a life expectancy of more than 12 months in the absence of any
             intervention

         11. All participants must be informed of the investigational nature of this study and must
             sign and give written informed consent

         12. Contraception requirements will be as per routine clinical practice.

        Exclusion Criteria:

          1. Patients who are unable or unwilling to give their consent to participate to the
             study.

          2. Previous or planned allogeneic stem cell transplantation

          3. Patients who have pathologies or treatments that are able to enhance the potential
             relapse risk after stopping Imatinib.

          4. Patient has received an investigational agent within last 2 years

          5. Atypical BCR-ABL transcript not quantifiable by standard RQ-PCR.

          6. Another primary malignant disease, except those that do not currently require
             treatment (adequately treated conditions, such as excised skin cancer or cervical
             intra-epithelial neoplasia would not be considered exclusion criteria. If in doubt,
             please refer to the Principal Investigator).

          7. Any medical condition that, in the opinion of the investigator, would exclude the
             patient from participating in this study.

          8. Active liver disease (e.g., chronic active hepatitis, cirrhosis).

          9. Known diagnosis of human immunodeficiency virus (HIV) infection.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Molecular relapse (MR) free survival
Time Frame:From date of TKI cessation to the date of MR or censoring, assessed up to 6 months
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate MR free survival rate at 6 months after TKI cessation with a 95% confidence interval.

Secondary Outcome Measures

Measure:ddPCR of BCR-ABL1 values affecting MR free survival
Time Frame:At baseline (just before TKI cessation begins)
Safety Issue:
Description:ddPCR of BCR-ABL1 values (copies/μl) at baseline (just before TKI cessation begins) will be assessed by Cox proportional hazard regression model.
Measure:Event free survival (EFS)
Time Frame:From date of TKI cessation to the date of the event defined or censoring, assessed at 6 months and up to 24 months
Safety Issue:
Description:The event for EFS is defined as any of the following events: (i) loss of complete hematologic response (CHR), (ii) to accelerated phase or blast crisis (AP/BC), (iii) death due to any cause, whichever occurs first.The Kaplan-Meier method will be used to estimate EFS at 6months and up to 24 months after TKI cessation with a 95% confidence interval.
Measure:Progression-free survival (PFS)
Time Frame:From date of TKI cessation to the date of the progression defined or censoring, assessed at 6 months and up to 24 months
Safety Issue:
Description:The event of progression is defined by AP/BC or death due to any causes, whichever occurs first. The Kaplan-Meier method will be used to estimate PFS at 6 months and up to 24 months after TKI cessation with a 95% confidence interval.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Baylor College of Medicine

Last Updated

November 12, 2020