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An Open Label Dose Escalation Trial of CA-4948 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

NCT04278768

Description:

This is a multicenter, open-label, dose escalation Phase 1 study of orally administered CA-4948 monotherapy in adult patients with Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS).

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: An Open Label Dose Escalation Trial of CA-4948 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
  • Official Title: A Phase 1, Open Label Dose Escalation Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: CA-4948-102
  • NCT ID: NCT04278768

Conditions

  • Acute Myelogenous Leukemia
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
CA-4948CA-4948 dose escalation

Purpose

This is a multicenter, open-label, dose escalation Phase 1 study of orally administered CA-4948 monotherapy in adult patients with Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS).

Detailed Description

      The primary objective of the study is to determine the maximum tolerated dose (MTD) and
      Recommended Phase 2 Dose (RP2D) for CA-4948 in patients with AML and high risk MDS based on
      the safety and tolerability, dose-limiting toxicities (DLTs), and Pharmacokinetic
      (PK)/Pharmacodynamic (PD) findings.

      CA-4948 is formulated as tablets for twice daily oral administration. Each treatment cycle
      will be 28 days in length and repeated in the absence of toxicity. Patients who tolerate
      CA-4948 may continue to receive CA-4948 until progression of disease, intolerable toxicity,
      withdrawal from the trial, or study termination.

      The starting dose level will be 200 mg twice daily (BID) which was determined to be safe,
      capable of achieving relevant levels of drug exposure as well as demonstrating signs of
      biologic activity and clinical efficacy in an ongoing study (Study CA-4948-101). Three
      patients with AML or MDS will be enrolled at the designated dose. If none of the first 3
      patients experience a DLT during the first cycle, patients may be enrolled into the next
      higher dose level. If 1 patient out of the first 3 experiences a DLT, the dose level may be
      expanded with an additional 3 patients. If 2 or 3 patients out of the first six experience a
      DLT, this will be considered a DLT rate above the MTD (> 33%), and additional enrollment will
      proceed at a lower dose level. Any adverse reaction that leads to dose reduction or
      discontinuation is considered a DLT unless the adverse reaction is clearly and solely related
      to disease.

      The RP2D will be determined by the Clinical Safety Committee in collaboration with the
      Sponsor, considering all aspects of safety, tolerability, biologic activity, pharmacokinetics
      and preliminary efficacy in the trial population. The intent of the RP2D is to provide a dose
      and schedule that will maximize the opportunity for clinical benefit, while minimizing the
      risk of toxicity. The RP2D may be below the MTD. The CSC may request enrollment of additional
      patients at any previously-explored dose level in order to make an appropriate RP2D or MTD
      determination.
    

Trial Arms

NameTypeDescriptionInterventions
CA-4948 dose escalationExperimentalPatients receive CA-4948 PO BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • CA-4948

Eligibility Criteria

        Inclusion Criteria:

          1. Males and females ≥18 years of age

          2. Life expectancy of at least 3 months

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2

          4. Patients with:

               1. Relapsed or refractory AML OR

               2. High/very high risk relapsed/refractory MDS, following at least 6 cycles of
                  hypomethylating agents [HMA] or evidence of early progression

          5. Acceptable organ function at screening

          6. Ability to swallow and retain oral medications

          7. Negative serum pregnancy test in women of childbearing potential

          8. Women of childbearing potential and men who partner with a woman of childbearing
             potential must agree to use highly effective contraceptive methods for the duration of
             the study and for 1 month after the last dose of CA-4948

          9. Willing and able to provide written informed consent and comply with the requirements
             of the trial

         10. Able to undergo serial bone marrow sampling and peripheral blood sampling

        Exclusion Criteria:

          1. Diagnosed with acute promyelocytic leukemia (APL, M3)

          2. Has known active central nervous system (CNS) leukemia

          3. Allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first
             dose of CA-4948, or clinically significant graft-versus-host disease (GVHD) requiring
             ongoing up titration of immunosuppressive medications prior to start of CA-4948

          4. Blast phase of chronic myeloid leukemia (CML)

          5. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug
             therapy, etc., received within 14 days prior to start of CA-4948. Localized radiation
             or surgical resection of skin cancers allowed.

          6. Use of any investigational agent within 28 days or 5 half-lives, whichever is shorter,
             prior to start of CA-4948

          7. Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy,
             with the exception of alopecia that has not resolved to Grade ≤1

          8. Known allergy or hypersensitivity to any component of the formulation of CA-4948

          9. Major surgery, other than diagnostic surgery, <28 days from the start of CA-4948;
             minor surgery <14 days from the start of CA-4948

         10. Known to be human immunodeficiency virus (HIV) positive or have an acquired
             immunodeficiency syndrome-related illness

         11. Hepatitis B virus (HBV) DNA positive or Hepatitis C virus (HCV) infection <6 months
             prior to start of CA-4948 unless viral load is undetectable, or HCV with cirrhosis

         12. Uncontrolled or severe cardiovascular disease

         13. Gastrointestinal disease or disorder that could interfere with the swallowing, oral
             absorption, or tolerance of CA-4948

         14. History of other invasive malignancy, unless definitively treated with curative
             intent, provided it is deemed to be at low risk for recurrence by the treating
             physician

         15. Pregnant or lactating female

         16. Systemic fungal, bacterial, viral, or other infection that is not controlled
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine Maximum Tolerated Dose (MTD)
Time Frame:28 days
Safety Issue:
Description:The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.

Secondary Outcome Measures

Measure:To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Cmax
Time Frame:12 months
Safety Issue:
Description:maximum plasma concentration (Cmax)
Measure:To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Cmin
Time Frame:12 months
Safety Issue:
Description:trough plasma concentration (Cmin)
Measure:To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Tmax
Time Frame:12 months
Safety Issue:
Description:Time to maximum plasma concentration
Measure:To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Area under the plasma concentration versus time curve(AUC) [0-24]
Time Frame:12 months
Safety Issue:
Description:area under the plasma concentration-time curve from 0 to 24 hours
Measure:To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by AUC[INF]
Time Frame:12 months
Safety Issue:
Description:area under the plasma concentration-time curve from 0 to infinity
Measure:To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by T 1/2
Time Frame:12 months
Safety Issue:
Description:Plasma terminal elimination half-life (T 1/2)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Curis, Inc.

Trial Keywords

  • Acute Myelogenous Leukemia
  • Myelodysplastic Syndrome
  • AML
  • MDS
  • IRAK4

Last Updated

February 19, 2020