Clinical Trials /

A Phase 1b/2 Study of Alvocidib Plus Decitabine in Patients With MDS

NCT03593915

Description:

Alvocidib, a cyclin-dependent kinase 9 (CDK 9) inhibitor, in time-sequential therapy demonstrated significant clinical activity in secondary AML patients with prior MDS. Patients with IPSS-R intermediate and above MDS have an increased risk of developing AML and may be treated with the same chemotherapy regimens used in patients with AML. Eight Phase I or II clinical trials have been completed in patients with AML, totaling more than 400 patients with both relapsed/refractory or newly diagnosed AML. Preclinical studies have demonstrated that decitabine exposure increased the expression of NOXA, which is a specific antagonist of the survival factor MCL 1. Pharmacologic downregulation of MCL-1 via CDK 9 inhibition, as well as upregulation of the MCL-1 antagonist, NOXA, following decitabine exposure may result in enhanced antileukemic activity in MCL-1-dependent malignancies.

Related Conditions:
  • Myelodysplastic Syndromes
  • Secondary Myelodysplastic Syndrome
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1b/2 Study of Alvocidib Plus Decitabine in Patients With MDS
  • Official Title: A Phase 1b/2, Open-label Clinical Study to Determine Preliminary Safety and Efficacy of Alvocidib When Administered in Sequence After Decitabine in Patients With MDS

Clinical Trial IDs

  • ORG STUDY ID: TPI-ALV-102
  • NCT ID: NCT03593915

Conditions

  • Myelodysplastic Syndromes (MDS)

Purpose

Alvocidib, a cyclin-dependent kinase 9 (CDK 9) inhibitor, in time-sequential therapy demonstrated significant clinical activity in secondary AML patients with prior MDS. Patients with IPSS-R intermediate and above MDS have an increased risk of developing AML and may be treated with the same chemotherapy regimens used in patients with AML. Eight Phase I or II clinical trials have been completed in patients with AML, totaling more than 400 patients with both relapsed/refractory or newly diagnosed AML. Preclinical studies have demonstrated that decitabine exposure increased the expression of NOXA, which is a specific antagonist of the survival factor MCL 1. Pharmacologic downregulation of MCL-1 via CDK 9 inhibition, as well as upregulation of the MCL-1 antagonist, NOXA, following decitabine exposure may result in enhanced antileukemic activity in MCL-1-dependent malignancies.

Detailed Description

      PHASE 1b:

      Patients will be enrolled in cohorts of 3-6 patients. Escalation of the alvocidib dose will
      follow a standard 3+3 design with sequential cohorts of 3 patients treated with incrementally
      higher doses of alvocidib until a dose-limiting toxicity (DLT) is observed and the MTD is
      established.

      Once the MTD or preliminary RP2D is identified, the study will progress to Phase 2.

      PHASE 2:

      Phase 2 design is based on the Simon 2-stage minimax design (Simon 1989).

        -  Stage 1: Up to 15 evaluable patients will be enrolled and treated at the RP2D identified
           in the Phase 1b study.

        -  Stage 2: Ten patients will be enrolled to bring the total enrollment in Phase 2
           (including Stage-1 patients) to 25 evaluable patients. Stage-2 patients will also
           receive the RP2D dose identified in the Phase 1b study. If 6 or more responses are
           observed in 25 patients, the conclusion will be that the combination regimen is worthy
           of further investigation.
    

Trial Arms

NameTypeDescriptionInterventions
Ph 1b and 2: Pts w/ previously untreated MDSExperimentalPatients with previously untreated MDS Patients with MDS who have received <6 cycles of HMAs Patients with de novo (cause unknown) or secondary MDS (treatment-related) who are not eligible for intensive induction chemotherapy or stem cell transplant All French-American-British (FAB) subtypes Intermediate and above per IPSS-R groups

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Aged ≥18 years
    
              2. Phase 1b: Patients with previously untreated MDS and patients with MDS who received
                 fewer than six (6) cycles of previous HMAs Phase 2: Untreated patients with de novo or
                 secondary MDS
    
              3. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
                 score ≤2 at enrollment
    
              4. Provide written informed consent prior to any study-related procedure. (In the event
                 that the patient is re-screened for study participation or a protocol amendment alters
                 the care of an ongoing patient, a new informed consent form must be signed.)
    
              5. Patients with a life expectancy of ≥3 months (90 days)
    
              6. Patients with adequate major organ functions meeting the following criteria on the
                 basis of laboratory data within 4 weeks (28 days) before enrollment (if multiple data
                 are available, most recent data during the period):
    
                   1. Serum creatinine: ≤1.8× the upper limit of the normal (ULN) range
    
                   2. Total bilirubin: ≤2× the ULN
    
                   3. Aspartate transaminase (AST) and alanine transaminase (ALT): ≤3× the ULN
    
                   4. Left ventricular ejection fraction (LVEF) >45% by echocardiogram or multigated
                      acquisition (MUGA) scan
    
              7. Be able to comply with the requirements of the entire study.
    
            Exclusion Criteria:
    
              1. Presence of concomitant severe cardiovascular disease:
    
                   1. Patients who had myocardial infarction within 6 months (180 days) before
                      enrollment
    
                   2. Patients with significant diseases at enrollment that may affect study treatment,
                      such as New York Heart Association (NYHA) Functional Class III or IV heart
                      disease, National Cancer Institute (NCI) Common Terminology Criteria for Adverse
                      Events (CTCAE) v5.0 grade ≥3 arrhythmia, angina pectoris, abnormal
                      electrocardiogram findings, interstitial pneumonia or pulmonary fibrosis
    
              2. Presence of concomitant malignancy requiring chemotherapy or any malignancy (except
                 basal and squamous cell carcinoma of the skin) for which the patient received
                 chemotherapy within 6 months prior to enrollment. NOTE: Diagnosis of any previous or
                 concomitant malignancy is thus not an exclusion criterion.
    
              3. Presence of uncontrolled or uncontrollable infection(s); or ≥Grade 3 infection
                 according to NCI CTCAE v5.0
    
              4. Presence of any psychological, familial, sociological or geographical condition that,
                 in the opinion of the investigator, could potentially hinder compliance with the study
                 protocol and follow-up schedule
    
              5. Patients with a dry tap on bone marrow aspiration before enrollment
    
              6. Patients with concurrent autoimmune disease or a history of chronic or recurrent
                 autoimmune disease, or patients who require long-term systemic steroid therapy greater
                 than the equivalent of 20 mg of prednisone daily (excluding therapy given on an 'as
                 needed' [PRN] basis)
    
              7. Patients with other documented malignancies within past year aside from synchronous or
                 metachronous multiple cancers with a disease-free period of ≤5 years (excluding
                 carcinoma in situ, mucosal carcinoma, or other such carcinomas curatively treated with
                 local therapy)
    
              8. Patients with ≥Grade 2 hemorrhage according to NCI CTCAE v5.0
    
              9. Patients who have previously received alvocidib or another cyclin-dependent kinase 9
                 (CDK9) inhibitor
    
             10. Patients who are pregnant or breastfeeding
    
             11. Female patients of childbearing potential who are sexually active and unwilling to use
                 a medically acceptable method of contraception associated with a low failure rate
                 prior to study entry, for the duration of study participation and for at least 6
                 months after the last dose of study drug. (Patients will be considered to be of
                 childbearing potential unless surgically sterilized by hysterectomy, or bilateral
                 tubal ligation / salphingectomy, or postmenopausal for at least 2 years.)
    
             12. Male patients with partners of childbearing potential who are unwilling to use condoms
                 in combination with a second effective method of contraception during the trial and
                 for at least 3 months after the last administration of study treatment.
    
             13. Patients who are inappropriate for participation in the study for other reasons in the
                 opinion of the investigator or sub-investigator(s)
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:PHASE 1b: Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events.
    Time Frame:28 days
    Safety Issue:
    Description:DLTs as observed in Cy 1. Must be at least possibly related to alvocidib. Any Gr 4 nonhematologic toxicity. Gr 3 nonhematologic toxicity that does not resolve to ≤Gr 2 in 48 hours. Gr 3 diarrhea, mucositis, nausea, or vomiting will be considered dose limiting only if resolution to ≤Gr 2 requires >7 days. ≥Grade 3 neurotoxicity of any duration ≥Grade 3 creatinine elevation of any duration Anorexia, fever, neutropenic fever, and infections of any grade Myelosuppression will not be considered in evaluating DLTs in patients except where bone marrow hypoplasia occurs for >50 days with bone marrow (BM) cellularity ≤5% and no evidence of MDS/leukemia.

    Secondary Outcome Measures

    Measure:PHASE 1b: Complete Response Rate (CRR: CRR: complete response [CR] / complete response with incomplete blood count recovery [CRi] / CRmarrow / partial response [PR] / hematologic improvement [HI])
    Time Frame:3 months
    Safety Issue:
    Description:Baseline disease assessment performed at screening and subsequent response assessments
    Measure:PHASE 1b and 2: Decitabine treatment effect on BH3 profiling results in peripheral blood to find the correlation between the rate of CR/CRi/CRmarrow/PR/HI and BH3 profiling by flow cytometry with an emphasis on MCL-1 dependence.
    Time Frame:3 months
    Safety Issue:
    Description:Assessment of BH3 profiling in peripheral blood

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Tolero Pharmaceuticals, Inc.

    Trial Keywords

    • Previously untreated MDS
    • MDS who have received <6 cycles of treatment with hypomethylating agents (HMAs)
    • De novo or secondary MDS (treatment-related) who are not eligible for intensive induction chemotherapy or stem cell transplant
    • FAB subtypes: refractory anemia [RA], RA w/ ringed sideroblasts, RA w/ excess blasts, RA w/ excess blasts in transformation or chronic myelomonocytic leukemia
    • Intermediate and above per the Revised International Prognostic Scoring System (IPSS-R) groups
    • Tolero
    • Cancer
    • Phase 1b/2

    Last Updated

    July 10, 2019